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Beyond safety, diabetes drugs offer CV benefits

Issue: August 2016

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The medical community has long recognized the strong correlation between diabetes and heart disease. Compounding concerns over the association have been questions about the cardiovascular safety of diabetes treatments, in particular the effect of these medications on the risk for cardiovascular mortality, myocardial infarction and stroke. However, until recently, managing these effects has been a secondary consideration for endocrinologists.

Endocrine Today assembled a distinguished panel of experts to discuss the topic of CV effects of diabetes medications and what these effects might mean for treating patients.

In the wake of an FDA requirement that all new diabetes drug trials must further investigate CV risk, several agents have been shown to pose no elevated risk — the increased rate of MI noted in a 2007 meta-analysis of clinical trial data for rosiglitazone (Avandia, GlaxoSmithKline), which precipitated the FDA requirement, was not confirmed with mandated testing, and the agency removed prescribing restrictions. Other investigations revealed unanticipated risk reductions for certain glucagon-like peptide-1 receptor agonists and at least one sodium-glucose cotransporter 2 inhibitor, which is under FDA consideration for an indication for secondary CV prevention (see article on page 11).

Photo by Jim Spelios, Orlando, Florida (407) 990-3139.

This expert roundtable tackles topics, including CV effects of different antidiabetes agents, possible mechanisms of action, precision medicine and more. Read on for insight from some of the leading experts in this area.

Impact of safety trials

Alan J. Garber, MD, PhD, FACE: For years, the issue of CV complications was sort of an off-book concern for endocrinologists, particularly since the Diabetes Control and Complications Trial (DCCT) and then the United Kingdom Prospective Diabetes Study (UKPDS), in its randomized portion, failed to show significant benefit of glycemic control on CV morbidity and mortality. Then the FDA required every new diabetes agent to have a CV assessment made for safety. We could talk about how valid those concerns were and how statistically valid the analyses were, but the requirement is still in place, even though the FDA’s concerns about rosiglitazone have been removed and the drug has been approved.

Vivian Fonseca, MD, FRCP: Maybe it’s a good thing the FDA mandated safety trials for these drugs because now we’re seeing results across different drugs that are somewhat unexpected, and there are differences between them that would not have emerged if we didn’t have this mandate for trials. We need more than 6-month or 12-month studies in a 30-year disease, and this gives us good insight.

Garber: Two long-term studies recently reported positive CV outcomes for GLP-1 receptor agonists: the LEADER trial of liraglutide (Victoza, Novo Nordisk) and the SUSTAIN-6 trial of semaglutide (Novo Nordisk), which has not been approved anywhere. The semaglutide trial was a small population study, and it was only a few years in duration, so it will probably be reported only as a safety study.

But the big issue, of course, is that we have had EMPA-REG results now for almost a year. That study found that empagliflozin (Jardiance, Boehringer Ingelheim), an SGLT2 inhibitor, is associated with decreased risk for heart failure and other CV endpoints. I think the trial has had a limited impact.

Yehuda Handelsman, MD, FACP, FACE, FNLA: You know, it is starting to get more traction, also internationally. The Canadian Diabetes Association just updated [recently] its type 2 diabetes management guideline and recommended that an SGLT2 inhibitor with demonstrated CV outcome benefit be added to therapy for secondary prevention (as yet, only empagliflozin). But in Japan, they have six approved SGLT2 inhibitors and less than 5% use — I think that drug’s safety issues scare them off. In many places, canagliflozin (Invokana, Janssen) was the first SGLT2 inhibitor to be approved, and seemingly it still holds its position despite EMPA-REG.

Robert Henry, MD: We need to look at the disease background for the psychology behind some of those fears. The Japanese were the first to report the euglycemic ketoacidosis associated with SGLT2 inhibitors, and that population tends to have type 2 diabetes associated with less obesity and is relatively more insulin deficient, and thus prone to unique side effects. It’s a different population than most patient with diabetes in the United States, and the doctors in Japan have a different perception of how best to manage glucose in their patients. They also have many other drugs that they use that we use less frequently or that aren’t used in the United States.

