Cardiovascular disease (CVD) is the leading cause of death in patients with diabetes mellitus,¹ but not all patients with diabetes have the same risk of developing CVD. CV risk increases with diabetes duration and is affected by other comorbidities like hypertension, dyslipidemia, metabolic syndrome, and chronic kidney disease.² Diabetic patients with existing CVD, as a function of pre-selection, have the highest risk of a subsequent CV events. Thus, secondary prevention of CV events may not be synonymous with cardio-protection in diabetes in general and evidence for the efficacy of anti-diabetic therapies should be evaluated in this light. Until recently there was a paucity of large prospective randomized clinical trials (RCTs) in diabetic patients with CVD. However, based on the 2008 Food and Drug Administration (FDA) mandate to demonstrate safety of all newer hypoglycemic agents prior to seeking approval, the scenario has changed. As a result, several new hypoglycemic medications have recently undergone randomized placebo-controlled CV outcome trials (CVOT) focused on patients with preexisting CVD or are at high risk of developing CVD. The following review is a concise synthesis of these new trial data for the clinical cardiologist.

Background

At the outset, it is important to demarcate micro- and macrovascular outcomes in diabetes as previous data had shown that blood glucose reduction with traditional drugs modulates the former but not necessarily the latter. Hypoglycemic drugs through various mechanisms of action lower blood glucose and effectively reduce microvascular target end-organ damage like retinopathy, nephropathy and neuropathy.^3,4 However, there did not appear to be a strong and convincing relationship between the lowering of blood sugar (as evidenced by glycated hemoglobin reduction) and reduction in CV events with the traditional drugs.^5-8 Additionally, some of the beneficial effects are mitigated by episodes of hypoglycemia.⁹

What is worse is that some hypoglycemic drugs, while effectively lowering blood glucose, can paradoxically increase adverse CV events.^10-12 Increased risk of heart failure (HF) and concerns about myocardial infarction (MI) with the use of thiazolidinediones (rosiglitazone and pioglitazone) led to heightened awareness of potentially harmful CV effects of these otherwise effective hypoglycemic drugs and has resulted in drastic reduction in their clinical use.

Regulatory Mandate

In response to the concerns of increased CV risk, the FDA and other regulatory agencies mandated all new diabetes drugs to demonstrate CV safety.^13-15 Since, the primary use of a hypoglycemic drug is to control blood glucose (as demonstrated by lowering glycated hemoglobin HgA1c), it is now required that all new drugs be approved for marketing only after adequately-powered RCTs could demonstrate that such treatment would not be associated with unacceptably high rates of CV events in the Phase III clinical trials (upper bound of the 95% confidence interval for major adverse CV event not to exceed 1.8). Post-approval, a Phase IV CV safety outcome trial in high-risk patients (with preexisting CVD) would need to further demonstrate a CV event rate not exceeding the upper bound of the 95% confidence interval of 1.3. A minimum of 2-year follow-up data would be required with independent adjudication of CV outcomes.

As a result of this mandate, the last half-decade has seen a steady stream of CV safety trials in patients with preexisting CVD. And although designed to demonstrate safety, some of trials have shown unprecedented CV benefit in secondary prevention of CVD and related outcomes. The following is a review of the newer hypoglycemic medications tested in the recent CVOTs.

DPP-4 Inhibitors

Dipeptidyl peptidase 4 (DPP-4) inhibitors prolong the activity of glucagon-like-peptide 1 (GLP1), the gastric-inhibitory-peptide, and other incretins by preventing their breakdown.¹⁶ The agents in this class have modest HbA1C reductions, but their appeal lies in that they do not cause hypoglycemia or weight gain.¹⁶ Three DPP4 inhibitors, namely saxaglipitin, aloglipitin, and sitaglipitin have been tested in CVOTs (SAVOR-TIMI 53 [Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to Other Diabetes Medications], EXAMINE [Cardiovascular Outcomes Study of Alogliptin in Patients With Type 2 Diabetes and Acute Coronary Syndrome], and TECOS [Sitagliptin Cardiovascular Outcomes Study] respectively).^17-19 None were found to increase adverse CV events, CV mortality, or all-cause mortality (Table 1, 2). Neither was there a signal of CV benefit.

