Guidelines Updates in Diabetes and Cardiovascular Disease

ADA/EASD Release Joint Statement on Managing Hyperglycemia in Type 2 Diabetes

Ongoing access to diabetes self-management education and support (DSMES) and promoting good medication adherence are among the keys to managing hyperglycemia, or high blood glucose, in patients with type 2 diabetes (T2D), according to a joint statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), released

October 5, 2018, at the EASD annual meeting in Munich, Germany.

The consensus statement also called for patients with cardiovascular disease to be treated with 1 of the 2 novel classes that have been shown to have cardiovascular benefits: a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) receptor agonist.

The statement was published in Diabetologia,¹ the official journal of EASD, and in Diabetes Care, the official journal of ADA. The joint statement followed ADA’s recommendations in late 2017 that certain SGLT2 inhibitors and a GLP-1 receptor agonist had cardiovascular benefits; these recommendations appeared in the organization’s 2018 Standards of Medical Care in Diabetes.²

The experts who developed the ADA/EASD consensus statement said that patient preference should be a major factor in driving treatment choices, because their preferences for the delivery method—such as a pill versus an injection—or things like adverse effects or cost, could affect adherence. Further, the medications cannot work if patients do not take them, regardless of what evidence showed in a clinical trial.

The emphasis on giving patients more access to DSMES is key, because current reimbursement models, including those in Medicare, may limit the number of hours or points at which a patient can meet with a diabetes educator.

Although there are new digital diabetes management tools available, evidence shows that these work best when patients can combine them with contact with a trained professional.³ A position statement from the American Association of Diabetes Educators, ADA, and the Academy of Nutrition and Dietetics called for education at discrete points in the life cycle of diabetes: (1) at diagnosis, (2) at annual assessments, (3) when new complications occur, and (4) during transitions in life and care.⁴

Among other recommendations, the ADA/EASD consensus statement⁵ calls for:

• Advising patients who are overweight or obese with diabetes to start a lifestyle management program, including food substitution where appropriate.

• Boosting physical activity to improve glycemic control.

• Making metabolic surgery available to adults with T2D who have a body mass index (BMI) of at least 40 (or ≥37.5 with Asian ancestry) or a BMI of 35 to 39.9 (32.5-37.4 with Asian ancestry) who have comorbidities and have not achieved weight loss goals with nonsurgical methods.

• Metformin continues to be the first-line therapy, but for patients with clinical cardiovascular disease, an SGLT2 inhibitor or GLP-1 receptor agonist with a demonstrated cardiovascular benefit is recommended.

• For patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease, an SGLT2 inhibitor with proven benefits should be considered.

• GLP-1 receptor agonists are the first injectable considered, except if type 1 diabetes is a possibility.

Experts called for more research into combinations of glucose-lowering therapies. “As cost implications for these various approaches is enormous, evidence is desperately needed,” the panel said in a statement. “Defining optimal cost-effective approaches to care, particularly in the management of patients—including those with multi-morbidity—is essential.”⁵

The panel said the giant cardiovascular outcomes trials raise important questions: Do benefits, including renal benefits, extend to low-risk patients? If so, for which population groups?

Shortly after the joint statement, an FDA advisory panel agreed to continue the cardiovascular outcomes trials that have demonstrated unexpected cardiovascular benefits in T2D (see Cover). However, the panelists discussed the possibility of making adjustments to the trials to examine different outcomes and to bring down their cost. Since the emergence of unanticipated benefits in newer therapeutic classes for T2D—notably SGLT2 inhibitors—some pharmaceutical companies have launched trials to specifically examine heart failure or renal outcomes.^6-8

“The management of hyperglycemia in type 2 diabetes has become extraordinarily complex with the number of glucose-lowering medications now available,” the authors wrote. “Patient-centered decision making and support and consistent efforts to improve diet and exercise remain the foundation of all glycemic management. Initial use of metformin, followed by addition of glucose-lowering medications based on patient comorbidities and concerns is recommended as we await answers to the many questions that remain.”

