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Evidence-Based Diabetes Management December 2018
Clinical Evidence for and Cost-Effectiveness of Advanced Cellular Tissue Products for the Treatment of Diabetic Foot Ulcers
Robert S. Kirsner, MD, PhD
Time for a "New Goalpost" in Cardiovascular Outcomes Trials, Kosiborod Suggests
Mary Caffrey
After FDA Panel Vote, Some See Next Generation of Cardiovascular Safety Trials for Diabetes Drugs
Mary Caffrey
For Payers, Cost Is the Downside of Continuing Cardiovascular Outcomes Trials in Current Form
Kenneth Snow, MD, MBA
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Foluso A. Fakorede, MD
A Paradigm Shift Highlights the Need to Reduce CV Risk in Diabetes
Robert A. Gabbay, MD, PhD, FACP
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Guidelines Updates in Diabetes and Cardiovascular Disease
Mary Caffrey
Medical World News: Managed Care Updates
Coverage by Mary Caffrey, Surabhi Dangi-Garimella, PhD, Jaime Rosenberg, Samantha DiGrande, and Kelly Davio
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Coverage by Mary Caffrey, Surabhi Dangi-Garimella, PhD, Jaime Rosenberg, Samantha DiGrande, and Kelly Davio

Guidelines Updates in Diabetes and Cardiovascular Disease

Mary Caffrey
A statement on hypoglycemia, an consensus document from cardiologists on diabetes and CVD, and guidelines on treating cholesterol.
The shift began in 2008, when the FDA began requiring that makers of T2D therapies conduct large cardiovascular outcomes trials to demonstrate safety (see Cover). Then, in September 2015, investigators for the EMPA-REG OUTCOME trial stunned the diabetes community with results that showed a 38% reduction in cardiovascular death and a 32% reduction in death from any cause, compared with placebo.3

Researchers also found significant reduction (35%) in hospitalization for heart failure, an area that would attract more interest as real-world data produced similar findings.3 In December 2016, empagliflozin became the first drug to receive an FDA indication to reduce the risk of cardiovascular death for adults with T2D.4

In 2017, the CANVAS trial found that the SGLT2 inhibitor canagliflozin (Invokana, Janssen) reduced the risk of cardiovascular events, but that trial did find an increased risk of lower limb amputation (primarily at the toe or metatarsal),5 and FDA requires a boxed warning on this therapy, even though it separately granted a cardiovascular indication.6

The cardiovascular benefit of liraglutide was seen in the LEADER trial, presented in June 2016. Results showed a 22% reduction in cardiovascular death, as well as reductions in nonfatal myocardial infarction and stroke.7 In August 2017, the FDA approved an indication that this injectable drug can reduce 3 major cardiovascular events for patients with T2D and existing cardiovascular disease.8

SGLT2 inhibitors work through a unique mechanism of action that targets a protein responsible for the reuptake of glucose; as a result, the body expels excess glucose through the urine. A person with T2D can lose as much as 100 mg of glucose a day.9 Seck said researchers are still working to fully understand this mechanism and its role in risk reduction; he pointed to the recent results from the EMPA-HEART Cardiolink-6 study presented at the American Heart Association, which found that patients taking empagliflozin for 6 months had

significantly reduced left ventricle mass compared with those taking placebo, as well as reduced systolic blood pressure.10

The apparent ability of empagliflozin to treat patients with chronic heart failure is being explored in the EMPEROR trials, which include some patients without diabetes; whereas EMPERIAL, which will assess the effects of empagliflozin on exercise capacity in heart failure patients, will produce results sooner.11

Beyond the randomized clinical trials, real-world evidence from both the CVD-REAL12 and EMPRISE13 studies confirm what was seen in EMPA-REG OUTCOME: that SGLT2 inhibitors generally, and empagliflozin in particular, prevent hospitalization for heart failure and all-cause mortality. Although some discount the value of this data, Seck does not. This is meaningful data to prescribers, he said, and “More and more, real-world evidence can be used for regulatory decision making as well.”


1. Das SR, Everett BM, et al; Writing Committee. 2018 ACC Expert Consensus Decision Pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. [published online ahead of print November 26, 2018]. J Am Coll Cardiol. doi: 10.1016/j.jacc.2018.09.020.

2. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2018;61(12):2461-2498. doi: 10.1007/s00125-018-4729-5.

3. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.

4. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes [press release]. Silver Spring, MD: FDA Newsroom; December 2, 2016. Accessed November 27, 2018.

5. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.

6. US FDA approves Invokana (canagliflozin) to reduce the risk of heart attack, stroke or cardiovascular death in adults with type 2 diabetes and established cardiovascular disease [press release]. Titusville, NJ: Janssen Pharmaceutical Companies; October 30, 2018. Accessed November 27, 2018.

7. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Trial investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi: 10.1056/NEJMoa1603827.

8. Mattina C. Liraglutide gains new indication for reducing CV event risk. The American Journal of Managed Care® website. Published August 25, 2017. Accessed November 27, 2018.

