Elsevier

The Lancet

Volume 383, Issue 9933, 7–13 June 2014, Pages 2008-2017
The Lancet

Series
Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes

https://doi.org/10.1016/S0140-6736(14)60794-7Get rights and content

Summary

Few trials of glucose-lowering drugs or strategies in people with type 2 diabetes have investigated cardiovascular outcomes, even though most patients die from cardiovascular causes despite the beneficial effects of lipid-reducing and blood pressure-lowering treatments. The evidence-based reduction in risk of microvascular disease with glucose lowering has resulted in guidelines worldwide recommending optimisation of glycosylated haemoglobin, but no trial results have shown unequivocal cardiovascular risk reduction with glucose lowering. However, results of the post-trial follow-up of the UK Prospective Diabetes Study, and of a meta-analysis of the four glucose-lowering outcome trials completed to date, suggest about a 15% cardiovascular relative risk reduction per 1% decrement in HbA1c. The 2008 US Food and Drug Administration industry guidance for licensing of antidiabetic drugs greatly increased the number of cardiovascular outcome trials in diabetes, but most trials opted for non-inferiority designs aiming primarily to show absence of cardiovascular toxicity in the shortest possible time. This unintended consequence of the new regulations has meant that the potential long-term benefits, and the possible risks of new therapies, are not being assessed effectively. Also, essential head-to-head trials of therapies for this complex progressive disease, to answer issues such as how best to achieve and maintain optimum glycaemia without promoting weight gain or hypoglycaemia, are not being undertaken. In this Series paper, we summarise randomised controlled cardiovascular outcome trials in type 2 diabetes, provide an overview of ongoing trials and their limitations, and speculate on how future trials could be made more efficient and effective.

Introduction

The rapidly emerging diabetes pandemic is one of the most challenging noncommunicable disease threats to public health in the 21st century. More than 380 million people worldwide have type 2 diabetes,1 most of whom will die from cardiovascular disease, the second most common cause of death being their increased risk of cancer.2 People with type 2 diabetes have a roughly doubled risk of cardiovascular disease, compared with people without diabetes, even after adjustment for established cardiovascular risk factors.2 After diagnosis, patients have a lifetime of attempted strict lifestyle, escalating drug therapy to offset glycaemic progression, and management of several risk factors to minimise the risk of diabetes-related complications. Life expectancy of a person diagnosed with type 2 diabetes at age 40 years is estimated to be shortened by about 6–7 years, compared with people without type 2 diabetes.2 A major need exists for evidence-based type 2 diabetes treatment strategies that better manage this complex condition by reducing disease progression, improving quality of life, and extending longevity, without causing unwanted or harmful side-effects. Crucially, the precise ability of glucose-lowering per se to reduce the risk of cardiovascular disease in type 2 diabetes has not been elucidated.

Despite the many people affected by type 2 diabetes, the huge disease burden, and the major health economic costs to society, few definitive outcome trials to properly inform clinical effectiveness of licensed therapies have been done. Before publication of the results of the UK Prospective Diabetes Study (UKPDS)3 and the Diabetes Control and Complications Trial,4 the prevailing opinion was that diabetic complications were primarily genetic in origin and unrelated to the “carbohydrate derangements of diabetes mellitus”.5 Although the UKPDS findings in type 2 diabetes showed that improved glycaemic control3 and blood pressure control6 could reduce the risk of diabetic complications, most drug trials undertaken for regulatory purposes continued to be short term, usually in selected populations, and often focused primarily on biomarkers rather than on hard outcomes. This situation changed after the 2008 US Food and Drug Administration (FDA) mandate and subsequent European Medicines Agency requirements for cardiovascular outcome trials in licensing of new glucose-lowering drugs.7, 8 These regulatory requirements, driven primarily by response to cardiovascular safety concerns associated with the antidiabetic drug rosiglitazone,9, 10 have changed the diabetes trials landscape. The FDA require that clinical trials done before drug approval show a two-sided 95% confidence interval upper boundary of 1·8 risk ratio for major adverse cardiovascular events, versus the control group, with subsequent outcomes trials having an upper boundary of 1·3.7 Bethel and Sourij11 reviewed the effect of this two-stage route to type 2 diabetes drug approval.

