Post-LEADER, 'Second Drug' Question in Diabetes Remains Unclear

Miriam E Tucker

June 24, 2016

NEW ORLEANS — With two landmark trials now demonstrating significant reductions in cardiovascular death with newer diabetes drugs, expert opinions range from exuberant to critical questioning of whether the demonstrated benefits will really outweigh the high cost of these novel agents and queries about the mechanisms of action.

In the most recent study, the multicenter, international Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results — A Long Term Evaluation (LEADER) of 9340 high-risk adults with type 2 diabetes followed for 3.5 to 5 years, those randomized to the glucagonlike peptide 1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) had a significant 13% reduction in major adverse cardiac events (MACE), driven primarily by a 22% reduction in cardiovascular death (P = .01 and .007, respectively).

The LEADER results were presented June 13 during a special 2-hour session at the American Diabetes Association (ADA) 2016 Scientific Sessions and simultaneously published online the New England Journal of Medicine.

LEADER followed on the heels of the EMPA-REG OUTCOME study announced last fall, which showed a 38% reduction in cardiovascular mortality for that drug (Jardiance, Boehringer Ingelheim/Lilly), a sodium glucose cotransporter-2 (SGLT2) inhibitor.

They are the first two trials mandated by the US Food and Drug Administration (FDA) to show cardiovascular benefit rather than just lack of harm in patients with type 2 diabetes at high cardiovascular risk. Other such studies have produced mostly neutral results, including that of another GLP-1 agonist, lixisenatide (Lyxumia, Sanofi), and two dipeptidyl peptidase 4 (DPP-4) inhibitors, alogliptin (Nesina, Takeda) and sitagliptin (Januvia, Merck).

"This is a very big deal," Steven E Nissen, MD, LEADER coinvestigator and Cleveland Clinic cardiology department chair, told Medscape Medical News, noting, "We had a 50-year drought during which there was essentially no comparative effectiveness research whatsoever done with diabetes drugs....At first, the trials were mostly neutral. DPP-4 inhibitors represent a relatively poor value for patients — they lower blood sugar a little bit, but do nothing for morbidity and mortality. Then all of a sudden in the past 12 months, what we've always hoped [did] happen — that if we require these trials, drugs would be developed that could actually reduce the terrible burdens of this disease."

Indeed, the reduction in cardiovascular death was strong enough that Boehringer Ingelheim is now seeking that indication for empagliflozin in high-risk patients, with an FDA advisory committee hearing scheduled for June 28.

Not Everyone Is as Awestruck...

Dr Nissen, whose publication of findings on heart failure with rosiglitazone launched the effort that led to the 2008 FDA requirement for cardiovascular outcome trials for type 2 diabetes drugs, described the scene in a Denmark conference room when the LEADER results were first unblinded to investigators by Novo Nordisk. "There was an audible gasp when the statisticians put up the slide. People realized this was history-making."

But not everyone is as awestruck. David M Nathan, MD, director of the Massachusetts General Hospital Diabetes Center and Clinical Research Center, Boston, pointed out — as does everyone else, including the investigators — that the findings of LEADER, EMPA-REG, and the other trials apply only to the populations studied — those with type 2 diabetes who already have established cardiovascular disease or are at extremely high risk.

Because of that, Dr Nathan said, "for the most part, the CV safety studies are secondary intervention studies for CVD, rather than diabetes treatment studies. The implication of these highly selected study populations is that the study findings can be applied only to patients who are similar in nature to the study populations....Whether the same risks and benefits would apply in younger, healthier populations treated over a longer period than the 3 to 4 years in EMPA-REG and LEADER is anyone's guess."

Moreover, he said, "What is clear is that the glycemia lowering in all of the CVD safety studies to date has been modest, about a 0.5% lowering of HbA1c.

"Whether the cost of these very expensive drugs, about $400 to $700 per month [in the US at least], can be justified for most patients is unclear," he stressed.

