Observing National Heart Month: Type 2 Diabetes Medications, Bariatric Surgery Show Heart Benefits in Long-term Cardiovascular Outcomes Trials

Christopher D. Still, DO, FACN, FACP

Co-Clinical Editor of Bariatric Times; Medical Director for the Center for Nutrition and Weight Management, and Director for Geisinger Obesity Research Institute at Geisinger Medical Center in Danville, Pennsylvania.

Dear Friends and Readers,

By now, it is well known that the effects of obesity are far reaching, impacting nearly every one of the body’s systems. Although the endocrine system gets a lot of attention, with a plethora of evidence showing weight loss leads to Type 2 diabetes mellitus (T2DM) disease improvement or resolution, clinical trials for antidiabetes medications have also been focusing on another body system effected—cardiovascular. Obesity increases the risk for both T2DM and cardiovascular disease (CVD), which is significant as CVD remains the leading cause of death in the United States among men and women. CVD is also the leading cause of death among individuals with T2DM; more than 70 percent of patients with T2DM will die from cardiovascular causes.¹ While February is largely recognized as American Heart month, I believe the potentially devastating comorbidities of obesity, including CVD, should receive attention year-round as should the options for managing them, which continue to evolve. In fact, we now have medications that might kill two birds with one stone by benefiting the cardiovascular system while employing diabetes treatment.

In December 2008, the United States Food and Drug Administration issued guidance to the pharmaceutical industry to expand the scope and cost of research necessary for approval of antidiabetes drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. Reported by Cefalu et al in Diabetes Care, at the time of article publication in January 2018, nine CVOTs were reported, 13 were under way, and four were terminated.² Of the nine completed CVOTs for newer antidiabetes medications, which included dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, each demonstrated the noninferiority of their respective drugs to placebo in their major adverse cardiac event (MACE) primary end point. Additionally, some trials provided evidence of CV benefit in the form of significant decreases in the MACE primary composite end point, reductions in CV death, and reductions in all-cause mortality.²

This evidence is groundbreaking because physiology is already fighting against patients with obesity and T2DM, and medication-induced weight gain, seen in previous T2DM medications, causes them to have to fight even harder, thus creating a treatment conundrum. For example, sulfonylureas, thiazolidinediones (TZDs), and insulin have all been found to significantly contribute to weight gain.^3,4 Additionally, sulfonylureas and basal insulin, often prescribed as second-line antidiabetic medications when first-line therapy (usually metformin) is not adequate or tolerated, have shown detrimental effects on the MACEs. One recent cohort study of 132,737 adults with T2DM found that, similar to the previously mentioned CVOTs, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors were associated with noninferior and, in some cases, improved cardiovascular outcomes. Alternately, sulfonylureas and basal insulin were associated with comparatively higher cardiovascular harm; 36 and 50 percent in patients who took sulfonylureas and basal insulin, respectively.⁵

Though data point to multiple mechanisms of action for improving health following obesity treatments, weight loss is always at the core. Whether achieved by lifestyle modification, pharmacotherapy, and/or bariatric surgery, weight loss has been associated with favorable changes in cardiovascular risk factors.( Benraoune F, Litwin SE. Reductions in cardiovascular risk after bariatric surgery. Curr Opin Cardiol. 2011 Nov; 26(6): 555–561.) This further emphasizes that the benefits of weight loss stretch across all disciplines.

With CVOTs required for newer antidiabetes medications and cardiovascular risks also being studied in patients following bariatric surgery, we now have safe, effective treatments that potentially offer patients a triple benefit—weight control, diabetes management, and cardiovascular system improvements. With therapies in weight loss, diabetes, and CVD converging and evolving, allowing us to address multiple health issues in one fell swoop, the chances of combatting these current public health epidemics are looking better.

Sincerely,

Christopher D. Still, DO, FACN, FACP

References

1. Laakso M. Cardiovascular disease in type 2 diabetes from population to man to mechanisms. The Kelly West Award Lecture 2008. Diabetes Care. 2010; 33(2):442–449.
2. Cefalu WT, Kaul S, Gerstein HC, et al. Cardiovascular outcomes trials in type 2 diabetes: Where do we go from here? Reflections from a Diabetes Care Editors’ Expert Forum. Diabetes Care. 2018; 41(1): 14–31.
3. McFarlane SI. Antidiabetic medications and weight gain: implications for the practicing physician. Curr Diab Rep. 2009;9:249–254.
4. McFarlane SI: Insulin therapy and type 2 diabetes: management of weight gain. J Clin Hypertens. 2009;11:601–607.
5. O’Brien MJ, Karam SL, Wallia A, et al. Association of second-line antidiabetic medications with cardiovascular events among insured adults with type 2 diabetes. JAMA Netw Open. 2018;1(8):e186125.   

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