Heart (and Kidneys) Feature in Diabetes Trials in San Francisco

Miriam E. Tucker

May 29, 2019

Results from 10 major clinical trials addressing prevention and management of type 2 diabetes will be featured at the American Diabetes Association 2019 Scientific Sessions.

Spread across the 5-day meeting from Friday June 7 through Tuesday June 11, the 10 "highly anticipated study announcements of 2019" will include new cardiovascular outcomes trial (CVOT) results for dulaglutide (Trulicity, Lilly), linagliptin (Tradjenta, Lilly/Boehringer Ingelheim), dapagliflozin (Farxiga/Forxiga, AstraZeneca), and oral semaglutide (Ozempic, Novo Nordisk), and new cardiorenal data for canagliflozin (Invokana, Janssen) and linagliptin.

Other major study results address the roles of vitamin D, lifestyle modification, and medication use in type 2 diabetes prevention.   

"The hottest clinical areas in diabetes have to do with the potential cardiovascular and renal outcomes for some of the newer agents, especially the sodium-glucose cotransporter type 2 [SGLT2] inhibitors and glucagon-like peptide 1 receptor [GLP-1] agonists. Particularly salient at this meeting will be several trials regarding these outcomes," program chair Jose C. Florez, MD, PhD, professor of medicine at Harvard and chief of the endocrine division at Massachusetts General Hospital, Boston, told Medscape Medical News.

Florez said that the recent flow of new data showing cardiovascular and renal benefits for glucose-lowering drugs "is really exciting to see. I think it's really shifting the algorithm for what agents people use in type 2 diabetes and in what sequence."

"Some of these trials will have a major impact on how we" practice medicine, said ADA Science and Medicine President Louis H. Philipson, MD, PhD, director of the Kovler Diabetes Center, and James C. Tyree professor of diabetes research and care, Departments of Medicine and Pediatrics, University of Chicago, Illinois.

And not forgetting type 1 diabetes, there are eagerly awaited data from a phase 2 trial of the anti-CD3 agent teplizumab for type 1 diabetes prevention in those with ≥ 2 islet autoantibodies and abnormal glucose tolerance. According to the ADA, "The question for this study is whether treatment at early stages of disease can delay progression to clinical (stage 3) type 1 diabetes." Two-year clinical results from TrialNet's low-dose ATG-GSCF trial in new-onset diabetes will also be presented as well as mechanistic data from TrialNet's natural history and immune effects of oral insulin studies. These important results and mechanistic studies will be presented on Sunday June 9 from 8:00 to 10:00 am.

And for the first time, ADA has listed all of these trials on its 79th Scientific Sessions homepage under "highly anticipated study announcements of 2019."

The Latest From CVOTs: REWIND, CAROLINA, and DECLARE-TIMI 58

As usual, the latest crop of CVOT results will each have their own 2-hour sessions. On Sunday June 9 at 2:15 pm, new data will be presented from the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) study, the first CVOT to enroll a much broader and healthier population of patients with type 2 diabetes — those without pre-existing cardiovascular disease but with multiple risk factors — as well as some patients with pre-existing cardiovascular disease.

Primary results from the trial were presented in November at the American Heart Association (AHA) Scientific Sessions 2018 and showed that dapagliflozin significantly reduced hospitalizations for heart failure and nonsignificantly reduced major adverse cardiovascular events (MACE).

At ADA, those results will be reviewed along with new subanalyses, renal endpoints, and safety data for the SGLT2 inhibitor.

Next, on Sunday June 9 at 4:30 pm, comes the Researching CV Events With a Weekly Incretin in Diabetes (REWIND) trial, with 5-year results for dulaglutide, a once-weekly injectable GLP-1 agonist, in a large population of lower-risk adults. This is the first such study with a GLP-1 agonist to include a majority of patients who did not have established cardiovascular disease at baseline. 

Top-line results from REWIND, announced in November 2018, showed dulaglutide significantly reduced the risk of MACE.

And on Monday June 10 at 4:30 pm, data will be presented from the Cardiovascular Safety of Linagliptin (CAROLINA) study, the longest CVOT so far (8 years) and the only one to include a head-to-head active comparator (the sulfonylurea glimepiride). In addition to the findings for linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, the results may also inform the longstanding debate about the cardiovascular safety of sulfonylureas.

Oral Semaglutide: A Game Changer?

A session on Tuesday morning at 9:45 am will cover the PIONEER program trials for oral semaglutide, the GLP-1 receptor agonist already approved as a once-weekly injectable.

Top-line results for PIONEER 6, announced in November 2018, showed reductions in cardiovascular and all-cause mortality but not the overall composite primary MACE endpoint.

Previously reported results from the PIONEER series of trials include PIONEER-1, which demonstrated the oral version's glucose-lowering and weight loss capabilities, while in PIONEER-3 the drug reduced HbA1c more than sitagliptin.

Philipson commented, "Semaglutide has been on the market for some time but we've never had an oral [GLP-1 agonist]...before...I think this is a very big deal and potentially game changing for people with type 2 diabetes, so I'm very excited about that."

