Article

What Next after Metformin? A Retrospective Evaluation of the Outcome of Second-Line, Glucose-Lowering Therapies in People with Type 2 Diabetes

October 2012
The Journal of Clinical Endocrinology and Metabolism 97(12)

October 2012
97(12)

DOI:10.1210/jc.2012-3034

Source
PubMed

Authors:

Christopher Ll Morgan

Epimog

Chris D Poole

Human Data Sciences Ltd

Marc Evans

Cardiff University

Anthony H Barnett

University Hospitals NHS Foundation Trust Birmingham

Show all 6 authorsHide

Context: After failure of metformin monotherapy, many second-line, glucose-lowering therapies are available to treat people with type 2 diabetes. Objective: The objective of the study was to compare clinical outcomes using common alternative regimens. Design and setting: This was a retrospective cohort study using data from the U.K.-based General Practice Research Database. Patients: These were primary care patients with type 2 diabetes who had metformin monotherapy as their first treatment and who then initiated on relevant second-line, glucose-lowering regimens during the study period 2000-2010. A total of 27,457 patients were prescribed a second-line therapy, of whom 26,278 (95.7%) were prescribed a regimen with 1,000 or more observations. Main outcome measures: All-cause mortality, major adverse cardiovascular events (MACE), cancer, and a combined end point of any of these were measured. Secondary end points were change in glycosylated hemoglobin between baseline and 12 months. Time to clinical end points was compared using Cox proportional hazards models. Results: Sulfonylurea monotherapy had significantly higher hazard ratios (HRs) for all-cause mortality (HR 1.459, 1.207-1.763); MACE (HR 1.578, 1.187-2.099); stroke (HR 1.444, 1.050-1.987); and the combined end point (HR 1.381, 1.194-1.597). Metformin plus pioglitazone had significantly lower adjusted HRs for all-cause mortality (HR 0.707, 0.515-0.970) and the combined end point (HR 0.747, 0.612-0.911). Mean glycosylated hemoglobin improved between baseline and 12 months for all regimens other than sulfonylurea monotherapy. Conclusion: The combination of metformin plus pioglitazone appears to provide superior clinical outcomes compared with the most commonly used regimen, metformin plus sulfonylurea. Sulfonylurea monotherapy resulted in worse outcome.

Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes

Article

Full-text available

Mar 2019
Diabetes Vasc Dis Res

Type 2 diabetes individuals are at high risk for macrovascular complications: myocardial infarction, stroke and cardiovascular mortality. Recent cardiovascular outcome trials have demonstrated that agents in two antidiabetic classes (SGLT2 inhibitors and GLP-1 receptor agonists) reduce major adverse cardiovascular events. However, there is strong evidence that an older and now generically available medication, the thiazolidinedione, pioglitazone, can retard the atherosclerotic process (PERISCOPE and Chicago) and reduce cardiovascular events in large randomized prospective cardiovascular outcome trials (IRIS and PROactive). Pioglitazone is a potent insulin sensitizer, preserves beta-cell function, causes durable reduction in HbA1c, corrects multiple components of metabolic syndrome and improves nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Adverse effects (weight gain, fluid retention, fractures) must be considered, but are diminished with lower doses and are arguably outweighed by these multiple benefits. With healthcare expenses attributable to diabetes increasing rapidly, this cost-effective drug requires reconsideration in the therapeutic armamentarium for the disease.

A systematic literature review on the efficacy–effectiveness gap: Comparison of randomized controlled trials and observational studies of glucose-lowering drugs

Article

Full-text available

Jan 2017

Aim To identify a potential efficacy–effectiveness gap and possible explanations (drivers of effectiveness) for differences between results of randomized controlled trials (RCTs) and observational studies investigating glucose-lowering drugs. Methods A systematic literature review was conducted in English language articles published between 1 January, 2000 and 31 January, 2015 describing either RCTs or observational studies comparing glucagon-like peptide-1 analogs (GLP-1) with insulin or comparing dipeptidyl peptidase-4 inhibitors (DPP-4i) with sulfonylurea, all with change in glycated hemoglobin (HbA1c) as outcome. Medline, Embase, Current Content, and Biosis were searched. Information on effect estimates, baseline characteristics of the study population, publication year, study duration, and number of patients, and for observational studies, characteristics related to confounding adjustment and selection- and information bias were extracted. Results From 312 hits, 11 RCTs and 7 observational studies comparing GLP-1 with insulin, and from 474 hits, 16 RCTs and 4 observational studies comparing DPP-4i with sulfonylurea were finally included. No differences were observed in baseline characteristics of the study populations (age, sex, body mass index, time since diagnosis of type 2 diabetes mellitus, and HbA1c) or effect sizes across study designs. Mean effect sizes ranged from −0.43 to 0.91 and from −0.80 to 1.13 in RCTs and observational studies, respectively, comparing GLP-1 with insulin, and from −0.13 to 2.70 and −0.20 to 0.30 in RCTs and observational studies, respectively, comparing DPP-4i and sulfonylurea. Generally, the identified observational studies held potential flaws with regard to confounding adjustment and selection- and information bias. Conclusions Neither potential drivers of effectiveness nor an efficacy–effectiveness gap were identified. However, the limited number of studies and potential problems with confounding adjustment, selection- and information bias in the observational studies, may have hidden a true efficacy-effectiveness gap.

Comparative effectiveness of incretin-based therapies and the risk of death and cardiovascular events in 38,233 metformin monotherapy users

Article

Full-text available

Jun 2016
MEDICINE

There is limited comparative effectiveness evidence to guide approaches to managing diabetes in individuals failing metformin monotherapy. Our aim was to compare the incidence of all-cause mortality and major adverse cardiovascular events (MACEs) among new metformin monotherapy users initiating a dipeptidyl-peptidase-4 inhibitor (DPP4i), glucagon-like peptide-1 receptor agonist (GLP-1RA), sulfonylurea (SU), thiazolidinedione, or insulin. We conducted a cohort study using the UK-based Clinical Practice Research Datalink. Participants included a cohort of 38,233 new users of metformin monotherapy who initiated a 2nd antidiabetic agent between January 1, 2007 and December 31, 2012 with follow-up until death, disenrollment, therapy discontinuation, or study end-date. A subcohort of 21,848 patients with linked hospital episode statistics (HES) and Office of National Statistics (ONS) data were studied to include MACE and cardiovascular-related death. The primary exposure contrasts, defined a priori, were initiation of a DPP4i versus an SU and initiation of a GLP-1RA versus an SU following metformin monotherapy. Cox proportional hazards models were used to assess the relative differences in time to mortality and MACE between exposure contrasts, adjusting for important baseline patient factors and comedications used during follow-up. The main study cohort consisted of 6213 (16%) patients who initiated a DPP4i, 25,916 initiated an SU (68%), 4437 (12%) initiated a TZD, 487 (1%) initiated a GLP-1RA, 804 (2%) initiated insulin, and 376 (1%) initiated a miscellaneous agent as their 2nd antidiabetic agent. Mean age was 62 years, 59% were male, and mean glycated hemoglobin was 8.8% (92.6 mmol/mol). Median follow-up was 2.7 years (interquartile range 1.3–4.2). Mortality rates were 8.2 deaths/1000 person-years for DPP4i and 19.1 deaths/1000 person-years for SU initiators. Adjusted hazards ratio (aHR) for mortality in DPP4i versus SU initiators = 0.58, 95% CI 0.46 to 0.73, P < 0.001. MACE rates were 19.1/1000 person-years for DPP4i initiators, 15.9/1000 person-years for GLP1-RA initiators versus 33.1/1000 person-years for SU initiators (aHR: DPP4i vs SU initiators = 0.64, 95%CI 0.52–0.80; GLP1RA vs SU initiators = 0.73, 95% CI 0.34–1.55). In this cohort of metformin monotherapy users, 2nd-line DPP4i use was associated with a 42% relative reduction in all-cause mortality and 36% reduction in MACE versus SUs, the most common 2nd-line therapy in our study. GLP-1RAs were not associated with adverse events in this cohort.

Do second-line oral antidiabetic drugs have different long-term effects on persons with young-onset type 2 diabetes? ---A nationwide population base cohort study

Preprint

Full-text available

Aug 2020

Background: People with young-onset diabetes (YOD) exhibit a higher risk of morbidity and mortality than those with late-onset diabetes. Few studies have explored the preferred management of diabetes in such patients; therefore, we compared the risks of hospitalization and mortality among people with YOD to whom second-line oral antidiabetic drugs (OADs) were administered. Methods: We conducted a nationwide cohort study using the National Health Insurance Research Database (Taiwan). A total of 7257 people taking second-line OADs after initial metformin therapy were enrolled during 2009–2014. Using add-on sulfonylureas (SUs) as a reference, the multivariable Cox regression model was used to compare the risks of hospitalization and mortality among 5 categories of second-line OADs: alpha-glucosidase inhibitors, meglitinide, dipeptidyl peptidase-4 (DPP-4) inhibitors, SUs, and thiazolidinediones. Results: The mean age of patients, duration of diabetes, and follow-up period were 31.6, 3.3, and 1.9 years, respectively. After baseline characteristics, comorbidities, duration of diabetes, and cardiovascular drug use were controlled, the adjusted hazard ratios and 95% confidence interval for all-cause, cardiovascular, and non-infection hospitalization and all-cause mortality for metformin plus DPP-4 inhibitors were 0.62 (0.52–0.73), 0.49 (0.29–0.85), 0.64 (0.54–0.76), and 0.50 (0.27–0.92), respectively, when compared with the data for metformin plus SUs. Conclusions: We found that among people with YOD, taking add-on DPP-4 inhibitors was associated with lower risks of all-cause hospitalization and mortality than taking add-on SUs. DPP-4 inhibitors thus seem to be a suitable second-line OAD for such patients. Trial registration: retrospectively registered

Review of the cardiovascular safety of dipeptidyl peptidase-4 inhibitors and the clinical relevance of the CAROLINA trial

Article

Full-text available

Mar 2019
BMC Cardiovasc Disord

Background Cardiovascular (CV) disease (CVD) is a well-recognized complication of type 2 diabetes mellitus (T2DM) and there is a clinical need for glucose-lowering therapies that do not further increase CV risk in this population. Although sulfonylureas (SUs) may be used as second-line therapy for patients requiring additional therapy after first-line metformin to improve glycemic control, their long-term effects on CV outcomes remain uncertain, and a wide range of alternative agents exist including dipeptidyl peptidase-4 (DPP-4) inhibitors. Methods Literature searches in PubMed (2013–2018) were conducted with terms for DPP-4 inhibitors combined with CV terms, with preference given to cardiovascular outcomes trials (CVOTs). Reference lists from retrieved articles and diabetes guidelines were also considered. Results This narrative review discusses current evidence for the CV safety of these agents, describes the long-term CV effects of DPP-4 inhibitors, including effects on CV events, mortality, the risk for heart failure hospitalization, and highlights the need for further research into the CV effects of SU therapy. Although SUs remain a treatment option for T2DM, the long-term effects of these agents on CV outcomes are unclear, and further long-term studies are required. For DPP-4 inhibitors, uncertainties have been raised about their long-term effect on hospitalization for heart failure in light of the results of SAVOR-TIMI 53, although the findings of other DPP-4 inhibitor CVOTs in T2DM and data analyses have suggested these agents do not increase the occurrence of adverse CV outcomes. Conclusions Based on recent CVOTs and guideline updates, the choice of add-on to metformin therapy for patients with T2DM and established CV disease should be a sodium-glucose co-transporter-2 inhibitor or a glucagon-like peptide-1 agonist with proven CV benefit. Additional treatment options for those individuals who require therapy intensification, as well as in patients with T2DM and without established CVD include DPP-4 inhibitors and SUs. Since few head-to-head trials have compared the effects of different oral glucose-lowering agents on CV outcomes in T2DM, with most CVOTs using placebo as a comparator, the CAROLINA trial will provide important information on the comparative CV safety of a commonly prescribed SU and a DPP-4 inhibitor.

All-cause mortality in patients on sulphonylurea monotherapy compared to metformin monotherapy in a nation-wide cohort

Article

Oct 2018
DIABETES RES CLIN PR

Safety profile of second-line agents as add-on to oral monotherapy or dual therapy in uncomplicated type 2 diabetes in South Indian population

Article

Full-text available

Apr 2018

Background: Nowadays, there is an abundance of many therapeutic options available for the management of type 2 diabetes mellitus (DM). Hence, shifting the trend toward personalized treatment that focuses on the differences among different classes of pharmacological agents with regard to the mechanism of action, efficacy, and most important - the safety. Most of the clinical guidelines reconcile the risk-benefit ratio of the individual therapies. Moreover, there is limited evidence comparing the efficacy and safety of second-line drugs in combination therapies. It becomes crucial to rationalize the combination therapies with respect to attainment of glycemic targets, reduction in the short- and longterm complications and providing a better quality of life. In clinical practice, optimal treatment of type 2 DM must take into account the various comorbidities and adverse drug reactions (ADRs). Aims and Objective: The aims of the study were to assess the ADRs associated with second-line antidiabetic drugs when used as add-on agent in uncomplicated type 2 DM. Materials and Methods: Patients aged ≥18 years of age, diagnosed as uncomplicated type 2 DM who were previously receiving at least one oral antidiabetic drug (metformin or sulfonylurea) or dual-combination therapy (metformin+sulfonylurea) and for the first-time initiated on a second-line add-on agent, i.e., pioglitazone or dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin/vildagliptin) or α-glucosidase inhibitor (voglibose) or insulin (pre-mixed insulin [30% regular/70% NPH]) were included in the study. The ADRs associated with second-line agents were assessed based on hypoglycemic events, weight changes, frequency of ADRs, liver and renal function tests, and medical events reported. Results: A total of 240 patients (mean age 56.79 ± 11.73 years) were prescribed one of four different class of hypoglycemic agents. Overall, the median weight gain of 1.5 kg was observed in the insulin group, with no change of median weight in DPP-4 inhibitor group; while pioglitazone and voglibose group demonstrated a median weight loss of 1 and 0.5 kg, respectively, at the end of 6 months. The maximum number of hypoglycemic episodes was reported in insulin treatment group, i.e., 33; while least with DPP-4 inhibitor, i.e., 12. Out of 274 ADRs, the most common were gastrointestinal adverse effects, i.e., 30.66% and least were the dermatological ADRs (5.11%). Conclusion: Henceforth, DPP-4 inhibitor add-on group was found to be safest in terms of least hypoglycemic episodes and side effects when used as add-on therapy.