9. Product theater: experts present evidence and advice on canagliflozin. The American Journal of Managed Care® website. Published September 30, 2017. Accessed December 7, 2018.

10. Verma S, Mazer CD, Yan AT, et al. EMPA-HEART CardioLink-6 trial: a randomized trial of empagliflozin on left ventricular structure, function, and biomarkers in people with type 2 diabetes and coronary heart disease. Presented at: American Heart Association Scientific Sessions: November 11, 2018; Chicago, IL. Abstract 19332.

latest-in-cardiology/clinical-trials/2018/11/10/01/55/empa-heart-cardiolink-6. Accessed December 7, 2018.

11. EMPERIAL. Updated November 27, 2018.

12. Kosiborod M, Lam CSP, Kohsaka S, et al; CVD-REAL Investigators and Study Group. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 study. J Am Coll Cardiol. 2018;71(23):2628-2639. doi: 10.10.1016/j.jacc.2018.03.009.

13. Patorno E, Pawar A, Franklin J, et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care: a first analysis from the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) Study. Circulation. 2018;138(suppl 1):A14741. Abstract 14741.

New Cholesterol Guidelines Call for Personalized Care

Nearly 1 in 3 Americans has high levels of low-density lipoprotein (LDL), or “bad,” cholesterol, but deciding on treatment requires that physicians look at each person’s age, health status, family history, and other factors, according to new guidelines presented on November 10, 2018, at the American Heart Association’s (AHA) 2018 Scientific Sessions in Chicago, Illinois, and published in Circulation.1

LDL cholesterol contributes to plaque buildup and narrowing of the arteries. About 94.6 million (39.7%) of American adults have total cholesterol levels of 200 mg/dL or higher. High-density, or “good” cholesterol carries excess cholesterol and carries it back to the liver, while LDL cholesterol builds up on the walls of the arteries. Evidence shows that keeping LDL cholesterol below 100 mg/dL makes a person less likely to develop heart disease or experience a stroke.1

Two dozen experts from the AHA and representatives from 11 other organizations weighed in on the guidelines, which call for physicians to start tracking their patients’ LDL cholesterol early in life and encouraging heart-healthy diet and lifestyle behavior across the life span. In some cases, children with a family history of heart disease or high cholesterol could be screened by age 2, and children without known risk factors could be screened for the first time between ages 9 and 11 and again between ages 17 and 21.

“We think doctors ought to pay more attention to young adults,” Scott M. Grundy, MD, PhD, chairman of the writing committee, said in a statement. If their cholesterol is elevated, “they might not need a statin, but they certainly need attention,” he added.2

The new guidelines suggest patients start with statins and add other therapies if statins do not lower LDL cholesterol to safe levels. High points from the recommendations include treating patients with very high-risk atherosclerotic cardiovascular disease (ASCVD) to an LDL cholesterol threshold of 70 mg/dL; if the patient cannot achieve this target with maximally tolerated statins, physicians should consider use of ezetimibe (Zetia) or other nonstatins.

“The truth about clinical medicine is there is no black-and-white. It’s all gray,” said Donald Lloyd Jones, MD, cardiologist and another member of the writing committee. “That’s why the emphasis in this document is [on] making sure the patient and doctor are having well-informed discussions about the benefits and potential risks of drug therapy.”2

Lloyd-Jones said decisions are more challenging when the patient has risk factors but has not had a heart attack or a stroke and prevention is the priority. “That’s when the decision is more difficult and detailed and personalized discussion is very important,” he said.

Another recommendation is to incorporate the use of the risk calculator first published in 2013 by the AHA and the American College of Cardiology.3 Other recommendations include:

• In patients with severe primary hypercholesterolemia (LDL cholesterol level, ≥190 mg/dL), begin a high-intensity statin without calculating 10-year ASCVD risk.

• In those 40 to 75 years of age who have diabetes and an LDL cholesterol level ≥70 mg/dL (≥1.8 mmol/L), begin a moderate-intensity statin without calculating 10-year ASCVD risk.

• For those 40 to 75 years of age who are being evaluated for primary ASCVD prevention, shared decision making with a physician is recommended before starting statin therapy.

• For those 40 to 75 years of age without diabetes and with LDL cholesterol levels ≥70 mg/dL (≥1.8 mmol/L) and a 10-year ASCVD risk of ≥7.5%, start a moderate-intensity statin if discussions with a physician point to statin therapy.

• In adults 40 to 75 years of age without diabetes and a 10-year ASCVD risk of 7.5% to 19.9%, risk-enhancing factors suggest initiation of statin therapy.

• For adults 40 to 75 years of age without diabetes and with LDL cholesterol levels ≥70 to 189 mg/dL (≥1.8-4.9 mmol/L) and a 10-year ASCVD risk of ≥7.5% to 19.9%, if a decision about statin therapy is uncertain, consider measuring coronary artery calcium. The guidelines call for physicians to gauge adherence and response to therapy after 4 to 12 weeks or

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