NEW ORLEANS — Details of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardio Outcome Results—A Lasting Evaluation (LEADER) trial of the glucose-lowering drug liraglutide (Victoza, Novo Nordisk), showing that it significantly low the rates of significant edge Cardio events in type 2 diabetes patients at elevated Cardio risk, were reported today.
The study is the second such mandated FDA Cardio safety study for a diabetes drug to reveal Cardio benefit, fairly compared to merely lack of harm, on top of standard therapy in type 2 diabetes patients at higher Cardio risk after the EMPA-REG trial, and the very first along with an agent from the glucagonlike peptide 1 (GLP-1) receptor agonist class. Results of a previous trial along with yet another GLP-1 agonist, ELIXA, were neutral.
Experts here said that LEADER and EMPA-REG could now start to modification the landscape of diabetes therapy, giving doctors a somewhat clearer choice as quickly as deciding which drug to use second line after metformin in type 2 diabetes.
The results from the multicenter, worldwide study were presented June 13, 2016 here at the American Diabetes Association (ADA) 2016 Scientific Sessions and were published online simultaneously in the New England Diary of Medicine, by Steven P Marso, MD, of University of Texas Southwestern Medical Center, Dallas, and colleagues.
LEADER began in 2010 and followed 9340 high-risk adults along with type 2 diabetes for 3.5 to 5 years, that were randomly assigned to receive either a subcutaneous injection of liraglutide 1.8 mg once day-to-day (or the maximum tolerated dose) or placebo along along with standard treatment.
The primary end point was the very first occurrence of the three-point significant edge cardiac event (MACE) components: Cardio death, nonfatal myocardial infarction (MI), or nonfatal stroke.
The degree of risk reduction for MACE was 13% (occurring in 608 of 4668 patients taking liraglutide) vs 14.9% (in 694 of 4672 taking placebo) (P = .01 for superiority), including a 22% lower price of Cardio death (4.7 vs 6.0%, P = .007), Dr Marso reported in a press briefing held at the ADA meeting ahead of time of a special 2-hour symposium devoted to the findings.
The number of patients that would certainly be called for to treat to avoid one event in 3 years was 66 for the MACE composite and 98 for death from any kind of cause.
Liraglutide additionally low HbA1c, physique weight, and hypoglycemia, and its safety profile was similar to just what has actually been seen in previous trials, along with gastrointestinal edge events and boosts in heart price being the most common.
New Trials Inform Clinical Choice of Second Drug for Type 2 Diabetes
Coming on the heels of the Cardio benefit seen for the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) in the EMPA-REG trial, the LEADER findings have actually experts talking regarding a “Brand-new era” in the management of type 2 diabetes.
While most agree that metformin remains the first-line drug of choice, these Brand-new landmark study data are starting to much better inform the clinical choice of second drug based on characteristics beyond their glucose-lowering capacity, speakers said throughout the press briefing.
“In type 2 diabetes, most of us agree that under most circumstances metformin is the drug of choice,” briefing moderator Robert H Eckel, MD, of the University of Colorado, Denver, said, noting that additional potential Cardio and additionally anticancer benefits have actually been seen along with that drug as well.
However, he said, “It’s interesting, along with LEADER the benefit for Cardio death is fairly similar to just what statins do. I believe along with validation, it could potentially modification practice….I’d adore to see second and third trials for the 2 [liraglutide and empagliflozin]. Take note there are 25 or 30 trials for statins showing benefit,” said Dr Eckel, that was not involved in LEADER or EMPA-REG.
Senior investigator of LEADER, John Buse, MD, of the University of North Carolina, Chapel Hill, added: “I believe this modifications the conversation along with patients. Now, as opposed to merely saying we’re giving you this drug to control your hyperglycemia in diabetes, [we can say] this drug additionally has actually the potential to modify your risk for Cardio ailment and death.
“It was beyond our expectations that we would certainly have the ability to demonstrate Cardio efficacy,” he told the press briefing.
Asked to comment, Simon Heller, MD, professor of clinical diabetes, University of Sheffield, United Kingdom, told Medscape Medical News, “I believe we are in a different era now. People die from hypoglycemia, whether by insulin or sulfonylureas. We shouldn’t forget that.
“These drugs [liraglutide and empagliflozin] don’t create hypoglycemia and have actually various other effects that might be beneficial. I agree absolutely we have to confirm along with various other studies, yet I believe we’re certainly going to see a shift toward modern therapies.”
Benefits Seen for Multiple Cardio End Points
The LEADER trial included patients along with type 2 diabetes that had HbA1c levels of 7.0% or higher. Entry criteria were either age 50 and above along with established Cardio ailment or chronic renal failure or age 60 and older along with CVD risk factors.