Dr Nathan did say, however, "For patients with type 2 diabetes and established CVD, either empagliflozin or liraglutide could be considered based on the EMPA-REG and LEADER trials, respectively."

So Which Drug After Metformin?

Thus far, the trials may not offer clinicians enough information to decide which drug to add when metformin is not enough for many of their patients with type 2 diabetes.

"These studies don't answer the second drug question. We don't know how to generalize these study results to everybody with diabetes....We also don't know how to compare drugs within classes yet. So we must have more studies. But it's a very exciting beginning," LEADER session moderator Matthew C Riddle, Jr, MD, professor of medicine in the division of endocrinology, diabetes, and clinical nutrition at Oregon Health Sciences University, Portland, told Medscape Medical News.

But Paul Jellinger, MD, clinical professor of medicine at the University of Miami, Florida, believes that the data do point to liraglutide and empagliflozin as second-line drugs.

"As more trials are completed and more data become available, GLP-1 agonists and SGLT2 inhibitors, either individually or as a class, are likely to emerge as a mainstay for the treatment of type 2 diabetes beyond their glucose-lowering properties. Robust glucose lowering and other important benefits have already propelled these two classes as choices after metformin in many clinical situations. A CVD benefit will only solidify that position," he stressed.

Dr Nissen said that, although empagliflozin might have the edge over liraglutide because it's oral rather than injected subcutaneously, both represent the new standard for diabetes treatment and cardiovascular disease prevention.

"Injectables require more effort. A pill always has a preference...but liraglutide is very effective and I think it will be used more frequently as a result of the LEADER trial, and it should be used more frequently."

Simeon I Taylor, MD, professor of medicine, University of Maryland School of Medicine, Baltimore, said he'd give liraglutide the edge over empagliflozin because it has a better safety profile than the SGLT2 inhibitors, which have been associated with ketoacidosis and bone fractures, among other things.

"I personally believe the safety profile of the GLP-1 agonist class is more attractive than the safety profile of the SGLT2 inhibitor class, especially with long-term use. The GLP-1s have been on the market longer so we have better data for them, but in the absence of a head-to-head trial you just truly can't make judgments about a lot of these things. But I think both drugs have very attractive efficacy and risk-prevention data."

For Karl Nadolsky, director of the Diabetes, Obesity & Metabolic Institute, Bethesda, MD, the results of the two trials suggest the potential for using liraglutide and empagliflozin together, given their different mechanisms of action — empagliflozin is believed to work more rapidly via hemodynamic changes, whereas liraglutide is thought to modify the atherosclerotic process, a slower process.

"The combination is something I favor to help patients treat the different pathways of obesity and type 2 diabetes while optimizing their nutrition and physical activity....Comparing the results of LEADER with EMPA-REG has stirred discussion of the dramatic earlier time to benefit of empagliflozin [compared with] liraglutide....This just supports my preference for their combination, as their mechanisms are complementary in treating the underlying disease."

And, he noted, "The combination of GLP-1 agonists with SGLT2 inhibitors is not against FDA labeling and is consistent with ADA/[American Association of Clinical Endocrinologists] guidelines."

EMPA-REG lead investigator Silvio E Inzucchi, MD, professor of medicine and director of the Yale Diabetes Center, New Haven, Connecticut, also floated the idea of combining the two.

"Clearly the liraglutide 'thumbprint' is different from that of empagliflozin....One question is whether they could be complementary. It's a reasonable notion, but we'd have to do the trial first."

But Dr Nathan told Medscape Medical News, "In my opinion the risks, side effects, and cost are not balanced by benefit for most patients, and other diabetes medicines should be given higher priority as the second drug after metformin."

Indeed, at the ADA meeting Dr Inzucchi presented the latest data from the Insulin Resistance Intervention after Stroke (IRIS) trial — which had previously shown a cardiovascular disease benefit for the now-generic thiazolidinedione pioglitazone in people with insulin resistance but not diabetes and cerebrovascular disease. These results now show that pioglitazone prevents progression to type 2 diabetes.

