For close to 100 years since the introduction of insulin for clinical use in 1922, no medication designed to treat hyperglycemia associated with diabetes mellitus has demonstrated benefit for cardiovascular risk in randomized cardiovascular clinical outcomes trials. Yet, since late 2015, when the results of the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) Trial were reported, three such medications (empagliflozin, a sodium glucose cotransporter 2 [SGLT2] inhibitor; and liraglutide and semaglutide, both glucagon-like peptide [GLP] 1 receptor agonists) have been shown to have cardiovascular benefits. This represents a sea change in the treatment paradigm for type 2 diabetes and cardiovascular disease (CVD).¹ In addition to CV benefits, these medications also improve upon other limitations of older antihyperglycemic medications, such as avoidance of weight gain and sodium retention, and each with minimal risk for hypoglycemia. Each medication has been demonstrated effective at lowering glycosylated hemoglobin (HbA1c) as monotherapy and in combination with other available antihyperglycemic therapies. In the wake of demonstration of CVD benefit across these trials, debate is ongoing as to whether clinicians should prescribe these medications for the primary purpose of CVD prevention, rather than focusing on glycemic control per se.

Empagliflozin is the first in its class of SGLT2 inhibitors to demonstrate benefit for a three-point major cardiovascular event outcome (MACE) of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (HR 0.86, 95% CI 0.74-0.99).¹ When the components of the primary MACE outcome were assessed independently, however, the beneficial effect of empagliflozin was driven by a statistically significant reduction in cardiovascular death (HR 0.62, 95% CI 0.49-0.77) with no significant effect on risk for nonfatal myocardial infarction. Furthermore, there was a numeric imbalance with a higher number of nonfatal strokes in the empagliflozin treated arm (3.2% vs. 2.6%), though this difference was also not statistically significant. Empagliflozin also significantly decreased the risk for the secondary outcomes of hospitalization for heart failure (HF) (HR 0.65, 95% CI 0.50-0.85) and all-cause mortality (HR 0.68, 95% CI 0.57-0.82). The observed benefits for mortality and for HF were particularly robust, reducing risk for each by over 33%, with benefits emerging within the first few weeks of the trial, and with effects consistent across multiple patient subgroups-including among those with or without HF at baseline.²

The mechanisms by which SGLT2 inhibition improves cardiovascular outcomes are not fully understood. The SGLT2 inhibitors induce glucosuria by inhibiting urinary glucose reabsorption- a mechanism of action independent of insulin with efficacy added to insulin and in patients with late-stage diabetes who have little to no residual pancreatic β-cell function. However, this mechanism of action has downstream effects including osmotic diuresis, natriuresis, lowering of body weight due to calorie and fluid losses, and lowering of blood pressure. Furthermore, off-target effects on lipid metabolism may play a role. The lack of demonstrated benefit in EMPA-REG OUTCOME on atherosclerotic outcomes suggests that the cardiovascular effects observed with empagliflozin are not mediated through reduction or prevention of atherothrombotic events such as myocardial infarction or stroke. Additionally, because HF and mortality outcome curves diverged early in treatment, it is unlikely that the benefit is entirely attributable to improved glycemic control. Several mechanisms have been postulated including effects on osmotic diuresis and natriuresis contributing to blood pressure lowering without a compensatory increase in sympathetic nervous system activation,³ decreased arterial stiffness and vascular resistance,⁴ improvements in weight and visceral adiposity,⁵ decreases in uric acid and oxidative stress,^6,7 and a shift in myocardial fuel energetics.⁸ A recent theory suggests that SGLT2 inhibition may improve myocardial work efficiency based on a shift in fuel energetics with myocardial substrate metabolism switching away from free fatty acids and towards ketones, which are a more energy efficient fuel. The resulting improvement in myocardial metabolic efficiency could translate into long term CVD benefit, especially as relates to HF and mortality. Increases in hemoglobin and hematocrit related to SGLT2 inhibitor treatment have also been observed in multiple studies and may play a role. For example, in EMPA-REG OUTCOME, the mean change from baseline in hemoglobin and hematocrit among those treated with empagliflozin 25 mg was 0.8 ± 1.3 g/dL and 5.0 ± 5.3%, respectively, compared with -0.1 ± 1.2 g/dL and 0.9 ± 4.7% with placebo.¹ Whether these changes reflect early and sustained plasma volume reduction or if they represent off-target effects such as stimulation of the erythropoietin axis, as well as the clinical relevance of such changes, remains to be determined. A recent analysis from EMPA-REG OUTCOME revealed that change in hemoglobin/hematocrit was strongly associated with both improved HF and death risk.

