SGLT2 Inhibition With Empagliflozin and Cardiovascular Outcomes
Duality of Interest for Vivian Fonseca, MD: Dr. Fonseca and diabetes research are supported in part by the Tullis – Tulane Alumni Chair in Diabetes. Research Support (to Tulane) has been obtained by grants from Novo Nordisk; Asahi; Eli Lilly and Company; Abbott; EndoBarrier; Gilead Sciences, Inc.; and Boehringer Ingelheim. Dr. Fonseca has received honoraria for consulting and lectures from Takeda, Novo Nordisk, sanofi-aventis, Eli Lilly and Company, Nestlé Health Sciences, AstraZeneca, Abbott, Amgen, Boehringer Ingelheim, and Janssen.
Over the last decade, the US Food and Drug Administration (FDA) has mandated that pharmaceutical companies demonstrate that any new drug for diabetes does not increase the risk of cardiovascular events.12,3 As a result, several clinical trials have been conducted to demonstrate such safety, and several are in progress. In these trials, the drug or placebo has been added to usual care for the patient's diabetes and associated cardiovascular risk factor treatment. The primary endpoint has usually been non-inferiority compared to placebo, often with a pre-specified caveat that should non-inferiority be met, then a test for superiority would be conducted. A comparison with placebo theoretically tells us about the drug's effect as used in practice but does not tell us much about the relative efficacy compared to other similar treatments, for which comparative trials are needed.4
A number of clinical trials have demonstrated such safety, but there has often been unfounded disappointment that most of them have not demonstrated cardiovascular benefits of such glucose lowering,2,3 and concerns have been raised about possible adverse secondary outcomes.5 The results of these trials are not surprising, considering the somewhat weak rationale for such a benefit with many of the drugs, and the lack of a major cardiovascular benefit of glucose lowering, particularly in patients with established cardiovascular disease (CVD).6-8 It is also important to recognize that if there has indeed been any beneficial effect on cardiovascular outcomes of an individual glucose-lowering drug, it has been modest,9-12 despite beneficial effects of these drugs on surrogate biomarkers.13
The Empaglifozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG Outcome Trial) was the first of these trials to demonstrate a cardiovascular benefit,14 which has been widely welcomed by practitioners who have remained concerned about the high residual risk of cardiovascular events in patients with diabetes, despite the widespread use of accepted risk reduction strategies.
The trial enrolled patients with very high cardiovascular risk (perhaps to demonstrate safety in a short period of time due to the likelihood of a large number of events) and randomized them to empagliflozin or placebo. This drug belongs to a new class of inhibitors of sodium-glucose cotransporter 2 (SGLT2), which block reabsorption of glucose in the proximal renal tubule – leading to glycosuria.15,16 They have the additional benefit of a significant lowering of blood pressure (BP) through mechanisms that are unclear, as well as a modest degree of weight loss caused by calorie loss in the urine. Thus, they would have the potential to decrease cardiovascular events through these mechanisms. On the other hand, they modestly elevate low-density lipoprotein cholesterol (LDL-C) and the hematocrit, which may be of concern in such patients.
In the EMPA-REG trial, patients were randomized to placebo or two doses of empagliflozin – 10 and 25 mg, respectively.14 The primary endpoint of non-inferiority was clearly met. In addition, when the two groups of patients treated with empagliflozin were combined, there was a moderate but statistically significant reduction in the primary endpoint (nonfatal myocardial infarction or nonfatal stroke, 3-point major adverse cardiovascular events) with a hazard ratio of 0.86. However, the individual doses of the drug did not meet superiority on their own, possibly due to lack of statistical power. Importantly, when components of the endpoints were analyzed separately, there was a highly significant 38% relative risk reduction in cardiovascular mortality and a 32% reduction in all-cause mortality between those treated with the drug compared to placebo, as well as a 35% risk reduction in hospitalization for heart failure.14
It is important to note that myocardial infarction was not significantly reduced by the study drug, and there was a non-significant modest increase in stroke. Furthermore, the benefits on cardiovascular death appeared very shortly after starting therapy, making it unlikely that the effects were related to lowering of blood glucose and BP, both of which were seen in the study. There was a significant reduction in BP. Although the HbA1c reduction was statistically significant, it was small, and there was no dose-response relationship with the outcomes studied. There was a very small increase in LDL-C, although it is unclear if adjustments were made in the lipid-lowering therapy.
These results have important implications for patients with type 2 diabetes and coexisting CVD. Patients in this study were generally obese, had an estimated glomerular filtration rate (eGFR) >30 ml/min, and poor glycemic control; almost all patients had a prior cardiovascular event. A large proportion was being treated with lipid-lowering and BP-lowering therapy. The median observation time in this study was 3.1 years. Cardiologists often see such patients in clinical practice and are usually concerned about recurrence of cardiovascular events, as well as development of heart failure, despite successful revascularization and appropriate drug therapy.