Managing glycaemia in older people with type 2 diabetes: A retrospective, primary care-based cohort study, with economic assessment of patient outcomes

Article

Full-text available

Dec 2016
DIABETES OBES METAB

Aims: To describe the relative health and economic outcomes associated with different therapeutic approaches to managing older patients with type 2 diabetes failing metformin (M) monotherapy and escalated to second-line treatment. Methods: The Clinical Practice Research Datalink (CPRD) database was used to inform a retrospective observational cohort study of patients with type 2 diabetes treated with M monotherapy requiring escalation (addition or switch) to a second-line oral regimen from 01-01-2008 to 31-12-2014. Primary outcomes included time to first event (any event, myocardial infarction (MI), stroke, or composite of MI/stroke [major adverse cardiovascular event; MACE]) and total event rate. The health economic consequences associated with the choice of second-line treatment in older patients were assessed using the CORE Diabetes Model (CDM). Results: A total of 10,484 patients were included; the majority escalated to second-line treatment with M + sulfonylurea (SU) (42%) or switched to SU monotherapy (28%). In multivariate adjusted analyses, total event rates for M + dipeptidyl peptidase-4 inhibitor (DPP-4) were significantly lower than M+SU for MACE (0.61, 95% confidence interval [CI]: 0.39-0.98), driven by a lower MI rate in the M+DPP-4 group (0.52, 95% CI: 0.27-0.99). Economic analyses estimated that M+DPP-4 was associated with the largest gain in health benefit, and cost-effectiveness ratios were favourable (< £30,000 per QALY) for all second-line treatment scenarios. Conclusions: With respect to treatment choice, data from this study supports the notion of prescribing beyond M+SU, as alternative regimens have been demonstrated to be associated with reduced outcomes risk and value for money.

Opportunities and Challenges in Developing a Cohort of Patients with Type 2 Diabetes Mellitus Using Electronic Primary Care Data

Article

Full-text available

Nov 2016
PLOS ONE

Purpose To develop a cohort of patients with T2DM treated with insulin using CPRD to obtain an accurate diagnosis date. This was used to analyse time from T2DM diagnosis to first ever insulin prescription between 01/01/2000 and 30/06/2012, for patients in England and Wales. Methods Patients aged 18 years and over at diagnosis, were included if prescribed an anti-diabetic drug and were excluded if first diagnosis-specific code was inconsistent with a T2DM diagnosis. Diagnosis codes were split into 8 categories based on whether they related to specific T2DM or non-specific diabetes codes. Patients were excluded if they had non-specific diagnosis codes and were prescribed insulin as their first-ever treatment for diabetes. Descriptive statistics for time from T2DM diagnosis to insulin initiation were calculated. Results Two hundred and fifty-six codes were identified which were consistent with a first-ever diagnosis of T2DM. 7 codes were considered to clearly define a diagnosis of T2DM, which were reported for 64% of patients. The final cohort comprised 11,917 patients and the median time to first insulin prescription from the date of diagnosis was 4.4 years. Conclusions A clear definition of cohort development is required to compare and interpret results from studies. Use of diagnosis and product codes is essential when examining use of drugs such as insulin, where competing diagnoses need to be considered separately.

Dipeptidyl peptidase-4 inhibitors versus sulfonylureas on the top of metformin in patients with diabetes and acute myocardial infarction

Article

Full-text available

Feb 2024

Background Recent trials have shown that both the extent of glycated hemoglobin reduction and the duration of enhanced glycemic control are major factors that may affect cardiovascular outcome results. We aimed to investigate the impact of metformin (MET) combined with dipeptidyl peptidase-4 (DPP4) inhibitors or sulfonylureas (SU) on long-term clinical outcomes in patients with acute myocardial infarction (AMI) and type 2 diabetes mellitus (DM). Methods This study was a prospective cohort trial. From November 2011 to December 2015, a total of 13,104 AMI patients were consecutively enrolled from the Korea AMI registry-National Institutes of Health. The patients were divided into the MET + DPP4 inhibitors group and the MET + SU group. The primary endpoint, major adverse cardiac events (MACE), was defined as the composite of all-cause death, recurrent myocardial infarction (MI), and any repeat revascularization up to 3-year follow-up. To adjust baseline potential confounders, an inverse probability weighting (IPTW) analysis was performed. Results Baseline well-matched two groups were generated (the MET + DPP4 inhibitors group, n=468 and the MET + SU group, n=468). During 3-year clinical follow-up, the cumulative incidence of MACE between the two groups was not significantly different after adjustment (16.8% for MET + DPP4 inhibitors group vs. 19.4% for MET + SU group, P=0.302). However, the MET + DPP4 inhibitors group was associated with reduced risk of MI [1.3% vs. 4.9%; hazard ratio (HR): 0.228, 95% confidence interval (CI): 0.090–0.580, P=0.001] than the MET + SU group. Conclusions In patients with AMI and type 2 DM, the use of MET combined with DPP4 inhibitors was associated with reduced incidence of recurrent MI than MET combined with SU during 3-year follow-up.

Rediscovery of pioglitazone

Article

Full-text available

Jul 2023
Orv Hetil

In the past decade and a half, clinical diabetology has undergone enormous development. New drug classes have appeared in everyday practice (GLP1 receptor agonists, SGLT2 inhibitors), which are able to improve the outcome of cardiovascular (macrovascular) complications in diabetes within a few years or even a few months, in contrast to the drugs used in previous large, prospective studies (UKPDS, VADT). The use of thiazolidinediones (including pioglitazone) unfortunately and significantly has declined in recent years, both internationally and domestically, although tested in a randomized, controlled setting (PROactive, 2005), this drug was the first, one might say 'ahead of its time', that significantly reduced the composite clinical endpoint of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, which became later well-known and took center stage as the 3-point MACE. In this paper, we summarize the most important evidence that accumulated with pioglitazone over the past years. We briefly overview the molecular, cellular and pathophysiological changes it causes, and then, in addition to discussing the cardiovascular, metabolic and other benefits, mention the previously suspected and now confirmed possible side effects. It is our belief that pioglitazone could be successfully used today as part of a combined treatment in properly selected patients, with due care, in the personalized treatment of type 2 diabetes. Orv Hetil. 2023; 164(26): 1012-1019.

Investigating the Different Dimensions of DPP-4 Inhibitors

Article

Full-text available

Oct 2014

Tabasum Mughal

This Takeda-sponsored European Association for the Study of Diabetes (EASD) symposium addressed the pharmacology, clinical use, and future therapeutic application of dipeptidyl-peptidase-4 (DPP-4) inhibitors. The scientific programme covered the clinical efficacy of DPP-4 inhibitors, their durability in clinical practice, and their use in combination therapy with other antidiabetic drugs. The important issue of the effect of this class of drugs on cardiovascular (CV) outcomes was also explored. The symposium was chaired by Prof Heinz Drexel and included insightful talks from an expert faculty comprising of Profs Jørgen Rungby, Jochen Seufert, and Kausik Ray.

Certain sulfonylurea drugs increase serum free fatty acid in diabetic patients: A systematic review and meta-analysis

Article

Full-text available

Sep 2022

Background: Sulfonylurea (SU) is a commonly used antidiabetic drugs effective for type 2 diabetes mellitus. Previous studies have reported that the SU treatment could alter the serum free fatty acid (FFA) concentration in diabetic patients; however, their exact effects remain unknown. Aim: To assess the impact of SU on the FFA level in diabetic patients. Methods: A systematic literature search was conducted by consulting the PubMed, EMBASE, Cochrane Library, Reference Citation Analysis (https://www.referencecitationanalysis.com/), and Web of Science databases from January 1, 1991 to July 30, 2021. Either a fixed-effects model or random-effects model was applied to study the association between SU treatment and FFA concentration according to the heterogeneity test. Two investigators independently performed data extraction. The mean difference (MD) and corresponding 95% confidence interval (CI) were used to measure effect size. R3.5.1 software was utilized for conducting statistical analyses. Results: A total of 13 studies with 2273 individuals were selected. Results indicated that FFA concentration increased slightly after treatment with SU (MD = 0.08, 95%CI: 0.03-0.12, P < 0.01). In addition, we found that SU treatment combined with other antidiabetics could also increase the concentration of serum FFA (MD = 0.14, 95%CI: 0.01-0.28, P < 0.01). Regarding the type of SU, there was no significant difference in FFA concentration with glimepiride or glibenclamide. FFA concentration was higher at ≥ 12 wk (MD = 0.09, 95%CI: 0.04-0.13) but not at < 12 wk (MD = 0.01, 95%CI: -0.07-0.09). Conclusion: SU treatment could increase the serum FFA concentration in diabetic patients. The fundamental underlying mechanism still needs further investigation.

Sulfonylurea and Cancer Risk Among Patients With Type 2 Diabetes: A Population-Based Cohort Study

Article

Full-text available

Jun 2022

Background Current evidence of the association between the use of sulfonylurea and cancer risk is highly conflicting and little evidence of this association is from the mainland Chinese population. This study aimed to evaluate the potential effects of sulfonylurea use on cancer risk among patients with type 2 diabetes mellitus (T2DM).MethodsA retrospective cohort study of T2DM patients who were new users of sulfonylurea or metformin was conducted using the Yinzhou Regional Health Care Database. A marginal structural Cox model was used to estimate the hazard ratio (HR) of cancer associated with the use of sulfonylurea compared with metformin, with time-varying confounders controlled by inverse probability weighting. Secondary analyses using different glucose-lowering drugs (GLDs) as comparator and sensitivity analyses for potential bias due to latency period, model misspecification, missing data, analyses strategy (intention-to-treat and per-protocol), and diagnosis validation were performed to examine the robustness of the results.ResultsAfter fully controlling for time-varying confounding, baseline confounding, and competing risk, the use of sulfonylurea was not associated with the risk of any cancer (HR 1.09; 95% CI, 0.93–1.27), compared with the use of metformin. In the secondary analyses, compared with α - glucosidase inhibitors, thiazolidinediones, glinides, other GLDs except sulfonylure and insulin, and T2DM patients not treated with sulfonylureas, the HRs of the association between sulfonylurea use and cancer risk were 0.92 (95% CI; 0.78–1.08), 0.89 (95% CI; 0.66–1.19), 0.85 (95% CI; 0.71–1.02), 1.04 (95% CI; 0.89–1.22), and 1.07 (95% CI; 0.99–1.16), respectively. The results of analyses for various subgroups, risk of site-specific cancers, cumulative duration, dose-response relationship, and sensitivity analyses of different latency periods and missing data were generally consistent with the findings of the primary analyses.Conclusion No association between sulfonylurea use and cancer risk was found in this study after properly controlling biases due to time-varying confounders and other sources. Further studies on the association between sulfonylurea use and the risk of cancer by using data from a Chinese population with higher representativeness are needed.

Rethinking the role of pioglitazone in modern diabetology as a cardiorenoprotective agent

Article

Full-text available

Jun 2022

Thiazolidinediones are insulin sensitizers – a class of antidiabetic drugs that reducing insulin resistance, convincingly improve glycemic control in patients with type 2 diabetes. In addition to glucose-reducing action, a representative of this class – pioglitazone in studies demonstrates other pleiotropic effects associated with a decrease in blood pressure, a decrease in the level of pro-inflammatory cytokines and prothrombotic factors, correction of dyslipidemia and improving the state of the vascular wall. In accordance with these anti-atherogenic and metabolic effects of pioglitazone in patients with confirmed cardiovascular diseases, he reduced the frequency of development of large atherosclerotic events in prospective randomized clinical studies (studies of PROactive and IRIS), as well as in meta-analyses of all published studies of pioglitazone. Pioglitazone reduces albuminuria and proteinuria, mortality from all causes and cardiovascular events in patients with diabetes and chronic kidney disease. In other studies, the intake of pioglitazone was associated with mobilization of fat from liver in patients with non-alcoholic fatty liver disease with an improvement in its function and a positive effect on fibrosis. This article also provides an analysis of unwanted phenomena that were noted during the study of pioglitazone. The identified weight increase, swelling, bone fractures of the limbs, have a rare frequency of occurrence and dose-dependent nature. Indeed, when using low doses of pioglitazone (7.5–30 mg/day), the ratio of benefit/risk for the drug seems very favorable. At the same time, the benefits of pioglitazone with a significant improvement in cardiovascular and cerebrovascular outcomes are higher with secondary than with primary prevention in patients with both 2TDM and prediabetes/insulin resistance, most likely due to positive effects on atherosclerosis

The Evaluation of Liraglutide Combined with Intensive Insulin Therapy on the Pancreatic Beta Cells Function in Type II Diabetes Mellitus

Article

Jul 2021

Clinical Characteristics and Prevalence of Comorbidities according to Metformin Use in Korean Patients with Type 2 Diabetes

Article

Full-text available

Jul 2020

Methods: This cross-sectional study based on the Korean National Diabetes Program 2 registry used its baseline clinical data collected from seven participating university hospitals in Korea. Patients with no significant changes in their oral hypoglycemic agents and no diabetes-related complications within the year prior to participation were enrolled. Patients' clinical characteristics according to metformin use were analyzed. Results: Among 858 subjects included in the analyses, 706 were metformin users and 152 were nonmetformin users. Metformin users were significantly younger and had higher and glycated hemoglobin with significantly lower rates of accompanying microvascular complications such as retinopathy, cataracts, overt proteinuria, renal insufficiency, and peripheral neuropathy than nonusers. Meanwhile, there was a significantly lower prevalence of malignancy and depression among metformin users. These associations remained significant in multivariate analyses. The prevalence rate of macrovascular complications was not significantly different between the two groups. Conclusions: There were significant differences with respect to clinical characteristics and comorbidity prevalence according to metformin use among Korean type 2 diabetes patients. Long-term follow-up of these patients is necessary to observe how this difference will affect clinical outcomes for these patients.

