Cardiologists Must “Get Into the Game” With Novel Agents in Patients With Diabetes

Patients with diabetes face heightened cardiovascular risk, but too few cardiologists are prescribing novel therapies that can help prevent heart failure, strokes, and renal decline, or treat obesity, according to Erin D. Michos, MD, MHS, director of Women’s Cardiovascular Health and associate professor of medicine, Johns Hopkins Medicine.

During a pair of talks during the 2022 Congress of the American Society for Preventive Cardiology (ASPC), held Friday through Sunday in Louisville, Kentucky, Michos discussed how treatment of diabetes requires a multipronged approach, one that must go beyond glucose-lowering therapies and include newer medications that have been shown to offer cardiovascular benefits, even in patients without diabetes.

Both Michos and Pam R. Taub, MD, director, Step Family Foundation Cardiovascular Rehabilitation and professor of medicine at UC San Diego Health, explained how sodium glucose cotransporter 2 (SGLT2) inhibitors are now indicated in heart failure and chronic kidney disease, and can reduce blood pressure and produce modest weight loss. Glucagon-like peptide-1 (GLP-1) receptor agonists, meanwhile, are more powerful therapies that produce more weight loss, with data that show benefits for reducing major adverse cardiovascular events (MACE), including stroke.

Women With Diabetes and CV Risk

Michos and Taub spoke first at Friday’s symposium, “Saving the Hearts of Women Through Prevention,” with Michos giving an overview of the differences in cardiovascular risk that women with diabetes face compared with men, and Taub reviewing pharmacological options. Michos was a co-chair for Friday's symposium.

The prevalence of diabetes is increasing in women in the United States, to 1 in 9 adult women, Michos said. Overall, patients face a 50% increased risk of cardiovascular death if they have diabetes, and having diabetes reduces life expectancy for both men and women by 8 years. But coronary risk between the genders plays out differently, such that “The presence of diabetes gives a woman the risk equivalent of being a man without diabetes,” she said.

While the prevalence of diabetes greater in men than in women—and this holds true across races and ethnicities—the risk of myocardial infarction (MI) is 4-fold for women with diabetes, but only 2-fold for men with diabetes. For those with diabetes more than 15 years, the risk of heart failure is 4.5-fold in women, compared with 1.4-fold in men.

At the time they are diagnosed with diabetes, women on average have a higher body mass index than men, Michos said. This excess weight means women have more inflammation and helps explain why some risk factors are elevated in women.

Taub later noted how prevalence of diabetes shifts with age. “As women age, they start to catch up with men,” she said. “When women are in their 70s, they tend to have a higher incidence of diabetes compared with men.”

Guidelines Promote Novel Therapies

Michos and Taub both discussed evidence from various cardiovascular outcomes trials for SGLT2 inhibitors and GLP-1 receptor agonists, both of which were developed to treat type 2 diabetes but were later found to have other cardiovascular benefits.

While trial data showed that for both drug classes women with diabetes benefited to a similar degree as men, with GLP-1 receptor agonists offering a 12% reduction in MACE. “But if you actually look at real world data, women may be benefiting more from GLP-1 receptor agonists,” Michos said, as she outlined MarketScan data by drug class that showed better survival data for women compared with men who received GLP-1 receptor agonists.

Taub continued the theme. “Many agents that improve glycemic control can also impact cardiovascular care,” she said, highlighting a point that many would repeat throughout the ASPC meeting: based on new ACC/AHA guidelines, metformin is no longer necessarily the first stop in diabetes care.

SGLT2 inhibitors have multiple renal and cardiovascular benefits, besides helping patients lose weight. “We need to be thinking about SGLT2 inhibitors as the new statins,” Taub said.

The benefits of GLP-1 receptor agonists, she said, “stems from their benefits in atherosclerotic cardiovascular disease,” and semaglutide can offer benefits in preventing ischemic stroke.

The new guidelines “really reinforce” using SGLT2 inhibitors and GLP-1 receptor agonists and offers language for first-line treatment that says, “generally includes metformin,” giving clinicians new flexibility. “If you don't want to use metformin, you can directly go to an SGLT2 of or a GLP-1 receptor agonist,” Taub said. “And the way to think about which agent to use is to look at the specific characteristics of the patient.”

SGLT2 inhibitors make sense as first-line agents for patients with heart failure, at high risk for heart failure, or with “even mild renal dysfunction.” GLP-1 receptor agonists are the choice for those who have had a prior MI, prior stroke, or have obesity.

Taub offered details on initiating the therapies in patients. SGLT2 inhibitors require downward titration of diuretics, and GLP-1 receptor agonists should be started at a low dose for 2 months to minimize gastrointestinal side effects.

Tirzepatide, a newer agent, which is a combination glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, offers patients up to 20% weight loss; results from its cardiovascular outcomes trial are pending, “but we predict it will be positive,” Taub said.

“This Is Our Wheelhouse”

What’s happening in real-world practice? Taub and Michos said the news is not good. During the women’s heart health symposium, Taub said, women have poor access to novel therapies and that women and minorities are less likely than white male patients to get a GLP-1 receptor agonist.

In her talk Saturday, Michos emphasized that prescribing of novel agents by cardiologists is a fraction of where it should be, for both male and female patients. She emphasized the need to test for albuminuria, since failure to do so will miss many cases of chronic kidney disease—and there are new agents that can stop the progression. She highlighted results from the REWIND trial for dulaglutide, which showed that the GLP-1 receptor agonist reduced cardiovascular and renal risk even in a primary prevention population.

And yet, there is severe underutilization of these agents. Michos showed results from an insurance database of 1 million lives from 2015-2019, which showed that the share of people with diabetes on a GLP-1 increased to only 10%, compared with 80% on metformin.

What’s more, cardiologists represent only a tiny fraction of the specialists doing the prescribing—just 1.5% of those prescribing SGLT2 inhibitors and 0.4% of the GLP-1 receptor agonists.

“This is sort of disheartening, because this is our wheelhouse,” Michos said, noting that 40% to 70% of patients with type 2 diabetes and cardiovascular disease see a cardiologist. “These are cardiovascular prevention drugs, so cardiologists need to get in the game and be initiating this and making sure our patients are on these therapies.”