LOS ANGELES (FRONTLINE MEDICAL NEWS) – In the opinion of Mikhail N. Kosiborod, MD, the paradigm of treating patients with type 2 diabetes should shift from a narrow focus on hemoglobin A1c control to a broader strategy of reducing cardiovascular risk.

“We already know that the number one killer of patients with diabetes is cardiovascular disease, and we already know that lowering HbA1c as a general strategy does not substantially lower the risk of most important CVD events,” Dr. Kosiborod , a cardiologist at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.

“So, if the goal of treatment is simply to have HbA1c look better in the medical record, then the current approach makes a lot of sense,” he noted. “But if your goal of treatment is to prevent death and disability in patients with type 2 diabetes, it does not make much sense. You’re pretending that lowering A1c with one drug class is exactly the same as doing it with another drug class, and we already know that’s not the case.”

Physicians know that some medications lower the risk of cardiovascular events – including cardiovascular death – substantially, and other drugs don’t. “The bottom line is that we are not talking about ignoring HbA1c, but it’s how you get there that’s important – how you do it and in whom,” Dr. Kosiborod explained.

He pointed to a meta-analysis of four large diabetes trials involving 27,049 participants and 2,370 major vascular events ( Diabetologia. 2009 Nov;52[11]:2288-98 ). It found that the general strategy of targeting more-intensive glucose lowering modestly reduced nonfatal myocardial infarction and increased major hypoglycemia over 4.4 years in people with type 2 diabetes – yet there was no difference in the effect of intensive glucose control on cardiovascular death or hospitalization for heart failure.

“Some point to the benefit of glucose control on the risk of nonfatal myocardial infarction, but that’s a modest benefit,” he said. “It’s observed beyond the randomization phase of clinical trials and takes many years to see it. It’s a large, very long-term investment for a modest reduction in MI risk, with no benefit in death or heart failure. So, when you test intensive glucose control as a general strategy, it has not been successful in reducing cardiovascular complications of type 2 diabetes.”

However, there is now evidence that specific classes of medications, such as sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, initially developed for glucose lowering in type 2 diabetes, can significantly reduce cardiovascular risk within a relatively short time frame.

In EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), the first trial to demonstrate such benefits, all patients had established CVD, compared with 67% of patients in CANVAS (Canagliflozin Cardiovascular Assessment Study), a second RCT program to report cardiovascular outcomes with SGLT2 inhibitors. In the meantime, about 15%-20% of patients in real-world clinical practice have established CVD.

This led Dr. Kosiborod and his associates to launch CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT2 Inhibitors), a real-world comparative effectiveness study that evaluated hospitalization for heart failure and total mortality among new users of SGLT2 inhibitors, compared with other glucose-lowering drugs.

In all, 154,528 patients in six countries were initiated on an SGLT2 inhibitor, and 154,528 were initiated on other glucose-lowering drugs ( Circulation. 2017 May 18. doi: 10/1161/circulationaha.117.029190 ). The greatest exposure time was observed from canagliflozin (53%) followed by dapagliflozin (42%) and empagliflozin (5%).

The pooled analysis showed that initiation of SGLT2 inhibitors was associated with a significantly lower risk of heart failure events, compared with other glucose-lowering drugs (risk ratio, 0.61; P less than .001). The researchers observed an overall 39% lower risk of heart failure hospitalization, 51% reduction in total death, and 46% reduction in the composite of heart failure hospitalization or death.

“There was no heterogeneity across countries, despite the fact that the health care systems were very different and the prescribing patterns were very different,” he said.

Dr. Kosiborod, who is also professor of medicine at the University of Missouri-Kansas City, noted that 13% of patients from CVD-REAL had established CVD, while 87% did not. When comparing the results within these two key subgroups, “what’s striking is the difference in event rates, stratified by treatment allocation,” he said of the unpublished data.

“If you look at the composite outcome of heart failure or death, you see an almost seven-fold difference in annualized event rates – about 7% per year in patients with established CVD, compared with about 1% per year in the primary prevention cohort,” he explained. “But the relative risk reduction associated with SGLT2 inhibitors versus other glucose-lowering drugs is identical across both patient groups. That’s a good lesson in epidemiology: You can have patients with dramatically different absolute risks, dramatically different absolute risk reductions, and therefore dramatically different numbers needed to treat, but identical relative risk reductions.”

Dr. Kosiborod also pointed out that heart failure is emerging as one of the most important outcomes in trials patents with type 2 diabetes.

“That’s because people with diabetes who develop heart failure have very poor outcomes,” he said. “Among elderly patients with type 2 diabetes who develop new heart failure, there’s less than 25% survival at 5 years. That’s the reason, I think, that if you really want to impact survival and complication rates in people with diabetes, preventing and treating heart failure is one of the surest ways of doing so.

“You shouldn’t just think of the patient in front of you as someone who has an A1c of 7%, 8%, or 9%,” he cautioned. “You should also start thinking of where the patient is on the spectrum of cardiovascular disease, all the way from CVD risk factors only to symptomatic heart failure.”

Some evidence already exists to help clinicians make treatment decisions based on where the patients fall on that spectrum, he continued.

For example, clinical trials have demonstrated that in patients with established atherosclerotic cardiovascular disease, GLP-1 receptor agonists and SGLT2 inhibitors can reduce the risk of cardiovascular events, including, in some cases, cardiovascular death.

“We don’t have a lot of data demonstrating benefit for patients with recent acute coronary syndrome,” he said. “Some compounds have proven to be neutral, but none has been proven to save lives in this patient group.

“Now, we also have data for people with prior stroke that pioglitazone may be beneficial in managing those patients to prevent recurrent stroke and MI, based on the recent IRIS Trial , provided they don’t have heart failure at baseline,” Dr. Kosiborod added. “We don’t have definitive data yet in people with established heart failure, but those studies are ongoing.”

Dr. Kosiborod disclosed that he is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eisai, Glytec, GSK, Intarcia, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi, and ZS Pharma. He has also received research grants from AstraZeneca and Boehringer Ingelheim.


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