Sulfonylurea derivatives and cancer, friend or foe?

Article

Full-text available

Aug 2019
EUR J PHARMACOL

Type 2 diabetes mellitus (T2DM) is associated with a higher risk of cancer and cancer-related mortality. Increased blood glucose and insulin levels in T2DM patients may be, at least in part, responsible for this effect. Indeed, lowering glucose and/or insulin levels pharmacologically appears to reduce cancer risk and progression, as has been demonstrated for the biguanide metformin in observational studies. Studies investigating the influence of sulfonylurea derivatives (SUs) on cancer risk have provided conflicting results, partly due to comparisons with metformin. Furthermore, little attention has been paid to within-class differences in systemic and off-target effects of the SUs. The aim of this systematic review is to discuss the available preclinical and clinical evidence on how the different SUs influence cancer development and risk. Databases including PubMed, Cochrane, Database of Abstracts on Reviews and Effectiveness, and trial registries were systematically searched for available clinical and preclinical evidence on within-class differences of SUs and cancer risk. The overall preclinical and clinical evidence suggest that the influence of SUs on cancer risk in T2DM patients differs between the various SUs. Potential mechanisms include differing affinities for the sulfonylurea receptors and thus differential systemic insulin exposure and off-target anti-cancer effects mediated for example through potassium transporters and drug export pumps. Preclinical evidence supports potential anti-cancer effects of SUs, which are of interest for further studies and potentially repurposing of SUs. At this time, the evidence on differences in cancer risk between SUs is not strong enough to guide clinical decision making.

Post-authorisation Safety Study of Pioglitazone Use and Safety Endpoints of Interest in Denmark After Direct Healthcare Professional Communication

Article

Full-text available

Aug 2019

Introduction A Direct Healthcare Professional Communication (DHPC) sent in Denmark on 11 August 2011 provided information on new pioglitazone labelling and guidance on monitoring treatment effectiveness. We describe pioglitazone use in Denmark after the DHPC, estimate the incidence of heart failure (HF), quantify pioglitazone cessation following a diagnosis of bladder cancer (BC) or uninvestigated macroscopic haematuria, and describe glycated haemoglobin (HbA1c) values. Methods This was a cohort study. From Danish population-based registries, cohorts of type 2 diabetes mellitus incident or prevalent users of pioglitazone or insulin in 2011–2015 were created. Patient characteristics, treatment patterns, laboratory results (available for a regional subset of the population), and incidence rates of HF and BC were estimated. Results There were 80 pioglitazone and 17,699 insulin incident users, 140 pioglitazone and 13,183 insulin prevalent users. There were no new BC cases among incident pioglitazone users, and < 5 new BC cases among prevalent pioglitazone users. Pioglitazone was rarely the first-line treatment. History of haematuria was documented in < 5 incident and 11 prevalent pioglitazone users. During follow-up, there were < 5 HF cases among 77 incident pioglitazone users and < 5 among 133 prevalent pioglitazone users without a history of HF. Median HbA1c at index date was 7.8% and 8.8% in incident pioglitazone and insulin cohorts, and 7.5% and 7.6% in prevalent pioglitazone and insulin cohorts, respectively. During follow-up of up to 4.4 years, 28.8% incident and 20.7% prevalent pioglitazone users discontinued pioglitazone. Conclusions Numbers of pioglitazone users in Denmark were low and decreased over time. Risks of BC or HF were low and risk estimates imprecise.

Sulfonylureas as treatment choice in Diabetes Mellitus : Where are we now?

Article

Full-text available

Apr 2019

Oral Hypoglycemics in Patients with type 2 Diabetes and Peripheral Artery Disease

Article

Full-text available

May 2019

Worldwide, in 2010, 202 million people were living with PAD, with a prevalence between 3-12 percent. The prevalence of PAD is three times greater in diabetic patients compared to those with normal glycaemia. PAD of the limbs is associated with increased cardiovascular morbidity and mortality, as well as major adverse limb events including acute limb ischemia and amputation. These risks are particularly high in patients who smoke and/or have type 2 diabetes. The goal of treatment in diabetic patients with PAD is to prevent cardiovascular events and prevent further peripheral artery stenosis leading to limb ischemia, and amputation. Poor glycemic control contributes to atherosclerotic progression; however, no randomized control trial evidence exists that demonstrates improved glycemic control reduces the risk of PAD. Oral diabetic medications are designed to lower glucose levels, reduce symptoms and the microvascular complications of diabetes without the inconvenience of daily injections. However, the data supporting benefit of these medications in diabetic populations with concurrent PAD are limited. We review the evidence for oral hypoglycemic agents in the treatment of patients with concurrent PAD and diabetes.

Second-line glucose-lowering drugs added to metformin and the risk of hospitalization for heart failure: A nationwide cohort study

Article

Full-text available

Feb 2019
PLOS ONE

Aim To compare the risks of hospitalization for heart failure (HHF) associated with sulfonylurea (SU), dipeptidyl peptidase-4 inhibitor (DPP-4i), and thiazolidinedione (TZD) as add-on medications to metformin (MET) therapy using the data of Korean adults with type-2 diabetes from the Korean National Health Insurance database. Methods We identified 98,383 people who received SU (n = 42,683), DPP-4i (n = 50,310), or TZD (n = 5,390) added to initial treatment of MET monotherapy in patients with type-2 diabetes. The main outcome was the hospitalization for HHF. Hazard ratios for HHF by type of second-line glucose-lowering medication were estimated by Cox-proportional hazard models. Sex, age, duration of MET monotherapy, Charlson Comorbidity Index and additional comorbidities, and calendar year were controlled as potential confounders. Results The observed numbers (rate per 100,000 person-years) of HHF events were 1,129 (658) for MET+SU users, 710 (455) for MET+DPP-4i users, and 110 (570) for MET+TZD users. Compared to that for MET+SU users (reference group), the adjusted hazard ratios for HHF events were 0.76 (95% confidence interval 0.69–0.84) for MET+DPP-4i users and 0.96 (95% confidence interval 0.79–1.17) for MET+TZD users. Conclusion DPP-4i as an add-on therapy to MET may lower the risks of HHF compared with SU.

Treatment variation related to comorbidity and complications in type 2 diabetes: A real world analysis

Article

Full-text available

Sep 2018
MEDICINE

A complex comorbidity status may cause treatment variance interfering with type 2 diabetes (T2D) guideline-confirm therapy and influence the occurrence of complications but evidence on its relationships and alternative treatments are lacking. This study aimed to identify treatment variance and common T2D drug treatment related to comorbid status and the association with comorbidity and complications. Based on Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC) databases, we conducted a retrospective, observational exploratory study including 7123 T2D patients without microvascular-, macrovascular complication. We explored patterns of comorbid status and drug treatment and its relation to the development of complications within 4-year period. Analysis was performed by two-step cluster analysis and nonlinear canonical correlation analysis. 64.9% had at least one other chronic disease and 61.7% of T2D patients were treated with >1 glucose lowering drugs. 15.8% developed microvascular complications and 6.5% had ischemic heart disease or cerebrovascular complications. 82.2% of the treatment patterns were identified among T2D patients with 1 or no comorbidity while 14.4% was identified in patients with ≥2 comorbidities. Combination treatment such as, sulfonylurea or dipeptidyl peptidase-4 inhibitors combined with metformin were observed. Occurrence of microvascular- or/and macrovascular complication and its relation to comorbidity and treatment pattern was not identified. In conclusion, as number of comorbidity increased with both type of comorbidity (diabetes related-, unrelated) present, common treatment patterns were less or not identified. More treatment variance was observed in patient's groups that had developed complications.

Effectiveness of Second-Line Agents in the Treatment of Uncomplicated Type 2 Diabetes Mellitus: An Observational Tertiary-Care Based Study

Article

Full-text available

Jul 2018

Background: The rational prescribing of second-line drugs in type 2 diabetes mellitus (DM) require clear guidelines. There is no sufficient empirical evidence to support the use of one second-line agent over the other and when to initiate second-line drug is still under discrepancy. Objectives: To analyze the utilization pattern and effectiveness of second-line agents in uncomplicated type 2 DM. Methodology: 240 uncomplicated type 2 DM patients who were ≥ 18 years receiving either metformin/sulfonylurea or metformin+sulfonylurea was divided into four add-on treatment group 1, 2, 3, 4; that were added pioglitazone, dipeptidyl peptidase-4(DPP-4) inhibitor, voglibose, and insulin [pre-mixed insulin (30%regular/70%NPH)] respectively and received the second-line agents for a duration of 6 months or longer. Effectiveness was based on the reduction in glycosylated hemoglobin (HbA1C), fasting plasma glucose (FPG) and postprandial blood glucose (PPBG) values over 3 and 6 months was done using repeated measures analysis of variance (ANOVA). Results: The mean difference for reduction in HbA1C (%) values at 3rd and 6th month with respect to baseline values was 1.32±0.72 and 2.11±0.97; 1.19±0.27 and 1.81±0.53; 1.16±0.41 and 1.66±0.63; 0.97±0.16 and 1.46±0.47 for pioglitazone, DPP-4 inhibitor, voglibose, insulin respectively. The mean difference in FPG and PPBG levels at the 6th month from baseline was 75±31.06 and 115.3±40.32; 77.91±37.95 and 117±41.27; 85.87±21.75 and 118.75±55.86; 91.38±31.8 and 132.03±56.24 for pioglitazone, DPP-4 inhibitors, voglibose and insulin respectively. Reduction in HbA1C, FPG, and PPBG was statistically significant within each group at each time interval with p-value < 0.001. Conclusion: All the add-on groups exhibited a significant reduction in HbA1C, FPG, and PPBG over 3 and 6 months. DPP-4 inhibitors exhibited least hypoglycemic episodes. DPP-4 inhibitors are trending and marginally more effective second-line OHA in uncomplicated type 2 DM.

Commentary on “Consensus Recommendations on Sulfonylurea and Sulfonylurea Combinations in the Management of Type 2 Diabetes Mellitus: International Task Force”

Article

Full-text available

Jan 2018

S. K. Singh

Heart failure risk and major cardiovascular events in diabetes: an overview of within-group differences in non-insulin antidiabetic treatment

Article

Full-text available

May 2018
HEART FAIL REV

Recently, great attention is paid to cardiovascular impact of non-insulin glucose-lowering drugs, particularly in terms of major cardiovascular events and risk of heart failure. In this regard, a surprising diversity among different molecules within the same pharmacological class has been noticed, yielding to an intra-class discrepancy which has no analogous in other cardiovascular fields. The aim of this paper is to review the literature, giving an insight of the heterogeneous effects among groups and within group shown by oral antidiabetic drugs, with a special concern to fragile patients, such as those with or at risk of heart failure.

The influence of drugs used in the treatment of diabetes type 2 on the cardio-vascular risk

Article

Full-text available

Oct 2017
Wiad Lek

With the obesity epidemic, we observe increase in the number of people suffering from diabetes mellitus type 2. This illness is considered cardiovascular disease equivalent, so influence of drugs used to manage diabetes on cardiovascular outcomes is important. Below we present review of main class of drugs used in diabetes treatment and summingup of trials conducted with their use to evaluate cardiovascular risk during treatment. PMID: 29064812

Actualización en medicamentos antidiabéticos y riesgo cardiovascular

Article

Full-text available

Dec 2016

María del Pilar Serra Sansone

Diferentes clases de medicamentos con variados mecanismos de acción para el tratamiento de la hiperglicemia han sido investigados y se han desarrollado en las últimas dos décadas. Concomitantemente, algunas instituciones reguladoras, como la Food and Drug Administration (FDA) de Estados Unidos, han impulsado el estudio del impacto de las drogas antidiabéticas sobre el sistema cardiovascular. Las instituciones internacionales que se ocupan de la diabetes mellitus han señalado la necesidad de optimizar el buen control de los pacientes con el fin de disminuir las complicaciones micro y macrovasculares impulsando un uso cada vez mayor de medicamentos, frecuentemente en asociación, para lograr las metas recomendadas. El objetivo de este trabajo es actualizar los conocimientos que han surgido de la investigación y la evidencia actual sobre el tema diabetes mellitus 2 (DM2), drogas antihiperglucémicas y enfermedad cardiovascular (ECV).

Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes

Article

May 2017
AM J CARDIOL

Patients with type 2 diabetes (T2DM) have a significantly higher risk of developing cardiovascular disease (CVD) - namely myocardial infarction, heart failure and stroke. Despite clear advances in the prevention and treatment of CVD, the impact of T2DM on CVD outcome remains high, and continues to escalate. Available evidence indicates that the risk of macrovascular complications increases with the severity of hyperglycemia, thus suggesting that the relation between metabolic disturbances and vascular damage is approximately linear. Although current antidiabetic drugs are highly effective for the management of hyperglycemia, most T2DM patients remain exposed to a substantial and concrete risk of CVD. Over the last decade, many glucose-lowering agents have been tested for their safety and efficacy in T2DM with CVD. Noteworthy, most of these studies failed to show a significant benefit in terms of CV morbidity and mortality, despite intensive glycemic control. The recent EMPA-REG OUTCOME®, SUSTAIN-6, LEADER and IRIS trials have shed some light of this important clinical issue, thus showing a convincing effect of empagliflozin, liraglutide and pioglitazone on CVD outcomes. Here, we provide a critical and updated overview of the main glucose-lowering agents and their risk-benefit ratio for the prevention of CVD in patients with T2DM.

Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes

Article

Full-text available

May 2017

Patients with type 2 diabetes (T2DM) have a significantly higher risk of developing cardiovascular disease (CVD)-namely myocardial infarction, heart failure, and stroke. Despite clear advances in the prevention and treatment of CVD, the impact of T2DM on CVD outcome remains high and continues to escalate. Available evidence indicates that the risk of macrovascular complications increases with the severity of hyperglycemia, thus suggesting that the relation between metabolic disturbances and vascular damage is approximately linear. Although current antidiabetic drugs are highly effective for the management of hyperglycemia, most T2DM patients remain exposed to a substantial and concrete risk of CVD. Over the last decade many glucose-lowering agents have been tested for their safety and efficacy in T2DM with CVD. Noteworthy, most of these studies failed to show a significant benefit in terms of CV morbidity and mortality, despite intensive glycemic control. The recent trials Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME); Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6); Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER); and Insulin Resistance Intervention After Stroke (IRIS) have shed some light on this important clinical issue, thus showing a convincing effect of empagliflozin, liraglutide, and pioglitazone on CVD outcomes. Here we provide a critical and updated overview of the main glucose-lowering agents and their risk/benefit ratio for the prevention of CVD in patients with T2DM.

