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11-14-2018 | Cardiovascular outcomes | Editorial | Article

What have I learned from cardiovascular outcome trials?

Author:
Sanjay Kalra

Author bio | Disclosures

As an endocrinologist with 2 decades of experience, I have certainly learned one thing: Learning never ceases.

In recent years, my fellow endocrinologists, and I, have begun to view cardiovascular disease (CVD) in diabetes in a more comprehensive manner. This change, welcomed by our patients, is due, in part, to the results of cardiovascular outcomes trials (CVOTs).

These trials set out to highlight the cardiovascular safety and benefit of glucose-lowering drugs. I strongly believe, however, that the current crop of CVOTs have achieved much more than the basic purpose they were established for [1].

CVD as a challenge

The various CVOTs, through their inclusion criteria and endpoints, have highlighted the vastness and complexity of CVD [2]. It should be noted that, in referring to CVD, we include not only macrovascular, but also microvascular morbidity. Both are equally important in influencing the outcomes of diabetes care, and neither can be ignored. Further, cerebral and cardiac vasculature each possess distinct identities, and may respond in a different fashion depending on the intervention.

Even within the domain of cardiac health, atherosclerotic CVD and heart failure represent two distinct cardiovascular phenotypes [3], while peripheral arterial disease is another important consideration that can complicate diabetes, and, perhaps, glucose-lowering therapy as well. An additional layer of complexity is introduced by the frequency of polyvascular involvement in people with diabetes [4].

All of this implies that new and existing glucose-lowering therapies should be evaluated for their overall effects on vascular health, the various cardiovascular phenotypes (eg, heart failure), and specific vascular complications such as amputations [2]. The design of modern CVOTs has made it possible to assess these aspects (albeit to varying degrees) and has highlighted the challenges that CVD poses to diabetes care.


Diabetes care is much more than a search for a (usually elusive) glycated hemoglobin (HbA1c) target. The strategies and techniques employed to reach this target can matter as much as the actual HbA1c achieved. The increased importance that we now place on considerations such as the minimization of weight gain and hypoglycemia within the overall picture of a medication’s clinical benefit exemplifies this, and it should be noted that CVOTs have helped to integrate this paradigm into glucose-lowering strategies [5].

CVOTs have sensitized diabetes care providers to the opportunities for multifactorial and comprehensive diabetes care, including cardiovascular risk reduction. In addition, CVOTs have highlighted the importance of the current standards of care in lowering cardiovascular morbidity and mortality; examples include the use of antihypertensive therapy, statins, and platelet aggregation inhibitors [2].

Over and above the accepted standards of care, some CVOTs have demonstrated cardiovascular benefit in further reducing CV morbidity and mortality. This applies to the glucagon-like peptide 1 receptor agonists (GLP-1 RAs) liraglutide and semaglutide, with early indications that dulaglutide will follow suit [6–8]. Similarly, the sodium-glucose cotransporter 2 inhibitors (SGLT2is) empagliflozin, canagliflozin and, recently, dapagliflozin have demonstrated evidence of cardiovascular benefit [9–11]. Thus, these CVOTs have opened doors, rather than windows of opportunity to further improve the cardiovascular health of individuals with diabetes.

CVOTs and the kidney

Some of the more recent CVOTs have embraced comprehensive cardiorenal primary endpoints, originally proposed by investigators from earlier trials. Adoption of these endpoints has contributed to our understanding of renal pathophysiology in diabetes. Indeed, the renewed significance of the kidney in today’s diabetes care is evident from the integration of renal function markers, such as albuminuria and estimated glomerular filtration rate, in accepted standards of care [12].

CVOTs and metabolic karma

Prior to the recent CVOTs an earlier trial, ADVANCE, had studied the effect of gliclazide modified-release and perindopril/indapamide combination on glycemic and blood pressure control [13, 14]. A follow-up of this study, the ADVANCE ON trial, assessed outcomes of the cohort originally enrolled in ADVANCE. ADVANCE ON reported a statistically significant lowering of macro- and microvascular outcomes at 10 years in participants who were initially randomized to control with a gliclazide MR-based strategy [15]. Though no long-term follow-up is planned for the recently reported CVOTs, ADVANCE ON shows that timely management of diabetes, using specific drugs, can improve cardiovascular outcomes. I have previously termed this phenomenon “metabolic karma” [16].

There is currently a lack of clarity regarding appropriate primary endpoints, as well as the relevance of post hoc analyses in some trials.

CVOTs and current consensus

The trial design of CVOTs is robust enough to have allowed their results to inform current recommendations and guidelines on diabetes care. The 2018 American Diabetes Association (ADA) and European Association for Study of Diabetes (EASD) consensus statement on management of hyperglycemia in type 2 diabetes suggests classifying individuals with diabetes into those with, and those without, atherosclerotic CVD [5].

The first-line therapy for individuals with diabetes and atherosclerotic CVD is now suggested to be lifestyle modification, metformin, and either a GLP-1 RA or SGLT2i. The choice between these two drug classes is based on the presence of established ASCVD and/or chronic kidney disease. A hierarchy of choice is suggested for each drug class based upon the strength of published evidence [5].

CVD care as a glass half-full

Though CVOTs have markedly enhanced our understanding of CVD and its management, we still have a long way to go. Some domains of cardiovascular health, such as cardiac autonomic neuropathy, have still not been explored in contemporary CVOTs. Patient populations such as those at high risk of developing ASCVD have not been included in sufficient numbers in some studies. There is currently a lack of clarity regarding appropriate primary endpoints, as well as the relevance of post hoc analyses in some trials.

When considered from a global context, the standards of care that I have referred to are not necessarily accessible to the vast majority of individuals living with diabetes. Even those who receive the best possible care do not always achieve recommended therapeutic targets.

The addition of newer drugs with cardiovascular benefit will only add strength to our efforts to provide diabetes care if they are made available, accessible, and affordable to all. Diabetes care professionals should also be trained to use these drugs in a safe and pragmatic manner. Ideally, this should extend to professionals in cardiology, nephrology, and neurology as well.

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