Interpretation of cardiovascular outcome trials in type 2 diabetes needs a multiaxial approach

Johansen, Odd Erik

doi:10.4239/wjd.v6.i9.1092

Cited by 12 publications

(11 citation statements)

References 26 publications

(21 reference statements)

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“…A major issue of CVOT design to date is patient selection criteria. Disease duration is a potential confounding factor that is not sufficiently controlled [ 74 ]. On the other hand, extrapolating CV results from this patient population to a broader one can be challenging, especially in case of superiority to placebo.…”

Section: Discussionmentioning

confidence: 99%

Current perspectives on cardiovascular outcome trials in diabetes

Schnell

Rydén

Standl

et al. 2016

Cardiovasc Diabetol

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Cardiovascular disease (CVD) is one of the most common diabetes-associated complications, as well as a leading cause for death in type 2 diabetes patients (T2D). Despite the well-known correlation between the two, up until the 2008 FDA industry guidance for licensing of new anti-hyperglycemic drugs, which required an investigation of cardiovascular outcomes (CVO) of glucose-lowering agents, only a few studies had looked into the relationship between glucose lowering drugs and cardiovascular (CV) risk. Thereafter, CVOT design has focused on non-inferiority short-term studies on high-risk patient populations aiming at capturing CV safety issues. Despite the wealth of information and useful data provided by CVOTs, this approach still suffers from certain limitations. The present review will condense the main results of the most recently completed CVOTs, reflect on the lessons learned, discuss on the issues presented by current CVOT design and offer some suggestions for improvement.

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Section: Discussionmentioning

confidence: 99%

Current perspectives on cardiovascular outcome trials in diabetes

Schnell

Rydén

Standl

et al. 2016

Cardiovasc Diabetol

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“…Given the enormous costs, estimated at 200–500 million US dollars per trial, time‐commitment and effort associated with the conduct of CV mega‐trials, there are some considerations that could help to further advance and refine regulatory guidance for CV assessment of antihyperglycaemic therapies by moving beyond a “one size fits all” approach …”

Section: Cardiovascular Outcome Trial Design Conduct and Analyses: Omentioning

confidence: 99%

“…30 Recognized limitations of such "real world" approaches, of CV mega-trials, there are some considerations that could help to further advance and refine regulatory guidance for CV assessment of antihyperglycaemic therapies by moving beyond a "one size fits all" approach. 34 One consideration relates to the target trial population along the spectrum of disease trajectory, key in the assessment of both effectiveness in modulating the CV-risk pathway and safety. 8 With a too low-risk population, it will take years to accumulate enough events to power the trial, and absolute treatment differences, if any, might compromise the clinical application on the basis of the low cost-efficiency and the requirement of high numbers of patients to treat.…”

Section: Cardiovascular Outcome Trial Requirements Should Not Be Abmentioning

confidence: 99%

FDA guidance on antihyperglyacemic therapies for type 2 diabetes: One decade later

McGuire

Johansen

Inzucchi

et al. 2019

Diabetes Obesity Metabolism

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In 2008, the US Food and Drug Administration (FDA) issued a guidance to industry statement concerning evaluation of the cardiovascular (CV) safety of new antihyperglycaemic therapies for type 2 diabetes. Fifteen CV outcome trials assessing three novel classes of antihyperglycaemic therapies, DPP‐4 inhibitors, GLP‐1 receptor agonists and SGLT‐2 inhibitors, were completed by the end of 2018 and several others are ongoing. In addition, one comparative insulin trial also has been completed. None of these trials reported an increase in risk for major adverse CV events (MACE), and six agents have demonstrated CV benefits. This experience has led to the first FDA‐approved indications for antihyperglycaemic medications to reduce the risk of CV death (empagliflozin) and to reduce the risk of MACE (liraglutide, canagliflozin), both indications specific to patients with established atherosclerotic cardiovascular disease (ASCVD). Because of the aggregate results from dedicated CV outcomes trials conducted in response to the FDA guidance statement, the contemporary paradigm for treatment of patients with type 2 diabetes has evolved substantially. However, the guidance has substantially increased the cost of developing new medications to address this important disease that afflicts hundreds of millions of adults worldwide, with reduction in quality of life as well as in life expectancy. The cost burden of drug development of medications proven effective that may directly impact cost to patients and to their insurers might be alleviated by modifications to the present guidance statement. These include areas of trial design, aspects of trial operation, expansion of composite outcomes to include broader component CV outcomes and continued evolution of analytic methodology. The guidance statement will benefit from consideration of a number of modifications to support continued innovation and, of course, the safety of marketed medications for type 2 diabetes. However, the requirement to assess each new antihyperglycaemic medication in at least one large‐scale standard randomized clinical outcomes trial should remain, so that clinicians can be reassured about the favourable efficacy/safety profiles of the medications they prescribe.

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“…newer glucose-lowering agents also failed to meet the primary cardiovascular outcome targets (4). Despite several decades of specific type 2 diabetes treatment, only two recent clinical trials, LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) (5) and EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) (6), demonstrated the effects of liraglutide and empagliflozin on macrovascular morbidity and mortality, whereas the SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) (7) trial reported the effects of semaglutide on composite outcomes.…”

mentioning

confidence: 99%