Table 1: Study Characteristics of Cardiovascular Outcome Trials of Newer Hypoglycemic Agents

	Population studied: Type 2 diabetes mellitus and one of the following:	n	Mean age (y)	Baseline HbA1C	Median follow-up (y)
DPP4 INHIBITORS
Saxagliptin     SAVOR-TIMI53	CVD (78%): Age ≥40 years with a clinical event associated with CAD, CVA, or PVD High CV risk: Men ≥55 years or women ≥60 years with hypertension, dyslipidemia or smoking	16,492	65	8%	2.1
Aloglipitin EXAMINE	MI or UA requiring hospitalization within the previous 15-90 days	5,380	61	8%	1.5
Sitagliptin TECOS	CAD, stroke or PAD	14,671	65	7.2%	3
SGLT2 INHIBITORS
Empagliflozin EMPA-REG	MI, multi-vessel CAD, CAD with ischemia or UA, stroke, PAD	7,020	63	8.7%	3.1
Canagliflozin   CANVAS	≥30 years with symptomatic atherosclerotic CVD ≥50 years with ≥2 of the following: diabetes for ≥10 years, smoking, SBP >140 mm Hg on antihypertensives, micro-/macroalbuminuria, HDL <38.7 mg/dL	10,142	63	8.2%	3.6
GLP-1 ANALOGUES
Lixisenatide ELIXA	MI or UA requiring hospitalization within the previous 180 days	6,068	60	7.6%	2.1
Liraglutide LEADER	≥50 years with CAD, CVA, PAD, HF, or CKD stage ≥3 ≥60 years with microalbuminuria/proteinuria, hypertension with LVH, LV dysfunction or ABI <0.9	9,340	64	8.7%	3.8
Semaglutide SUSTAIN-6	≥50 years with CAD, CVA, PAD, HF, or CKD stage ≥ 3 ≥60 years with microalbuminuria/proteinuria, hypertension with LVH, LV dysfunction or ABI <0.9	3,297	65	8.7%	2
Exenatide EXSCEL	CVD (73%): CAD, ischemic stroke, ≥50% carotid artery stenosis or PAD	14,752	62	8%	3.2
Abbreviations: ABI, ankle brachial index; CAD, coronary artery disease; CKD, chronic kidney disease; CVD, cardiovascular disease; CVA; cerebrovascular accident; HDL, high-density lipoprotein; HF, heart failure; LVH, left ventricular hypertrophy; MI, myocardial infarction; PAD, peripheral arterial disease; SBP, systolic blood pressure; UA, unstable angina

