Diabetes has been increasing in prevalence globally and remains a major cause of morbidity and mortality. Type 2 diabetes mellitus is associated with the development of microvascular and macrovascular complications.¹ Management of hyperglycemia has shown demonstrable improvement in microvascular complications (retinopathy, neuropathy, nephropathy) but macrovascular (death from cardiovascular events, stroke and myocardial infarction) benefits have been elusive. The United Kingdom Prospective Diabetes Study (UKPDS) studied glyburide, metformin and insulin, all of which produced impressive reduction in microvascular complications by 37% for every 1% reduction in hemoglobin A1c.² However, tight glycemic control has not translated into a statistically significant decrease in macrovascular complications.² Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) were two relatively recent trials that were unsuccessful in proving macrovascular benefit from intensive glycemic control.³ ACCORD even demonstrated harm, a factor that led to the FDA's 2008 requirement for all new diabetes medications to demonstrate cardiovascular safety as a condition for approval.⁴ The Veteran Affairs Diabetes Trial (VADT) examined macrovascular outcomes with intensive glycemic control (goal A1c 6%) in poorly controlled diabetics (A1c >9.4%).⁵ VADT similarly did not reveal any early benefits in macrovascular events.⁵ Consequently, diabetologists and cardiologists alike have focused on HgA1c as the primary target in diabetes management, without proof of any associated macrovascular benefit.

The holy grail of CVD risk reduction appeared to be unattainable. Yet in 2015, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) changed our perspective.⁵ For the first time, a diabetes medication was shown to significantly reduce death in the diabetic with established cardiovascular disease. Consequently, in June 2016, empagliflozin was granted an FDA indication to reduce cardiovascular death in such patients.⁴ As a preventive cardiologist's role is to reduce the risk of cardiovascular events, we can no longer consider the diabetic patient outside our realm. Diabetic patients still succumb predominantly to cardiovascular disease; thus, prevention of cardiovascular complications in our diabetic population must now assume primacy. Outcomes trials with new classes of medications such as sodium glucose co-transporter 2 (SGLT2) inhibitors (empaglifozin, canagliflozin) and glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, semaglutide) must now become a part of the preventive cardiologist's armamentarium when treating diabetic patients with established cardiovascular disease.

SGLT2 inhibitor therapies prevent renal absorption of glucose in the proximal tubule causing an osmotic diuresis and thereby reducing plasma glucose levels. The EMPA-REG OUTCOME trial was the first randomized, double-blinded, placebo-controlled cardiovascular outcomes trial evaluating empagliflozin, an SGLT2 inhibitor.⁵ Study results revealed a 14% relative risk reduction in 3-point major adverse cardiac events (death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke).⁶ Over 3.1 years, there was a relative risk reduction of 38% and a 2.2% absolute risk reduction (providing a number needed to treat, or NNT, of 46) in cardiovascular causes of death.^6,4 Other analyses revealed a 35% reduction in hospitalization related to heart failure, a 38% risk reduction in macroalbuminuria and a 32% decrease in death from any cause.6 A statically significant difference between drug and placebo was not found with regard to non-fatal myocardial infarction and non-fatal stroke risk.⁶ Thus, the trial's positive results were driven exclusively by a reduction in cardiovascular death.

The CANagliflozin cardioVascular Assessment Study (CANVAS) evaluated canagliflozin, another SGLT2 inhibitor. Results revealed a statically significant decrease in the composite primary outcome of non-fatal MI or stroke and cardiovascular death.⁷ Although the triple endpoint of death from cardiovascular causes, non-fatal myocardial infarction and non-fatal stroke met statistical significance, the individual endpoints were not significantly lower in the canagliflozin group when compared to placebo.⁷ Adverse events included a modestly increased rate of lower extremity amputation.⁷

Other ongoing clinical trials evaluating SGLT2 inhibitors include the Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI 58) examining dapagliflozin, and the Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease (VERTIS-CV) study, assessing ertugliflozin in treatment of diabetics with vascular disease.^8,9

GLP-1 receptor agonists are incretin mimetics that influence glucose control through multiple mechanisms including enhancement of glucose-dependent insulin secretion, reduction of postprandial glucagon and slowing of gastric emptying. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial studied liraglutide, a GLP1 receptor agonist.^10,4 LEADER is a multi-center, double-blinded, placebo controlled trial with a primary composite outcome of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke.¹⁰ There was a statistically significant decrease in the primary composite endpoint, making liraglutide the second diabetic drug to receive FDA approval for breaking the barrier of CVD reductions in type 2 diabetes.¹⁰ Although there were fewer non-fatal myocardial infarctions and non-fatal strokes in the liraglutide arm, the differences did not meet statistical significance.10 Again, cardiovascular death reductions drove the outcomes.

The Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) studied semaglutide, a long acting once weekly injectable GPL1 receptor agonist in a randomized, double-blinded, placebo controlled trial.11 Both the primary composite outcome (occurrence of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke) and non-fatal stroke demonstrated statistically significant decreases in the semaglutide arms of 26% and 36% respectively.¹¹ Non-fatal myocardial infarction and death from cardiovascular causes did not reach statistical significance.¹¹

Exenatide, another GPL1 receptor agnoist was studied in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) which is a randomized, double-blinded, placebo-controlled trial.¹² Primary composite outcome of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke did not show any superiority of once weekly subcutaneous injections of extended-release exenatide at 2mg when compared to placebo.¹²

The emergence of new anti-diabetic medications that confer cardiovascular benefit shift the paradigm of the preventive cardiologist's approach to the diabetic patient with established cardiovascular disease. Though none of the aforementioned medications decreased the incidence of non-fatal myocardial infarctions, they did cause significant reductions in their primary endpoints and two significantly lowered the risk of cardiovascular death, the ultimate goal of every preventive cardiologist. So now the preventive cardiologist, if true to his or her role, must engage in the management of diabetic patients.

As things now stand, when not contraindicated, every diabetic patient with established cardiovascular disease should be considered for either empagliflozin or liraglutide or another SGLT2 inhibitor or GLP1 receptor agonist therapy. Thus, the preventive cardiologist must either initiate drug himself or herself, or consult with a diabetologist, nephrologist or the primary care physician to determine why such patients should not be taking these therapeutics. Lowering the risk of cardiovascular death cannot be ignored. It is therefore time for cardiologists to re-engage in the management of diabetic patients. This does not mean, however, that preventive cardiologists should manage blood sugars in those with diabetes. Such a skill remains squarely under the rubric of the diabetologist. Preventive cardiologists should, however, manage each and every cardiovascular risk, whether from lipids, blood pressure, obesity, tobacco abuse or now diabetes. Without exception, all cardiovascular risks must be evaluated and managed by the preventive cardiologist. By so doing we have a far better chance of making cardiovascular death the second, rather than the leading, cause of death in the US.

References

1. Wong, ND. In Focus: Cardiodiabetology: Endocrinologists and Cardiologists Working Together to Improve Clinical Outcomes. CardioSource WorldNews. Dec 1 2018. Accessed Nov 15 2018. http://www.acc.org/latest-in-cardiology/articles/2016/12/21/13/34/in-focus.
2. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89.
3. Dluhy RG, McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med 2008;358:2630-3.
4. Smith RJ, Goldfine AB, Hiatt WR. Evaluating the cardiovascular safety of new medications for type 2 diabetes: time to reassess? Diabetes Care 2016;39:738-42.
5. Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;372:2197-206.
6. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
7. Neal B, Parkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.
8. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). 2012 Nov 21. Identifier NCT01730534, Multicenter Trial to Evaluate the Effect of Dapagloflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58); 2017 Sep 18. Available from: https://clinicaltrials.gov/ct2/show/NCT01730534.
9. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). 2013 Nov 19. Identifier NCT01986881, Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease, The VERTIS CV Study (MK-8835-004); 2017 Apr 7. Available from: https://clinicaltrials.gov/ct2/show/NCT01986881.
10. 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.
11. 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.
12. Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228-39.

Keywords: Blood Glucose, Incretins, Glucagon, Diabetes Mellitus, Type 2, Diabetes Mellitus, Gliclazide, Insulin, Glycated Hemoglobin A, Cause of Death, Cardiovascular Diseases, Blood Pressure, Glucose, Glyburide, Gastric Emptying, Lipids, Risk Factors, Glucagon-Like Peptides, Glucosides, Benzhydryl Compounds, Peptides, Drug Combinations, Metformin, Perindopril, Hyperglycemia, Myocardial Infarction, Heart Failure, Injections, Subcutaneous, Stroke, Obesity, Risk Reduction Behavior, Amputation, Lower Extremity, Diuresis, Metabolic Syndrome

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