Docs Question Ethics of Diabetes Drugs CV Outcomes Studies

Miriam E Tucker

February 22, 2018

Recent cardiovascular outcomes trials for type 2 diabetes drugs have raised ethical concerns as they have left patients in the control groups exposed to high HbA1c levels for long periods of time, two former pharmaceutical company employees charge. 

The viewpoint article was published online February 12 in the Journal of Clinical Investigation by Simeon I Taylor, MD, of the University of Maryland, Baltimore, and Bruce R Leslie, MD, with Seventh Doctor Consulting, Princeton, New Jersey.

Trials to rule out cardiovascular risk for all new oral type 2 diabetes medications were mandated by the US Food and Drug Administration (FDA) in 2008.

At the hearing that led to the FDA requirement, the advisory panel recommended individual patients — including those in the comparator arms not receiving the study drug — should receive glucose-lowering medications to maintain their HbA1c to less than 8% because to do otherwise in a multi-year trial would be unethical because of the increased risk of microvascular complications.

Taylor and Leslie point out that many of the recent cardiovascular outcomes trials have not followed that guidance, thus raising "significant ethical questions."

In particular, they fault the SUSTAIN-6 study, in which the control patients had a mean HbA1c of about 8.4%, vs about 7.2% for the semaglutide group, for the entire 104-week trial.

The authors add that blood pressure was also better controlled in the drug vs control groups in several cardiovascular outcomes trials, raising the question of whether the cardiovascular benefits found for empagliflozin (Jardiance, Boehringer Ingelheim/Lilly), canagliflozin (Invokana, Janssen Pharmaceuticals), liraglutide (Victoza, Novo Nordisk), and semaglutide (Ozempic, Novo Nordisk), and the renal benefits found for empagliflozin, canagliflozin, and liraglutide are unique to the two drug classes, or whether the same effect might be achieved less expensively by prescribing, for example, a dipeptidylpeptidase-4 (DPP-4) inhibitor along with a generic antihypertensive drug.

And that, in turn, raises the issue of justification for recent clinical guidelines, such as those from the ADA, recommending the study drugs found to have demonstrated cardiovascular benefit for patients with type 2 diabetes and established cardiovascular disease over others, such as sitagliptin, that didn't.

"This conclusion seems premature," write Taylor and Leslie, both of whom were previously employed by Bristol-Myers Squibb as well as other diabetes drug manufacturers.

"Before advocating that physicians should select one of these drugs, it would be informative to conduct a study in which both study arms have comparable mean levels of both HbA1c and blood pressure," they urge.

"For example, an SGLT2 inhibitor or a GLP-1 receptor agonist could be compared to a DPP-4 inhibitor in combination with generic antihypertensive medications. Such a study would reflect more accurately the real-world options available to physicians and patients," the two write.

SUSTAIN-6 Investigator's Rebuttal

Asked for his response, lead investigator of both SUSTAIN-6 and LEADER Steven P Marso, MD, a cardiologist, strongly disagreed.

"I think that is just incorrect. I think the guidelines are not premature. I think they’re overdue. We've been waiting for decades for diabetes medications to affect not only microvascular but cardiovascular outcomes. We now have four trials, two different [drug] classes, and supporting trials in each class to suggest there's cardiovascular benefit. The guidelines are appropriate," he told Medscape Medical News.  

Marso, who is chief medical officer for HCA Midwest Health cardiovascular services, Kansas City, Missouri, pointed out that recent trials have found very little cardiovascular benefit with intensive glucose lowering, and harm in at least one trial.

"There remains some uncertainty, but today there's no clear evidence that if you lower glucose to a certain target you improve cardiovascular benefit. Most data suggest that's just not true."

And regarding the ethics charge, Marso said that although he agrees that high glucose levels may put patients at risk for microvascular complications, the studies allowed individual clinicians to treat patients as best as they could within the clinical trial parameters.

"Patients were randomized to active treatment and placebo in addition to standard of care. Everybody was on standard of care treatment. Especially in LEADER and SUSTAIN-6, we made great efforts to communicate to the investigators to use current guidelines to drive down glycemic control to a level they were comfortable with."

"I think to suggest that these clinical trials were somehow suboptimal because patients didn't achieve glycemic equipoise is just palpably wrong."

As for the differences in blood pressure, Marso called the 2 to 3 mmHg systolic lowering in SUSTAIN-6 with semaglutide minimal.

Despite the greater reductions in glucose, systolic blood pressure, and lipids (to a lesser degree), with the active drug, "if you add up all these risk factors it still doesn’t account for the significant cardiovascular risk reduction... I think the mechanism of benefit has yet to be elucidated."

Current thinking, he said, is that the cardiovascular benefit for GLP-1 agents including liraglutide and semaglutide is likely to relate to atherosclerotic plaque stability, whereas for the SGLT2 inhibitors, including empagliflozin and canagliflozin, the mechanism more likely relates to plasma volume.

"I truly think the SGLT2 inhibitors and the GLP-1 [receptor agonists] ... are not just glucose-lowering agents. They have so many other off-market benefits we're just now understanding... It's amazing how this field has blown up. It's just now the beginning with these clinical trials."

Lessons for Future Trials?

While some experts have questioned the ongoing necessity for the FDA to mandate large cardiovascular safety studies for all new diabetes drugs — and not for drugs for other chronic conditions — Taylor and Leslie say these trials "have provided important clinical data that go well beyond the original objective of ruling out increased risk of major adverse cardiovascular events."

This includes the unveiling of uncommon, unanticipated side effects, such as the increased risk for amputation seen with canagliflozin and heart failure hospitalization risk with saxagliptin.

"In the future, one would hope that studies would be designed to assure better protection of research subjects. This might be accomplished if treatment algorithms were provided to make sure that the responsible physicians actually prescribe diabetes drugs and antihypertensive agents to achieve comparable mean levels of HbA1c and blood pressure in all treatment arms," they write.

Taylor and Leslie add, "While large outcome studies are expensive, the expense must be judged in comparison to the very substantial sales of successful diabetes drugs."

"With an eye to the future, we believe that these historical studies have provided valuable lessons that can be applied to improve study design — thereby increasing the value of future studies," they conclude.

Taylor was previously employed at Bristol-Myers Squibb, and has been a consultant for Ionis Pharmaceuticals, has received research support provided to the University of Maryland School of Medicine by Regeneron Pharmaceuticals, and owns stock in Celgene, Amgen, and Abbott Laboratories. Leslie was employed by Bristol-Myers Squibb, Janssen Research and Development, and Pfizer where he worked on the development of SGLT2 inhibitors. He owns stock in Bristol-Myers Squibb, Merck, and Pfizer. Marso has received personal fees from Abbott Vascular, Novo Nordisk, the University of Oxford, AstraZeneca, Bristol-Myers Squibb, Boston Scientific, and Abbott Vascular. He has received research support from Novo Nordisk, The Medicines Company, and Terumo Medical.

J Clin Invest. Published February 12, 2018. Excerpt

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