Table 2: Outcomes of Cardiovascular Outcome Trials of Newer Hypoglycemic Agents

	Primary outcome	Secondary outcome	CV death	All-cause death	HF Hospitalization
DPP4 INHIBITORS
Saxagliptin     SAVOR-TIMI53	1.00 (0.89-1.12) CV death, MI, ischemic stroke	1.02 (0.94-1.11) CV death, MI, stroke, UA or HF hospitalization, revascularization	1.03 (0.87-1.22)	1.11 (0.96-1.27)	1.27 (1.07-1.51)
Aloglipitin EXAMINE	0.96 (≤1.16) CV death, MI, stroke	0.95 (≤1.14) CV death, MI, stroke, urgent revascularization for UA	0.85 (0.66-1.10)	0.88 (0.71-1.09)	1·07 (0·79–1·46)
Sitagliptin TECOS	0.98 (0.89–1.08) CV death, MI, stroke, UA hospitalization	0.99 (0.89–1.10) CV death, MI, stroke	1.03 (0.89–1.19)	1.01 (0.90-1.14)	1.00 (0.83-1.20)
SGLT2 INHIBITORS
Empagliflozin EMPA-REG	0.86 (0.74–0.99) CV death, MI, stroke	0.89 (0.78–1.01) CV death, MI, stroke, UA hospitalization	0.62 (0.49–0.77)	0.68 (0.57–0.82)	0.65 (0.50–0.85)
Canagliflozin   CANVAS	0.86 (0.75–0.97) CV death, MI, stroke	As in the next column	0.87 (0.72–1.06)	0.87 (0.74–1.01)	0.67 (0.52–0.87)
GLP1 ANALOGUES
Lixisenatide ELIXA	1.02 (0.89–1.17) CV death, MI, stroke, UA	1.00 (0.90–1.11) CV death, MI, stroke, UA, HF hospitalization, revascularization	0.98 (0.78–1.22)	0.94 (0.78–1.13)	0.96 (0.75–1.23)
Liraglutide LEADER	0.87 (0.78–0.97) CV death, MI, stroke	0.88 (0.81–0.96) CV death, MI, stroke, UA or HF hospitalization, revascularization	0.78 (0.66–0.93)	0.85 (0.74-0.97)	0.87 (0.73–1.05)
Semaglutide SUSTAIN-6	0.74 (0.58–0.95) CV death, MI, stroke	0.74 (0.62–0.89) CV death, MI, stroke, UA or HF hospitalization, revascularization	0.98 (0.65–1.48)	1.05 (0.74–1.50)	1.11 (0.77–1.61)
Exenatide EXSCEL	0.91 (0.83-1) CV death, MI, stroke	Next column	0.88 (0.76-1.02)	0.86 (0.77-0.97)	0.94 (0.78-1.13)
Abbreviations: CAD, coronary artery disease; CKD, chronic kidney disease; CVD, cardiovascular disease; HF, heart failure; MI, myocardial infarction; PAD, peripheral arterial disease; UA, unstable angina

HF hospitalizations were, however, a concern with this class of drugs. SAVOR-TIMI 53 showed an unexpected 27% increased risk of HF hospitalizations (3.5% vs. 2.8%) with saxaglipitin. This adverse effect was not initially apparent with aloglipitin in the main report of the EXAMINE study. But a subsequent post-hoc analysis suggested increased HF hospitalizations (2.2% vs 1.3%) in patients without a history of HF (HR 1·76 [1·07–2·90]) but no increase in those with preexisting HF (1·00 [0·71–1·42]).²⁰ In 2015, the FDA issued a safety warning for the risk of HF with saxaglipitin and aloglipitin.²¹ No signal of HF hospitalizations was seen with sitaglipitin in TECOS.

SGLT2 Inhibitors

Sodium-glucose co-transporter 2 (SGLT2) is a low affinity, high capacity sodium-glucose co-transporter in the proximal renal tubules and is responsible for glucose reabsorption. SGLT2 inhibitors are orally administered drugs that block this receptor, thereby preventing glucose reabsorption into the blood stream and facilitating elimination of glucose in the urine (glycosuria). As a result, these agents also have a diuretic effect and promote weight and blood pressure reduction by sodium and water loss.²²

The EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated the CV effects of 10 or 25 mg of empagliflozin added to standard therapy in diabetic patients with known CVD and demonstrated impressive results.²³ The primary composite outcome of CV death, MI, and stroke occurred less frequently with empagliflozin (10.5% compared to 12.1% in the placebo group; P = 0.04 for superiority). This difference was largely driven by significantly lower CV death in the treatment group (3.7% vs 5.9%; P < 0.001) without significant differences in MI or stroke rates. All-cause death was also reduced with empagliflozin (5.7% vs. 8.3%; P < 0.001). Most interestingly, empagliflozin reduced HF admissions by 35% (2.7% vs. 4.1%; P = 0.002). This was a major paradigm shift from the previous hypoglycemic medications that either had no effect or increased HF hospitalizations (rosiglitazone, saxaglipitin). Also, the beneficial CV effects of emapagliflozin appeared much earlier than GLP1 analogues like liraglutide suggesting a prominent hemodynamic rather than anti-atherosclerotic mechanism of action. The robustness of HF outcomes in the EMPA-REG OUTCOME trial have been debated due to the lack of cardiac function and biomarker assessment (such as brain natriuretic peptide) which are otherwise a norm in most HF trials. Additionally, in subgroup analysis, HF hospitalizations were statistically significantly reduced in patients without HF at baseline but not in those with HF.²⁴ Trials specifically evaluating HF outcomes are now underway.²⁵ Regardless, prior to these findings, no glucose-lowering drug had shown an improvement in HF outcomes in patients with diabetes.