References

1. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycaemia 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.

2. Caffrey M. ADA 2018 standards address dugs with CV benefits, hold firm on blood pressure. The American Journal of Managed Care® website. www.ajmc.com/newsroom/ada-2018-standards-address-drugs-with-cv-benefits-holdfirm-on-blood-pressure. Published December 10, 2017. Accessed December 2, 2018.

3. Gabbay R. In the era of payment reform, diabetes educators can lead the way toward value-based care. Am J Manag Care. 2018;24(SP11):SP448.

4. Powers MA, Bardsley J, Cypress M, et al. Diabetes self-management education and support in type 2 diabetes: a joint position statement of the American Diabetes Association, the American Association of Diabetes Educators, and the Academy of Nutrition and Dietetics. Diabetes Care. 2015;38(7):1372-1382. doi: 10.2337/dc15-0730.

5. New EASD-ADA consensus guidelines on managing hyperglycaemia in type 2 diabetes launched at EASD meeting. new recommendations include specific drug classes for some patients and enhancing medication adherence. Diabetologia website. http://diabetologia-journal.org/2018/10/05/new-easd-ada-consensus-guidelines-onmanaging?rel=0" -

hyperglycaemia-in-type-2-diabetes-launched-at-easd-meeting-new-recommendations-includespecific-drug-classes-for-some-patients-and-enhancing-medication-a. Published October 5, 2018. Accessed October 8, 2018.

6. Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE). ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT02065791. Published February 19, 2014. Updated November 19, 2018. Accessed December 3, 2018.

7. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced). ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT03057977. Published February 20, 2017. Updated November 27, 2018. Accessed December 3, 2018.

8. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved). ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT03057951. Published February 20, 2017. Updated November 27, 2018. Accessed December 3, 2018.

ACC Pathway Finds Empagliflozin “Preferred” SGLT2 Therapy for Patients With Type 2 Diabetes, ASCVD

A new American College of Cardiology (ACC) Expert Consensus Decision Pathway states that empagliflozin is the preferred therapy among sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD).

The pathway document, which features a chart to guide cardiologists in clinical practice, was published November 26, 2018, in the Journal of the American College of Cardiology (JACC).¹ The consensus document also finds that liraglutide is the preferred treatment among a second novel class of T2D treatments, the glucagon-like peptide-1 (GLP-1) receptor agonists.

Empagliflozin is sold as Jardiance by Boehringer Ingelheim and Eli Lilly; liraglutide is sold as Victoza by Novo Nordisk. Although cardiovascular disease remains the leading cause of morbidity and mortality in patients with T2D, the authors write that, until recently, medications to achieve glycemic control were not expected to offer any cardiovascular benefit. “The recent development of [2] novel classes of therapies—SGLT2 inhibitors and GLP-1 [receptor agonists]—has, for the first time, demonstrated that treatments developed for glucose lowering can directly improve outcomes,” wrote Writing Committee co-chairs Sandeep R. Das, MD, MPH, FACC; Brendan M. Everett, MD, MPH, FACC; and their colleagues.

Having ACC weigh in on how cardiologists should treat patients with T2D represents a paradigm shift in treating the disease, but one that is a natural evolution given developments since 2015 in research, treatment, and guidelines from major organizations engaged in diabetes care. Having ACC weigh in on how cardiologists should treat patients with T2D

represents a paradigm shift in treating the disease, but one that is a natural evolution given developments since 2015 in research, treatment, and guidelines from major organizations engaged in diabetes care.

On October 5, 2018, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes jointly updated their consensus statement on

the management of hyperglycemia to include SGLT2 inhibitors and GLP-1 receptor agonists.² ADA endorsed the ACC pathway, and William T. Cefalu, MD, ADA’s chief

scientific, medical, and mission officer, served as an author on the JACC article.

