Impact of Hypoglycemia Associated With Antihyperglycemic Medications on Vascular Risks in Veterans With Type 2 Diabetes

School of Pharmacy, Saint Joseph College, Hartford, Connecticut, USA.
Diabetes care (Impact Factor: 8.42). 03/2012; 35(5):1126-32. DOI: 10.2337/dc11-2048
Source: PubMed


Hypoglycemia is associated with failure to show cardiovascular benefit and increased mortality of intensive glycemic control in randomized clinical trials. This retrospective cohort study aimed to examine the impact of hypoglycemia on vascular events in clinical practice.
Patients with type 2 diabetes were identified by ICD-9-CM codes (250.xx except for 250.x1 and 250.x3) between 1 January 2004 and 1 September 2010 from the Veterans Integrated Service Network 16. Index date was defined as the first date of new antihyperglycemic medications (index treatment). Patients with 1-year preindex records of hypoglycemia, cardiovascular, and microvascular diseases were excluded. The hypoglycemia group was identified by ICD-9-CM codes (250.8, 251.0, 251.1, and 251.2) within the index treatment period. A propensity score-matched group was used as control subjects. Cardiovascular events, microvascular complications, and all-cause death were compared using Kaplan-Meier analysis and Cox proportional hazards regression model.
Among the unmatched sample (N = 44,261), the hypoglycemia incidence rate was 3.57/100 patient-years. The matched sample (hypoglycemia group: n = 761; control group: n = 761) had a median follow-up of 3.93 years, mean age of 62.6 ± 11.0 years, and preindex HbA(1c) of 10.69 ± 2.61%. The 1-year change in HbA(1c) was similar (hypoglycemia group -0.51 vs. control group -0.32%, P = 0.7244). The hypoglycemia group had significantly higher risks of cardiovascular events (hazard ratio 2.00 [95% CI 1.63-2.44]) and microvascular complications (1.76 [1.46-2.11]) but no statistical mortality difference. Patients with at least two hypoglycemic episodes were at higher risks of vascular events than those with one episode (1.53 [1.10-1.66]).
Hypoglycemia is associated with higher risks of incident vascular events. Patients with hypoglycemia should be monitored closely for vascular events.

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    • "Episodes of hypoglycaemia can produce physical and psychological effects including sweating, palpitations, shaking, hunger, confusion, drowsiness, odd behaviour, speech difficulty, loss of coordination, and headaches [7]. The clinical consequences of hypoglycaemia can be serious, including seizures, loss of consciousness, injury [5] [7], cardiac ischemia [8], cardiac arrhythmias [9] and other cardiovascular events [10] [11], hospitalization, or death [12]. In the USA, adverse drug reactions to insulin and oral antidiabetes drugs (OADs) accounted for an estimated 22,726 emergency hospitalizations nationally per year between 2007 and 2009, in people aged ≥ 65 years, with 94.6% attributed to hypoglycaemia [3]. "
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    ABSTRACT: Aim: To explore the frequency of hypoglycaemic episodes, their risk factors, and associations with patient-reported outcomes in patients with type 2 diabetes enrolled in the PANORAMA cross-sectional study. Methods: Five thousand seven hundred and eighty-three patients aged ≥ 40 years with type 2 diabetes duration ≥ 1 year were recruited in nine European countries. Patients reported severe and non-severe hypoglycaemic episodes during the past year at a single study visit. Patient-reported outcomes were measured by the Audit of Diabetes-Dependent Quality of Life, Diabetes Treatment Satisfaction Questionnaires, Hypoglycaemia Fear Survey-II, and EQ-5D Visual Analog Scale. Results: During the previous year, 4.4% of the patients experienced ≥1 severe hypoglycaemic episode; among those without severe hypoglycaemia, 15.7% experienced ≥1 non-severe episode. Patients experiencing any hypoglycaemic episode reported a greater negative impact of diabetes on quality of life, greater fear of hypoglycaemia, less treatment satisfaction and worse health status than those with no episodes. In multivariate analyses hypoglycaemia was significantly associated with longer diabetes duration; presence of microvascular and, to a lesser extent, macrovascular complications; treatment with insulin, glinides or sulfonylureas; and use of self-monitoring blood glucose. Conclusion: In patients with type 2 diabetes, severe hypoglycaemic episodes were not uncommon and one in five experienced some form of hypoglycaemia during the previous year. Hypoglycaemia was associated with more negative patient-reported outcomes. The risk of hypoglycaemia increased with diabetes duration, presence of diabetes-related complications, use of self-monitoring blood glucose, insulin secretagogues, and insulin treatment.
    No preview · Article · Oct 2015 · Diabetes & Metabolism
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    • "As in other studies (Bullano, Fisher, Grochulski, Menditto, & Willey, 2006; Zhao, Campbell, Fonseca, & Shi, 2012), hypoglycemia was defined as having an ICD-9-CM code 250.8 (Diabetes with other specified manifestations; applies to diabetic hypoglycemia NOS and hypoglycemic shock NOS), 251.0 (Hypoglycemic coma), 251.1 (Other specified hypoglycemia), and 251.2 (Hypoglycemia, unspecified). The hypoglycemia was categorized as primary if it was the primary cause of admission and secondary if it occurred during the hospital stay. "
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    ABSTRACT: We aimed to evaluate the frequency of hypoglycemia and its impact on the length of stay and all-cause in-hospital mortality in hospitalized patients with diabetes. We used data from the Basic Minimum Data Set of the Spanish National Health System. Hypoglycemia was defined as having an ICD-9-CM code 250.8, 251.0, 251.1, and 251.2, and categorized as primary if it was the main cause of admission and secondary if it occurred during the hospital stay. The association between hypoglycemia and the study outcomes was evaluated in two cohorts - with and without secondary hypoglycemia - matched by propensity scores and using multivariate models. Among the 5,447,725 discharges with a diagnosis of diabetes recorded from January 1997 to December 2010, there were 92,591 (1.7%) discharges with primary hypoglycemia and 154,510 (2.8%) with secondary hypoglycemia. The prevalence of secondary hypoglycemia increased from 1.1% in 1997 to a peak of 3.8% in 2007, while the prevalence of primary hypoglycemia remained fairly stable. Primary hypoglycemia was associated with reduced in-hospital mortality (Odds ratio [OR] 0.06; 95% Confidence interval [CI], 0.03-0.10) and a significant decrease in time to discharge (Hazard ratio [HR] 2.53; 95% CI, 2.30-2.76), while secondary hypoglycemia was associated with an increased likelihood of in-hospital mortality (OR 1.12; 95% CI, 1.09-1.15) and a significant increase in time to discharge (HR 0.80; 95% CI, 0.79-0.80). In conclusion, the prevalence of secondary hypoglycemia is increasing in patients with diabetes and is associated with an increased likelihood of in-hospital mortality and a longer hospital stay. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · Journal of diabetes and its complications
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    • "In a large nationwide cohort study from Taiwan, even mild symptomatic hypoglycemia was associated with increased cardiovascular risk, all-cause hospitalization, and all-cause mortality [23]. Furthermore, Zhao et al reported that patients with hypoglycemia had a significantly higher risk of cardiovascular events (hazard ratio [HR] 2.00) and microvascular complications (HR 1.76) [24]. In addition to these serious effects, This article is protected by copyright. "
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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)
    Full-text · Article · Apr 2015 · Diabetes Obesity and Metabolism
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