Canagliflozin was the second SGLT2 inhibitor to undergo a CV safety trial (CANVAS [CANagliflozin cardioVascular Assessment Study]),²⁶ and consistent with results of EMPA-REG OUTCOME, showed reduction in HF hospitalization (5.5% vs 8.7%). Canagliflozin was shown to be superior to placebo in reducing the primary combined outcome of CV death, MI, and stroke (26.9% vs. 31.5%; P = 0.02) but did not improve any of these outcomes individually. However, the reduction in the HF related outcome was identical to that observed with empagliflozin in the EMPA-REG OUTCOME trial.

Apart from CV benefits modulated through osmotic diuresis, reduction in weight, arterial stiffness, and left ventricular afterload, and overall modulation of the cardio-renal axis, SGLT2 inhibitors also reduce the progression of renal disease and delay the need for dialysis.^25,27 This is a major advantage in diabetic patients where renal disease is an important cause of progressive morbidity and mortality.

Prescribing physicians must be cognizant of some known adverse effects of SGLT2 inhibitors. Since SGLT2 inhibitors act by inducing glycosuria, superficial genital mycotic infections (especially in women and uncircumcised men) are more common with their use. Their use can also be associated with increased risk of UTIs and diabetic ketoacidosis (rare). Increased amputation and bone fractures with canagliflozin in the CANVAS trial are also concerning. The FDA has issued a warning to avoid canagliflozin in patients that may be at a higher risk for amputations.²⁸

GLP1 Analogues

Glucagon-like peptide 1 (GLP-1) analogues are a class of injectable hypoglycemic drugs that activate the endogenous GLP-1 receptor. They promote glucose dependent insulin release, inhibit glucagon secretion, and delay gastric emptying.²⁹

Lixisenatide, liraglutide, semaglutide and most recently exenatide have been tested in CV outcome trials (ELIXA [Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010], LEADER [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results], SUSTAIN-6 [Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes], and EXSCEL [Exenatide Study of Cardiovascular Event Lowering Trial], respectively),^30-33 while dulaglutide is currently being tested (REWIND [Researching Cardiovascular Events With a Weekly Incretin in Diabetes]).³⁴ It is apparent from the results of the published trials that the benefits of GLP-1 analogues may not be a class effect. While LEADER and SUSTAIN-6 were able to demonstrate CV event reduction, the results of ELIXA were not as encouraging and EXSCEL showed borderline beneficial effects.

ELIXA showed a neutral CV effect of the shorter acting lixisenatide (daily injection) added to standard therapy in diabetic patients who had an MI or unstable angina episode in the preceding 6 months. The positive results of the subsequent LEADER trial came as a surprise. Not only was liraglutide (daily injection) non-inferior to placebo, it was superior in reducing the primary composite outcome of CV death, MI and stroke (13% vs 14.9% in placebo; P = 0.01). The reduction in the primary end point was driven by significantly lower CV mortality (4.7% vs. 6%; P = 0.007). Moreover, liraglutide reduced all-cause mortality as well (8.2% vs. 9.6%; P = 0.02). While there was numerical reduction in MI and stroke rates, this did not reach statistical significance. SUSTAIN-6, which had similar inclusion criteria as LEADER (Table 1), also showed composite CV event reduction (6.6% vs 8.9%; P=0.02) with semaglutide (weekly injection), which was driven by a significant reduction in strokes (1.6% vs. 2.7%; P = 0.04) rather than CV mortality or MI.

Neither liraglutide nor semaglutide had a significant effect on HF admissions, suggesting a different mechanism of action than SGLT2 inhibitors. Though not completely understood, it has been postulated that these drugs may have more of an anti-atherothrombotic effect. Other positive effects like blood pressure lowering, weight reduction and avoidance of hypoglycemia may contribute to improved CV outcomes.³⁵

As mentioned, the CV benefits of GLP-1 agonists are not consistent across this class of medications. The recently published EXSCEL trial comparing exenatide (weekly injection) to placebo in diabetic patients (73% with previous CV disease) did not show a signal of benefit in any of the CV outcomes. Results of the REWIND trial evaluating CV outcomes with dulaglutide (weekly injection) are expected in 2018.

