Diabetes Medications and Cardiovascular Outcomes

Educational Objectives

The goal of this program is to improve the treatment of diabetes. After hearing and assimilating this program, the clinician will better be able to:

1. Devise appropriate treatment strategies for patients with diabetes and comorbid cardiovascular disease.

2. Counsel patients about the cardiovascular effects of various antidiabetic medications.

Summary

Diabetes and cardiovascular disease (CVD): Approximately 75% of mortality in patients with diabetes is related to CVD. Patients with diabetes have a 2- to 4-fold increased risk for CVD compared with individuals without diabetes. The 1-year mortality rate after a single myocardial infarction (MI) is markedly higher in patients with diabetes than in the general population (ie, 44% for men and 37% for women).

Patients with diabetes and no prior MI have the same risk for CV events as patients who have experienced an MI. The risk increases significantly for patients with diabetes and a prior MI.

CV outcomes of intensive glycemic control: The landmark Diabetes Control and Complications Trial reported improvement in hemoglobin A1c (A1C) levels and microvascular complications with intensive glycemic control. The long-term follow-up Epidemiology of Diabetes Interventions and Complications study showed that patients who received intensive treatment during the trial had better macrovascular outcomes than those who received conventional therapy.

The UK Prospective Diabetes Study (UKPDS), which followed patients with type 2 diabetes for a median of 10 years, also reported improvement in A1C levels and in microvascular complications with intensive glycemic control. Long-term follow-up found statistically significant improvements in CV events and all-cause mortality.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study investigated the effects of intensive glucose-lowering therapy on CV outcomes. A1C levels of ≈6.5% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. The study did not show statistically significant differences between groups in terms of CV death, stroke, or MI, but found that patients receiving intensive therapy had higher mortality rates.

Effects of Oral Agents on CV Outcomes

Sulfonylureas: Data from the 1960s suggested that sulfonylureas may be associated with an increased risk for cardiotoxicity. Subsequent studies have reported conflicting results regarding their CV safety profile.

Metformin: UKPDS found improvement in all-cause mortality, diabetes-related mortality, and incidence of MI in patients treated with metformin in the intensive-therapy group. Follow-up studies have found similar results, suggesting that metformin may reduce the incidence of CV events. However, in trials comparing metformin to sulfonylureas, the apparent superiority of metformin may reflect cardiotoxicity associated with sulfonylureas rather than the benefit of metformin.

There is a scarcity of data from prospective randomized clinical trials. One such study that compared the effects of metformin with those of glipizide in 304 patients with type 2 diabetes found that the incidence of CV events was lower in patients who received metformin.

Thiazolidinediones: A 2007 meta-analysis found that rosiglitazone was associated with a significant increase in the risk for adverse CV events. While the study had limitations, it shaped perception of the safety profile of rosiglitazone. Subsequent randomized trials found that rosiglitazone did not worsen CV outcomes.

Several studies have shown that pioglitazone may reduce CV events. However, pioglitazone and rosiglitazone can increase the risk for congestive heart failure because of fluid retention.

Alpha glucosidase inhibitors: A clinical trial found that acarbose effectively reduced the risk for type 2 diabetes and the incidence of CVD in patients with impaired glucose tolerance. A more recently published study of patients with prediabetes and CVD reached a different conclusion, finding no improvement in CV events with acarbose.

Meglitinides: There is insufficient evidence about the CV effects of agents in this class (eg, repaglinide; nateglinide).

Insulin: Multiple epidemiologic and mechanistic studies have suggested that insulin may be associated with a higher incidence of CV events. However, the results may be affected by confounders (eg, patients who use insulin tend to have comorbidities as well as advanced diabetes).

Dr. Siraj and colleagues used data from the ACCORD trial to study the effects of various associations on CV outcomes. They found that adjusting for baseline covariates (eg, history of diabetes complications or CV disease) eliminated the statistically significant difference in outcomes, indicating that insulin is not an independent risk factor for CV mortality.

Randomized controlled trials have not found an association between insulin therapy and worse CV outcomes.

Newer agents and CV outcomes: After the rosiglitazone controversy, the relationship between diabetes medications and CV outcomes garnered national attention. The Food and Drug Administration (FDA) began to require proof of CV safety before approving new antidiabetic agents. Multiple studies have investigated the CV effects of various agents over the past 10 years. Some of the newer medications have not only met safety standards but also shown CV benefits.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors: A population study investigating the effects of empagliflozin on CV morbidity and mortality in 7000 patients with type 2 diabetes was the first to show that SGLT2 inhibitors can improve CV outcomes. Patients receiving empagliflozin showed improvement in CV death, nonfatal MI, and nonfatal stroke within weeks; there were also notable reductions in hospitalization for heart failure (HF), and all-cause mortality.