A systematic and critical review on bioanalytical method validation using the example of simultaneous quantitation of antidiabetic agents in blood

Article

Apr 2017

A systematic and critical review was conducted on bioanalytical methods validated to quantify combinations of antidiabetic agents in human blood. The aim of this article was to verify how the validation process of bioanalytical methods is performed and the quality of the published records. The validation assays were evaluated according to international guidelines. The main problems in the validation process are pointed out and discussed to help researchers to choose methods that are truly reliable and can be successfully applied for their intended use. The combination of oral antidiabetic agents was chosen as these are some of the most studied drugs and several methods are present in the literature. Moreover, this article may be applied to the validation process of all bioanalytical

Metformin and cancer in type 2 diabetes: a systematic review and comprehensive bias evaluation

Article

Full-text available

Dec 2016

Background Existing observational studies provide conflicting evidence for the causal effect of metformin use on cancer risk in patients with type-2 diabetes, and there are concerns about bias affecting a number of studies. Methods MEDLINE was used to identify observational studies investigating the association between metformin and overall or site-specific cancer in people with type-2 diabetes. A systematic data extraction and bias assessment was conducted, in which risk of eight bias domains (outcome, exposure, control selection, baseline confounding, time-dependent confounding, immortal time, missing data, censoring methods) were assessed against pre-defined criteria, and rated as unlikely, low, medium or high. Results Of 46 studies identified, 21 assessed the effect of metformin on all cancer. Reported relative risks ranged from 0.23 to 1.36, with 10/21 reporting a statistically significant protective effect and two a harmful effect. The range of estimates was similar for site-specific cancers; 3/46 studies were rated as low or unlikely risk of bias in all domains. Two of these had results consistent with no effect of metformin; one observed a moderate protective effect overall, but presented further analyses that the authors concluded were inconsistent with causality. However, 28/46 studies were at risk from bias through exposure definition, 22 through insufficient baseline adjustment and 35 from possible time-dependent confounding. Conclusions Observational studies on metformin and cancer varied in design, and the majority were at risk of a range of biases. The studies least likely to be affected by bias did not support a causal effect of metformin on cancer risk.

Analytical Enantio-Separation of Linagliptin in Linagliptin and Metformin HCl Dosage Forms by Applying Two-Level Factorial Design

Article

Full-text available

Nov 2016

A novel, stability indicating, reverse phase high-performance liquid chromatography (RP-HPLC) method was developed to determine the S-isomer of linagliptin (LGP) in linagliptin and metformin hydrochloride (MET HCl) tablets (LGP–MET HCl) by implementing design of experiment (DoE), i.e., two-level, full factorial design (2 3 + 3 centre points = 11 experiments) to understand the critical method parameters (CMP) and its relation with the critical method attribute (CMA), and to ensure robustness of the method. The separation of the S-isomer, LGP and MET HCl in the presence of their impurities was achieved on Chiralpak ® IA-3 (Amylose tris (3, 5-dimethylphenylcarbamate), immobilized on 3 µm silica gel) stationary phase (250 × 4.6 mm, 3 µm) using isocratic elution and detector wavelength at 225 nm with a flow rate of 0.5 mL·min −1 , an injection volume of 10 µL with a sample cooler (5 • C) and column oven temperature of 25 • C. Ethanol:Methanol:Monoethanolamine (EtOH:MeOH:MEA) in the ratio of 60:40:0.2 v/v/v was used as a mobile phase. The developed method was validated in accordance with international council for harmonisation (ICH) guidelines and was applied for the estimation of the S-isomer of LGP in LGP–MET HCl tablets. The same method also can be extended for the estimation of the S-isomer in LGP dosage forms.

Management of type 2 diabetes: the current situation and key opportunities to improve care in the UK: Management of type 2 diabetes in the UK

Article

Aug 2016
DIABETES OBES METAB

In common with global trends, the number of individuals with Type 2 diabetes in the UK is rising, driven largely by obesity. The increasing prevalence of younger individuals with type 2 diabetes is of particular concern, due to the accelerated course of diabetes-related complications that is observed in this population. The importance of good glycaemic control in the prevention of microvascular complications of diabetes is widely accepted and there is a growing body of evidence to support a benefit in the reduction of cardiovascular events in the long-term. Despite the importance of maintaining a healthy weight for the prevention of type 2 diabetes; the results from trials of lifestyle intervention strategies to reduce body weight have been disappointing. New glucose-lowering agents offer some promise in this regard, offering an opportunity to combat the dual burden of hyperglycaemia and obesity simultaneously. The timing and appropriate choice of glucose lowering therapy has never been more complex owing to rising prevalence in the young, concomitant obesity in some 90% of adults with type 2 diabetes and an ever increasing range of therapeutic options. The present review evaluates performance measures specific to weight and glycaemic control in type 2 diabetes in the UK using data from the Quality and Outcomes Framework in England and Wales, and Scottish Diabetes Survey. Potential barriers to improvement in standards of care for people with type 2 diabetes are considered, including patient factors, clinical inertia and the difficulties in translating therapeutic guidelines into everyday clinical practice.

Can metformin use reduce the risk of stroke in diabetic patients? A systematic review and meta-analysis

Article

Feb 2023

Background and aim: Stroke and cardiovascular diseases are major causes of death and disability, especially among diabetic patients. Some studies have shown that metformin has been effective in preventing cardiovascular diseases. In this study, we aim to evaluate the effect of metformin on stroke in type 2 diabetic patients. Methods: A comprehensive search was conducted in Medline, Embase, Scopus, and Web of Science databases from their inception till 1st July 2022. Randomized clinical trials (RCT) and cohort studies were included. Two independent researchers screened the records, extracted the data, and assessed the risk of bias and certainty of evidence. Findings were reported as risk ratio (RR) and 95% confidence interval (CI). All statistical analyses were performed using the STATA 17.0 software package. Results: Analysis of 21 included studies with 1,392,809 patients demonstrated that metformin monotherapy was effective in reducing stroke risk in both RCTs (RR = 0.66, 95% CI: 0.50, 0.87 p = 0.004) and cohort studies (RR = 0.67, 95% CI: 0.55, 0.81, p < 0.0001). However, combined administration of metformin with other antihyperglycemic agents had no significant effect on stroke risk reduction in either the RCTs (RR = 0.92, 95% CI: 0.69, 1.22 p = 0.558) or the cohort studies (RR = 0.79, 95% CI: 0.59, 1.06, p = 0.122). Conclusion: Low to moderate level of evidence in RCTs showed that metformin monotherapy could reduce stroke risk in type 2 diabetic patients. However, the preventive effect of metformin in stroke was not observed in patients who received a combination of metformin plus other hypoglycemic agents.

The role of pioglitazon in modern treatment of type 2 diabetes

Article

Sep 2022

Pavlina Pithova

An overview of alogliptin + pioglitazone for the treatment of type 2 diabetes

Article

Sep 2021

Introduction Type 2 diabetes (T2D) is a progressive condition and sequential additions of therapy are usually required to maintain glycemic control. The options for glucose lowering therapies have increased considerably in recent years. Fixed-dose combinations such as alogliptin with pioglitazone provide a convenient choice which can improve medication adherence. Areas covered The authors performed a literature search to identify publications describing the efficacy and safety of alogliptin and pioglitazone when used separately and in combinations. Expert opinion : Pioglitazone activates peroxisome proliferator-activated receptor-gamma which improves insulin sensitivity and helps to preserve β-cell function with a durable improvement in glycemic control. Pioglitazone can retard the progression of atherosclerosis and reduce cardiovascular events, but it is associated with adverse events including weight gain, fluid retention and increased risk of fractures. Alogliptin improves glycemic control and appears neutral in terms of cardiovascular events. It does not appear to increase the adverse events associated with pioglitazone and use of the combination may permit the use of lower doses of pioglitazone with reduced adverse effects. There are no cardiovascular outcome studies with the combination but the cardiovascular benefits of pioglitazone and additional glucose lowering effects of alogliptin provide a useful combination with convenient once daily dosing.

Clinical Impact of Combination Therapy in Diabetic Neuropathy and Nephropathy

Article

Jun 2021

Diabetes is a complex metabolic disorder. At chronic condition it causes severe damage to the multiple organs like heart, eyes, blood vessels, kidneys, and nerves which further brings about macrovascular and microvascular complications. In present situation sufficient drugs are available for the treatment of diabetes but risk and rate of mortality of a patient suffering from diabetes is very high. Reported partial relief and regular suffering of patient is a leading challenge of medical as well as health care professionals. Available drugs given in the form of monotherapy restricted to certain conditions only and it is not able to provide inadequate relief. Hence, timely diagnosis with combination therapy adopted at right time can improve the hyperglycaemic condition and worst condition of diabetic complications. It is evident that insulin with metformin provides beneficial effect in avoiding weight gain and hypoglycaemia. Herbal, poly-herbal and synthetic drug administration in combination form is a novel therapeutic approach for treatment diabetes and its complications. Hence this review will focus to justify the dual therapy can be a potentially good therapeutic approach to solve the problems of diabetic complications with special impact to diabetic neuropathy and nephropathy over monotherapy using preclinical and clinical evidences.

Outcomes of second-line oral antidiabetic drugs in persons with young-onset type 2 diabetes

Article

Jun 2021
DIABETES RES CLIN PR

Aim: People with young-onset diabetes (YOD) exhibit a higher risk of morbidity and mortality than those with late-onset diabetes. Few studies have explored the preferred management of diabetes in such patients. We compared the risks of hospitalization and mortality among people with YOD to whom second-line oral antidiabetic drugs (OADs) were administered. Methods: 7257 people taking second-line OADs after initial metformin therapy were enrolled during 2009-2014. Using add-on sulfonylureas (SUs) as a reference, the multivariable Cox regression model was used to compare the hospitalization and mortality risks among 5 categories of second-line OADs: alpha-glucosidase inhibitors, meglitinide, dipeptidyl peptidase-4 (DPP-4) inhibitors, SUs, and thiazolidinediones. Results: After baseline characteristics, comorbidities, duration of diabetes, and drug use were controlled, the adjusted hazard ratios and 95% confidence interval for all-cause, cardiovascular, and non-infection hospitalization and all-cause mortality for metformin plus DPP-4 inhibitors were 0.62 (0.52-0.73), 0.49 (0.29-0.85), 0.64 (0.54-0.76), and 0.50 (0.27-0.92), respectively, when compared with the data for metformin plus SUs. Conclusions: Among people with YOD, taking add-on DPP-4 inhibitors was associated with lower risks of all-cause hospitalization and mortality than taking add-on SUs. DPP-4 inhibitors thus seem to be a suitable second-line OAD for such patients.

Therapeutic Manipulation of Myocardial Metabolism

Article

Apr 2021
J AM COLL CARDIOL

The mechanisms responsible for the positive and unexpected cardiovascular effects of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes remain to be defined. It is likely that some of the beneficial cardiac effects of these antidiabetic drugs are mediated, in part, by altered myocardial metabolism. Common cardiometabolic disorders, including the metabolic (insulin resistance) syndrome and type 2 diabetes, are associated with altered substrate utilization and energy transduction by the myocardium, predisposing to the development of heart disease. Thus, the failing heart is characterized by a substrate shift toward glycolysis and ketone oxidation in an attempt to meet the high energetic demand of the constantly contracting heart. This review examines the metabolic pathways and clinical implications of myocardial substrate utilization in the normal heart and in cardiometabolic disorders, and discusses mechanisms by which antidiabetic drugs and metabolic interventions improve cardiac function in the failing heart.

Associations between second-line glucose-lowering combination therapies with metformin and HbA1c, body weight, quality of life, hypoglycaemic events and glucose-lowering treatment intensification: The DISCOVER study

Article

Apr 2021

Aims: Using data from DISCOVER, a 3-year, prospective, global observational study of patients with type 2 diabetes initiating second-line glucose-lowering therapy, we sought to explore the effects of second-line dual combinations therapies plus metformin on body weight, glycated haemoglobin (HbA1c ), health-related quality of life, and risks of hypoglycaemia and further treatment intensification. Materials and methods: Adjusted changes from baseline in weight, HbA1c , and 36-item Short Form Health Survey version 2 (SF-36v2) summary scores at 6, 12, 24, and 36 months were assessed using linear mixed models. Risk of hypoglycaemia and further intensification were assessed using interval censored analyses. Results: At baseline, 7613 patients received metformin in combination with a sulphonylurea (SU; 40.9%), a dipeptidyl peptidase-4 (DPP-4) inhibitor (48.3%), a sodium-glucose co-transporter 2 (SGLT-2) inhibitor (8.3%), or a glucagon-like peptide-1 (GLP-1) receptor agonist (2.4%). After 36 months, all combinations showed similar reductions in HbA1c (0.8-‍1.0%), however, metformin plus a DPP-4 inhibitor, an SGLT-2 inhibitor, or a GLP-1 receptor agonist were associated with greater weight loss (1.9, 2.9, and 5.0 kg, respectively) than metformin plus an SU (1.3 kg, P < 0.0001). Proportions of further treatment intensification were similar across combinations (19.9-26.2%). Patients prescribed metformin plus an SU more often reported one or more hypoglycaemic events (11.9%) than other combinations (3.9-‍6.4%, P < 0.0001). SF-36v2 summary scores were typically lowest among patients prescribed metformin and an SU. Conclusions: Combinations of metformin with an SU were associated with the lowest weight reduction, highest risk of hypoglycaemia, and lower SF-36v2 scores. This article is protected by copyright. All rights reserved.