Gastrointestinal side effects, driven by slowed gastric emptying, are an important consideration while prescribing GLP-1 agonists and may be a reason for non-adherence or discontinuation of the medication.

Lessons Learned and Future Direction

Though initially designed to keep potentially harmful hypoglycemic agents off the market, the CV safety trials have inadvertently provided clinicians with a new set of drugs with proven CV benefit in patients with diabetes and CVD thus expanding the field of CV secondary prevention. New medications like empagliflozin and liraglutide improve not only CV mortality but also all-cause mortality in diabetic patients with CVD. The FDA has approved specific labels for both empagliflozin and liraglutide to reduce the risk of CV death in adults with diabetes and CVD. Additionally, SGLT2 inhibitors like emplagliflozin and canagliflozin reduce HF hospitalizations. If the results of the ongoing trials with empagliflozin in HF patients prove their utility these drugs can be considered as additional choice for the treatment of CHF patients.

The choice of hypoglycemic medication may possibly tip in the favor of the orally administered SGLT2 inhibitors rather than injectables like GLP-1 analogues, though this may be less of a concern in patients already on injectable insulin/insulin analogues. Patients with diabetes and CVD who are at an increased risk of HF would probably benefit more from an SGLT2 inhibitor. Future trials should aim at providing a comparative assessment between diabetes medications rather than merely establishing efficacy against placebo.

With the increasing prevalence of obesity and subsequent diabetes in the United States and around the world, cardiologists are bound to encounter more diabetic patients in their clinical practice. And though the treatment of diabetes has traditionally been considered under the purview of primary care or diabetes specialists, the advent of medications with proven CV efficacy makes it imperative for the cardiologist not only to be cognizant of, but also actively advocate for the prescription for CV protective diabetes medications. Diabetes care goes well beyond the reduction of glycated hemoglobin as the goal of therapy should be CV and all-cause mortality reduction in patients who are at the highest risk for such events, namely those with preexisting CVD.

There is an immediate need for clinicians to embrace the evidence and switch from traditional diabetes medications to newer therapies with proven CV benefit. Physician education and increasing awareness of these persuasive clinical trial results will increase their comfort level in making this transition. Cost considerations, however, remain to be addressed.

References

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10. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 2007;370:1129-36.
11. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes--an interim analysis. N Engl J Med 2007;357:28-38.
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18. 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.
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Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, ACS and Cardiac Biomarkers, Lipid Metabolism, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Hypertension

Keywords: Acute Coronary Syndrome, Adamantane, Amputation, Angina, Unstable, Benzhydryl Compounds, Biomarkers, Blood Glucose, Blood Pressure, Cause of Death, Comorbidity, Confidence Intervals, Diabetes Mellitus, Type 2, Diabetic Ketoacidosis, Dipeptides, Dipeptidyl Peptidase 4, Dipeptidyl-Peptidase IV Inhibitors, Diuresis, Diuretics, Dyslipidemias, Follow-Up Studies, Fractures, Bone, Gastric Emptying, Glucagon, Glucagon-Like Peptide 1, Glucose, Glucose Transport Proteins, Facilitative, Glucosides, Glycated Hemoglobin A, Glycosuria, Heart Failure, Hospitalization, Hypertension, Hypoglycemia, Hypoglycemic Agents, Immunoglobulin Fc Fragments, Incretins, Insulins, Kidney Tubules, Proximal, Metabolic Syndrome, Myocardial Infarction, Natriuretic Peptide, Brain, Peptides, Pharmaceutical Preparations, Piperidines, Prospective Studies, Recombinant Fusion Proteins, Renal Dialysis, Renal Insufficiency, Chronic, Secondary Prevention, Sodium, Stroke, Symporters, Thiazolidinediones, United States Food and Drug Administration, Uracil, Vascular Stiffness, Weight Gain, Weight Loss

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