A Summary of Criticisms of the Findings and Conclusions of the University Group Diabetes Program (UGDP)

Seltzer, Holbrooke S.

doi:10.2337/diab.21.9.976

Cited by 143 publications

(40 citation statements)

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“…The increased risk of cardiovascular mortality associated with the sulfonylurea tolbutamide led to its withdrawal in the United States, although the results of the UGDP study have been much criticised [2]. It has been suggested that sulfonylureas have a direct deleterious effect on the heart but this is outweighed by the beneficial effects mediated by their metabolic action [3].…”

Section: Introductionmentioning

confidence: 99%

Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin

et al. 2006

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Aims/hypothesis: The aim of this study was to evaluate the risk of adverse cardiovascular outcomes in patients with type 2 diabetes newly treated with sulfonylureas and metformin. Subjects and methods: The Diabetes Audit and Research in Tayside Scotland (DARTS) diabetes information system and the Medicines Monitoring Unit (MEMO) dispensed prescribing database for the population of Tayside, Scotland (400,000 people) were employed. Patients newly prescribed with oral hypoglycaemic agents between 1994 and 2001 were classified into five study cohorts according to the treatment received: metformin only, sulfonylureas only, sulfonylureas added to metformin, metformin added to sulfonylureas, and both drugs simultaneously. In Cox regression analyses, we estimated relative risks for all-cause mortality, cardiovascular mortality and cardiovascular hospital admission for patients in the five study cohorts, with metformin monotherapy as the reference group. Results: Of the 5,730 study patients, 1,000 died during a maximum of 8 years follow-up. Patients in the sulfonylureas only cohort had increased risks of mortality and cardiovascular mortality, with unadjusted relative risks of 3.12 (95% CI 2.54-3.84) and 3.71 (95% CI 2.64-5.22), respectively. After adjusting for differences between groups (age, sex, duration of diabetes, blood pressure, cholesterol, HbA 1c , smoking, previous hospital admission, treatment with cardiovascular medication), these relative risks were 1.43 (95% CI 1.15-1.77) and 1.70 (95% CI 1.18-2.45), respectively. Patients in the combination cohorts had significantly increased risks of cardiovascular hospital admission, as well as increased risks of mortality and cardiovascular mortality. Conclusions/interpretation: In this cohort study of patients newly treated with oral hypoglycaemic agents, those treated with sulfonylureas only, or combinations of sulfonylureas and metformin, were at higher risk of adverse cardiovascular outcomes than those treated with metformin alone.

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Section: Introductionmentioning

confidence: 99%

Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin

et al. 2006

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“…4 Despite the UGDP observations, however, sulfonylureas have been the mainstay of therapy for the past 40 years. 5 This treatment choice persists probably because the UGDP study design has had some controversy [6][7][8][9] and perhaps because a plausible mechanism remains inevident. [10][11][12][13] Moreover, the largest (3867 subjects) and longest (median follow-up 10.0 years) study of glucose control in people with type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS), showed that intensive therapy with glibenclamide (glyburide) significantly reduced the rate of microvascular events.…”

mentioning

confidence: 99%

Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study

Simpson

Majumdar²,

Tsuyuki³

et al. 2006

Canadian Medical Association Journal

202

144

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Research D iabetes mellitus is a chronic, progressive disease characterized by deteriorating glucose control and increased risk of micro-and macrovascular complications. About 8% of our population have diabetes, among whom the great majority have type 2.1,2 The 2 most common oral pharmacologic strategies to manage type 2 diabetes include the use of agents that promote insulin release (e.g., sulfonylureas) or improve insulin sensitivity (e.g., metformin and thiazolidinediones).3 These strategies reduce hyperglycemia to a similar degree; how they affect mortality, however, remains unclear.Since publication of the results of the University Group Diabetes Project (UGDP), 4 the relation between the use of sulfonylureas and the risk of cardiovascular events has been questioned. Subjects treated with tolbutamide in the UGDP had a significantly higher cardiovascular rate of death than those given placebo. 4Despite the UGDP observations, however, sulfonylureas have been the mainstay of therapy for the past 40 years.5 This treatment choice persists probably because the UGDP study design has had some controversy 6-9 and perhaps because a plausible mechanism remains inevident.10-13 Moreover, the largest (3867 subjects) and longest (median follow-up 10.0 years) study of glucose control in people with type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS), showed that intensive therapy with glibenclamide (glyburide) significantly reduced the rate of microvascular events.14 Contrary to the UGDP results, sulfonylurea therapy was not associated with an increased risk of death. 14In 2 large population-based cohort studies, 15,16 we previously observed that the use of metformin by people with newly treated type 2 diabetes was associated with reduced risks of morbidity and death compared with sulfonylurea monotherapy. Questions remain, however, as to whether the observed relation resulted from a protective effect imparted by metformin, or a potentially harmful effect of the sulfonylureas. 12,17,18 The purpose of the study we report here was to determine whether the risk of death changes with the level of exposure to sulfonylureas. We hypothesized that increased exposure to a harmful medication would be associated with an increased risk of death from all causes or from an acute ischemic event.

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“…Since then, despite a flaw in methodology (19), there is ongoing controversy as to whether the sulfonylueas increase cardiovascular mortality in patients with diabetes mellitus. However, recent experimental and clinical data have shown that impairment of preconditioning, which was presumed to be the most important mechanism for the excess cardiovascular mortality, is not a class effect of sulfonylureas.…”

Section: Discussionmentioning

confidence: 99%

Glimepiride Treatment Upon Reperfusion Limits Infarct Size via the Phosphatidylinositol 3-Kinase/Akt Pathway in Rabbit Hearts

Nishida¹,

Sato²,

Nomura³

et al. 2009

J Pharmacol Sci

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Abstract. The phenomenon termed postconditioning, that is, brief episodes of ischemia / reperfusion at the onset of reperfusion reduce infarct size, is thought to involve the activation of the phosphatidylinositol 3-kinase (PI3K)/ Akt pathway. Treatment with a drug activating PI3K at the onset of reperfusion may confer a similar cardioprotection. The sulfonylurea glimepiride has been shown to activate PI3K in human endothelial cells. We therefore tested in rabbit hearts whether glimepiride can produce postconditioning-mimetic actions. Langendorff-perfused rabbit hearts were subjected to 30 min of global ischemia and 120 min of reperfusion, and infarct size was determined by triphenyltetrazolium staining. Phosphorylation of Akt was analyzed by Western blotting. Glimepiride (10 μM) treatment for the first 10 min of reperfusion significantly reduced infarct size from 67.2 ± 1.3% in controls to 35.8 ± 4.5% (P<0.01). This infarct size-limiting effect of glimepiride was abolished by a selective inhibitor of PI3K (5 μM LY294002, 65.4 ± 3.4%). Phosphorylation of the PI3K substrate Akt was significantly increased in glimepiridetreated hearts when compared to controls (P<0.05). Glimepiride-induced Akt phosphorylation was inhibited by LY294002. In conclusion, our study demonstrates that glimepiride treatment upon reperfusion reduces infarct size in rabbit hearts via a PI3K / Akt-mediated pathway. The postconditioning-mimetic action of glimepiride may be beneficial for the treatment of diabetic patients with ischemic heart disease.

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A Summary of Criticisms of the Findings and Conclusions of the University Group Diabetes Program (UGDP)

Cited by 143 publications

References 0 publications

Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin

Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin

Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study

Glimepiride Treatment Upon Reperfusion Limits Infarct Size via the Phosphatidylinositol 3-Kinase/Akt Pathway in Rabbit Hearts

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