The regulatory need to obtain robust cardiovascular safety data to approve new diabetes drugs has led to a substantial increase in the number of type 2 diabetes cardiovascular outcome trials. However, most of these trials have simple, placebo-controlled, non-inferiority designs aiming to show an absence of cardiovascular toxicity to satisfy regulatory requirements in the shortest possible time. This approach has meant that many essential questions are unanswered, such as comparative effectiveness, estimation of the balance of benefits to risks over time, identification of heterogeneity of treatment effects to establish best patient selection, and assessment of possible drug-related adverse events in the long term.

In this Series paper, we review published cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes (table 1), provide an overview of ongoing trials and their limitations, and speculate on potentially more effective and efficient trial designs.

Section snippets

Published cardiovascular outcome trials in type 2 diabetes

The University Group Diabetes Programme, published in 1970,26 was the first randomised multicentre head-to-head effectiveness trial of available type 2 diabetes glucose-lowering treatments that assessed cardiovascular outcomes. The trial randomly assigned about 200 patients to each of variable-dose insulin, standard-dose insulin, sulfonylurea (tolbutamide), biguanide (phenformin), and placebo. The trial was halted because of concerns that all of the therapies seemed to increase cardiovascular

Trials not exclusively investigating glucose-lowering drugs or strategies

ADDITION, a cluster-randomised trial, compared multifactorial intensive treatment with routine care in screen-detected type 2 diabetes.21 The results showed a non-significant 17% relative risk reduction in the composite cardiovascular endpoint (95% CI −35–5%) in favour of multifactorial intensive risk-factor management. This result might be because only marginal differences in cardiovascular risk-factor levels were achieved between the two groups.

The LOOK-AHEAD trial compared the effect of

Increased research

The 2008 FDA and European Medicines Agency guidance requiring proof of cardiovascular safety in addition to HbA1c lowering, as a prerequisite for approval of new antidiabetic drugs, changed the type 2 diabetes clinical trial landscape. Initial concerns that the costs of such large-scale trials might deter pharmaceutical companies from further investing in the diabetes specialty were proved wrong, with at least 16 cardiovascular outcome trials (that will report by 2020) ongoing in more than

Challenges for cardiovascular outcome trials going forward

A downside of long-term trials is that retention and adherence are increasingly difficult over time to maintain. Retention and adherence rates vary substantially among the trials we describe, with no clear trend or pattern, but with permanent drug discontinuation rates reaching about 10% per year in EXAMINE38 and SAVOR-TIMI 53.39 Although these drug discontinuation rates are consistent with clinical practice patterns, the traditional clinical trial method seeks to optimise adherence in trials

Concepts for future outcome trials in patients with type 2 diabetes

The concept of randomised controlled trials is the gold standard in clinical research to investigate outcomes attributable to a certain intervention, because of the many advantages of randomisation over mere registry analyses. Intervention allocation is too important to leave to chance. Randomisation helps to ensure that the groups being compared are balanced in terms of the known and unknown confounders, which information is not accessible to registry analyses.

However, incremental changes in

Conclusions

A critical view of the large cardiovascular trials done over the last four decades shows that, until recently, few had adequate statistical power to inform practice, and that the designs of the trials constrained the range of questions that could be addressed. The UKPDS taught us that improved glycaemic control in newly-diagnosed type 2 diabetes patients reduces the risk of microvascular complications, and, in the long term, of cardiovascular events and all-cause mortality.3, 7 Findings from

Search strategy and selection criteria

We searched for cardiovascular outcome trials of glucose-lowering drugs or strategies in patients with type 2 diabetes with the following definition: randomised, controlled clinical trial, primary study endpoint “cardiovascular outcome”, sample size >1 000, patients followed-up for ≥12 months. We searched the Cochrane Central Register of Controlled Trials, Medline, and Embase for reports published in English between Jan 1, 1996, and Jan 4, 2014, with the search terms “diabetes”, in combination

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