A potential role of calpains in sulfonylureas (SUs) –mediated death of human pancreatic cancer cells (1.2B4)

Article

Feb 2021
TOXICOL IN VITRO

Sulfonylureas (SUs) are suggested to accelerate the pancreatic β-cells mass loss via apoptosis. However, little is known whether calpains mediate this process. The aim of the present study is to evaluate the involvement of calpains in SUs-induced death of human pancreatic cancer (PC) cell line 1.2B4. The cells were exposed to: glibenclamide, glimepiride and gliclazide for 72 h. The expression analysis of caspase-3 (CASP-3), TP53, calpain 1 (CAPN-1), calpain 2 (CAPN-2) and calpain 10 (CAPN-10) was detected using RT-PCR method. Intracellular Ca²⁺ concentrations, CASP-3 activity and total calpain activity were also evaluated. Our results have shown that glibenclamide and glimepiride decrease 1.2B4 cells viability with accompanied increase in intracellular Ca²⁺ concentration and increased expression of apoptosis-related CASP-3 and TP53. Gliclazide did not affect 1.2B4 cell viability and Ca²⁺ concentration, however, it downregulated CASP-3 and upregulated TP53. Interestingly, 50 μM glimepiride increased expression of CAPN-1, CAPN-2 and CAPN-10 whereas 50 μM glibenclamide solely upregulated CAPN-2 expression. We have shown that 10 μM and 50 μM glibenclamide and glimepiride increased the activity of CASP-3, but decreased total calpain activity. Our results suggest that calpains may be involved in glibenclamide- and glimepiride-induced death of PC cells. However, further investigation is required to confirm the engagement of calpains in SUs-mediated death of PC cells, especially studies on protein level of particular isoforms of calpains should be conducted.

Pioglitazone

Article

Apr 2020

David Karasek

Pioglitazone belongs to the drugs primarily reducing insulin resistance. Currently, it is the only insulin sensitizer available. In addition to hypoglycaemic action, it has a number of other metabolically beneficial effects that are responsible for its positive effect on the vascular wall. The paper provides an overview of cardiovascular clinical trials with pioglitazone, its safety profile and practical recommendations for its administration.

Reporting and variability of constructing medication treatment episodes in pharmacoepidemiology studies: A methodologic systematic review using the case study of DPP ‐4 inhibitors and cardiovascular outcomes

Article

Jul 2020

Purpose In pharmacoepidemiologic studies, estimating medication adherence, persistence, and exposure patterns is critical. Constructing medication treatment episodes from prescription claims data involves assumptions related to grace period, carry‐over, and lag effect, but there are no guidelines for these assumptions. We evaluated reporting and variability of these parameters in pharmacoepidemiology studies, using a case study of antihyperglycemic medications and major adverse cardiovascular events (MACE). Methods We conducted a systemic review using MEDLINE and EMBASE for studies published prior to January 2, 2020 comparing the risk of MACE between dipeptidyl peptidase 4 (DPP‐4) inhibitors and active comparators. We extracted study characteristics and results, including grace period, carry‐over, and lag effect. Risk of bias was assessed by the Newcastle‐Ottawa scale, and assessments for prevalent user, immortal time, time lag, and time window biases. Results A total of 14/1850 studies identified were included. Grace period was not reported in 5 (35.7%) studies and ranged from 0 days to 180 days when reported. Carry‐over was not reported in 10 studies (71.4%). Lag effect was not reported in nine (71.4%) studies and ranged from 0 days to 180 days when reported. No studies conducted sensitivity analyses examining the effects of these assumptions on study findings. Predominant biases were inadequate follow‐up time, comparability of cohorts, prevalent use, and lag time bias. Conclusions Use of grace period, carry‐over, and lag effect were poorly reported and highly variable. Future pharmacoepidemiology studies should improve reporting, justify ranges for these parameters, and conduct sensitivity analyses to evaluate effects of these assumptions.

Long‐term comparative safety analysis of the risks associated with adding or switching to a sulfonylurea as second‐line Type 2 diabetes mellitus treatment in a US Veterans Affairs population

Article

Oct 2018

Aim To examine the risks of all‐cause mortality and cardiovascular events associated with adding vs switching to second‐line therapies in a comparative safety study of people with Type 2 diabetes mellitus. Methods We conducted a retrospective cohort study using an as‐treated analysis of people served by the Veterans Health Administration who were on metformin and subsequently augmented this treatment or switched to other oral glucose‐lowering treatments between 1998 and 2012. This study included 145 250 people with long follow‐up. Confounding was addressed through several strategies, involving weighted propensity score models with rich confounder adjustment and strict inclusion criteria, coupled with an incident‐user design. Results Second‐line use of sulfonylureas was related to higher mortality (hazard ratio 1.39, 95% CI 1.14, 1.70) and cardiovascular risks (hazard ratio 1.19, 95% CI 1.09, 1.30) compared with thiazolidinedione therapy. Differential hazards were associated with discontinuing or not discontinuing metformin; switching to sulfonylurea therapy was associated with a higher risk of all‐cause mortality and cardiovascular events compared with all other therapies. Furthermore, add‐on sulfonylurea therapy was associated with an elevated risk for both outcomes when compared with thiazolidinedione add‐on therapy. Conclusions The results of the present study may inform decisions on whether to augment or discontinue metformin; when considering the long‐term risks, switching to a sulfonylurea appears unfavourable compared with other therapies. Instead, adding a thiazolidinedione to existing metformin therapy appears to be superior to adding or switching to a sulfonylurea. This article is protected by copyright. All rights reserved.

Impact of treatment with pioglitazone on stroke outcomes: A real-world database analysis

Article

Mar 2018

Aims Randomised controlled trials have reported an association between pioglitazone and reduced incidence of stroke in type 2 diabetic (T2DM) and insulin‐resistant populations. We investigated this association within a real‐world database. Materials and methods T2DM patients initiating pioglitazone between 2000‐2012 were extracted from the Clinical Practice Research Datalink (CPRD); a UK routine. Two non‐exposed control cohorts were matched on age, gender, HbA1c, diabetes duration, stroke history, co‐morbidities and prior T2DM regimen. Control cohort‐1 comprised patients initiating a new T2DM therapy as their respective case initiated pioglitazone. Control cohort‐2 remained on the same T2DM regimen as their respective case prior to the case initiating pioglitazone. The primary outcome was incident stroke; other outcomes included mortality, hospital length of stay and stroke recurrence. Results 4,234 pioglitazone patients matched to controls in cohort‐1 and 3,604 in cohort‐2. For the primary outcome there were significantly reduced hazard ratios (HRs) for cases:controls. Cohort 1, the HR was 0.627 (95% CI, 0.404‐0.972) during the therapy period and 0.640 (0.485‐0.843) over the entire observation period; respective HRs were 0.516 (0.336‐0.794) and 0.773 (0.611‐0.978) for cohort 2. There was no significant difference in 30‐day mortality rate or rate of recurrent stroke. For hospitalised stroke events there was a significant difference in length of stay for patients discharged to usual residence (median 3.0 days versus 7.0 days; p=0.008) for control cohort‐2 whilst on‐treatment. Conclusions In support of evidence from two large randomized trials, these observational data show that pioglitazone has a potent effect in reducing stroke events in patients with type 2 diabetes.

Effect of quercetin on parameters of central hemodynamics and myocardial ischemia in patients with stable coronary heart disease

Article

Jan 2017
Wiad Lek

The aim: The aim of our research was to study the effect of quercetin on parameters of central hemodynamics and myocardial ischemia in patients with stable coronary heart disease (CHD). Material and methods: The research involved 85 patients with CHD: stable angina pectoris, FC II, and 30 healthy individuals made up the control group. After 1.5 months of stabilizing therapy (ß-blockers, statins, aspirin) patients with CHD were randomized into 2 groups - the research group (30 people) and the comparison group (55 people). Quercetin at a dose of 120 mg per os daily was added to standard treatment of the patients of the research group (with CHD), patients of the comparison group continued receiving the same treatment. The day before randomization and 2 months after prescribing differentiation therapy to the patients, echocardiography (echo) and 24 hour Holter ECG monitoring were made. Results: Clinical evaluation of echocardiography revealed that diastolic dysfunction of the left ventricle (LV) had been found in 100% of patients studied: in 97.6% - in the form of violation of relaxation (type I), in 2.4% of patients - in the form of pseudonormalization (type II). The 24 hour Holter ECG monitoring revealed episodes of myocardial ischemia (10.7+2.7 episodes a day), premature atrial contractions (PACs) and premature ventricular contractions (PVCs) in patients with stable CHD. After a two-month term of therapy in patients of both research and comparison groups left ventricular systolic function in terms of ejection fraction (EF) of LV significantly improved (by 4.5% and 3.2% respectively). LV diastolic function improved in both groups in terms of the ratio of the phases of the transmitral flow E/A, also IVRT significance decreased (p<0.05). DT value dropped significantly influenced by quercetin, in the comparison group it didn`t change. According to the 24 hour Holter ECG monitoring, the total time and number of episodes of ST segment depression decreased with dominative results in quercetin group. PVC number was significantly reduced only by influence of therapy with quercetin (?=0.0022). Conclusions: The data have shown cardioprotective properties of quercetin in conditions of CHD.

Managing Chronic Coronary Artery Disease in Patients with Diabetes

Chapter

Jan 2018

How to Use Type 2 Diabetes Treatments in Clinical Practice: Combination Therapies

Chapter

Dec 2016

The management of people with type 2 diabetes has changed dramatically over the past two decades. Practitioners now have up to 11 classes of glucose-lowering agents available for clinical use. While efficacy varies slightly from class to class, the drugs are very different in mechanism of action and as regards side-effect profiles, potential non-glycemic advantages, and, of course, cost. In this chapter, we review the major and minor antihyperglycemic agents used in people with type 2 diabetes, with a focus on their roles in addressing the multiple pathophysiological defects that characterize this disease. We discuss their individual risks and benefits and describe the rationale of using them in a variety of combination and complementary regimens, with a specific focus on a recent position statement from the American Diabetes Association and the European Association for the Study of Diabetes. We conclude by providing some practical points for the successful implementation of a multidimensional drug therapy in people with hyperglycemia.

The cancer risk of sulfonylureas in patients with type 2 diabetes mellitus: a systematic review: cancer risk of sulfonylureas in T2DM

Article

Jun 2016

Background: Increasing evidences suggest that oral hypoglycemic agents used in type 2 diabetes mellitus (T2DM) may affect the risk of cancer. Sulfonylureas (SUs) are most frequently used anti-diabetic medications for T2DM patients. Whether the use of SUs has any effect on cancer has received wide attention. This study is aimed to assess the effects of SUs used in T2DM patients on cancer risk. Methods: We searched PubMed, EMBASE, and Cochrane Register of Clinical Studies for published studies and ClinicalTrials.gov for additional information to identify randomized controlled trials (RCTs), cohort studies, and case-control studies. Two reviewers independently screened abstracts and full texts, collected data and assessed the risk of bias of each individual studies. Results: A total of 77 studies (33 RCTs, 27 cohort studies and 17 case-control studies) proved eligible. RCTs did not report the different risk of malignant tumor between SUs and controls in T2DM patients (OR = 0.96, 95% CI 0.78 to 1.18). Cohort studies showed cancer risk was higher in patients using SUs than metformin users (RR = 1.60, 95%CI 1.37 to 1.87; HRadj = 1.13, 95%CI 1.06 to 1.19). Case-control studies suggested an increase trend of cancer risk in SUs users versus non-SUs users (ORadj = 1.13, 95%CI 0.93 to 1.37). Conclusions: The current evidence clearly shows that SUs can significantly increase the risk of cancer compared to metformin. Although the evidence suggests possibility that the SU users might have higher risk of cancer than other alternative medications in addition to for metformin, the evidence remains inadequate to draw a definitive conclusion.

Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia

Article

Full-text available

Jul 2012
NEW ENGL J MED

The provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events, but such a possibility has not been formally tested. We randomly assigned 12,537 people (mean age, 63.5 years) with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes to receive insulin glargine (with a target fasting blood glucose level of ≤95 mg per deciliter [5.3 mmol per liter]) or standard care and to receive n-3 fatty acids or placebo with the use of a 2-by-2 factorial design. The results of the comparison between insulin glargine and standard care are reported here. The coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure. Microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers were also compared between groups. The median follow-up was 6.2 years (interquartile range, 5.8 to 6.7). Rates of incident cardiovascular outcomes were similar in the insulin-glargine and standard-care groups: 2.94 and 2.85 per 100 person-years, respectively, for the first coprimary outcome (hazard ratio, 1.02; 95% confidence interval [CI], 0.94 to 1.11; P=0.63) and 5.52 and 5.28 per 100 person-years, respectively, for the second coprimary outcome (hazard ratio, 1.04; 95% CI, 0.97 to 1.11; P=0.27). New diabetes was diagnosed approximately 3 months after therapy was stopped among 30% versus 35% of 1456 participants without baseline diabetes (odds ratio, 0.80; 95% CI, 0.64 to 1.00; P=0.05). Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years. Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the standard-care group. There was no significant difference in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13; P=0.97). When used to target normal fasting plasma glucose levels for more than 6 years, insulin glargine had a neutral effect on cardiovascular outcomes and cancers. Although it reduced new-onset diabetes, insulin glargine also increased hypoglycemia and modestly increased weight. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).