Consequently, Dr Inzucchi has called for a "readjudication" of pioglitazone as a second-line type 2 diabetes drug, especially now that it costs about 100-fold less than the newer agents.

"Pioglitazone may have the most potent effect of all against atherosclerosis. The only issue is that pioglitazone is a double-edged sword. You have to be careful about the heart-failure risk," he observed.

Will Guidelines Change? We Need More Data

Asked about upcoming guidelines, ADA chief scientific and medical officer Robert E Ratner, MD, told Medscape Medical News, "The simple fact is, it's impossible to argue with a study that shows increased survival. That's the most exciting part of all of this. We still don't understand mechanisms....This is opening up a new avenue of patient care and we're going to have to figure out how to incorporate this into our standards of care and treatment algorithms."

The data thus far are likely insufficient to recommend specific second agents of choice, particularly now that there is evidence these may not be class effects, Dr Ratner said.

"I think we are going to need more data, but this is certainly very encouraging. The ADA Standards of Care are revised on an annual basis and will come out again in January 2017. Both EMPA-REG and LEADER will be incorporated into the Standards of Care. That I can guarantee."

Other cardiovascular outcomes trials with SGLT2 inhibitors are ongoing and the results eagerly awaited. These include the Canagliflozin Cardiovascular Assessment Study (CANVAS) with canagliflozin (Invokana, Janssen), which is randomizing 4330 patients with type 2 diabetes and cardiovascular disease or risk factors for cardiovascular disease to canagliflozin 100 mg or 300 mg once daily or to placebo on top of standard therapy. CANVAS is due to complete in February 2017.

And the DECLARE-TIMI 58 study with the SGLT2 inhibitor dapagliflozin (Forxiga/Farxiga, AstraZeneca) is randomizing more than 17,000 patients with type 2 diabetes at high cardiovascular risk to once-daily oral dapagliflozin 10 mg or placebo on top of standard care. The trial is expected to complete in 2019.

Also ongoing is a cardiovascular outcomes study with the GLP-1 agonist exenatide (Bydureon, AstraZeneca), given once weekly as a subcutaneous injection. The Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL) will randomize an estimated 14,000 patients with type 2 diabetes to once-weekly injection of 2 mg of exenatide or placebo on top of usual care. The trial is expected to complete in April 2018.

And finally, a different exenatide product, in the form of a "minipump" fitted under the skin that continuously releases the drug for 6 months, or even a year, is being developed by Intarcia Therapeutics.

In May, the company said it has top-line data for the product, known so far as ITCA 650, demonstrating "noninferiority" for cardiovascular safety in the large FREEDOM-CVO trial. The study randomized type 2 diabetes patients with or at high risk of cardiovascular disease to 60 µg/day of ITCA 650 or placebo on top of standard care. The company plans to file for regulatory approval of ITCA 650 in the United States in the final quarter of 2016.

What Is the Mechanism in LEADER?


Some mechanistic questions have emerged from EMPA-REG and LEADER that also remain to be answered.

In LEADER, for one, why was the outcome so positive for cardiovascular death when differences in nonfatal myocardial infarction and stroke were nonsignificant? Second, why was there more hypoglycemia in the placebo group in LEADER, and might that fact have pushed the outcome in favor of liraglutide?

To the second point, the authors explained that the study protocol — which gave clinicians options for treating patients to target in both groups — had necessarily excluded DPP-4 inhibitors. Therefore the placebo patients may have been more likely to receive insulin or sulfonylureas to achieve target glycemia thus resulting in perhaps more hypoglycemia in that group.

As for the question about the nonsignificance of the individual end points of nonfatal myocardial infarction and stroke with liraglutide in LEADER, Yehuda Handelsman, MD, medical director and principal investigator, Metabolic Institute of America, Tarzana, California, told Medscape  Medical News: "What we saw that death drove the results and the individual components were not actually individually positive....So we don't even totally know why people die."

