Trials’ results suggest outside-the-box approaches to reduce CVD risk

Investigators in four trials revealed surprising findings on novel approaches to reduce CVD risk during their Late-Breaking Science session at Scientific Sessions:

  • The glucose-lowering drug dapagliflozin may benefit heart failure patients without diabetes.
  • Inclisiran, a new class of cholesterol lowering drugs, given twice a year, lowered LDL-C in ASCVD patients with elevated LDL-C.
  • A gout drug could potentially be repurposed for reducing cardiovascular events.
  • In a proof-of-concept CV outcomes trial, epigenetic modulation with apabetalone suggests promise but more studies are needed.

Glucose-lowering drug may help manage heart failure in nondiabetic patients

Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, was equally effective in reducing cardiovascular death and hospitalization in diabetic and nondiabetic patients with heart failure, according to Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure Trial (DAPA-HF): Results in Nondiabetic Patients.

The 18-month study randomized 4,744 patients with heart failure and reduced ejection fraction to dapagliflozin 10 mg once daily or matching placebo; 45% of enrolled patients had diabetes.

Overall, dapagliflozin equally benefited patients compared to the placebo. The primary composite endpoint of cardiovascular death, heart failure hospitalization or an urgent heart failure visit was reduced by an average 26% in heart failure patients with or without diabetes.

The safety profile was also favorable.

Investigators saw no real difference in potential side effects, with only four diabetic patients in the dapagliflozin group and four diabetic patients in the placebo group reporting major hypoglycemia. Similarly, only three cases of ketoacidosis were reported; all three were patients with diabetes at baseline.

“This class of drugs, SGLT2 inhibitors, are more than just a treatment for patients with diabetes,” said John McMurray, MD, FRCP, FAHA, professor of cardiology at the BHF Cardiovascular Research Centre at the University of Glasgow and Queen Elizabeth University Hospital in the United Kingdom and the study’s principal investigator. “They’re potentially a lifesaving treatment that reduces heart failure hospital admission and improves symptoms in people with heart failure, irrespective of whether they’ve got diabetes or their HbA1c level.”

Inclisiran safely reduced LDL-C

Inclisiran, a small interfering RNA agent that blocks translation in the hepatocyte of the production of the PCSK9 protein, may reduce LDL-C by more than 50% in patients with chronically elevated LDL-C levels, according to Phase III trial results of Safety and Efficacy of Inclisiran in Patients With ASCVD and Elevated LDL Cholesterol (ORION-10).

The clinical study evaluated the safety and efficacy of inclisiran dosed initially, at three months and then every six months thereafter in 1,561 patients with stable ASCVD and elevated LDL-C (≥70 mg/dL), despite maximum tolerated oral statin therapies (with or without ezetimibe).

Patients were randomized to 1:1 inclisiran sodium 300 mg or placebo at 145 U.S. sites between December 2017 and September 2019.

ORION-10 evaluated two coprimary endpoints: Reduction in LDL at day 510 between placebo and inclisiran and the placebo-adjusted, time-adjusted percent change in LDL from baseline between days 90-540.

ORION-10 resulted in placebo-adjusted LDL-C 58% reductions at day 510 and demonstrated time-averaged, placebo-adjusted LDL-C reductions of 56% from days 90-540.

“Inclisiran is efficacious, durable and potent,” said R. Scott Wright, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, and principal investigator for ORION-10.

Despite few injections — given on day one, day 90 and every six months thereafter — inclisiran significantly lowered LDL-C.

“Up to 540 days, we can also confidently say the safety profile is no different than placebo,” Wright said.

Repurposing colchicine may help reduce risk of secondary MI

Colchicine, a powerful anti-inflammatory drug for gout and pericarditis, may effectively reduce ischemic cardiovascular events, according to results of the COLchicine Cardiovascular Outcomes Trial (COLCOT).

COLCOT randomized 4,745 patients within 30 days post myocardial infarction, comparing low dose colchicine, 0.5 mg once daily, plus the standard care with placebo. Patients were followed for a median 23 months. The composite primary endpoint included cardiovascular deaths, resuscitated cardiac arrest, myocardial infarction, stroke and urgent hospitalization for angina requiring revascularizations.

Colchicine reduced the risk of first and total ischemic cardiovascular events by 23% and 34%, respectively, compared to placebo in patients with recent myocardial infarction.

The drug was well tolerated.

“Rates of adverse effects were low, including a small increase in pneumonias, but no significant increase in diarrhea with colchicine, on background therapy with aspirin, a second antiplatelet agent and a statin in 99, 98 and 99% of patients,” said Jean-Claude Tardif, MD, director of the Research Centre at the Montréal Heart Institute in Montreal, Canada.

“Colchicine is orally administered, available in every country in the world and inexpensive.” The COLCOT results apply to patients who have recently suffered a myocardial infarction. Further research is needed to assess the benefits of colchicine in other high-risk patients.

Apabetalone targets new treatment pathway, but more research needed

Apabetalone didn’t reduce clinical cardiovascular events, according to results of the Effect of BET Protein Inhibition With Apabetalone on Cardiovascular Outcomes in Patients With Acute Coronary Syndrome and Diabetes Trial (BETonMACE).

The compound was developed to inhibit bromodomain and extra-terminal (BET) proteins, epigenetic transcription modulators of the inflammation, thrombogenesis and the lipoprotein metabolism that contributes to atherothrombosis.

In the proof-of-concept double-blind cardiovascular outcomes trial, 2,425 patients with acute coronary syndrome, low HDL-C and diabetes from 195 sites in 13 countries were randomized to apabetalone 100 mg twice a day or placebo in addition to guideline recommended standard of care and intensive or maximum-tolerated statin treatment and followed for an average 26.5 months.

By displacing BET proteins from binding sites on chromosomal DNA, apabetalone was hypothesized to reduce the ability of BET proteins to upregulate processes that contribute to cardiovascular events. But the drug failed to achieve a statistically significant result. The observed event rate in the placebo group (9.7%) was lower than anticipated (10.5%) at 18 months. But apabetalone was generally well tolerated with an overall incidence of adverse events similar to the placebo group.

“This is the first epigenetically modifying drug to be tested in cardiovascular disease, with this very selective pathway, and we remain optimistic,” said Kausik (Kosh) Ray, professor of public health at Imperial College London in the United Kingdom and the study’s principal investigator.

A larger apabetalone study is needed, he said.