Garber: Especially sulfonylureas.

Henry: And also alpha-glucosidase inhibitors.

Handelsman: But their main fear is sarcopenia, not diabetic ketoacidosis, and so they’re not going to give an SGLT2 inhibitor to anybody who is not considered obese by them. Their No. 1 drug is a DPP-IV inhibitor, even ahead of metformin.

Henry: DPP-IV inhibitors have worked very well in the Japanese diabetic population.

Drug choices

Garber: Dr. Fonseca, what do you think about EMPA-REG? Do you think we’re giving it adequate respect?

Fonseca: Everyone is intrigued by the results. This is an important study, but we need to find the right place for the drug in practice. Clearly, there was a reduction in heart failure admissions, less worsening of heart failure, etc. So for somebody who has heart failure and diabetes, there’s absolutely no doubt that empagliflozin is the drug of choice. But you can’t make a statement that this drug is beneficial for all CVD because when you start looking at the individual endpoints, MI — which we all traditionally relate as CVD — was not reduced significantly. There was a small reduction in MI, and a small increase in stroke.

That tells me that empagliflozin does not change the atherosclerotic process — which is fine, I wouldn’t expect it to by its very mechanism of action. Also, the benefit appears very quickly. So, this drug is doing something that is different from other drugs that are designed to reduce true atherosclerotic heart disease, such as statins, angiotensin-converting enzyme inhibitors or even pioglitazone, for example.

Click the image to enlarge.

Likewise, with pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, which had an unfortunate primary endpoint that many of us don’t use anymore in the PROactive Study. The PROactive investigators found a reduction in stroke and went on to do the IRIS trial and showed a reduction in stroke, which is more related to atherosclerosis. Of course, that increases heart failure.

So, every drug is going to have its direct effects and side effects, and we have to choose even within this CV space the right drug for the right person. Now we have the GLP-1 results with LEADER: Liraglutide reduced all the components of major adverse cardiac events. If that is true, then maybe if you want to reduce MI you would choose a GLP-1 receptor agonist, and if the patient has heart failure, you would choose an SGLT2 inhibitor.

Garber: A really interesting question is whether we want to use initial combinations of these agents with positive indications, whether empagliflozin or liraglutide, maybe with metformin.

Handelsman: Right. For example, everyone out there is exclaiming how great a combination an SGLT2 inhibitor and a GLP-1 receptor agonist would be. That might be true, but what if the heart rate increase of the GLP-1 receptor agonist negates the heart rate stability of the SGLT2 and causes a net negative effect? We have to be that much more careful as outcome may be different than what was anticipated. As an example, there appears to be a difference between the study results of the linagliptin-empagliflozin combination (Glyxambi, Boehringer Ingelheim and Eli Lilly) and the saxagliptin-dapagliflozin combination (AstraZeneca).

Personalized medicine

Henry: It would be interesting to hear your views on the recently published IRIS study, which found that in patients with prediabetes who had a recent ischemic stroke or transient ischemic attack, treatment with pioglitazone reduced risk for recurrent stroke or MI? If that study had been done in even mildly hyperglycemic diabetic patients — for example with clear-cut elevation of fasting blood sugars in the diabetic range — and researchers got the same result as in the IRIS study, then we might consider use of pioglitazone as another therapy with CV benefits in addition to those such as liraglutide and empagliflozin, which have recently been reported to have CV benefits in type 2 diabetes.

Fonseca: Pioglitazone reduced strokes in people who had a prior stroke. Just the second stroke. This is not primary prevention. Also, most of the benefit in EMPA-REG was in people who had prior heart failure. So you’re talking about actually the ability to construct an algorithm. You have somebody with diabetes and you say, “Do you have, have you had a stroke? Have you had a prior MI?” in which case maybe a GLP-1 agonist is the right choice. For the patient who has heart failure, maybe prescribe empagliflozin; prior MI, maybe liraglutide; prior stroke, maybe pioglitazone.

