Joslin's Mitri Reviews Options for Improving CV Outcomes in Diabetes

Cardiovascular disease is the single biggest cause of death for Americans with diabetes, ^1,2 but according to Joanna Mitri, MD, MS, of Joslin Diabetes Center, researchers have yet to answer many fundamental questions that would reduce this risk.

Studies have demonstrated that a few individual medications can save lives, Mitri noted during her presentation, “Options and Opportunities to Reduce Cardiovascular Risk in Type 2 Diabetes,” during the meeting, Patient-Centered Diabetes Care. The effects of lifestyle interventions and even glycated hemoglobin (A1C) reduction, on the other hand, remain unclear.

“We know lifestyle is the cornerstone of clinical care in diabetes, and it is the foundation for cardiovascular disease prevention,” Mitri said—right before she noted the surprising findings of the largest-ever study of lifestyle intervention on the cardiovascular health of patients with diabetes.

The Look AHEAD³ study randomized more than 5000 patients to education or lifestyle intervention, from 2001 to 2012. The interventions were intense and, in many respects, successful.

“This lifestyle intervention gave the participants a tremendous amount of benefit,” Mitri said. “There was weight loss. There was decrease in waist circumference. There were improvements in obstructive sleep apnea. There were decreases in urine infection, decreases in joint pain, and decreases in all the intermediate outcomes, which were glucose control, blood pressure control, and cholesterol level. So we know it gives a lot of benefit. However, unfortunately, the primary outcome [a composite of cardiovascular outcomes] was negative.”

Trial results have provided similarly ambiguous information about A1C control, Mitri said. Hyperglycemia is undoubtedly associated with large increases in cardiovascular risk. Individuals with very high A1C levels suffer worse cardiovascular outcomes than people with lower A1C levels. However, a number of landmark studies— ACCORD,⁴ ADVANCE,⁵ and, for the most part, UKPDS⁶— have found little evidence that reductions in a particular patient’s A1C levels also reduce that patient’s cardiovascular risk.

“The specific role of anti-hyperglycemic therapy remains poorly understood,” said Mitri, who noted that studies have also struggled to find cardiovascular benefits from reducing the blood pressure of patients with diabetes below 140/90 mm Hg. Lower blood pressure does appear to reduce stroke risk, though. Fortunately, there are some strategies that doctors can take to protect diabetics from cardiovascular disease.

Study results do indicate that metformin can improve cardiovascular outcomes. (Even so, Mitri added, such outcomes have never been tracked in a study that compared metformin with placebo, so the benefits are not certain.) Research has provided more concrete evidence to support the use of aspirin as a secondary therapy and to support the use of statins in patients with high cholesterol.

“I think it’s very well established that aspirin does decrease your cardiovascular disease as a secondary prevention. In terms of primary prevention, you need to weigh the risk versus the benefit,” she said. “Most lipid guidelines indicate that statin works in primary and secondary prevention, regardless if you do or don’t have diabetes.”

A number of medications approved in recent years to control blood sugar have undergone postmarketing testing to determine their effects on cardiovascular outcomes. None of the trials published to date have shown any benefit, but a press release on liraglutide indicates that its trial results will be the first.⁷ Results from the EMPAG-REG trial released in September 2015 found that empagliflozin produced a benefit for the end point of CV death; the overall composite for this therapy was significant, but results for nonfatal heart attacks and strokes were not.⁸

“The first data [on liraglutide] will be released during the [American Diabetes Association] meeting,” Mitri said. “But they were able to claim even superiority [in a press release], which means they were able to claim a decreased cardiovascular outcome, and not only in total, but in each of the MACE [major adverse cardiac event] outcomes, which means cardiovascular events, stroke, and cardiovascular mortality. And we will wait to see the results.”

For patients willing to undergo the most radical of treatments, research into various types of bariatric surgery has found cardiovascular benefit, although randomized trials have never been conducted. Patients need not go that far to protect themselves, however. Research shows that they can reduce cardiovascular risk by giving up cigarettes. There is also evidence that they can also protect themselves by adopting a Mediterranean diet and monitoring their weight on a daily basis.

Indeed, Mitri said, no one doubts the importance of a healthy lifestyle or A1C control. Studies that fail to find benefits to particular regimens for controlling A1C or living better do not discredit such efforts. They do, however, indicate that researchers have much to learn about how to use them most effectively to improve outcomes. 1. Di Angelantonio E, Kaptoge S, Wormser D, et al; Emerging Risk Factors Collaboration. Association of cardiometabolic multimorbidity with mortality. JAMA. 2015;314(1):52-60. doi: 10.1001/jama.2015.7008.

2. Seshasai SR, Kaptoge S, Thompson A, et al; Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364(9):829-841. doi: 10.1056/NEJMoa1008862.

3. Wing RR, Reboussin D, Lewis CE; Look AHEAD Research Group. Intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(24):2358- 2359. doi: 10.1056/NEJMc1312802.

4. ACCORD Study Group. Nine-year effects of 3.7 years of intensive glycemic control on cardiovascular outcomes. Diabetes Care. 2016;39(5):701-708. doi: 10.2337/dc15-2283.

5. Lowe G, Woodward M, Hills G, et al. Circulating inflammatory markers and the risk of vascular complications and mortality in people with type 2 diabetes and cardiovascular disease or risk factors: the ADVANCE study. Diabetes. 2014;63(3):1115-1123. doi: 10.2337/db12-1625.

6. Davis TM, Coleman RL, Holman RR; UKPDS Group. Prognostic significance of silent myocardial infarction in newly diagnosed type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 79. Circulation. 2013;127(9):980-987. doi: 10.1161/CIRCULATIONAHA.112.000908.

7. Victoza significantly reduced the risk of major adverse cardiovascular events in the LEADER trial [press release]. Plainsboro, NJ: Novo Nordisk; March 4, 2016. http://www.prnewswire.com/news-releases/victoza-significantly- reduced-the-risk-of-major-adverse-cardiovascular-events-in-the-leadertrial- 300231181.html. Accessed June 10, 2016.

8. Tucker ME. Top-line data show CV benefit for liraglutide in type 2 diabetes. Medscape website. http://www.medscape.com/viewarticle/859905. Published March 4, 2016. Accessed May 24, 2016.

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