The CANVAS trial showed that canagliflozin improved the primary end point by 14% in patients with type 2 diabetes and an elevated risk for CVD. Overall, patients treated with canagliflozin had a significantly lower risk for death from CV causes, nonfatal MI, or nonfatal stroke than those who received placebo, as well as reduced incidence of HF and improved glomerular filtration rates. However, canagliflozin increased the risk for lower extremity amputation, which prompted the FDA to issue a black box warning.

Mechanisms of SGLT2 inhibitor effects on CV outcomes: Inhibition of SGLT2 impairs reabsorption of glucose in the kidneys, leading to release of glucose in the urine. The elimination of glucose and water leads to improvement in blood pressure (BP), without a compensatory increase in heart rate. SGLT2 inhibition also improves albuminuria, weight, visceral adiposity, and insulin levels. Studies are exploring possible mechanisms beyond lowering of glucose levels, including a reduction in sympathetic nervous system activity, oxidative stress, and arterial stiffness.

Glucagon-like peptide-1 receptor (GLP-1) agonists: A study found that liraglutide reduced CV mortality and all-cause mortality compared with placebo but found no statistically significant reduction in hospitalization for HF.

Semaglutide, recently approved by the FDA as a once-weekly injectable drug, also achieved noninferiority and superiority compared with placebo. Patients treated with semaglutide had overall improvement in primary end point, with a statistically significant difference in nonfatal stroke.

Mechanisms of GLP-1 agonist effects on CV outcomes: Vasodilatation of myocardial arteries, increased myocardial viability, improved energy efficiency, and reduced inflammation are some of the mechanisms contributing to improved CV outcomes. Benefits beyond glycemic control include weight loss, improvement in BP, and reduced atherosclerotic lesions.

Implications of New CV Data

Effects of medications: Glucose levels improved with dipeptidyl peptidase-4 (DPP-4) inhibitors. A slight increase in HF was reported with saxagliptin. GLP-1 agonists improved body weight and fat, BP, and lipid levels. GLP-1 agonists have caused a slight increase in heart rate across studies.

SGLT2 inhibitors can decrease triglyceride levels and uric acid and increase hematocrit. The overall CV benefits compensate for the slight increase in low-density lipoprotein cholesterol.

Limitations of trials: Most studies include only high-risk patients with established CVD, so results are difficult to generalize. Most studies also fail to explore long-term effects (eg, average follow-up is 2-3 yr). Differences in study methodologies and populations make comparisons between different agents challenging.

New guidelines: The FDA has expanded indications for newer agents to include lowering the risk for CV death in adults with type 2 diabetes and CVD (empagliflozin) and prevention of major CV events in adults with established CVD (liraglutide).

The American Diabetes Association advises clinicians to inquire about a history of CVD when adding a second antidiabetic agent. For these patients, medications proven to reduce risk for major CV events and CV mortality (eg, empagliflozin, liraglutide) should be considered first.

The American College of Endocrinology also considers GLP-1 agonists and SGLT2 inhibitors first-line options when adding a second agent.

Readings

Action to Control Cardiovascular Risk in Diabetes Study Group, The: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358:2545-2559. DOI: 10.1056/NEJMoa0802743; Cahn A et al: Clinical assessment of individualized glycemic goals in patients with type 2 diabetes: formulation of an algorithm based on a survey among leading worldwide diabetologists. Diabetes Care. 2015 Dec;38(12):2293-300. DOI: 10.2337/dc15-0187; Diabetes Control and Complications Trial Research Group, The: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986. DOI: 10.1056/NEJM199309303291401; Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group: Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort. Diabetes Care. 1999 Jan;22(1):99-111; Marso SP et al: Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016; 375:311-322. DOI: 10.1056/NEJMoa1603827; Neal B et al: Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377:644-657. DOI: 10.1056/NEJMoa1611925; UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998 Sep 12;352(9131):837-53.

Disclosures

For this program, the following was disclosed: Dr. Anderson reported relationships with Amylin Pharmaceuticals (G), Daichi Sankyo Company (B), Eli Lilly and Company (B), Novo Nordisk (B), and sanofi-aventis UC (A). Dr. Siraj reported relationships with sanofi-aventis UC (C). The members of the planning committee reported nothing to disclose.

A=Advisory panel B=Speakers bureau
C=Consultant G=Grant or other research support

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

DI091903

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.