Henry: This is the emerging use of personalized medicine.

Garber: That’s what endocrinologists have been doing for years, exploiting the small differences between drugs within the same class, and I think that’s only going to continue.

Fonseca: Yes. I think we should welcome this.

Considering CV options

Handelsman: So, are those CV outcome trials going to change the way we endocrinologists manage the hyperglycemia of patients? This is a paradox that we find ourselves with right now. For several years we were criticized for being too “glucocentric,” for looking only at glucose. Now all of a sudden we’ve got these outcome trials that clearly show that some antihyperglycemic agents reduce CV events and not because of the improvement in glucose. We have a tool in our hand that is also a glucose reducer, if you will; it’s actually a drug that does something else like empagliflozin, or something else like liraglutide or something else like pioglitazone. However, the trials were not designed to manage high glucose levels. On the contrary, they were designed to have as minimal an effect on glucose as possible to focus “purely” on CV safety.

So is incorporating these superior CV outcome results our job? I actually think that it is for the cardiology community to address and consider in their guidelines. For patients with diabetes, should our end result change from HbA1c to a CV outcome? The funny thing is, when the clinical trials initially yielded negative results for tight glucose control, experts said we should not use HbA1c. Now, with the superior results of the recent trials, they still tell us that we should not focus on HbA1c because those trials were not HbA1c focused and featured CV outcome.

Fonseca: This is a gross misunderstanding of what HbA1c is all about. Glycemia drives microvascular complications and is a small, but not the only, driver of CVD. It is very clear that lowering glycemia lowers microvascular disease. That’s how the pathophysiology works. To assume that you are going to do something very different just by lowering glucose is just plain wrong.

Garber: If you look at the pathophysiology of atherosclerosis in type 1 as compared to type 2 patients, they are two totally different processes.

Handelsman: Here is the issue we face. Let me pose a hypothetical. Let’s suppose that the TECOS trial had been superior, instead of neutral, and showed that sitagliptin (Januvia, Merck) reduced CV events along with the anticipated modest reduction of 0.3% in HbA1c that is typical with triple therapy. What would be our supposed clinical recommendation? Currently, we say we don’t really recommend a DPP-IV inhibitor as a third agent because its glycemic effect is rather weak, but with a superior CV outcome, should we not now develop two different sets of recommendations, incorporating both glucose effect as well as the CV effects? I think we will have to start looking at expanding our clinical guidance to incorporate these other details.

Mechanisms of action

Henry: The EMPA-REG empagliflozin study is going to have very important therapeutic ramifications, and I think it’s going to change the treatment paradigm for type 2 diabetes, not only because of the multiple benefits on glucose levels, BP, body weight, etc, but more so because of its profound CV and renal benefits. Several research groups have now come up independently with the same idea about how empagliflozin might exert some of these unique cardiorenal benefits. It has been postulated that use of empagliflozin therapy induces beneficial changes in cardiac and renal energetics through increased production of ketone bodies, which are used by both cardiac and renal tissue and are very energy efficient, generating energy at lower oxygen cost.

Data from EMPA-REG now indicate that empagliflozin changes in substrate metabolism occur quite quickly, and these changes are associated with beneficial cardiac and renal effects. The substrate energy changes can be quite small, but they are active every second of every minute, 24 hours a day and thus translate to major energy savings for a failing diabetic heart and kidney. In the data from EMPA-REG, the changes in hospitalizations for heart failure occurred very quickly. Changes in all of the other CV endpoints occurred within weeks to months. There may be rapid changes in cardiac and renal substrate metabolism and energetics that can quickly benefit the failing heart and kidney in type 2 diabetes.

I believe researchers will now focus on changes in cardiorenal substrate metabolism and energetics to confirm these postulated changes in energy expenditure and oxygen utilization occur with empagliflozin therapy. Such studies should be able to document whether chronic renal impairment and chronic cardiomyopathy of type 2 diabetes are to some extent the consequence of energy deficiency in these tissues. It’s certainly a hypothesis worthy of testing.

