Diabetes mellitus (DM) and ensuing cardiovascular (CV) complications have arisen as the epidemic of the early 21st century. DM remains a profound risk factor for CV disease. Excess mortality in type 2 DM is largely related to an increased incidence of CV disease,¹ with approximately 75% of deaths in people with diabetes attributable to stroke, myocardial infarction (MI), and peripheral arterial disease. In order to combat this, the last 10 years has seen an explosion of novel antidiabetic therapies. Concomitant with this, we have seen advances in surgical and percutaneous revascularization in an attempt to improve outcomes of these at-risk patients. Stable ischemic heart disease (SIHD), which refers to the presence of coronary artery disease in the absence of acute symptoms, remains a significant health issue and identifies a cohort of patients at high risk for future events.² Herein we discuss strategies utilizing significant health care resources to reduce CV risk in diabetic patients with SIHD who represent a growing population.

We present the case of a 58-year-old male patient with hypertension, dyslipidemia, SIHD, and type 2 diabetes. He is currently on optimal guideline-based therapy, but we argue the preferential use of newer antidiabetic agents, namely glucagon-like peptide receptor agonists such as liraglutide and sodium glucose co-transporter inhibitors such as empagliflozin.

Despite intensive research, treatment of diabetes by a range of antidiabetic therapies, including insulin, sulfonylureas, and metformin, has failed to reduce CV disease. Furthermore, insulin, sulfonylureas, and thiazolidinediones may be associated with side effects including episodes of hypoglycemia, weight gain, and a propensity for heart failure (HF).⁴ These issues led the U.S. Food and Drug Administration to mandate large CV safety outcomes trials for all emerging antidiabetic therapies.⁵ The overall goal of these trials has been to minimize the differences in glycemic control (and other important variables associated with excess CV disease) between the placebo and active therapy in order to best determine the independent impact of the therapeutic option in question on major cardiac endpoints. These included at a minimum major adverse cardiac events (MACE) and CV death, MI, stroke, and in some cases hospitalization for unstable angina. Importantly, hospitalization for HF was a pre-specified adjudicated endpoint in the majority of clinical trials. In each trial, CV safety (as defined by MACE) was achieved. In contrast to dipeptidyl peptidase 4 (DPP-4) inhibitors and the glucagon-like peptide receptor agonists (GLP-1) lixisenatide and exenatide, liraglutide (as a GLP-1 receptor agonist) and empagliflozin (as a sodium-glucose cotransporter 2 [SGLT2] inhibitor) demonstrated CV safety and were proven to reduce CV and all-cause mortality.^6-10 Somewhat unexpectedly, the DPP-4 inhibitor saxagliptin was associated with an increased risk for hospitalization for HF, and the GLP-1 receptor agonist semaglutide showed an excess of visual complications including blindness.^11-13 Otherwise, the drugs were well-tolerated overall.

Empagliflozin, as previously noted, is a glucose-lowering agent that inhibits the renal SGLT2 inhibitor. Because the medication promotes glycosuria through sodium/glucose cotransporter inhibition, it also induces natriuresis. This confers many physiologic benefits, including weight loss and reduction in blood pressure, along with a low risk of hypoglycemia.¹⁴ The results of EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), published in 2015, indicate a reduction in CV and all-cause mortality and nonfatal MI or stroke.¹⁰ However, the reduction in CV death was primarily driven by a reduction in HF-related deaths. Interestingly, analysis of the Kaplan-Meier curves demonstrated a profound early reduction in hospitalization for HF and CV death; there was no clear signal for a reduction in nonfatal MI or stroke.