Patterns of Medication Initiation in Newly Diagnosed Diabetes Mellitus: Quality and Cost Implications

Article

Full-text available

Mar 2012

Six oral medication classes have been approved by the Food and Drug Administration for the treatment of type 2 diabetes. Although all of these agents effectively lower blood glucose, the evidence supporting their impact on other clinical events is variable. There also are substantial cost differences between agents. We aimed to evaluate temporal trends in the use of specific drugs for the initial management of type 2 diabetes and to estimate the economic consequences of non-recommended care. We studied a cohort of 254,973 patients, aged 18 to 100 years, who were newly initiated on oral hypoglycemic monotherapy between January 1, 2006, and December 31, 2008, by using prescription claims data from a large pharmacy benefit manager. Linear regression models were used to assess whether medication initiation patterns changed over time. Multivariate logistic regression models were constructed to identify independent predictors of receiving initial therapy with metformin. We then measured the economic consequences of prescribing patterns by drug class for both patients and the insurer. Over the course of the study period, the proportion of patients initially treated with metformin increased from 51% to 65%, whereas those receiving sulfonylureas decreased from 26% to 18% (P<.001 for both). There was a significant decline in the use of thiazolidinediones (20.1%-8.3%, P<.001) and an increase in prescriptions for dipeptidyl peptidase-4 inhibitors (0.4%-7.3%, P<.001). Younger patients, women, and patients receiving drug benefits through Medicare were least likely to initiate treatment with metformin. Combined patient and insurer spending for patients who were initiated on alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, or dipeptidyl peptidase-4 inhibitors was $677 over a 6-month period compared with $116 and $118 for patients initiated on metformin or a sulfonylurea, respectively, a cost difference of approximately $1120 annually per patient. Approximately 35% of patients initiating an oral hypoglycemic drug did not receive recommended initial therapy with metformin. These practice patterns also have substantial implications for health care spending.

From Theory to Clinical Practice in the Use of GLP-1 Receptor Agonists and DPP-4 Inhibitors Therapy

Article

Full-text available

Jan 2011
EXP DIABETES RES

Promoting long-term adherence to lifestyle modification and choice of antidiabetic agent with low hypoglycemia risk profile and positive weight profile could be the most effective strategy in achieving sustained glycemic control and in reducing comorbidities. From this perspective, vast interest has been generated by glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i). In this review our ten-year clinical and laboratory experience by in vitro and in vivo studies is reported. Herein, we reviewed available data on the efficacy and safety profile of GLP-1 receptor agonists and DPP-4i. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both GLP-1 receptor agonists and DPP-4i, improve β cell function indexes. All these agents showed trophic effects on beta-cell mass in animal studies. The use of these drugs is associated with positive or neucral effect on body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic steazosis markets, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes.

What to add in with metformin in type 2 diabetes?

Article

Full-text available

Mar 2011
QJM-INT J MED

This review considers the therapeutic choices currently faced by people with type 2 diabetes and those caring for them when glucose levels initially controlled with lifestyle management and metformin start to rise. While sulphonylureas are familiar agents and cheaper than other alternatives, they cause hypoglycaemia and modest weight gain, and robust outcome data are still lacking. Dipeptidyl peptidase 4 inhibitors ('gliptins') have an attractive pharmacological and adverse effect profile, but their effects on the cardiovascular system are also uncertain. Thiazolidinediones ('glitazones') are effective glucose-lowering agents, but cause weight gain and increase the risk of fracture, while the cardiovascular benefits hoped for in association with 'insulin-sensitization' have not been as expected. Glucagon-like peptide-1 agonists will not be acceptable as initial second-line agents for many people as they are injectable rather than oral. Well-powered 'head-to-head' clinical trials of adequate duration are therefore required to allow evidence-based decisions on second-line therapy.

The case for hypoglycaemia as a proarrhythmic event: Basic and clinical evidence

Article

Full-text available

Aug 2010
DIABETOLOGIA

Charles Nordin

Recent clinical studies show that hypoglycaemia is associated with increased risk of death, especially in patients with coronary artery disease or acute myocardial infarction. This paper reviews data from cellular and clinical research supporting the hypothesis that acute hypoglycaemia increases the risk of malignant ventricular arrhythmias and death in patients with diabetes by generating the two classic abnormalities responsible for the proarrhythmic effect of medications, i.e. QT prolongation and Ca(2+) overload. Acute hypoglycaemia causes QT prolongation and the risk of ventricular tachycardia by directly suppressing K(+) currents activated during repolarisation, a proarrhythmic effect of many medications. Since diabetes itself, myocardial infarction, hypertrophy, autonomic neuropathy and congestive heart failure also cause QT prolongation, the arrhythmogenic effect of hypoglycaemia is likely to be greatest in patients with pre-existent cardiac disease and diabetes. Furthermore, the catecholamine surge during hypoglycaemia raises intracellular Ca(2+), thereby increasing the risk of ventricular tachycardia and fibrillation by the same mechanism as that activated by sympathomimetic inotropic agents and digoxin. Diabetes itself may sensitise myocardium to the arrhythmogenic effect of Ca(2+) overload. In humans, noradrenaline (norepinephrine) also lengthens action potential duration and causes further QT prolongation. Finally, both hypoglycaemia and the catecholamine response acutely lower serum K(+), which leads to QT prolongation and Ca(2+) loading. Thus, hypoglycaemia and the subsequent catecholamine surge provoke multiple, interactive, synergistic responses that are known to be proarrhythmic when associated with medications and other electrolyte abnormalities. Patients with diabetes and pre-existing cardiac disease may therefore have increased risk of ventricular tachycardia and fibrillation during hypoglycaemic episodes.

Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: Retrospective cohort study using UK general practice research database

Article

Full-text available

Dec 2009
Br Med J

To investigate the risk of incident myocardial infarction, congestive heart failure, and all cause mortality associated with prescription of oral antidiabetes drugs. Retrospective cohort study. UK general practice research database, 1990-2005. 91,521 people with diabetes. Incident myocardial infarction, congestive heart failure, and all cause mortality. Person time intervals for drug treatment were categorised by drug class, excluding non-drug intervals and intervals for insulin. 3588 incident cases of myocardial infarction, 6900 of congestive heart failure, and 18,548 deaths occurred. Compared with metformin, monotherapy with first or second generation sulphonylureas was associated with a significant 24% to 61% excess risk for all cause mortality (P<0.001) and second generation sulphonylureas with an 18% to 30% excess risk for congestive heart failure (P=0.01 and P<0.001). The thiazolidinediones were not associated with risk of myocardial infarction; pioglitazone was associated with a significant 31% to 39% lower risk of all cause mortality (P=0.02 to P<0.001) compared with metformin. Among the thiazolidinediones, rosiglitazone was associated with a 34% to 41% higher risk of all cause mortality (P=0.14 to P=0.01) compared with pioglitazone. A large number of potential confounders were accounted for in the study; however, the possibility of residual confounding or confounding by indication (differences in prognostic factors between drug groups) cannot be excluded. Our findings suggest a relatively unfavourable risk profile of sulphonylureas compared with metformin for all outcomes examined. Pioglitazone was associated with reduced all cause mortality compared with metformin. Pioglitazone also had a favourable risk profile compared with rosiglitazone; although this requires replication in other studies, it may have implications for prescribing within this class of drugs.

From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus

Article

Full-text available

May 2009

Ralph Defronzo

nsulin resistance in muscle and liver and -cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the -cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near- maximally insulin resistant and have lost over 80% of their -cell function. In addition to the muscle, liver, and -cell (triumvirate), the fat cell (accelerated lipolysis), gastroin- testinal tract (incretin deficiency/resistance), -cell (hyperglucagonemia), kidney (increased glucose reab- sorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players com- prise the ominous octet and dictate that: 1) multiple drugs used in combination will be required to correct the multi- ple pathophysiological defects, 2) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3) therapy must be started early to prevent/slow the progressive -cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which com- bination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiathero- genic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves -cell function, and exerts antiatherogenic effects), and exenatide (which preserves -cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improve- ment in glycemic control, they are associated with a progressive rise in A1C and progressive loss of -cell function.

Blood pressure lowering by Pioglitazone. Evidence for a direct vascular effect

Article

Full-text available

Aug 1995

To examine potential mechanisms for the blood pressure-lowering action of the thiazolidinedione compound, pioglitazone (PIO), we studied the effects of the drug on blood pressure and insulin action in vivo and on vascular tissue in vitro. In vivo, PIO lowered blood pressure in fructose-fed and chow-fed rats to an extent that could not be explained by alterations in fasting plasma insulin or free magnesium concentrations or by alterations in whole-body insulin sensitivity. In vitro, PIO caused significant blunting of the contractile responses of aortic rings to NE, arginine vasopressin (AVP), and potassium chloride; the blunting of responses to NE was maintained after removal of the endothelium. To assess the potential importance of extracellular calcium to the vasodepressor effect of PIO, we measured contractile responses to NE in the absence of calcium, and then after acute restoration of calcium in the presence of NE. PIO had no effect on the contractile response in the absence of calcium. By contrast, PIO blunted by 42% the contractile response that occurred when the extracellular calcium supply was acutely restored in the presence of NE, suggesting that the blunting was mediated by blockade of calcium uptake by vascular smooth muscle. Such an effect was confirmed in cultured a7r5 vascular smooth muscle cells, which exhibited a brisk increase in intracellular calcium in response to AVP that was blocked by PIO in a dose-dependent fashion. Our data indicate that PIO has a direct vascular effect that appears to be mediated at least in part by inhibition of agonist-mediated calcium uptake by vascular smooth muscle. The direct vascular effect may contribute to the blood pressure-lowering actions of PIO in vivo, because that effect could not be explained by alterations in whole-body insulin sensitivity.

A Prospective, Randomized Comparison of the Metabolic Effects of Pioglitazone or Rosiglitazone in Patients With Type 2 Diabetes Who Were Previously Treated With Troglitazone

Article

Full-text available

May 2002
DIABETES CARE

To characterize potential differences in glycemic control, plasma lipid level, and weight in a cohort of patients previously treated with troglitazone (TROG) who were switched to either pioglitazone or rosiglitazone. After a 2-week washout from TROG, 186 patients were randomly assigned to receive either pioglitazone (PIO) or rosiglitazone (ROSI). Weight, HbA(1c), and fasting lipid profile were documented before discontinuing TROG and at 4 months after starting either pioglitazone or rosiglitazone. Secondarily, the effect of concurrent medications on study outcomes was assessed. A total of 127 patients completed follow-up: 67 individuals in the PIO group (32 women, 35 men) and 60 individuals in the ROSI group (33 women, 27 men). There were no significant differences in gender mix, age, weight, fasting lipid profile, or HbA(1c) between the ROSI and PIO groups. After 4 months of randomized treatment, no change in HbA(1c) from baseline between or within groups was noted. Both groups experienced an equal and significant increase in weight from baseline of approximately 2.0 kg. Thiazolidinedione and HMG-CoA reductase inhibitor therapy had significant and independent effects on lipid profile (P < 0.005). Significant improvements in lipid profile were noted in the PIO group (P < 0.01), whereas none were detected with conversion to ROSI. Specifically, the PIO group experienced an average decrease in total cholesterol of approximately 20 mg/dl. Differing effects on lipid profile were apparent after random conversion from TROG to either PIO or ROSI, despite similar weight increase and glycemic control. The clinical significance of these differences remains to be determined, and further comparative research is warranted.

Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events)

Article

Full-text available

Nov 2005
LANCET

Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.

Effect of Pioglitazone Compared With Glimepiride on Carotid Intima-Media Thickness in Type 2 Diabetes: A Randomized Trial

Article

Full-text available

Jan 2007
J Am Med Assoc

Carotid artery intima-media thickness (CIMT) is a marker of coronary atherosclerosis and independently predicts cardiovascular events, which are increased in type 2 diabetes mellitus (DM). While studies of relatively short duration have suggested that thiazolidinediones such as pioglitazone might reduce progression of CIMT in persons with diabetes, the results of longer studies have been less clear. To evaluate the effect of pioglitazone vs glimepiride on changes in CIMT of the common carotid artery in patients with type 2 DM. Randomized, double-blind, comparator-controlled, multicenter trial in patients with type 2 DM conducted at 28 clinical sites in the multiracial/ethnic Chicago metropolitan area between October 2003 and May 2006. The treatment period was 72 weeks (1-week follow-up). CIMT images were captured by a single ultrasonographer at 1 center and read by a single treatment-blinded reader using automated edge-detection technology. Participants were 462 adults (mean age, 60 [SD, 8.1] years; mean body mass index, 32 [SD, 5.1]) with type 2 DM (mean duration, 7.7 [SD, 7.2] years; mean glycosylated hemoglobin [HbA1c] value, 7.4% [SD, 1.0%]), either newly diagnosed or currently treated with diet and exercise, sulfonylurea, metformin, insulin, or a combination thereof. Pioglitazone hydrochloride (15-45 mg/d) or glimepiride (1-4 mg/d) as an active comparator. Absolute change from baseline to final visit in mean posterior-wall CIMT of the left and right common carotid arteries. Mean change in CIMT was less with pioglitazone vs glimepiride at all time points (weeks 24, 48, 72). At week 72, the primary end point of progression of mean CIMT was less with pioglitazone vs glimepiride (-0.001 mm vs +0.012 mm, respectively; difference, -0.013 mm; 95% confidence interval, -0.024 to -0.002; P = .02). Pioglitazone also slowed progression of maximum CIMT compared with glimepiride (0.002 mm vs 0.026 mm, respectively, at 72 weeks; difference, -0.024 mm; 95% confidence interval, -0.042 to -0.006; P = .008). The beneficial effect of pioglitazone on mean CIMT was similar across prespecified subgroups based on age, sex, systolic blood pressure, duration of DM, body mass index, HbA(1c) value, and statin use. Over an 18-month treatment period in patients with type 2 DM, pioglitazone slowed progression of CIMT compared with glimepiride. clinicaltrials.gov Identifier: NCT00225264

Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy

Article

Full-text available

Jan 2007
NEW ENGL J MED

The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known. We evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and beta-cell function. Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons). The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].).

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes

Article

Full-text available

Jul 2007
NEW ENGL J MED

Rosiglitazone is widely used to treat patients with type 2 diabetes mellitus, but its effect on cardiovascular morbidity and mortality has not been determined. We conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manufacturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarction and death from cardiovascular causes. Of 116 potentially relevant studies, 42 trials met the inclusion criteria. We tabulated all occurrences of myocardial infarction and death from cardiovascular causes. Data were combined by means of a fixed-effects model. In the 42 trials, the mean age of the subjects was approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06). Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.

