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Clinical Topics

Evidence of CV Benefit Influences Diabetes Treatment Recommendations

by Annette Boyle

June 19, 2018

EAST ORANGE, NJ — In a significant change, the American Diabetes Association’s 2018 guidelines advocate use of a glucose-lowering agent with proven cardiovascular benefit or mortality reduction in patients with Type 2 diabetes mellitus (T2DM) and co-morbid cardiovascular disease.

The new recommendation has the potential to significantly change practice at the VA, which treats more than one million veterans with diabetes.

“New recommendations for antihyperglycemic therapy for adults with Type 2 diabetes have been added to reflect recent cardiovascular outcomes trial (CVOT) data, indicating that people with atherosclerotic cardiovascular disease (ASCVD) should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and/or cardiovascular mortality after considering drug-specific and patient factors,” the American Diabetes Association (ADA) said.

The statement recommends the use of the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin or the glucagonlike peptide1 (GLP-1) agonist liraglutide for patients with suboptimally controlled Type 2 diabetes and established atherosclerotic cardiovascular disease.

Cardiovascular disease is the cause of death in two-thirds of patients with diabetes, according to the VA, so medications that address both conditions could benefit more than half a million veterans.

“All VHA patients who meet the labeling indications for medications should be aware of the cardiovascular benefits (as well as other potential benefits/harms) of any and all medications that are therapeutic options. Medications should be selected using a process of shared decision-making and take into account patient preferences and individual clinical profile—including other medication use,” said Leonard Pogach, MD, MBA, the Veterans Health Administration national program director for endocrinology and diabetes and chair of the VA/DoD Diabetes Working Group.

The U.S. Food and Drug Administration (FDA) approved a new indication for empagliflozin for improving survival in adults with Type 2 diabetes and cardiovascular disease in December 2016. Liraglutide was approved for reducing the risk for myocardial infarction, stroke and cardiovascular death in the same population last August.

“This expanded indication will guide clinicians in their recommendations for anti-glycemic medications for patients with Type 2 diabetes in that risk category,” Pogach told U.S. Medicine.

The FDA based the expanded indication for empagliflozin on the EMPA-REG OUTCOME trial, which found the drug provided a relative risk reduction of 38% for cardiovascular mortality, 35% for heart failure hospitalization and 32% in all-cause mortality compared to placebo. The study enrolled 7,020 diabetic patients with established cardiovascular disease in whom cardiovascular risk factors were well treated. The survival benefit was notable within three months of initiating therapy with empagliflozin.2

A more recent study validated the EMPA-REG OUTCOME results. In a comparison of three SGLT-2 inhibitors to other glucose lowering drugs, an international team of researchers found that the SGLT-2 inhibitors reduced the risk of heart failure hospitalization by 39% and the risk of death 51%. The trial enrolled 309,056 patients in six countries.3

Reduction in Cardiovascular Death

The expanded liraglutide indication came on the heels of publication of the LEADER trial, which demonstrated a 22% reduction in risk of cardiovascular death and 15% reduction in risk for all-cause mortality. That study enrolled 9,340 patients with Type 2 diabetes and high cardiovascular risk.4

A meta-analysis recently published in The Lancet supported the LEADER findings. The new study assessed the impact of four GLP-1 agonists on cardiovascular events and mortality and determined that the GLP-1 agonists reduced the risk of death from heart disease, heart attack or stroke by 10% and reduced all-cause mortality risk 12%.5

Currently, the VA recommends metformin for the first-line treatment of diabetes in most patients unless there are contraindications. Insulin is recommended for veterans with symptomatic diabetes. “VHA does not rank order medications for second-line therapy,” Pogach noted.

In recent years, the ADA has also advocated metformin as a first-line therapy and not ranked second-line therapies for diabetes. This year’s update represents a break from that position. Additional information coming from new studies that compare second-line therapies might make ranking second and subsequent line therapies easier.

A study published in the April issue of the Journal of the American Medical Association compared SGLT-2 inhibitors, GLP-1 receptor agonists and DPP-4 inhibitors to each other, to placebo and to no treatment. A third of diabetes patients currently use one of these medications to manage their disease.

While all three classes of drugs reduced glucose levels, only the SGLT-2 inhibitors and GLP-1 receptor agonists also reduced the risk of death, demonstrating a 20% and 17% mortality risk reduction, respectively. In this study, SGLT-2 inhibitors also reduced the risk of death from cardiovascular events by 21%, while GLP-1 agonists reduced the risk of death from heart attack or stroke by 15%. DPP-4 inhibitors did not lower overall or cardiovascular-related mortality risk compared to placebo or no treatment.6

“The three drug classes assessed here are being increasingly prescribed, yet until now there have been no clinical trials studying how these drugs compare to each other and which type of drug could be the best option for patients,” said lead author Sean Zheng, MD, of the Imperial College London.


1Summary of Revisions: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018 Jan;41(Suppl 1):S4-S6.

2Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28.

3Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, Norhammar A, Birkeland KI, Jørgensen ME, Thuresson M, Arya N, Bodegård J, Hammar N, Fenici P; CVD-REAL Investigators and Study Group*. Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulationem>. 2017 Jul 18;136(3):249-259.

4Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22.

5Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, Pagidipati NJ, Chan JC, Gustavson SM, Iqbal N, Maggioni AP, Öhman P, Poulter NR, Ramachandran A, Zinman B, Hernandez AF, Holman RR; EXSCEL Study Group. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018 Feb

6Zheng SL, Roddick AJ, Aghar-Jaffar R, et al. Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors with All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis. JAMAem>. 2018 April 18;319(15):1580-1591.

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