Triple combination therapy may be optimal for CV protection in type 2 diabetes
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Triple therapy combining an SGLT2 inhibitor, a GLP-1 receptor agonist and the thiazolidinedione pioglitazone could serve as an optimal solution for cardiovascular and renal protection in type 2 diabetes, according to a speaker.
The impact of triple therapy on CV outcomes remains difficult to discern; there are no randomized controlled trial data on combination therapy assessing outcomes, Ralph A. DeFronzo, MD, director of the diabetes research unit at the University of Texas Health Science Center at San Antonio, said during an online presentation.
“To me, if we are going to talk about combination therapy, we need to look at those antidiabetic medications that have documented cardiovascular benefit,” DeFronzo said. “I am going to focus on three: the SGLT2 inhibitors, pioglitazone and GLP-1 receptor agonists. You will note that I do not have metformin on this list. ... In my opinion, there is not a prospective, well-documented study showing that metformin decreases cardiovascular events as monotherapy.”
Evidence-based benefits
Studies assessing CV outcomes with SGLT2 inhibitors, pioglitazone and GLP-1 receptor agonists are “quite robust,” with data showing benefits above and beyond CV outcomes, DeFronzo said. SGLT2 inhibitors, in particular, meet an “unmet need” in diabetes care, he said. The DECLARE, CANVAS and EMPA-REG CV outcomes trials assessing the SGLT2 inhibitors dapagliflozin (Farxiga, AstraZeneca), canagliflozin (Invokana, Janssen) and empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly), respectively, all showed CV and renal benefit in adults with type 2 diabetes with established CVD, DeFronzo said.
“They correct a novel pathophysiologic defect at the level of the kidney, they induce glucosuria ... we get nice, sustainable drops in HbA1c, weight loss is impressive, and you can combine the SGLT2 inhibitors with any of the other antidiabetic agents,” DeFronzo said. “You get a nice drop in blood pressure with no hypoglycemia.”
Pioglitazone has similarly shown a durable HbA1c reduction over 5 years and also improves insulin secretion and insulin sensitivity, reverses lipotoxicity and improves markers of nonalcoholic fatty liver disease, DeFronzo said.
“We have two studies showing anatomical regression of atherosclerosis and a recent study from our group showing [pioglitazone] improves diastolic dysfunction, suggesting that it may actually have some benefit in heart failure with preserved ejection fraction,” DeFronzo said.
GLP-1 receptor agonists also effectively reduce HbA1c while preserving beta-cell function, promote weight loss and do not cause hypoglycemia, DeFronzo said. The class has been shown to have a direct myocardial effect, decrease postprandial lipemia and reduce BP. Reported gastrointestinal adverse events with the class are typically transient and short term, he said.
Individualized therapy options
DeFronzo said individualized therapy is needed for CV protection in the setting of type 2 diabetes. For example, statin therapy is better for preventing recurrent myocardial infarction among adults with prior MI; hypertensive medications are better for preventing recurrent stroke among adults with prior stroke.
DeFronzo recommended several possible combination options for adults with type 2 diabetes:
- Prior stroke: pioglitazone plus a GLP-1 receptor agonist;
- Prior MI: pioglitazone plus an SGLT2 inhibitor and a GLP-1 receptor agonist;
- Risk reduction for heart failure hospitalization: SGLT2 inhibitor plus a GLP-1 receptor agonist; and
- Renal outcomes prevention: SGLT2 inhibitor plus a GLP-1 receptor agonist.
“My prediction is we will be using individualized therapy for individualized people for CV risk reduction,” he said.
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DeFronzo RA. The combination of SGLT2 inhibitors and GLP-1 receptor agonists impact on CVD. Presented at: Heart in Diabetes CME Conference; Aug. 21-24, 2020 (virtual meeting).
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