June 02, 2017
3 min read

Some diabetes drugs reduce CV risks, but clinical judgment required

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PHILADELPHIA — Clinical trials support that certain glucose-lowering agents for diabetes reduce the risk for CVD. However, clinical judgment is imperative toward navigating the different agents, according to a presentation at the National Lipid Association Scientific Sessions.

“We now have further evidence that lowering LDL is associated with improved CVD outcomes, but what about improvement in glucose? Is intensive glucose-control therapy better than less aggressive conventional therapy?” Harold Bays, MD, FTOS, FACC, FACE, FNLA, medical director and president of the Louisville Metabolic and Atherosclerosis Research Center, said during his presentation.

Bays summarized the leading trials for the major glucose-lowering drugs and their benefits and risk in relation to CVD.

Harold Bays, MD
Harold Bays

He said several trials have supported intensive glucose control as improving microvascular disease after only a few years. Conversely, demonstrating macrovascular benefits with intensive glucose control has been more challenging, but longer-term follow-up of diabetes clinical trials does seem to support reduced CVD risk with more intensive glucose control, he said.

However, “when it comes to intensive vs. conventional treatment for diabetes mellitus, this is clearly a situation where clinical judgment is paramount,” Bays said. “The potential benefits of intensive glucose control may be dependent upon the patient population, as well as the mechanism, speed and extent of HbA1c reduction achieved.”


For most patients, metformin is currently a first-line monotherapy for drug treatment of type 2 diabetes. In a substudy of UKPDS, the effect of metformin on CVD risk was evaluated in 342 participants.


In the study, participants randomly assigned metformin had a 39% reduction in MI and a 50% reduction in coronary death compared with conventional therapy.

At the 10-year follow-up, participants on metformin had a risk reduction of 30% in diabetes-related death (P = .01), 33% in MI (P = .005), and 27% in all-cause mortality (P = .002).

Bays also said two observational studies showed reasonable safety, and perhaps benefit in HF for patients on metformin compared to sulfonylurea and placebo.

Newer anti-diabetes drugs

Following the 2008 guidance from the FDA, which set rules for approval and outcome trials for glucose-lowering drugs, researchers conducted trials of dipeptyl peptidase-IV  inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors to analyze associated CVD risks.

In three trials ֫— of saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca), alogliptin (Nesina, Takeda) and sitagliptin (Januvia, Merck) vs. placebo — the researchers found DPP-IV inhibitors did not reduce CVD risk. Additionally, saxagliptin and aloglipitin had prescribing information added to warn about the potential increased risk for HF; sitagliptin showed a neutral effect on CV events and did not increase risk for HF, Bays said.

For GLP-1 receptor agonists, liraglutide (Victoza, Novo Nordisk) and the novel agent semaglutide (Novo Nordisk) conferred reduction in CVD risk, while lixisenatide (Adlyxin, Sanofi) was not linked to CVD risk reduction, each in their respective trials. This class of drug did not reduce CV mortality or all-cause mortality.


The cause for the differences among GLP-1 receptor agonists is unknown.

“Overall if there is going to be a CVD benefit with the GLP-1 receptor agonists it might be because of weight loss, reduction in BP, improvement of lipids, vasodilation and decreased inflammation,” Bays said.


One of the more recent classes of anti-diabetes drugs are the SGLT2 inhibitors. Somewhat reflective of the class are the lipid effects of the SGLT2 inhibitor dapagliflozin (Farxiga, Bristol-Myers Squibb/AstraZeneca), Bays said, noting pooled data demonstrate minor increases in non-HDL, LDL and HDL.

The CVD effects of SGLT2 inhibitors were demonstrated in the EMPA-REG Outcome trial of empagliflozin (Jardiance, Boehringer Ingelheim), which showed a 14% risk reduction in major adverse CV events, defined as time to first occurrence of CV death, non-fatal MI or non-fatal stroke, a 35% reduction in hospitalization for HF, a 38% reduction in CV death and a 32% reduction in all-cause mortality.

“The degree of these beneficial CVD effects was unexpected to many of us,” Bays said. “In fact, I would submit that regarding empagliflozin and the EMPA-REG study, we haven’t come to grips with this profoundly positive data that we just did not expect. I don’t think we yet fully realize how these findings may alter practice, particularly among cardiologists.”

Looking forward, Bays said the CV benefits associated with newer agents might alter expectations of new anti-diabetes drugs in the future.

With the beneficial CVD effects of some of the GLP-1 receptor agonists, and with the favorable CVD outcomes of empagliflozin, is there going to be even greater expectation that future agents will need to reduce the No. 1 killer of patients with diabetes — which would be CVD? I don’t know, but it’s going to be exciting going forward in the research and development of even newer anti-diabetes agents,” he said. – by Cassie Homer


Bays HE. Masters in Lipidology: Managing Diabetes Mellitus and Cardiometabolic Risk. Presented at: National Lipid Association Scientific Sessions; May 18-21, 2017; Philadelphia.

Disclosure: Bays reports serving as an advisor/consultant or speaker for various pharmaceutical companies. His research site has received grants from many pharmaceutical companies.