"How much the oral semaglutide can recapitulate the benefits of the injected one is critical," he stressed. 

Proving Prevention: Vitamin D, Medications, and Lifestyle Interventions    

On Saturday June 8 at 4:00 pm, results from the Prevention of Diabetes in Europe and Around the World (PREVIEW) study, the largest-ever (N = 2326) to investigate diabetes prevention through lifestyle interventions, will be reviewed.

Data from PREVIEW, previously reported at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting, suggested a 2-month weight loss regimen using meal substitutes followed by long-term weight maintenance through diet and exercise may be an optimal approach to preventing type 2 diabetes through lifestyle.

Another prevention study, the multicenter Vitamin D and Type 2 Diabetes (D2d) clinical trial, supported by the National Institutes of Health, is the largest ever study specifically designed to determine whether vitamin D supplementation can reduce the risk of developing type 2 diabetes among people at risk. Final results will be presented on Friday at 11:30 am. 

"There's been a lot of epidemiological evidence that vitamin D is helpful for either beta-cell function or insulin action, but there's never been a real randomized prospective trial, particularly for type 2 diabetes prevention," Florez explained.

And Philipson commented, "This is a hot topic in diabetes...Many of us are measuring vitamin D levels and supplementing, but should we be? It's not always reimbursed. Right now clinicians are deciding on their own."

On Sunday at noon, results will be presented from the Adult Medication study of the three-part Restoring Insulin Secretion (RISE) program looking at both prevention and early treatment of type 2 diabetes.

The RISE pediatric medication study, presented at ADA last year, showed that in adolescents with impaired glucose tolerance (prediabetes) or recent-onset type 2 diabetes, early intervention with long-acting insulin followed by metformin or metformin alone — both given for a year — failed to prevent deterioration of beta-cell function.

"These are really critical studies for our understanding of what's happening in type 2 diabetes," Philipson emphasized.  

Kidney and Cardio: Latest Data from CREDENCE and CARMELINA

A single 2-hour session on Tuesday starting at 7:30 am will review data from the landmark Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial, which assessed progression of kidney disease and secondarily cardiovascular outcomes, and the Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA), which assessed cardiovascular outcomes and secondarily kidney disease progression.

Primary findings from CREDENCE, presented in April at the International Society of Nephrology (ISN): 2019 World Congress, showed canagliflozin lowers the risk for progression to end-stage renal disease by 30% in patients with type 2 diabetes and chronic kidney disease, as well as lowers the risk for MACE. 

And data from CARMELINA, first presented in October 2018 at the EASD meeting, showed adding linagliptin to standard of care in patients with type 2 diabetes at high cardiovascular risk did not worsen cardiovascular, heart failure, or renal events, even in those who already had kidney disease.

Key findings from both trials will be reviewed and new analyses presented.  

"CREDENCE and CARMELINA are very big deals," Philipson underlined. "These are follow-up studies that will help affirm the original report. They're really exciting."

A Tough Subject: Type 2 Diabetes in Youth

On Saturday June 8 at 1:45 pm, a 2-hour session will be devoted to the latest findings from the follow-up to the multicenter, multi-ethnic, randomized Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.

The post-intervention follow-up, TODAY2, is tracking the youth into young adulthood to investigate rates of renal, cardiac, eye, and nerve complications, as well as pregnancy outcomes and healthcare utilization.

Philipson commented, "If there's one ray of light that comes from this study it would be wonderful. But we have a strong feeling that children with type 2 diabetes actually do worse in some cases than children with type 1. It can be a profound disease that leads to early death, and in many cases we don't even have a good approach to treating it. These talks will give us some indication of the outcomes of the study and what we might learn."

Venture Outside Your Comfort Zone

Of course there's much, much more to the meeting. Other highlights include sessions on the rational use of opioids for treating painful diabetic neuropathy, learning from atypical diabetes, an ADA consensus paper on nutrition therapy for adults with diabetes, new artificial pancreas trial results, and two keynote award lectures on obesity that "will be more clinical than usual," Philipson observed.

Both Philipson and Florez urge delegates to attend sessions that may be outside their usual areas of focus. 

Referring to the nutrition session, held under the "Behavioral Medicine, Clinical Nutrition, Education, and Exercise" track, Florez said, "We tend to just go to sessions that are in our comfort zones. But if you're a clinician who takes care of people with diabetes you can't just leave it to the nutritionists and the [certified diabetes educators] to attend this track on behavioral medicine and clinical nutrition."

"I think it's incumbent on all of us who take care of diabetes…to be up to date on the latest in nutrition therapy...This disease requires a multidisciplinary, multipronged approach. Physicians need to go beyond drugs to other forms of therapy. Don't use the meeting to go over things you already know."

Indeed, said Philipson, "I encourage people to go to lectures and meetings they wouldn't normally go to...This meeting is really for everybody with an interest in diabetes, from basic scientists to practitioners, whether they're MDs or psychologists or exercise physiologists, ophthalmologists, etc. That breadth is unmatched by any other meeting that includes diabetes."

Florez has consulted for Janssen. Philipson has received research funding from Janssen, ADA, JDRF, Helmsley Foundation, and National Institutes of Health.

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