Systematic review: Comparative effectiveness and safety of oral medications for type 2 diabetes Mellitus

Article

Full-text available

Oct 2007
ANN INTERN MED

As newer oral diabetes agents continue to emerge on the market, comparative evidence is urgently required to guide appropriate therapy. To summarize the English-language literature on the benefits and harms of oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and alpha-glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus. The MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception through January 2006 for original articles and through November 2005 for systematic reviews. Unpublished U.S. Food and Drug Administration and industry data were also searched. 216 controlled trials and cohort studies and 2 systematic reviews that addressed benefits and harms of oral diabetes drug classes available in the United States. Using standardized protocols, 2 reviewers serially abstracted data for each article. Evidence from clinical trials was inconclusive on major clinical end points, such as cardiovascular mortality. Therefore, the review was limited mainly to studies of intermediate end points. Most oral agents (thiazolidinediones, metformin, and repaglinide) improved glycemic control to the same degree as sulfonylureas (absolute decrease in hemoglobin A1c level of about 1 percentage point). Nateglinide and alpha-glucosidase inhibitors may have slightly weaker effects, on the basis of indirect comparisons of placebo-controlled trials. Thiazolidinediones were the only class that had a beneficial effect on high-density lipoprotein cholesterol levels (mean relative increase, 0.08 to 0.13 mmol/L [3 to 5 mg/dL]) but a harmful effect on low-density lipoprotein (LDL) cholesterol levels (mean relative increase, 0.26 mmol/L [10 mg/dL]) compared with other oral agents. Metformin decreased LDL cholesterol levels by about 0.26 mmol/L (10 mg/dL), whereas other oral agents had no obvious effects on LDL cholesterol levels. Most agents other than metformin increased body weight by 1 to 5 kg. Sulfonylureas and repaglinide were associated with greater risk for hypoglycemia, thiazolidinediones with greater risk for heart failure, and metformin with greater risk for gastrointestinal problems compared with other oral agents. Lactic acidosis was no more common in metformin recipients without comorbid conditions than in recipients of other oral diabetes agents. Data on major clinical end points were limited. Studies inconsistently reported adverse events other than hypoglycemia, and definitions of adverse events varied across studies. Some harms not assessed in trials or observational studies may have been overlooked. Compared with newer, more expensive agents (thiazolidinediones, alpha-glucosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points.

Effects of Intensive Glucose Lowering in Type 2 Diabetes

Article

Full-text available

Jul 2008
NEW ENGL J MED

Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001). As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus

Article

Sep 2007

Shari Bolen

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes

Article

Sep 2007
J VASC SURG

Effects of Intensive Glucose Lowering in Type 2 Diabetes The Action to Control Cardiovascular Risk in Diabetes Study Group

Article

Jan 2008

Background Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. Methods In this randomized study, 10,251 patients (mean age, 62.2 years) with a median gly- cated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous car- diovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. Results At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval (CI), 0.78 to 1.04; P = 0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard- therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P = 0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P

Endogenous hyperinsulinaemia and exogenous insulin: A common theme between atherosclerosis, increased cancer risk and other morbidities

Article

Feb 2012

AHRQ’s Comparative Effectiveness Research on Oral Medications for Type 2 Diabetes: A Summary of the Key Findings

Article

Jan 2012
J MANAGE CARE PHARM

In 2007, the Agency for Healthcare Research and Quality(AHRQ) published a systematic review on the comparative effectiveness of oral medications for type 2 diabetes. The review included studies on the benefits and risks of oral medications used for achieving glycemic control in patients with type 2 diabetes. AHRQ published an updated review in March 2011 that summarized the benefits and harms of medications (metformin,second-generation sulfonylureas, thiazolidinediones, meglitinides,dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists), as monotherapy and in combination, for the treatment of adults with type 2 diabetes. To (a) familiarize health care professionals with the methods and findings from AHRQ's 2011 comparative effectiveness review on medications for adults with type 2 diabetes, (b) encourage consideration of the clinical and managed care applications of the review findings, and(c) identify limitations and gaps in the existing research with respect to the benefits and risks of oral diabetes medications. Type 2 diabetes mellitus is a major public health burden. Since the 2007 AHRQ systematic review of oral medications for type 2 diabetes, the FDA has approved several new drug classes. Therefore, in 2011, the original systematic review was updated with comparisons including the newer oral diabetes medications. The updated report expands beyond the scope of the original 2007 review by including comparisons of 2-drug combinations and the addition of more head-to-head comparisons, as well as additional adverse outcomes. A high strength of evidence showed that most medications were similarly efficacious at lowering hemoglobin A1c by about 1 absolute percentage point compared with baseline values. The addition of most oral medications to initial monotherapy further improved glycemiccontrol by lowering A1c by another 1 percentage point. The only exception was the DPP-4 inhibitor class, which did not lower A1c to the same extent as metformin when used as monotherapy. Overall, metformin was found to have a more favorable effect on body weight when compared with other medications. Two-drug combinations compared with each other demonstrated similar reductions in A1c levels. Metformin decreased low-density lipoprotein cholesterol (LDL-C) relative to pioglitazone, sulfonylureas,and DPP-4 inhibitors. Sulfonylureas had a 4-fold higher risk of mild-to-moderate hypoglycemia compared with metformin alone, and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus a thiazolidinedione. Thiazolidinediones had an increased risk of congestive heart failure relative to sulfonylureas, and an increased risk for bone fractures relative to metformin. Diarrhea occurred more often for metformin users compared with thiazolidinedione users. Although the long-term risks and benefits of diabetes medications remain unclear, the evidence supports the use of metformin as a first-line agent.

Weight change in people with type 2 diabetes: Secular trends and the impact of alternative antihyperglycaemic drugs

Article

Dec 2011
DIABETES OBES METAB

This study aimed to describe the pattern of weight change in people with type 2 diabetes (T2DM) over time and when using alternative treatment regimens. Data were from routine clinical practice in the UK. The weight trend was determined for each year from 1995 to 2010 for both prevalent and incident cases. Baseline weight was compared to absolute (mean Δ) and relative weights (% Δ) at 6, 12 and 24 months. Mean, standardized weight in prevalent cases increased from 83.4 to 92.1 kg for males and from 73.5 to 79.9 kg for females between 1995 and 2010 (p < 0.0001). For incident cases, the respective figures were 86.7 to 93.6 kg for males and 76.0 to 80.7 kg for females (p < 0.001). Between baseline and 6, 12 and 24 months, there were significant changes in weight for the majority of the treatment regimens selected for analysis. The largest weight increase at 12 months was for the patients who were prescribed a combination therapy with insulin and a thiazolidinedione, with a median increase of 4.1 kg (95% CI -0.60 to 8.0, p < 0.001). The largest weight decrease at 12 months was for the patients who were prescribed a combination therapy of metformin and exenatide, with a median decrease of -7.0 kg (95% CI -12.0 to -2.0, p < 0.001). There was a continual increase in body weight in people with T2DM over time, and considerable differences in the impact on weight using alternative treatment regimens. At the same time, glycaemic control remained relatively unchanged.

Dipeptidyl peptidase-4 inhibitors and preservation of pancreatic islet-cell function: A critical appraisal of the evidence

Article

Jul 2011
DIABETES OBES METAB

Type 2 diabetes mellitus (T2DM) develops as a consequence of progressive β-cell dysfunction in the presence of insulin resistance. None of the currently-available T2DM therapies is able to change the course of the disease by halting the relentless decline in pancreatic islet cell function. Recently, dipeptidyl peptidase (DPP)-4 inhibitors, or incretin enhancers, have been introduced in the treatment of T2DM. This class of glucose-lowering agents enhances endogenous glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels by blocking the incretin-degrading enzyme DPP-4. DPP-4 inhibitors may restore the deranged islet-cell balance in T2DM, by stimulating meal-related insulin secretion and by decreasing postprandial glucagon levels. Moreover, in rodent studies, DPP-4 inhibitors demonstrated beneficial effects on (functional) β-cell mass and pancreatic insulin content. Studies in humans with T2DM have indicated improvement of islet-cell function, both in the fasted state and under postprandial conditions and these beneficial effects were sustained in studies with a duration up to 2 years. However, there is at present no evidence in humans to suggest that DPP-4 inhibitors have durable effects on β-cell function after cessation of therapy. Long-term, large-sized trials using an active blood glucose lowering comparator followed by a sufficiently long washout period after discontinuation of the study drug are needed to assess whether DPP-4 inhibitors may durably preserve pancreatic islet-cell function in patients with T2DM.

The safety profile of exogenous insulin in people with type 2 diabetes: Justification for concern

Article

Jul 2011
DIABETES OBES METAB

There is no doubt about the value of exogenous insulin for people with type 1 diabetes. The purpose of this commentary is to discuss emerging evidence that this may not be the case for the majority of people with type 2 diabetes.

Excess Exposure to Insulin Is the Primary Cause of Insulin Resistance and its Associated Atherosclerosis

Article

Nov 2011
Curr Mol Pharmacol

The main goal of this review is to provide more specific and effective targets for prevention and treatment of insulin resistance and associated atherosclerosis. Modern technologies and medicine have vastly improved human health and prolonged the average life span of humans primarily by eliminating various premature deaths and infectious diseases. The modern technologies have also provided us abundant food and convenient transportation tools such as cars. As a result, more people are becoming overfed and sedentary. People are generally ingesting more calories than their bodies' need, leading to the so-called "positive energy imbalance", which is inseparable from the development of insulin resistance and its associated atherosclerosis. A direct consequence of insulin resistance is hyperinsulinemia. The current general view is that insulin is not functional properly in the presence of insulin resistance. Thus, the role of insulin itself in the development of insulin resistance and associated atherosclerosis has not been recognized. We have recently observed that the basal level of insulin signaling is increased in the presence of insulin resistance and hyperinsulinemia. In this review, we will explain how the increased basal insulin signaling contributes to the development of insulin resistance and associated atherosclerosis. We will first explain how insulin causes insulin resistance through two arbitrary stages (before and after the presence of obvious insulin resistance), and, then, explain how the excess exposure to insulin and the relative insulin insufficiency contributes to the atherosclerotic diseases. We propose that blockade of the excess insulin signaling is a viable approach to prevent and/or reverse insulin resistance and its associated atherosclerosis.

Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: Results from a 2-year study

Article

Sep 2010
DIABETES OBES METAB

To show that vildagliptin added to metformin is non-inferior to glimepiride in reducing HbA1c levels from baseline over 2 years. A randomized, double-blind, active-comparator study of patients with type 2 diabetes mellitus inadequately controlled (HbA1c 6.5-8.5%) by metformin monotherapy. Patients received vildagliptin (50 mg twice daily) or glimepiride (up to 6 mg/day) added to metformin. In all, 3118 patients were randomized (vildagliptin, n = 1562; glimepiride, n = 1556). From similar baseline values (7.3%), after 2 years adjusted mean (s.e.) change in HbA1c was comparable between vildagliptin and glimepiride treatment: -0.1% (0.0%) and -0.1% (0.0%), respectively. The primary objective of non-inferiority was met. A similar proportion of patients reached HbA1c <7% (36.9 and 38.3%, respectively), but with vildagliptin more patients reached this target without hypoglycaemia (36.0% vs. 28.8%; p = 0.004). The initial response (IR) was sustained for a mean (s.d.) of 309 (244) days with vildagliptin versus 270 (223) days for glimepiride (p < 0.001) (IR = nadir HbA1c where change from baseline > or =0.5% or HbA1c < or =6.5% within the first six months of treatment. After IR was detected, sustained response = time between nadir and an increase of >0.3% above IR). Independent of disease duration, age was a predictor of effect sustainability. Fewer patients experienced hypoglycaemia with vildagliptin (2.3% vs. 18.2% with glimepiride) with a 14-fold difference in the number of hypoglycaemic events (59 vs. 838). Vildagliptin had a beneficial effect on body weight [mean (s.e.) change from baseline -0.3 (0.1) kg; between-group difference -1.5 kg; p < 0.001]. Overall, both treatments were well tolerated and displayed similar safety profiles. Vildagliptin add-on has similar efficacy to glimepiride after 2 years' treatment, with markedly reduced hypoglycaemia risk and no weight gain.

Currie CJ, Peters JR, Tynan A, Evans M, Heine RJ, Bracco OL, Zagar T, Poole CD. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet. 2010;375:481-9

Article

Feb 2010
LANCET

Results of intervention studies in patients with type 2 diabetes have led to concerns about the safety of aiming for normal blood glucose concentrations. We assessed survival as a function of HbA(1c) in people with type 2 diabetes. Two cohorts of patients aged 50 years and older with type 2 diabetes were generated from the UK General Practice Research Database from November 1986 to November 2008. We identified 27 965 patients whose treatment had been intensified from oral monotherapy to combination therapy with oral blood-glucose lowering agents, and 20 005 who had changed to regimens that included insulin. Those with diabetes secondary to other causes were excluded. All-cause mortality was the primary outcome. Age, sex, smoking status, cholesterol, cardiovascular risk, and general morbidity were identified as important confounding factors, and Cox survival models were adjusted for these factors accordingly. For combined cohorts, compared with the glycated haemoglobin (HbA(1c)) decile with the lowest hazard (median HbA(1c) 7.5%, IQR 7.5-7.6%), the adjusted hazard ratio (HR) of all-cause mortality in the lowest HbA(1c) decile (6.4%, 6.1-6.6) was 1.52 (95% CI 1.32-1.76), and in the highest HbA(1c) decile (median 10.5%, IQR 10.1-11.2%) was 1.79 (95% CI 1.56-2.06). Results showed a general U-shaped association, with the lowest HR at an HbA(1c) of about 7.5%. HR for all-cause mortality in people given insulin-based regimens (2834 deaths) versus those given combination oral agents (2035) was 1.49 (95% CI 1.39-1.59). Low and high mean HbA(1c) values were associated with increased all-cause mortality and cardiac events. If confirmed, diabetes guidelines might need revision to include a minimum HbA(1c) value. Eli Lilly and Company.