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Dr Robert H Eckel on podium; left to right, Drs Simon Heller, John Buse, Steven P Marso, and Bernard Zinman |
Patients could be drug-naive or taking oral agents or basal insulin yet not various other GLP-1 agonists or DPP-4 inhibitors, pramlintide, or rapid-acting insulin. In the 2 treatment and placebo groups, current standards of care were targeted for HbA1c, blood pressure, lipids, and antiplatelet therapy.
Subjects had a mean baseline age of 64 years, diabetes duration 13 years, and HbA1c 8.7%.
At 36 months’ postrandomization, HbA1c levels were 0.40 percentage Things lower in the liraglutide group, a substantial difference (P < .001). physique weight additionally dropped significantly, by 2.3 kg (P < .001).
Overall, results for each of the components of the composite primary MACE outcome were in favor of liraglutide, along with a 22% reduction in Cardio death (4.7% vs 6.0%, P = .007), which was significant, and a nonsignificant 12% reduction in nonfatal MI (6.0% vs 6.8%, P = .11) and an 11% lower price of nonfatal stroke (3.4% vs 3.8%, P = .30).
Also substantial were a 15% reduction in all-create death (8.2% vs 9.6%, P = .02) and an expanded composite CV outcome that included coronary revascularization, unstable angina, or hospitalization for heart failure (20.3% vs 22.7%, P = .005).
Hospitalization for heart failure itself was 13% much less frequent in the liraglutide group (4.7% vs 5.3%, P = .14). Even though not statistically substantial in terms of benefit, the lack of any kind of signal for concern along with regard to heart failure is noteworthy, Dr Marso said. “There has actually been a great deal of discussion in the incretin space regarding whether agents such as SGLT2 inhibitors, DPP-4 inhibitors, or GLP-1 receptor agonists are neutral, hazardous, or practical for heart failure.”
He added: “What’s striking is the consistency in the relative risk reduction in every one of the significant Cardio end Things that we measured in LEADER.”
The prespecified primary microvascular outcome in LEADER was a composite of nephropathy and retinopathy outcomes, and there was a benefit along with liraglutide over placebo: time to very first renal event was 22% longer along with liraglutide, a substantial difference. However, this latter effect drove the benefit, as there was no substantial difference in retinopathy events between the 2 groups.
Safety Profile Shows No Signals
Overall edge events occurred in two-thirds of the 2 treatment groups and were not significantly different (P = .12). Major edge events occurred in 50% of the 2 groups and severe events in a third of the 2 (P = .51).
Adjudicated cases of acute pancreatitis occurred in 0.4% of patients taking liraglutide compared along with 0.5% on placebo (P = .44). There were two cases of chronic pancreatitis, the 2 in the placebo group.
However, acute gallstone ailment was much more common along with liraglutide, 3.1% vs 1.9% (P < .001).
Hypoglycemia was much more common in the placebo group, the 2 along with overall confirmed cases of blood glucose levels below 56 mg/dL (43.7% along with liraglutide vs 45.6% along with placebo, P < .001) and in severe hypoglycemia requiring recommendations (2.4% vs 3.3%, P = .016). The most likely requirement for this, Dr Eckel noted, is that the placebo patients could have actually been treated much more intensively along with insulin in attempt to achieve HbA1c targets.
Neoplasms were not different between the groups except for a 46% reduction in prostate cancer (0.9% vs 1.6%) and a lower price of leukemias (0.1% vs 0.3%) in the liraglutide group.
There was a numeric raise in the number of pancreatic-cancer cases along with liraglutide (13 vs five) for a greater price of pancreatic cancer in the liraglutide group (0.3% vs 0.1%), yet four much more cases were identified on imaging in the placebo group that did not have actually pathology to establish the diagnosis, so the 2 groups were not significantly different, Dr Buse noted.
Everything Changing Modestly, yet in the Right Direction
Dr Eckel said that the results of LEADER follow in the same vein as those of EMPA-REG.
“In EMPA-REG, lots of points related to CVD risk were modified in a modest yet favorable way. LEADER gives a hint of the same sort of modification.…Every little thing is sort of changing modestly in the right direction.”
But the LEADER investigators note some differences in exactly how the drugs might be working.
“The pattern of Cardio benefits that were associated along with liraglutide in our trial appears to differ from that along with the SGLT-2 inhibitor empagliflozin in the previously reported EMPA-REG OUTCOME trial.”
The time to benefit emerged earlier in EMPA-REG compared to in LEADER, they note, and the variability of the direction and magnitude of the effects on the components of the composite primary outcome in that trial “contrasts along with the consistency of effect in the present trial.”
The observed benefits in EMPA-REG “might be much more closely linked to hemodynamic changes, whereas in the present trial, the observed benefits are perhaps related to the modified progression of atherosclerotic vascular disease,” they conclude.
Dr Marso reports grants and personal fees from Novo Nordisk throughout the conduct of the study and personal fees from Abbott Vascular and AstraZeneca outside the submitted work. Disclosures for the coauthors are listed on the journal website .
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N Engl J Med . Published online June 13, 2016. Article
