Summing up
All glucose-lowering medications used to treat T2D are not equally effective in reducing CV complications. Recent CVOTs have uncovered evidence that certain antidiabetic agents might confer CV and all-cause mortality benefits (TABLE 26,7,9,11,14-17,19-24).
Discussion of proposed mechanisms for CV outcome superiority of these agents is beyond the scope of this review. It is generally believed that benefits result from mechanisms other than a reduction in the serum glucose level, given the relatively short time frame of the studies and the magnitude of the CV benefit. It is almost certain that mechanisms of CV benefit in the 2 landmark studies—LEADER and EMPA-REG OUTCOME—are distinct from each other.32
See “When planning T2D pharmacotherapy, include newer agents that offer CV benefit,” 33-38 for a stepwise approach to treating T2D, including the role of agents that have efficacy in modifying the risk of CV disease.
SIDEBAR
When planning T2D pharmacotherapy, include newer agents that offer CV benefit33-38
First-line management. The 2019 Standards of Medical Care in Diabetes Guidelines established by the American Diabetes Association (ADA) recommend metformin as first-line pharmacotherapy for type 2 diabetes (T2D).33 This recommendation is based on metformin’s efficacy in reducing the blood glucose level and hemoglobin A1C (HbA1C); safety; tolerability; extensive clinical experience; and findings from the UK Prospective Diabetes Study demonstrating a substantial beneficial effect of metformin on cardiovascular (CV) disease.34 Additional benefits of metformin include a decrease in body weight, low-density lipoprotein level, and the need for insulin.
Second-line additive benefit. In addition, ADA guidelines make a highest level (Level-A) recommendation that patients with T2D and established atherosclerotic CV disease be treated with one of the sodium–glucose cotransporter-2 (SGLT-2) inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists that have demonstrated efficacy in CV disease risk reduction as part of an antihyperglycemic regimen.35 Seven agents described in this article from these 2 unique classes of medications meet the CV disease benefit criterion: liraglutide, semaglutide, albiglutide, dulaglutide, empagliflozin, canagliflozin, and dapagliflozin. Only empagliflozin and liraglutide have received a US Food and Drug Administration indication for risk reduction in major CV events in adults with T2D and established CV disease.
Regarding dulaglutide, although the findings of REWIND are encouraging, results were not robust; further analysis is necessary to make a recommendation for treating patients who do not have a history of established CV disease with this medication.
Individualized decision-making. From a clinical perspective, patient-specific considerations and shared decision-making should be incorporated into T2D treatment decisions:
- For patients with T2D and established atherosclerotic CV disease, SGLT-2 inhibitors and GLP-1 receptor agonists are recommended agents after metformin.
- SGLT-2 inhibitors are preferred in T2D patients with established CV disease and a history of heart failure.
- GLP-1 receptor agonists with proven CV disease benefit are preferred in patients with established CV disease and chronic kidney disease.
Add-on Tx. In ADA guidelines, dipeptidyl peptidase-4 (DDP-4) inhibitors are recommended as an optional add-on for patients without clinical atherosclerotic CV disease who are unable to reach their HbA1C goal after taking metformin for 3 months.33 Furthermore, the American Association of Clinical Endocrinologists lists DPP-4 inhibitors as alternatives for patients with an HbA1C < 7.5% in whom metformin is contraindicated.36 DPP-4 inhibitors are not an ideal choice as a second agent when the patient has a history of heart failure, and should not be recommended over GLP-1 receptor agonists or SGLT-2 inhibitors as second-line agents in patients with T2D and CV disease.
Individualizing management. The current algorithm for T2D management,37 based primarily on HbA1C reduction, is shifting toward concurrent attention to reduction of CV risk (FIGURE38). Our challenge, as physicians, is to translate the results of recent CV outcomes trials into a more targeted management strategy that focuses on eligible populations.
ACKNOWLEDGMENTS
Linda Speer, MD, Kevin Phelps, DO, and Jay Shubrook, DO, provided support and editorial assistance.
CORRESPONDENCE
Robert Gotfried, DO, FAAFP, Department of Family Medicine, University of Toledo College of Medicine, 3333 Glendale Avenue, Toledo, OH 43614; Robert.gotfried@utoledo.edu.