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2 decades of diabetes and CVD
A Cardiology Today Editorial Board Member discusses progress made in CV management of patients with diabetes.
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Editor’s Note: Cardiology Today is celebrating its 20th anniversary in 2017. We are reaching out to experts in cardiology for their take on changes in CV medicine since the publication launched in 1997. In this issue, Keith C. Ferdinand, MD, FACC, FAHA, focuses on diabetes and heart disease.
We knew prior to 20 years ago that there was a strong link between the presence of diabetes and hyperglycemia and other CV risk factors, including hypertension and dyslipidemia. Furthermore, it was observed that there was a two- to threefold increase in major CV events in persons with diabetes compared with those without.
Prior to 20 years ago, the treatment of diabetes was done in silos. The primary care providers used sulfonylureas, metformin and insulin. The endocrinologists and diabetologists were then referred those patients with more difficult-to-treat hyperglycemia. We as cardiologists were aware that these patients were at increased CV risk, and saw disproportionate high numbers of persons with diabetes presenting with ACS and HF, but we would rarely initiate medication or consider the control of diabetes as a primary goal of our therapy.
Advances in knowledge
Landmark trials such as the U.K. Prospective Diabetes Study in 1998 demonstrated that controlling type 2 diabetes with insulin or sulfonylureas reduced microvascular complications — with additionally some possible CV benefit with metformin, especially in overweight patients with type 2 diabetes. Unfortunately, overall, proof that antidiabetic medications reduced major CV events had been elusive.
Around the time of 2008 to 2009, intensive glucose lowering in at least three major trials, including ACCORD, ADVANCE and VADT, again demonstrated no definite benefit in reducing major CV events.
Perhaps the major break in our approach to treating glucose elevations per se, to reduce CVD was the meta-analysis done by Steven E. Nissen, MD, MACC, and Kathy Wolski, MPH, from Cleveland Clinic, in The New England Journal of Medicine in 2007. It suggested an adverse effect of rosiglitazone (Avandia, GlaxoSmithKline) on risk for MI and death from CVD.
Around that time, due to this meta-analysis, many cardiologists became even more reluctant to initiate antidiabetic medicines, since they had not demonstrated, at that point, any conclusive CV outcomes reduction.
Although this meta-analysis has since been criticized as flawed, it led to the withdrawal of rosiglitazone in Europe and restricted use in the United States. It was one of the main reasons the FDA proposed a guidance for industry in 2008 that, going forward, diabetic medications need to demonstrate safety in terms of CV risk. Newer agents could also be evaluated for potential benefit or harm related to heart disease and stroke.
CV implications of newer agents
Fortunately, since that time, new pharmacologic agents have been developed for the treatment of diabetes that may indeed have some benefit, or at least be neutral, in most patients with high CV risk.
Studies of three major classes, including dipeptidyl-peptidase IV (DPP-IV) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, have increasingly suggested that these newer agents have no major harm other than perhaps a signal of increased new-onset HF with at least two of the DPP-IV inhibitors.
Nevertheless, a major positive development has been a demonstrated decrease in major CV events, specifically HF with empagliflozin (Jardiance, Boehringer Ingelheim) in the EMPA-REG OUTCOME study, which also had a surprising decrease in total mortality. A similar CV risk-reduction effect was suggested with canagliflozin (Invokana, Janssen), despite an unexpected increase in amputation risk, primarily at the level of the toe or metatarsal, which needs to be further defined.
The GLP-1 receptor agonists have shown favorable results with liraglutide (Victoza, Novo Nordisk) and semaglutide (Novo Nordisk), the latter of which is not approved at this time by the FDA for use in the United States, but recently received the support of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee for approval.
Despite neutral CV outcomes with exenatide (Bydureon, AstraZeneca), the liraglutide data in LEADER have suggested for cardiologists that we may need to be proactive in not only reducing blood glucose in persons with diabetes, but also reducing CV risk with these novel agents.
New treatment paradigms
As a hypertension specialist and a clinical cardiologist, I have become involved in not only safety and efficacy trials with these newer agents, but more recently potential outcomes trials for patients with high CV risk and HF, specifically using SGLT2 inhibition as a way of decreasing CV events in high-risk patients. The challenge for non-diabetologists, including clinical cardiologists, will be whether we should initiate therapy with GLP-1 receptor agonists or SGLT2 inhibitors in high-risk patients, or simply suggest that these agents may be beneficial in certain patients, and subsequently refer them to either the primary care provider or endocrinologist.
Going forward for the next 20 years, however, it will be expected that the treatment of persons with diabetes will be approached with these newer agents by all providers, regardless of specialty, since death from CVD is the primary cause of decreased life expectancy in persons with diabetes, even beyond the effects of hyperglycemia itself and microvascular disease.
Over the last 20 years, specifically in the United States, we have recognized that diabetes disproportionately affects certain racial/ethnic minorities, including black and Hispanic individuals. There has been a call from the FDA and others who are interested in reducing disparities in CVD, specifically in persons with diabetes, that we increase representation of minority populations in CV outcomes trials.
In the next several years, it is expected that clinicians who treat persons with diabetes will not have a one-size-fits-all approach, but develop a patient-centered precision medicine therapeutic regimen that attempts to find the best antidiabetic medication for the best patient, taking into account potential differences in pharmacogenetic and pharmacokinetic responses. Regardless, simply treating ACS or HF as manifestations of increased risk in persons with diabetes is no longer considered the proper approach. Primordial prevention, with healthy diet, exercise and weight maintenance, and primary prevention, with intensive risk reduction, including statins and nonstatin therapies such as PCSK9 inhibitors, along with intensive BP control, will be as important as treating patients who present in an urgent setting with acute MI or new-onset HF. It’s important that we prevent heart disease in patients with diabetes before they develop it, and that we control risk factors when they become manifest, not just wait for patients to have acute events.
– Keith C. Ferdinand, MD, FACC, FAHA
Cardiology Today Editorial Board Member Tulane University School of Medicine
- References:
- Duckworth W, et al. N Engl J Med. 2009;doi:10.1056/NEJMoa0808431.
- Holman RR, et al. N Engl J. Med. 2017;doi:10.1056/NEJMoa1612917.
- Marso SP, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1603827.
- Marso SP, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1607141.
- Neal B, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1611925.
- Nissen SE, et al. N Engl J Med. 2007;doi:10.1056/NEJMoa072761.
- The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008;doi:10.1056/NEJMoa0802743.
- The ADVANCE Collaborative Group. N Engl J Med. 2008;doi:10.1056/NEJMoa0802987.
- UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;doi:10.1016/S0140-6736(98)07019-6.
- Zinman B, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1504720.
Disclosure: Ferdinand reports he is a consultant for Amgen, Boehringer Ingelheim, Novartis, Quantum Genomics and Sanofi.