Cardiovascular outcome trials of diabetes drugs: lessons learned

Taylor, Simeon I.; Leslie, Bruce R.

doi:10.1172/jci99820

Cited by 9 publications

(8 citation statements)

References 25 publications

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“…In response to concerns that some T2D drugs increase cardiovascular risks (27), the FDA requires sponsors to provide additional Where possible, we selected clinical trials conducted in patients with inadequate glycemic control on metformin therapy. Priority was given to data included in FDA-approved prescribing information (PI).…”

Section: Cardiovascular Outcome Trialsmentioning

confidence: 99%

Pharmacological treatment of hyperglycemia in type 2 diabetes

Taylor¹,

Yazdi²,

Beitelshees³

2021

Journal of Clinical Investigation

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Diabetes mellitus is a major public health problem, affecting about 10% of the population (1). Chronic complications of diabetes cause enormous human suffering, including blindness, kidney failure, amputations, myocardial infarction, and stroke. Inspired by the desire to develop better therapies, many researchers have investigated the pathophysiology of type 2 diabetes (T2D). While type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-secreting β cells of the pancreas, T2D is often associated with obesity and is characterized by both impaired insulin secretion and insulin resistance (2). T2D is a progressive disease. Insulin resistance manifests early in the natural history prior to occurrence of overt hyperglycemia. So long as pancreatic β cells secrete sufficient insulin to compensate for insulin resistance, glucose levels are maintained at relatively normal levels (3). Overt diabetes occurs when β cells no longer secrete sufficient insulin to maintain normoglycemia. Fasting hyperglycemia is driven by increased hepatic glucose production due to relatively low insulin levels combined with hepatic insulin resistance. Severity of metabolic defects increases over time, primarily because of increasingly severe impairment in insulin secretion. This Review will discuss the state of the art in pharmacotherapy of T2D. Treatment aims to prevent or delay occurrence of microvascular and macrovascular complications -the main causes of morbidity and mortality in T2D. We focus specifically on hemoglobin A 1c -lowering (HbA1c-lowering) drugs, although antihypertensives, lipid-lowering drugs, optimal nutrition, and physical exercise also contribute to a holistic approach to treatment.

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Section: Cardiovascular Outcome Trialsmentioning

confidence: 99%

Pharmacological treatment of hyperglycemia in type 2 diabetes

Taylor¹,

Yazdi²,

Beitelshees³

2021

Journal of Clinical Investigation

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150

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“…All the CVOTs were designed to reach glycemic equipoise between groups, for minimizing the confounding effect of different glycemic control, and for not exposing participants to the increased risk of microvascular complications, a likely consequence of the suboptimal glycemic control [ 8 ] . At the end of CVOTs, however, subjects in the placebo groups had worse glycemic control as compared with those in the treatment groups.…”

Section: Introductionmentioning

confidence: 99%

Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression

Maiorino

Longo

Scappaticcio

et al. 2021

Cardiovasc Diabetol

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Background Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs. Methods An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. Results The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P < 0.001), with significant heterogeneity between studies (I2 = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta = − 0.298, P = 0.007), with significant heterogeneity (I2 = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta = − 0.531, R2 = 100%), without heterogeneity (I2 = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death. Conclusions The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R2 = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use.

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“…1 KIM-1 as a tubular injury marker should also be validated in patients with fair glycemic control, because the hemoglobin A1c level during follow-up was slightly below 8% in the control group of this study, 1 as in most clinical trials of type 2 diabetes. 8 Moreover, blood pressure (BP) is another factor of importance contributing to the development of chronic kidney disease, but the effect of BP control on the KIM-1 level remains to be clarified. SGLT2 inhibitors are known to affect BP as well, and indeed, BP was significantly lower in the ertugliflozin group in the VERTIS RENAL study.…”

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confidence: 99%

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confidence: 99%