Cardiometabolic Medicine: Development of a New Subspecialty

David R. Saxon; Cara Reiter-Brennan; Michael J. Blaha; Robert H. Eckel

Disclosures

J Clin Endocrinol Metab. 2020;105(7):2095-2104. 

In This Article

Recent Advancements in Drug Development for Cardiometabolic Risk Factors

As evidence for the broad cardiovascular benefits of pharmacologic approaches in the cardiometabolic disease space grows, including treatments of obesity, T2DM, and dyslipidemia, the traditional silos within which medicine subspecialties have existed for decades begin to blur. Recent professional society guideline updates highlight this trend.[13–16] For example, the American Diabetes Association's Standards of Medical Care in Diabetes now emphasizes obesity management—with an entire chapter dedicated to this—and CVD reduction (including a mid-year update giving a grade "A" recommendation for the use of icosapent ethyl in 2019). The 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease includes guidance on the management of T2DM with a recommendation for the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium glucose cotransporter-2 inhibitors (SGLT-2is) as second-line T2DM therapy after metformin for primary prevention patients with CVD risk factors.[14]

While several new classes of therapeutic options now exist enabling a targeted approach to the varying chronic metabolic disorders that affect patients with established atherosclerotic cardiovascular disease (ASCVD), care has become more challenging because few clinicians have the clinical training and work environments to support a comprehensive patient-centered approach to residual cardiovascular risk reduction. In order to begin to fill these gaps in training and care, a unified concept of "Cardiometabolic Medicine" must be articulated. A review of recent cardiovascular outcomes trials for several new classes of metabolic therapies helps define this space and illustrates the current clinical complexity that exists and why a new model of specialty training and care delivery in the cardiometabolic disease space is needed.

Antihyperglycemic Agents

Cardiovascular outcomes trials for antihyperglycemic therapies have had mixed results regarding their ability to decrease cardiovascular risk. Trials of dipeptidyl peptidase 4 inhibitors—SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin), TECOS (sitagliptin), and CARMELINA (linagliptin)—demonstrated no cardiovascular benefits compared with placebo; however, their cardiovascular safety, limited side-effect profile, and weight neutrality make them useful second-line medications for some patients with T2DM who need better glycemic control but prefer to avoid insulin-related weight gain and injections.[17–20]

In total, 4 GLP-1 RAs (liraglutide [LEADER], semaglutide [SUSTAIN-6], albiglutide [Harmony Outcomes], and dulaglutide [REWIND]) and 3 SGLT-2is (empagliflozin [EMPA-REG OUTCOME], canagliflozin [CANVAS], and dapagliflozin [DECLARE-TIMI 58]) have demonstrated reductions in cardiovascular events in secondary and high-risk primary prevention patients with T2DM.[21] Furthermore, SGLT-2i trials have demonstrated reduced heart failure admissions among patients with T2DM who did and did not have established heart failure at the time of starting the medication.[22] In the DAPA-HF trial, reduced cardiovascular death and heart failure admissions were demonstrated among patients with and without T2DM who had established heart failure (HFrEF) and were already being treated with diuretics.[23] Drastic improvement in the primary composite outcome of end-stage kidney disease, doubling of serum creatinine, or death from renal or CVD causes, was found in those with diabetic kidney disease given canagliflozin in the CREDENCE trial.[24] The most recent version of American Diabetes Association's Standards of Medical Care in Diabetes includes a detailed review of the GLP-1 RA and SGLT2i outcomes trials.[21]

Further analysis of the positive trial results for GLP-1 RAs and SGLT2i medications have revealed that their benefits derive from changes beyond glycemic control, thus resulting in a shift in how we perceive these medications—now more so as "cardiometabolic" medications instead of primarily antidiabetes medications. Accordingly, there has been a paradigm shift in how we treat T2DM, moving from a strategy of glycemic targets achievement to one focused on comprehensive cardiovascular risk reduction.[13]

Lipid-lowering Agents

Other recent drug developments have improved our ability to treat metabolic disease. Positive outcomes in the lipid treatment space (eg, ezetimibe, PCSK9 inhibitors, bempedoic acid, and icosapent ethyl) have further expanded the armamentarium for CVD prevention, including but not limited to patients with T2DM.[25–28] In IMPROVE-IT the benefit of ezetimibe versus placebo in simvastatin-treated patients was preferential in patients with T2DM.[28] The REDUCE-IT study of icosopent ethyl included an important subgroup of primary prevention patients with diabetes and additional risk factors, now recognized in the updated FDA label.

Antiobesity Agents

Treatment of obesity is also entering a new era. One available weight loss medication, lorcaserin, which was recently removed from the market because of increased cancer risk, was found to have cardiovascular safety in a large trial of patients with established ASCVD or multiple cardiovascular risk factors, and 3 other weight loss medications—phentermine/topiramate ER, liraglutide 3.0 mg, and naltrexone/bupropion SR—have come to market since 2012 and have indications for long-term use.[29] Although use of these medications has been limited—likely primarily due to safety concerns raised from previous experience with weight loss medications and because of the only modest efficacy of these medications in the face of high out-of-pocket costs—interest in them exists among clinicians who treat obesity, T2DM, and nonalcoholic fatty liver disease.[30,31] The development of more powerful long-acting GLP-1 RAs and gut hormone combinations, such as GLP-1 RAs with gastric inhibitory polypeptide, will continue to blur the lines between metabolic diseases treatment and CVD prevention.[32,33] Specifically, the SELECT trial, a large international randomized controlled trial comparing semaglutide versus placebo in patients without T2DM who have overweight or obesity and prior CVD, has potential to be practice changing.[33]

Other innovations continue to blur traditional lines. Semaglutide is now available as an oral medication, breaking down barriers for clinicians who are uncomfortable prescribing injections. Further expansion in SGLT2i use may be on the horizon for patients with heart failure with preserved ejection fraction with and without T2DM.[34,35] Overall, the future of pharmacologic treatment at the intersection of metabolic risk factors and CVD will likely be one of increased complexity.

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