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New therapies offer options for patients with diabetes, heart failure
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AUSTIN, Texas — New anti-diabetic therapies offer options for patients with type 2 diabetes and heart failure, whereas several ongoing and longer-term studies are shedding new light on more controversial agents for this patient population, Richard Gilbert, MD, PhD, FRCPC, said during a presentation here.
“When we think about treating diabetes, there has been a shift,” Gilbert, head of the division of endocrinology at St. Michael’s Hospital and professor of medicine at the University of Toronto, said while speaking at the American Association of Clinical Endocrinologists Scientific and Clinical Congress. “We’ve known for a long while that we can prevent microvascular disease, but we’ve been far less confident, until very recently, about macrovascular disease. Now, we’ve got something extra to think about, and that is the prevention and treatment of heart failure in our diabetic patients.”
Good glycemic control can have a “profound impact” on risk reduction for HF death, Gilbert said; however, it can take many years before any benefit is observed. Studies also show HF is also age-dependent; diabetes confers about a five- to six-fold risk for HF in those aged 55 to 64 years, he said. In addition, Gilbert said, early signs of HF often go undetected.
‘We’re missing a lot ’
In a cross-sectional study published in the August 2012 issue of Diabetologia, researchers assessed the prevalence of unknown HF and left ventricular dysfunction in 605 patients with type 2 diabetes aged at least 60 years living in the Netherlands; 2.5% of the cohort had cardiologist-diagnosed HF.
Between February 2009 and March 2010, the patients without known HF underwent a standard diagnostic work-up, including medical history, physical examination, ECG and echocardiography. An expert panel, including two cardiologists diagnosed HF based on European Society of Cardiology criteria.
“And what you find is that there’s an extra 4.8% who have HF with reduced ejection fraction, and 22.9% who have HF with preserved ejection fraction that wasn’t diagnosed,” Gilbert said. “We’re missing a lot. Why is that happening? I think it’s something we’re not picking up because it develops slowly and chronically and is initially very mild.”
Patients might not be aware of the early signs of HF, Gilbert said, like reduced exercise tolerance.
“My patients will come in and tell me it’s difficult to exercise ... but maybe they can’t exercise as much as we like, not because they’re deconditioned but because their capacity is reduced by their cardiac dysfunction,” Gilbert said.
Recent outcomes studies conducted in newer drug classes, as well as studies with older agents, have yielded interesting findings with respect to HF in the setting of diabetes, Gilbert said.
‘How things change’
Data from the Kaiser Permanente Northwest Diabetes Registry, which included 8,063 patients with diabetes and no prior history of heart failure followed between 1998 and 2002, suggested that the likelihood of HF in patients with type 2 diabetes was associated with use of sulfonylureas and insulin; a combination of those agents, Gilbert said, predicted worse outcomes.
“This would be a very typical finding, but, I think it’s important to remind ourselves about levels of evidence, and how things change as we move from observational studies ... compared with the level 1 evidence, the randomized controlled trials,” Gilbert said. “You’ll see things are really quite different.”
In the ORIGIN study, a worldwide, randomized controlled trial with more than 12,500 patients with prediabetes or early-stage type 2 diabetes, researchers compared risks for CV outcomes in patients assigned either insulin glargine (Lantus, Sanofi) or standard care, and to omega-3 fatty acid supplementation or placebo, for a median of 6.2 years. Rates for incident CV outcomes, including hospitalization for HF, were similar between groups, Gilbert said.
Similarly, in an analysis of the UK Prospective Diabetes Study Group (UKPDS) published in The Lancet in 1998, researchers found that intensive blood glucose control by either sulfonylureas or insulin did not decrease risk for macrovascular disease in patients with type 2 diabetes; however, the individual drugs did not have an adverse effect on CV outcomes, including hospitalization for HF.
DPP-IV inhibitors
Data from large cardiovascular outcomes trials for three DPP-IV inhibitors — SAVOR, EXAMINE and TECOS —helped to begin “the surprise of our therapeutic journey” with respect to diabetes and HF, Gilbert said.
Primary three-point or four-point major adverse cardiac event outcomes for all three trials were event-neutral with respect to CV death, nonfatal stroke and nonfatal MI.
“But I think what came as a great surprise to many of us were data from the SAVOR-TIMI 53 study, where there was a difference in terms of hospitalization for heart failure,” Gilbert said. “One component of the secondary endpoint of the study that showed a 27% increase in the likelihood of heart failure in those patients treated with saxagliptin.”
Through a review of the clinical trials, the FDA discovered that more patients taking both saxagliptin and alogliptin were hospitalized with heart failure compared with patients on placebo. In April 2016, the FDA released a warning that alogliptin and saxagliptin may increase the risk for HF.
“If you’re someone who believes in class effects, then you’d be worried about the DPP-IVs, but if you’re more concerned about the individual structure, then you’ll have a different attitude,” Gilbert said. “The final word, I think, we have to give to the FDA with this warning, which is the presumption that we should do no harm and act on the data we have at the present time. This puts sitagliptin in a neutral position, and a cloud around saxagliptin and alogliptin.”
SGLT2 inhibitors
In the worldwide EMPA-REG Outcome study, patients with type 2 diabetes and established CVD saw a 35% reduction in risk for hospitalization for HF compared with those assigned placebo, Gilbert said. In addition, he noted, patients who had no HF at baseline seemed to be protected equally as well as patients who had established HF.
“This suggests that there was undiagnosed or subclinical heart failure in those patients that can be prevented with empagliflozin,” Gilbert said.
“The data are of sufficient import for various cardiac societies to make recommendations based on those data.”
The mechanistic explanation behind SGLT2 inhibition remains unclear, Gilbert said, though likely explanations point to changes in volume (more a correction than a contraction, he said) and reduced myocardial preload and afterload.
“Empagliflozin leads to an acute increase in hematocrit which tells you that there has been some reduction in intravascular volume,” Gilbert said. “This is a reverse effect of what was observed in [trials with] thiazolidinediones.”
“It looks like that reduction in the intravascular volume may be the most important marker, both of heart failure hospitalization and heart failure mortality,” Gilbert said.
The ongoing CANVAS and DECLARE trials with canagliflozin and dapagliflozin, respectively, will likely provide more information in the coming year on the SGLT2 class and HF in diabetes, Gilbert said.
GLP-1 receptor agonists
There was initially a lot of enthusiasm for GLP-1 receptor agonists, Gilbert said; the LEADER study, completed in 2016, showed liraglutide (Victoza, Novo Nordisk) reduced CV death, nonfatal stroke and nonfatal MI vs. placebo.
However, there was no significant difference for hospitalization for HF despite reducing MI, Gilbert said, the major cause of HF in patients with diabetes.
Liraglutide, Gilbert said, is probably a neutral agent, except in the setting of established, severe HF. – by Regina Schaffer
Reference:
Gilbert R. Effects of Anti-hyperglycemic Drug Therapy in Diabetic Heart Failure. AACE Annual Scientific and Clinical Congress; May 3-7, 2017; AUSTIN, Texas.
Disclosures: Gilbert reports sharing patents with, receiving grant support from or serving on advisory boards in an ad hoc capacity for Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck and Novo Nordisk.