Handelsman: There is also a question about the effect seen on the sympathetic nervous system, which may come even later on. There may be several mechanisms.

Take-home messages

Fonseca: These CV trials allow us to precisely choose the appropriate therapy for an individual patient.

Henry: We now have the technology to understand what’s happening in diabetes at a much more sophisticated level, with improved understanding of the pathophysiology and how it ends up impacting organ pathology. I think the future is very bright for people with diabetes through the development of more optimal and targeted therapies for diabetes and its complications.

Handelsman: We can now differentiate among medications beyond their abilities to regulate glucose according to their vascular and hemodynamic effects, to get a much better outcome and reduce the CV risks of our patients with diabetes.

Garber: Endocrinologists have always practiced precision medicine based on other criteria, based on pharmacodynamic differences between drugs, based on patient characteristics. We’re now getting the clinical trials data that give us another level of information as to how we can be even more precise in our practice of medicine for our endocrine patients. – by Jill Rollet

• References:
• Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016;doi:10.1016/j.jcjd.2016.02.006.
• ClinicalTrials.gov. Trial to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes (SUSTAIN 6). Available at: clinicaltrials.gov/show/NCT01720446. NLM Identifier: NCT01720446.
• Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;doi:10.1056/NEJM199309303291401.
• Dormandy JA, et al. Lancet. 2005;doi:10.1016/S0140-6736(05)67528-9.
• FDA. FDA requires removal of certain restrictions on the diabetes drug Avandia. Nov. 25, 2013. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376516.htm. Accessed July 17, 2016.
• Green JB, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1501352.
• Kernan WN, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1506930.
• Marso SP, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1603827.
• UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;doi:10.1016/S0140-6736(98)07019-6.

• For more information:
• Vivian Fonseca, MD, FRCP, can be reached at Tulane University Health Sciences Center, 1430 Tulane Ave. - SL 53, New Orleans, LA 70112; email: vfonseca@tulane.edu.
• Alan J. Garber, MD, PhD, FACE, can be reached at Baylor Clinic, 6620 Main St., Suite 1100, Houston, TX 77030; email: agarber@bcm.edu.
• Yehuda Handelsman, MD, FACP, FACE, FNLA, can be reached at Metabolic Institute of America, 18372 Clark St. #212, Tarzana, CA 91356; email: info@yehudahandelsman.com.
• Robert Henry, MD, can be reached at UC San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093; email: rrhenry@ucsd.edu.

Disclosures: Fonseca reports receiving contracted research payments (paid to institution) from Abbott, Asahi, Eli Lilly, Endo Barrier, Gilead Sciences and Novo Nordisk; receiving consultant fees from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, Pamlab, Sanofi-Aventis and Takeda; and serving on speakers’ bureaus for Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, Pamlab, Sanofi-Aventis, Takeda. Garber reports serving on the advisory board for Janssen, Kowa, Lexicon, Merck, Novo Nordisk, Takeda, Viking Therapeutics and Vivus and serving as a consultant for Janssen, Kowa, Lexicon, Merck, Novo Nordisk, Takeda, Viking Therapeutics and Vivus. Handelsman reports receiving research grants, consulting and speakers’ fees, or honoraria from Amarin, Amgen, AstraZeneca, BI-Lilly, Boehringer Ingelheim, Bristol-Myers Squibb, diaDeux, Daiichi Sankyo, Eisai, Gilead, GlaxoSmithKline, Grifols, Hamni, Halozyme, Intarcia, Janssen, Lexicon, Lilly, LipoScience, Merck, Novo Nordisk, Regeneron, Sanofi, Salix, Takeda and Vivus. Henry reports serving as a board member for or receiving consultant fees or grants from Abbott, Alere, Amgen, AstraZeneca, Boehringer Ingelheim, Elcelyx, Eli Lilly, Gilead, Ionis Pharmaceuticals, Janssen, Ligand, Merck, Novo Nordisk, Roche-Genentech, Sanofi and ViaCyte.