Comparative Effectiveness and Safety of Medications for Type 2 Diabetes: An Update Including New Drugs and 2-Drug Combinations

University of North Carolina at Chapel Hill, North Carolina, United States
Annals of internal medicine (Impact Factor: 17.81). 03/2011; 154(9):602-13. DOI: 10.1059/0003-4819-154-9-201105030-00336
Source: PubMed


Given the increase in medications for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices.
To summarize the benefits and harms of metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 receptor agonists, as monotherapy and in combination, to treat adults with type 2 diabetes.
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through April 2010 for English-language observational studies and trials. The MEDLINE search was updated to December 2010 for long-term clinical outcomes.
Two reviewers independently screened reports and identified 140 trials and 26 observational studies of head-to-head comparisons of monotherapy or combination therapy that reported intermediate or long-term clinical outcomes or harms.
Two reviewers following standardized protocols serially extracted data, assessed applicability, and independently evaluated study quality.
Evidence on long-term clinical outcomes (all-cause mortality, cardiovascular disease, nephropathy, and neuropathy) was of low strength or insufficient. Most medications decreased the hemoglobin A(1c) level by about 1 percentage point and most 2-drug combinations produced similar reductions. Metformin was more efficacious than the DPP-4 inhibitors, and compared with thiazolidinediones or sulfonylureas, the mean differences in body weight were about -2.5 kg. Metformin decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a 4-fold higher risk for mild or moderate hypoglycemia than metformin alone and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones increased risk for congestive heart failure compared with sulfonylureas and increased risk for bone fractures compared with metformin. Diarrhea occurred more often with metformin than with thiazolidinediones.
Only English-language publications were reviewed. Some studies may have selectively reported outcomes. Many studies were small, were of short duration, and had limited ability to assess clinically important harms and benefits.
Evidence supports metformin as a first-line agent to treat type 2 diabetes. Most 2-drug combinations similarly reduce hemoglobin A(1c) levels, but some increased risk for hypoglycemia and other adverse events. Primary Funding Source: Agency for Healthcare Research and Quality.

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Available from: Milo A Puhan
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    • "Metformin is recommended as first-line treatment for type 2 diabetes (T2D) after diet and exercise [1] [2] [3] [4] [5] [6]. Most patients require treatment intensification over time, but subsequent treatment options remain uncertain, partially due to the lack of well-designed head-to-head randomized controlled trials of sequenced treatments [7]. Few controlled trials have reported effective options for patients failing on metformin plus a glucagon-like peptide-1 receptor agonist (GLP-1RA), a combination increasingly used in clinical practice [8] [9] [10] [11] [12] [13], and none have investigated additional non-insulin therapy. "
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    ABSTRACT: AimsThe EUREXA trial extension evaluated third-line thiazolidinedione or glimepiride therapy in patients inadequately controlled on metformin + exenatide twice daily (BID), and third-line exenatide BID in patients inadequately controlled on metformin + glimepiride.Materials and methodsIn this randomized, open-label, multicenter trial, 144 patients with type 2 diabetes inadequately controlled (glycated hemoglobin [HbA1c] >9% [75 mmol/mol] after 3 months’ treatment or >7% [53 mmol/mol] at 2 consecutive visits 3 months apart after 6 months’ treatment) on metformin + exenatide BID were re-randomized to add-on thiazolidinedione or glimepiride, and 166 patients inadequately controlled on metformin + glimepiride received add-on exenatide BID. Changes in HbA1c, body mass index (BMI), lipids, hypoglycemia, and vital signs were evaluated.ResultsMedian triple therapy duration was ~2 years. In patients inadequately controlled on metformin + exenatide BID, add-on thiazolidinedione decreased HbA1c significantly better than add-on glimepiride (130-week difference 0.48%, 95% CI 0.19–0.77 [5.2 mmol/mol, 2.1–8.4], p = 0.001), but with significantly increased BMI and systolic blood pressure. Ratio of documented symptomatic (blood glucose ≤70 mg/dl) hypoglycemia rates for add-on glimepiride to add-on thiazolidinedione was 8.48 (p < 0.0001). Add-on exenatide BID after metformin + glimepiride significantly reduced HbA1c (mean [SD] change from baseline −0.35 [0.89]% [−3.8 (9.7) mmol/mol]) and BMI (−0.82 [1.9] kg/m2) at 130 weeks, with a slightly increased rate of documented symptomatic hypoglycemia from metformin + glimepiride (ratio 1.49).Conclusions Thiazolidinedione, but not glimepiride, was an effective and well tolerated third-line therapy in patients without glycemic control after long-term therapy with metformin + exenatide BID. Exenatide BID was an effective and well tolerated third-line therapy in patients inadequately controlled on metformin + glimepiride.(NCT00359762)
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    • "At present, there are five classes of commercial oral hypoglycemic drugs including biguanides, sulfonylureas, insulinsensitizing agent, ␣-glucosidase inhibitors and traditional Chinese medicine [3]. The oral hypoglycemic drugs could produce weight gain, increased risk of congestive heart failure, bone fractures, and/or gastrointestinal side effects when used in combination with another medication or as monotherapy [4]. Then, traditional Chinese medicine with similar activity and less side effects would be a good alternative to treat hyperglycemia in monotherapy or at least as complement to chemical medicine [5]. "
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    ABSTRACT: Fagomine, 1-deoxynojirimycin (DNJ) and 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) are the major bioactive constituents in the active fraction of alkaloids from the traditional Chinese medicine mulberry twig (Ramulus Mori, Chinese name Sang Zhi), which has a strong activity on α-glucosidase in vitro and in vivo. A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of DNJ, fagomine and DAB in rat plasma. Plasma samples were prepared using a simple protein precipitation by the addition of 1% volume of Tris and two volumes of methanol-acetonitrile. The analytes and internal standard (IS, miglitol) were chromatographed in an XBridge™ amide column with a gradient mobile phase of acetonitrile-water (0.1% ammonium hydroxide) at a flow rate of 0.7mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer equipped with electrospray ionization (ESI) source in positive ion mode by multiple reaction monitoring (MRM) mode. Linear detection responses were obtained for DNJ ranging from 5.00 to 5000.00ng/mL, 10.00 to 2500.00ng/mL for fagomine and DAB. The lower limits of quantification (LLOQs) were 5.00, 10.00, 10.00ng/mL for DNJ, fagomine and DAB, respectively. Intra-day and inter-day precisions (R.S.D.%) were within 10% for three analytes with accuracies (R.E.%) less than 12%. The mean recoveries of analytes were greater than 85%. All analytes were proved to be stable during the sample storage, preparation and analytic procedures. The method was successfully applied to the pharmacokinetic study of the three alkaloids in rats after oral administration of the active fraction of alkaloids from mulberry twig. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Feb 2015 · Journal of Pharmaceutical and Biomedical Analysis
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    • "Improved glycemic control has been associated with a reduction in microvascular events [3] and there is a clear association between microvascular complications such as albuminuria and an increased risk of CV events in patients with T2DM [4]. However, the impact of reducing blood glucose, and the potential benefit of specific glucose-lowering agents, on CV events in patients with T2DM remains unclear and highly controversial [5,6]. Moreover, treatment must likely occur over a substantial duration of time, since macrovascular outcome events are known to be late complications of a progressive multifaceted pathogenic process that spans decades [7,8]. "
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    ABSTRACT: Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOMETM trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on microvascular outcomes.
    Full-text · Article · Jun 2014 · Cardiovascular Diabetology
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