Thomas Seck, MD, vice president of US Clinical Development and Medical Affairs, Primary Care, at Boehringer Ingelheim, shared the authors’ appreciation for the change in thinking about shared responsibilities of cardiologists and primary care physicians in diabetes care: “This is an important milestone—it underscores the important change we’ve seen in the last few years,” as guidelines have changed to reflect new evidence, he said in an interview with The American Journal of Managed Care®. “There are now multiple options for patients with [T2D] and established cardiovascular disease, and that’s critically important.”

For ACC to put the cardiologist in charge of management of cardiovascular risk for a patient with T2D is a major step forward, Seck said. “Before, diabetes was about managing glucose, and the cardiologist was much less involved,” he said.

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.”

References

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. fda.gov/newsevents/newsroom/pressannouncements/ucm531517.htm. 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. janssen.com/us-fda-approves-invokanar-canagliflozin-reduce-risk-heart-attack-stroke-or-cardiovascular-death. 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. ajmc.com/newsroom/liraglutide-gains-new-indication-for-reducing-cv-event-risk. 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. ajmc.com/journals/evidence-based-diabetes-management/2017/september-2017/product-theater-experts-present-evidence-and-advice-on-canagliflozin. 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. www.acc.org/

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

11. EMPERIAL. clinicaltrials.gov/ct2/show/NCT03448406. 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

after adjusting the statin dose. This step should be repeated every 3 to 12 months, as often as necessary.

The guidelines also include a recommendation for a quality-and-value discussion of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which were approved to great fanfare in 2015 after results from clinical trials showed they could reduce LDL cholesterol levels by up to 60%. But list prices of more than $14,000 a year caused formulary

managers to restrict access to only the most at-risk patients. In recent months, manufacturers have cut prices, after Sanofi worked out an agreement with Express Scripts (SP617).

Under the deal, Express Scripts will reduce prices and speed access for those who meet FDA-approved criteria of clinical ASCVD or heterozygous familial hypercholesterolemia and inability to achieve safe levels of LDL cholesterol even while taking maximally tolerated statins. In return, Sanofi’s alirocumab (Praluent) will receive exclusive

formulary access instead of Amgen’s evolocumab (Repatha). In October, Amgen reduced prices for evolocumab as well.

“There have been concerns over the cost of PCSK9 inhibitors, and some insurance companies have been slow to cover them, so it’s important to note that the economic value of these new medications may be substantial only for a very specific group of people for whom other treatments haven’t worked,” Ivor Benjamin, MD, FAHA, president of the AHA,

said in a statement. “The association is bringing together stakeholders to discuss financial barriers to the care of heart disease and stroke. We have been heartened that drugmakers have recently agreed to reduce the prices of PSCK9 inhibitors and are making arrangements with payers to ease the financial burden for patients who could benefit from

the additional medication options.”⁴

References

1. Gundy SM, Stone NJ, Bailey Al, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on the clinical practice guidelines [published online November 10, 2018]. Circulation. doi:

10.1161/CIR.0000000000000625.

2. American Heart Association News. New guidelines for cholesterol should be on everyone’s radar beginning early in life. American Heart Association website. heart.org/en/news/2018/11/10/new-guidelinescholesterol-should-be-on-everyones-radar-beginning-early-in-life. Published November 10, 2018. Accessed November 15, 2018.

3. Goff DC, Lloyd-Jones DM, Bennett G, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013

ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [erratum in J Am Coll Cardiol 2014;63(25 pt B):3026]. J Am Coll Cardiol. 2014;63(25 pt B):2935-2959. doi: 10.1016/j.jacc.2013.

4. Updated cholesterol guidelines offer more personalized risk assessment, additional treatment options for people at the highest risk [news release]. Chicago, IL: American Heart Association; November 10, 2018. newsroom.heart.org/news/updated-cholesterol-guidelines-offer-more-personalized-risk-assessment-additional-treatment-options-for-people-at-the-highest-risk. Accessed November 15, 2018.

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