But cardiologist and EMPA-REG coinvestigator Darren McGuire, MD, of the University of Texas Southwestern Medical Center, Dallas, noted: "The reason we use composite end points is to establish statistical power that is a sum of the components, so one should not expect any component of the primary composite to individually achieve statistical significance.

"With LEADER, the point estimates across the primary composite component [first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke] were monotonic, providing robust support for the composite end point finding."

But Dr Nissen said the bottom line is that the answer is just not known.

"What’s interesting about both trials [EMPA-REG and LEADER] is that the most compelling end point is the most important end point: cardiovascular death and all-cause mortality. A lot of us were left very puzzled. Typically in cardiovascular medicine, we see a drug that reduces MI and maybe stroke and may or may not reduce CV death. Here, the strongest result for both trials is on CV death. I can't necessarily explain it."

Empagliflozin may act as a diuretic in reducing blood pressure and in fact did show a significant positive effect on heart-failure hospitalizations, which were reduced by 35% among those taking the active drug compared with placebo. It has also just been shown in a presentation at the ADA meeting to significantly reduce the incidence of worsening nephropathy by 39%.

Liraglutide meanwhile reduces body weight and also appears to have a favorable effect on the kidney, Dr Nissen noted.

However, Dr Nissen said, "At the end of the day, one of my favorite sayings is ‘the road to hell is paved with biological plausibility.' You get a result and everybody scrambles around and spends a lot of time trying to figure out how something works. If you're a patient or a doctor, it doesn't matter that much. You'd like to live longer and better."

Dr Nissen reports nonfinancial support from Novo Nordisk during the conduct of the study; grant support from Pfizer, Amgen, Esperion Therapeutics, Cerenis, the Medicines Company, AstraZeneca, Takeda Pharmaceuticals, Orexigen Therapeutics, and Eli Lilly; and nonfinancial support from Boehringer Ingelheim outside the submitted work. Dr Nathan has reported no relevant financial relationships. Dr Riddle has received research support from AstraZeneca, Biodel, GlaxoSmithKline, Eli Lilly, Sanofi, and Valeritas. Dr Jellinger is on the speakers' bureau for Novo Nordisk, AstraZeneca, and Boehringer Ingelheim. Dr Inzucchi has reported personal fees and nonfinancial support from Boehringer Ingelheim during the conduct of the study; personal fees from Merck, Janssen, Novo Nordisk, Sanofi, Sanofi/Regeneron, Intarcia, Lexicon, Poxel, Boehringer Ingelheim, Eli Lilly, and AstraZeneca; and nonfinancial and other support from Takeda outside the submitted work. In addition, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbott, Merck, and Sanofi have provided continuing medical education funding to Dr Inzucchi's employer, Yale University. Dr Taylor was employed by Bristol-Myers Squibb from 2002 to 2013, where he was vice president of cardiovascular and metabolic disease research. Dr Nadolsky owns small amounts of personal stock in Vivus, Orexigen, and Arena Pharmaceuticals. Dr McGuire has reported receiving personal fees from Boehringer Ingelheim, Janssen, Sanofi, Genentech, Merck Sharp & Dohme, Daiichi Sankyo, Lilly, Novo Nordisk, GlaxoSmithKline, Takeda Pharmaceuticals North America, Bristol-Myers Squibb, AstraZeneca, Orexigen, Lexicon, Eisai, Regeneron, Merck, Pfizer, and Genfit. Dr Handelsman has served as a consultant and/or speaker for Amarin, Amgen, Amylin, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Halozyme, Janssen, Merck, Novo Nordisk, Sanofi, and Vivus. He has received research grants from Amgen, Boehringer Ingelheim, GlaxoSmithKline, Gilead, Intarcia, Lexicon, Merck, Novo Nordisk, Sanofi, and Takeda.

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