Currently, several clinical trials are underway that are evaluating the CV effects of other SGLT2-inhibitors, including CV mortality, MI, and hospitalization for HF and unstable angina or revascularization. These trials include DECLARE–TIMI 58 (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events), CANVAS (Canagliflozin Cardiovascular Assessment Study), and the REFORM (Safety and Effectiveness of SGLT-2 Inhibitors in Patients With Heart Failure and Diabetes) trial. CANVAS demonstrated CV safety with a significant reduction in MACE endpoints, but there was a doubling in lower limb amputations noted and excess risk of bone fractures. Additionally, a number of multi-country observational studies using real-world clinical practice records recently demonstrated potential class-wide effects of SGLT2 inhibitors including empagliflozin and associations with a lower risk of hospitalization for HF and death.¹⁵

The LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial, showed the GLP-1 receptor agonist liraglutide to be associated with a reduction in CV events.⁹ As a GLP-1 receptor agonist, it acts to stimulate insulin release and delay gastric emptying. It has also been shown to reduce blood pressure and promote weight loss. The results of the LEADER trial, published in 2016, also indicated a reduction in CV and all-cause mortality and nonfatal MI or stroke. It is now a second agent to join empagliflozin in demonstrating CV disease event reduction in patients with type 2 DM, despite only a modest drop in HbA1c. In contrast to empagliflozin, there was no reduction in hospitalization for HF. SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) examined MACE endpoints with the investigational GLP-1 receptor agonist semaglutide and also demonstrated reductions in MACE endpoints, which appeared to be driven by a reduction in nonfatal stroke.¹² This agent is not yet available for use.

Further examination of the divergence of Kaplan-Meier curves in EMPA-REG OUTCOME and the LEADER trial suggests different mechanisms behind their CV effects. In the LEADER trial, the survival curves for MI and CV death did not begin diverging until nearly a year, whereas EMPA-REG OUTCOME demonstrated divergence of the curves within a few months of randomization.^9,10 These trends will continue to be examined with a number of randomized clinical trials whose findings will be reported over the next few years.

As we enter an era when diabetes and its associated complications reach endemic proportions, further attention should be paid to the optimization of medical management as our armamentarium of treatment options grows. Returning to our 58-year-old gentleman with SIHD and type 2 DM, we find ourselves with two new agents in the reduction of major CV events and all-cause mortality: the SGLT2 inhibitor empagliflozin and the GLP-1 receptor agonist liraglutide. Although the mechanism of risk reduction of these two agents is likely multifaceted and still being fully elucidated, this is the first time in nearly two decades that we are presented with new agents to optimize CV benefit beyond metformin. These findings have raised new questions in diabetic patients with and without SIHD. Although much work lies ahead, the recent trials have given hope us that we can meaningfully impact CV outcomes in our patients with diabetes.

References

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2. Tancredi M, Rosengren A, Svensson AM, et al. Excess Mortality among Persons with Type 2 Diabetes. N Engl J Med 2015;373:1720-32.
3. Roger VL, Go AS, Lloyd-Jones DM, et al. Executive summary: heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation 2012;125:188-97.
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6. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.
7. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35.
8. Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015;373:232-42.
9. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375;311-22.
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11. Scirica BM, Braunwald E, Raz I, et al. Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial. Circulation 2015;132:e198.
12. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834-44.
13. Advani A, Bugyei-Twum A, Connelly KA. Cardiovascular effects of incretins in diabetes. Can J Diabetes 2013;37:309-14.
14. Valentine V. The Role of the Kidney and Sodium-Glucose Cotransporter-2 Inhibition in Diabetes Management. Clin Diabetes 2012;30:151-5.
15. Kosiborod M. Lower Rates of Hospitalization for Heart Failure and All-Cause Death in New Users of SGLT-2 Inhibitors: The CVD-REAL Study. Presented at 66th Annual ACC Scientific Session & Expo. March 17-19, 2017; Washington, DC.

Keywords: Thiazolidinediones, Dipeptidyl-Peptidase IV Inhibitors, Metformin, Diabetes Mellitus, Type 2, Glycated Hemoglobin A, Dipeptidyl Peptidase 4, omega-Chloroacetophenone, Coronary Artery Disease, Insulin, Risk Factors, Blood Pressure, Peripheral Arterial Disease, Natriuresis, Weight Gain, Glucose, Pharmaceutical Preparations, Gastric Emptying, Weight Loss, Glucosides, Benzhydryl Compounds, Hypoglycemic Agents, Dipeptides, Peptides, Adamantane, Myocardial Infarction, Angina, Unstable, Glycosuria, Heart Failure, Hypoglycemia, Stroke, Hypertension, Dyslipidemias, Risk Reduction Behavior, Sodium-Glucose Transport Proteins, Lower Extremity, Angina, Stable

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