Subgroup analysis showed that the treatment was effective in a wide range of patients but was particularly effective in those who at baseline were greater than 65 years old with a hemoglobin A1c <8.5% and an eGFR of 60 to 90 ml/min. It is noteworthy that the glucose-lowering efficacy of drugs in this class declines with a declining GFR, though not enough is known about the BP-lowering and diuretic effects in patients with renal impairment.
The underlying mechanism of the observed benefit is unknown, although some possible cardiovascular benefits have been suggested beyond the BP- and glucose-lowering effect.17 It is possible that this class of agent has previously unrecognized effects on vascular tissue, and future studies are likely to determine the true mechanism. The rapidity of benefit makes it plausible that the osmotic diuretic-like effect of induced glycosuria is a key component of the benefit. A reduction in death and heart failure through simple BP-lowering may be possible, although a reduction in stroke would have been expected.
The lack of a hypothesis on mortality reduction and the absence of a definite mechanism to explain it raise a question as to whether these results occurred by chance. However, it appears that the effects on mortality and hospitalization for congestive heart failure are unlikely to be due to chance because of the magnitude of the effect. Furthermore, these benefits occur very early and remain consistent for the duration of the trial. On the other hand, the mortality reduction drives the effect on the primary endpoint, resulting in superiority; there is not a homogenous reduction in all components of major adverse cardiovascular events. This finding highlights the limitations of composite outcomes, which may be used for convenience but lack a coherent underlying hypothesis.
Another question is whether this benefit relates to this drug alone or applies to other drugs in the class. There is insufficient information to answer this question at present, although preliminary data so far suggest similar benefits,18,19 and cardiovascular outcomes trials with dapaglifozin and canaglifozin are ongoing. These studies have included patients with less severe CVD; if a similar benefit is seen, the results may apply to a broader range of patients. Should this class of drug be used for primary prevention of cardiovascular events and, therefore, used much earlier than the treatment paradigm for diabetes? Unfortunately, the EMPA-REG trial does not provide any guidance in this respect. The trial essentially tested the effect on secondary event prevention, and most of the patients have had diabetes for a fairly long duration and were on a wide range of medications with a large proportion being on insulin.
Thus, it appears that this class of drugs should be strongly considered in patients who have had a previous cardiovascular event and who either have or are at high risk for congestive heart failure. They should not be used for prevention of cardiovascular events like myocardial infarction or stroke, for which other therapies are likely to be more successful, particularly lipid-lowering therapy and established BP-lowering therapies. Nevertheless, they are likely to play a major role in the secondary prevention of mortality after a coronary event and in reducing the important and expensive complication of hospitalization for heart failure.
- Avitabile NA, Banka A, Fonseca VA. Glucose control and cardiovascular outcomes in individuals with diabetes mellitus: Lessons learned from the megatrials. Heart Fail Clin 2012;8:513-22.
- 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.
- 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.
- Rosenstock J, Marx N, Kahn SE, et al. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: Rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res 2013;10:289-301.
- 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.
- Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
- ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72.
- Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K, He J. Systematic review: Glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med 2009;151:394-403.
- Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK prospective diabetes study (UKPDS) group. Lancet 1998;352:854-65.
- Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: The STOP-NIDDM trial. JAMA 2003;290:486-94.
- Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone clinical trial in macroVascular events): A randomised controlled trial. Lancet 2005;366:1279-89.
- Gaziano JM, Cincotta AH, O'Connor CM, et al. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care 2010;33:1503-8.
- Fonseca V, Desouza C, Asnani S, Jialal I. Nontraditional risk factors for cardiovascular disease in diabetes. Endocr Rev 2004;25:153-75.
- 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.
- Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: Sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med 2011;44:375-93.
- Rosenstock J, Seman LJ, Jelaska A, et al. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab 2013;15:1154-60.
- Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab 2015;17:1180-93.
- Dziuba J, Alperin P, Racketa J, et al. Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes. Diabetes Obes Metab 2014;16:628-35.
- Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the canagliflozin cardiovascular assessment study (CANVAS)--a randomized placebo-controlled trial. Am Heart J 2013;166:217-223.e11.
Clinical Topics: Diabetes and Cardiometabolic Disease, Clinical Topic Collection: Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Nonstatins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Benzhydryl Compounds, Biological Markers, Blood Glucose, Blood Pressure, Cardiovascular Diseases, Cholesterol, LDL, Diabetes Mellitus, Type 2, Diuretics, Diuretics, Osmotic, Glomerular Filtration Rate, Glucose, Glucosides, Glycosuria, Heart Failure, Hematocrit, Hemoglobin A, Glycosylated, Hospitalization, Insulin, Kidney Tubules, Proximal, Lipoproteins, LDL, Myocardial Infarction, Pharmaceutical Preparations, Primary Prevention, Risk, Risk Reduction Behavior, Risk Factors, Secondary Prevention, Sodium, Sodium-Glucose Transporter 2, Stroke, Weight Loss, Metabolic Syndrome X
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