News Updates

The word diabesity has now been in the mainstream medical lexicon for a decade or so. It refers to the frequent coexistence of diabetes with obesity, emphasizing the pathogenic interrelationship between these two conditions. In 2013, Cardillo observed as follows: “The increasing coexistence of diabetes and obesity presents complex treatment challenges owing to the elevated risk of developing cardiovascular complications. Hence, therapeutic strategies integrating glycemic control, weight loss and vascular protection are of the greatest importance to successfully counteract the health and economic burden posed by diabesity.”

The term cardiodiabesity has not yet attained the same level of mainstream visibility, but it can be found in the literature, and its meaning is readily intuited: since diabetes and obesity are each risk factors for cardiovascular disease, adding “cardio” to diabesity highlights the relationship between type 2 diabetes (T2D), obesity, the metabolic syndrome, and cardiovascular disease. Lifestyle approaches (e.g., diet, exercise, and stress management approaches that enhance the likelihood of adopting beneficial dietary and exercise regimens for individuals with demanding schedules) are clearly extremely important in combating cardiodiabesity, and the scientific discipline of behavioral medicine has provided leadership in this regard.

When pharmacological interventions are also deemed necessary, multiple factors come into consideration. A key question in the present context is: Does an intervention that is likely beneficial for one component of cardiodiabesity run the risk of inadvertently potentiating an adverse influence for another component? An example of salient investigations into this undesirable occurrence was discussed in my March 2017 editorial. Given that diabetes is associated with a two- to four-fold increased risk of cardiovascular disease, it is important that antidiabetic drugs do not unintentionally increase that risk further. Since 2008, the US Food and Drug Administration (FDA) has therefore required investigations to determine whether new antidiabetic drugs for the treatment of T2D have a liability to increase the likelihood of adverse cardiovascular outcomes. These investigations typically involve the conduct of a large cardiovascular safety outcome trial (see the 2015 paper in this journal by Geiger et al and a recent review by Herbst et al).

I noted last March that no cardiovascular safety outcome trial reported to date had found compelling evidence that a new antidiabetic drug for T2D increased the occurrence of adverse cardiovascular outcomes (an observation that remains true as I write this editorial). Moreover, the cardiovascular safety outcome trial conducted with the intention of exonerating the antidiabetic drug empagliflozin from an unacceptable increase in cardiovascular risk, EMPA-REG OUTCOME, provided evidence of cardiovascular benefit. Empagliflozin, a sodiumglucose cotransporter 2 (SGLT2) inhibitor, was originally approved by FDA in August 2014 as an addition to diet and exercise to improve glycemic control in adults with T2D. As a result of EMPA-REG OUTCOME’s results, in December 2016 the FDA announced a new indication for empagliflozin to reduce the risk of cardiovascular death in adult patients with T2D and established cardiovascular  disease.

Another new indication of interest was granted by FDA in August 2017 to the antidiabetic agent liraglutide. Liraglutide, a human glucagon-like peptide 1 analog, was originally approved by FDA in January 2010 as an adjunct to diet and exercise to improve glycemic control in adults with T2D. Based on the results of its cardiovascular safety outcome trial, LEADER, the new cardiovascular indication is for reducing the risk of myocardial infarction, stroke, and cardiovascular death in adults with T2D who have established cardiovascular disease.

In October 2017, canagliflozin’s sponsor submitted a Supplemental New Drug Application (sNDA) seeking a new indication to reduce the risk of major adverse cardiovascular outcomes (cardiovascular death, myocardial infarction, and stroke) in adults with T2D who have established cardiovascular disease or are at risk for cardiovascular disease. Canagliflozin, an SGLT2 inhibitor, was originally approved as an adjunct to diet and exercise to improve glycemic control in adults with T2D. The sNDA is based on the results of the CANVAS Program, which integrated two trials involving more than 10,000 participants with T2D and high cardiovascular risk, and demonstrated cardiovascular risk reduction (but also showed a greater risk of amputation).

The DECLARE-TIMI 58 trial for dapagliflozin, another SGLT2 inhibitor, is ongoing, with an estimated primary completion date of April 2019.

As of the writing of this editorial, semaglutide, a glucagonlike peptide-1 receptor agonist, is currently awaiting an FDA decision on approval. In October 2017, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 16-0 in favor of the approval of semaglutide to improve glycemic control in adults with T2D (one committee member abstained). Semaglutide has already been shown to provide a cardiovascular benefit in a cardiovascular safety outcome trial, SUSTAIN-6. However, in the trial for another drug in this class, exenatide, which involved participants with T2D with or without cardiovascular disease, the incidence of major cardiovascular events did not differ significantly between those receiving exenatide and those receiving placebo.

Another drug in this class, liraglutide, is associated with weight loss, and higher doses are marketed specifically to treat obesity. While encouraging, given previous safety concerns (and some marketing withdrawals) associated with antiobesity drugs, it is likely that acquisition of long-term safety data will be needed for new pharmaceutical options to assuage lingering concerns.

It is of interest to many physicians, scientists, and patients to consider how these drugs, other drugs, and drug combinations might be used as future combatants against cardiodiabesity and its clinical sequelae. As is often the case after a large high-profile clinical trial, there have been several papers published by the EMPA-REG OUTCOME investigators presenting additional analyses exploring empagliflozin’s effects on additional clinical characteristics, including heart failure, kidney disease, and cerebrovascular disease, and discussing new ongoing trials. Similarly, the LEADER investigators have published the results of a prespecified secondary analysis showing that, when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than did placebo.

Authoritative organizations typically review evidence from multiple clinical trials and create practice guidelines to guide individual physicians whose busy daily routines make it difficult for them to study all individual reports in the literature. One recent example comes from the Central and Eastern European Diabetes Expert Group (CEEDEG). The authors commented as follows: “The latest available high-level evidence on glucose-lowering drugs has enabled CEEDEG to develop practical consensus recommendations for patients with established CVD [cardiovascular disease] and/or CKD [chronic kidney disease]. These recommendations represent an update to international and country-level guidelines used for these patients, with the aim of providing a resource not only to endocrinologists, but to cardiologists, nephrologists and primary care physicians in the region.”

Involving all of these medical specialties is an excellent approach, and it is hoped that practice guidelines from other authoritative organizations take a similar approach.

References available upon request.

This editorial originally appeared in the January 2018 Therapeutic Innovation & Regulatory Science (Volume 52, Issue 1).