Herrett E, Thomas SL, Schoonen WM, Smeeth L, Hall AJValidation and validity of diagnoses in the General Practice Research Database: a systematic review. Br J Clin Pharmacol 69: 4-14

Article

Jan 2010
BRIT J CLIN PHARMACO

To investigate the range of methods used to validate diagnoses in the General Practice Research Database (GPRD), to summarize findings and to assess the quality of these validations. A systematic literature review was performed by searching PubMed and Embase for publications using GPRD data published between 1987 and April 2008. Additional publications were identified from conference proceedings, back issues of relevant journals, bibliographies of retrieved publications and relevant websites. Publications that reported attempts to validate disease diagnoses recorded in the GPRD were included. We identified 212 publications, often validating more than one diagnosis. In total, 357 validations investigating 183 different diagnoses met our inclusion criteria. Of these, 303 (85%) utilized data from outside the GPRD to validate diagnoses. The remainder utilized only data recorded in the database. The median proportion of cases with a confirmed diagnosis was 89% (range 24-100%). Details of validation methods and results were often incomplete. A number of methods have been used to assess validity. Overall, estimates of validity were high. However, the quality of reporting of the validations was often inadequate to permit a clear interpretation. Not all methods provided a quantitative estimate of validity and most methods considered only the positive predictive value of a set of diagnostic codes in a highly selected group of cases. We make recommendations for methodology and reporting to strengthen further the use of the GPRD in research.

Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy

Article

Nov 2008
DIABETOLOGIA

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

Charlson ME, Pompei P, Ales KL & MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis40: 373-383

Article

Feb 1987
J Chron Dis

The objective of this study was to develop a prospectively applicable method for classifying comorbid conditions which might alter the risk of mortality for use in longitudinal studies. A weighted index that takes into account the number and the seriousness of comorbid disease was developed in a cohort of 559 medical patients. The 1-yr mortality rates for the different scores were: "0", 12% (181); "1-2", 26% (225); "3-4", 52% (71); and "greater than or equal to 5", 85% (82). The index was tested for its ability to predict risk of death from comorbid disease in the second cohort of 685 patients during a 10-yr follow-up. The percent of patients who died of comorbid disease for the different scores were: "0", 8% (588); "1", 25% (54); "2", 48% (25); "greater than or equal to 3", 59% (18). With each increased level of the comorbidity index, there were stepwise increases in the cumulative mortality attributable to comorbid disease (log rank chi 2 = 165; p less than 0.0001). In this longer follow-up, age was also a predictor of mortality (p less than 0.001). The new index performed similarly to a previous system devised by Kaplan and Feinstein. The method of classifying comorbidity provides a simple, readily applicable and valid method of estimating risk of death from comorbid disease for use in longitudinal studies. Further work in larger populations is still required to refine the approach because the number of patients with any given condition in this study was relatively small.

Short-Term Pioglitazone Treatment Improves Vascular Function Irrespective of Metabolic Changes in Patients With Type 2 Diabetes

Article

Jan 2006

To determine whether pioglitazone influences endothelial function directly, we examined in a randomized, crossover, placebo-controlled, double-blind trial the effects of 4 weeks of pioglitazone treatment in 20 male type 2 diabetic patients. We conclude that short-term pioglitazone treatment ameliorates endothelial dysfunction in conduit arteries irrespective of significant beneficial changes in plasma levels of insulin, FFA, adiponectin, or CRP in type 2 patients with diabetes. Pioglitazone, a PPARgamma agonist, not only improves insulin resistance and glycemic control but may also have additional beneficial vascular effects in patients with type 2 diabetes. Low-grade inflammation, free fatty acids, and adiponectin may play a role in modulation of vascular function. We studied the effect of 4 weeks of pioglitazone treatment on endothelial function, metabolic changes, and C-reactive protein in patients with type 2 diabetes. A randomized, crossover, placebo-controlled, double-blind trial was performed in which pioglitazone 30 mg once daily was administered to 20 patients with type 2 diabetes on oral antihyperglycemic agents for 4 weeks. Shear stress-induced flow-mediated dilation (FMD) of the brachial artery was used as outcome parameter for vascular function. Brachial artery endothelial function was significantly increased by pioglitazone treatment compared with placebo (FMD 5.4 +/- 0.5% versus 3.1 +/- 0.5%, P = 0.001). Endothelium-independent vasodilation was not different between the 2 study periods. Pioglitazone treatment reduced insulin, FFA, and C-reactive protein concentrations compared with placebo (18.3 +/- 2.4 versus 14.8 +/- 2.1 mU/L, P = 0.03; 641 +/- 46 versus 542 +/- 33 mumol/L, P = 0.04; and 3.5 +/- 0.6 mg/L versus 2.6 +/- 0.5 mg/L, P = 0.01; respectively). A significant increase in plasma adiponectin concentration (3.95 +/- 0.57 microg/mL versus 7.59 +/- 0.95 microg/mL, P = 0.002) was also observed. No correlations were found between these metabolic changes and the improvement of conduit artery endothelial function. Short-term pioglitazone treatment ameliorates endothelial dysfunction in conduit arteries irrespective of changes in insulin, FFA, adiponectin, or CRP in type 2 patients with diabetes.

American Diabetes Assocaition: Nutrition Recommendations and Interventions for Diabetes: a position statement of the American Diabetes AssociationADADiabetes Care200730S48S6510.2337/dc07-S04817192379

Article

Oct 2006
DIABETES CARE

Efficacy and Safety of Incretin Therapy in Type 2 Diabetes

Article

Aug 2007
J Am Med Assoc

Pharmacotherapies that augment the incretin pathway have recently become available, but their role in the management of type 2 diabetes is not well defined. To assess the efficacy and safety of incretin-based therapy in adults with type 2 diabetes based on randomized controlled trials published in peer-reviewed journals or as abstracts. We searched MEDLINE (1966-May 20, 2007) and the Cochrane Central Register of Controlled Trials (second quarter, 2007) for English-language randomized controlled trials involving an incretin mimetic (glucagonlike peptide 1 [GLP-1] analogue) or enhancer (dipeptidyl peptidase 4 [DPP4] inhibitor). We also searched prescribing information, relevant Web sites, reference lists and citation sections of recovered articles, and abstracts presented at recent conferences. Randomized controlled trials were selected if they were at least 12 weeks in duration, compared incretin therapy with placebo or other diabetes medication, and reported hemoglobin A(1c) data in nonpregnant adults with type 2 diabetes. Two reviewers independently assessed trials for inclusion and extracted data. Differences were resolved by consensus. Meta-analyses were conducted for several efficacy and safety outcomes. Of 355 potentially relevant articles identified, 51 were retrieved for detailed evaluation and 29 met the inclusion criteria. Incretins lowered hemoglobin A(1c) compared with placebo (weighted mean difference, -0.97% [95% confidence interval {CI}, -1.13% to -0.81%] for GLP-1 analogues and -0.74% [95% CI, -0.85% to -0.62%] for DPP4 inhibitors) and were noninferior to other hypoglycemic agents. Glucagonlike peptide 1 analogues resulted in weight loss (1.4 kg and 4.8 kg vs placebo and insulin, respectively) while DPP4 inhibitors were weight neutral. Glucagonlike peptide 1 analogues had more gastrointestinal side effects (risk ratio, 2.9 [95% CI, 2.0-4.2] for nausea and 3.2 [95% CI, 2.5-4.4] for vomiting). Dipeptidyl peptidase 4 inhibitors had an increased risk of infection (risk ratio, 1.2 [95% CI, 1.0-1.4] for nasopharyngitis and 1.5 [95% CI, 1.0-2.2] for urinary tract infection) and headache (risk ratio, 1.4 [95% CI, 1.1-1.7]). All but 3 trials had a 30-week or shorter duration; thus, long-term efficacy and safety could not be evaluated. Incretin therapy offers an alternative option to currently available hypoglycemic agents for nonpregnant adults with type 2 diabetes, with modest efficacy and a favorable weight-change profile. Careful postmarketing surveillance for adverse effects, especially among the DPP4 inhibitors, and continued evaluation in longer-term studies and in clinical practice are required to determine the role of this new class among current pharmacotherapies for type 2 diabetes.

Drug Safety Communication: Ongoing Safety Review of Actos (Pioglitazone) and Potential Increased Risk of Bladder Cancer After Two Years Exposure jcem.endojournals.org 4611 able from http://www.fda.gov/Drugs/DrugSafety/ucm226214.htm

Jan 2011
4605-4612

Drug Food
Administration

Food and Drug Administration 2010 FDA Drug Safety Communication: Ongoing Safety Review of Actos (Pioglitazone) and Potential Increased Risk of Bladder Cancer After Two Years Exposure. Avail-J Clin Endocrinol Metab, December 2012, 97(12):4605– 4612 jcem.endojournals.org 4611 able from http://www.fda.gov/Drugs/DrugSafety/ucm226214.htm. Accessed July 4, 2012

Haffner SM 2006 Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial Dicembrini I, Pala L, Rotella CM 2011 From theory to clinical practice in the use of GLP-1 receptor agonists and DPP-4 inhibitors therapy

Jan 2011
2572-2581

T Mazzone
Pm Meyer
Sb Feinstein
Mh Davidson
D Gt Kondos
Rb Sr
A Perez
Provost

Mazzone T, Meyer PM, Feinstein SB, Davidson MH, Kondos GT, D'Agostino Sr RB, Perez A, Provost JC, Haffner SM 2006 Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 296:2572– 2581 27. Dicembrini I, Pala L, Rotella CM 2011 From theory to clinical practice in the use of GLP-1 receptor agonists and DPP-4 inhibitors therapy. Exp Diabetes Res 2011:898913

Choudhry NK 2012 Patterns of medication initiation in newly diagnosed diabetes mellitus: quality and cost implicationse1– e7 4612 Morgan et al. What Next after Metformin?

Jan 2013
3024605-4612

Nr Desai
Wh Shrank
Fischer
J Avorn
Jn Liberman
S Schneeweiss
J Pakes
Brennan

Desai NR, Shrank WH, Fischer MA, Avorn J, Liberman JN, Schneeweiss S, Pakes J, Brennan TA, Choudhry NK 2012 Patterns of medication initiation in newly diagnosed diabetes mellitus: quality and cost implications. Am J Med 125:302.e1– e7 4612 Morgan et al. What Next after Metformin? J Clin Endocrinol Metab, December 2012, 97(12):4605– 4612

Faysal JM 2012 AHRQ’s comparative ef-fectiveness research on oral medications for type 2 diabetes: a sum-maryofthekeyfindings

Wl Bennett
Balfe

Bennett WL, Balfe LM, Faysal JM 2012 AHRQ’s comparative ef-fectiveness research on oral medications for type 2 diabetes: a sum-maryofthekeyfindings.JManagCarePharm18(1SupplA):S3–S2

Cou-turierA,FoleyJE,ZinmanB2010Vildagliptinadd-ontometformin producessimilarefficacyandreducedhypoglycaemicriskcompared with glimepiride, with no weight gain: results from a 2-year study

780-78

Dr Matthews
S Dejager
B Ahren
V Fonseca
Ferrannini

Matthews DR, Dejager S, Ahren B, Fonseca V, Ferrannini E, Cou-turierA,FoleyJE,ZinmanB2010Vildagliptinadd-ontometformin producessimilarefficacyandreducedhypoglycaemicriskcompared with glimepiride, with no weight gain: results from a 2-year study. Diabetes Obes Metab 12:780–78

RotellaCM2011Fromtheorytoclinicalprac-tice in the use of GLP-1 receptor agonists and DPP-4 inhibitors therapy

89891

Dicembrinii
Palal

DicembriniI,PalaL,RotellaCM2011Fromtheorytoclinicalprac-tice in the use of GLP-1 receptor agonists and DPP-4 inhibitors therapy. Exp Diabetes Res 2011:89891

ValidationandvalidityofdiagnosesintheGeneralPracticeResearch Database: a systematic review

Thomas E Herrett
Sl
Wm Schoonen
L Smeeth
Hall

Herrett E, Thomas SL, Schoonen WM, Smeeth L, Hall AJ 2010 ValidationandvalidityofdiagnosesintheGeneralPracticeResearch Database: a systematic review. Br J Clin Pharmacol 69:4–1

Nutrition recommendations and inter-ventions for diabetes—2006: a position statement of the American Diabetes Association

Jan 2006
2140-2157

Bantle
Jp
J Wylie-Rosett
Al Albright
Apovian
Clark Ng Cm
Franz Mj Bj Hoogwerf
Lichtenstein
Ah
E Mayer-Davis
Ad
Wheeler
Ml

Bantle JP, Wylie-Rosett J, Albright AL, Apovian CM, Clark NG, Franz MJ, Hoogwerf BJ, Lichtenstein AH, Mayer-Davis E, Moora-dian AD, Wheeler ML 2006 Nutrition recommendations and inter-ventions for diabetes—2006: a position statement of the American Diabetes Association. Diabetes Care 29:2140 –2157

Jan 2006
2140-2157

Jp Bantle
J Wylie-Rosett
Al Albright
Cm Apovian
Ng Clark
Mj Franz
Bj Hoogwerf
Ah Lichtenstein
E Mayer-Davis
Ad Mooradian
Ml Wheeler

Bantle JP, Wylie-Rosett J, Albright AL, Apovian CM, Clark NG, Franz MJ, Hoogwerf BJ, Lichtenstein AH, Mayer-Davis E, Mooradian AD, Wheeler ML 2006 Nutrition recommendations and interventions for diabetes—2006: a position statement of the American Diabetes Association. Diabetes Care 29:2140 –2157

Validation and validity of diagnoses in the General Practice Research Database: a systematic review.

Jan 2010
4

Herrett

Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study.

Jan 2010
481

Currie

Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis.

Jan 2007
194

Amori

Nutrition recommendations and interventions for diabetes—2006: a position statement of the American Diabetes Association.

Jan 2006
2140

Bantle

Excess exposure to insulin is the primary cause of insulin resistance and its associated atherosclerosis.

Jan 2011
154

FDA Drug Safety Communication: Ongoing Safety Review of Actos (Pioglitazone) and Potential Increased Risk of Bladder Cancer After Two Years Exposure

Drug Food
Administration

What Next after Metformin? A Retrospective Evaluation of the Outcome of Second-Line, Glucose-Lowering Therapies in People with Type 2 Diabetes

Abstract

No full-text available

Recommended publications

Mortality and Other Important Diabetes-Related Outcomes With Insulin vs Other Antihyperglycemic Ther...