Since hypertension is a major risk factor for both atherosclerotic CVD and HF and it is also a modifiable target, the effects of SGLT2 inhibitors on blood pressure may be an important contributor to the observed CVD benefit. In one trial using 24 hour ambulatory monitoring of blood pressure, empagliflozin versus placebo significantly reduced systolic blood pressure by 3.4 to 4.2 mmHg and diastolic blood pressure by 1.4 to 1.7 mmHg at 12 weeks with the 10 mg and 25 mg daily doses, respectively.⁹ In an analysis of pooled data from four placebo-controlled phase III studies, canagliflozin had similar blood pressure lowering effects.¹⁰ In addition to the effects of SGLT2 inhibition on diuresis, the effects on blood pressure may also be related to concomitant weight loss, smooth muscle relaxation in response to a negative sodium balance, or improved glycemic control. Beneficial effects on intracardiac filling pressures may also contribute to the observed CVD benefits seen with the SGLT2 inhibitors. The diuretic effect of these medications, although not as robust as traditional diuretics, may be associated with a lower incidence of edema compared with placebo without substantial risk for intravascular volume depletion.^2,10 It has also been postulated that reduction of myocardial stretch achieved through lower filling pressures may attenuate susceptibility to ventricular arrhythmias.¹¹

The SGLT2 inhibitors may also improve CVD outcomes via effects on the cardiac-kidney axis. Maintenance of adequate fluid and electrolyte balance and consequent prevention of sympathetic nerve activation along with decrease in inflammation associated with diabetic nephropathy may contribute to CVD benefit. Hyperfiltration is an early kidney hemodynamic abnormality seen in type 2 diabetes that increases risk for development of diabetic nephropathy. In the native state, SGLT2 reabsorbs glucose and sodium back into the circulation and consequently distal sodium delivery to the macular densa is reduced. The juxtaglomerular apparatus senses this as a low volume stimulus causing an afferent renal vasodilatory response. This tubuloglomerular feedback system results in kidney hyperfiltration. SGLT2 inhibitors have been shown to reduce kidney hyperfiltration as well as decrease albuminuria in patients with diabetes and chronic kidney disease.^12,13 A recent secondary analysis from EMPA-REG OUTCOME showed that empagliflozin was associated with 39% lower risk of nephropathy incidence and progression and ~50% lower rates of doubling of serum creatinine, initiation of renal replacement therapy, or death due to kidney disease.¹⁴

Weight loss seen with the SGLT2 inhibitors may also be an important factor. The inhibition of SGLT2 causes an estimated excretion of 60-100g/day of glucose which results in a loss of 240-400 kcal/day. The result is a clinical weight loss of approximately 1.8 kg, as well as reductions in waist circumference and indices of total and visceral adiposity.⁵ Visceral adiposity has been associated with adverse remodeling of the left ventricle and deranged hemodynamics such as lower cardiac output and increased systemic vascular resistance as well as higher risk for CVD.^15,16 Therefore the benefit of SGLT2 inhibitors on CVD outcomes could also be mediated to some degree through improvements in body composition and fat distribution.

A key question is whether the cardiovascular benefit seen with empagliflozin applies to other medications in the SGLT2 inhibitor class. Cardiovascular outcomes trials for two other SGLT2 inhibitors in current clinical use, canagliflozin and dapagliflozin, are ongoing and will assess the efficacy and safety of these medications in specific cardiovascular populations. Clinical trials of other SGLT2 inhibitors being conducted at present include trials enrolling patients with increased cardiovascular risk (Canagliflozin Cardiovascular Assessment Study [CANVAS],¹⁷ Dapagliflozin Effect on Cardiovascular Events [DECLARE-TIMI 58], and Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants with Vascular Disease [VERTIS]), trials enrolling patients with impaired kidney function (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus [CANVAS-R], and Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy [CREDENCE]), and trials enrolling patients with chronic heart failure (Safety of Canagliflozin in Diabetic Patients With Chronic Heart Failure: Randomized, Non-Inferiority Trial [CANDLE],¹⁸ and Dapagliflozin Effect on Symptoms and Biomarkers in Diabetes Patients With Heart Failure [DEFINE-HF]). In meta-analyses of Phase II/IIIa data regarding CV outcomes used to support their FDA new drug applications, similar trends toward benefit were seen on CV death and HF in pooled analyses of clinical trials with both canagliflozin and dapagliflozin,^19,20 but there was also a trend toward increased stroke seen with canagliflozin and a neutral effect on stroke with dapagliflozin. It is important to note, however, that each of these meta-analyses were based on extremely small numbers of events for analyses yielding substantial statistical imprecision and uncertainty. Given some suggestion of pharmacodynamic differences and variability in specificity for SGLT2 between different medications in the SGLT2 inhibitor class,²¹ as well as the unknown cardiovascular effects of dual SGLT1/2 inhibition such as with sotagliflozin currently in clinical development,²² a final determination of whether or not the CVD benefit is a class effect requires a pause for additional data. For now, the search for the "how and why" of the cardiovascular benefit with SGLT2 inhibitors continues.

References

1. 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.
2. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J 2016;37:1526-34.
3. Cherney DZ, Perkins BA, Soleymanlou N, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol 2014;13:28.
4. 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.
5. Neeland IJ, McGuire DK, Clinton R, et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus. Diab Vasc Dis Res 2016;13:119-26.
6. Cheeseman C. Solute carrier family 2, member 9 and uric acid homeostasis. Curr Opin Nephrol Hypertens 2009;18:428-32.
7. Nishimura R, Tanaka Y, Koiwai K, et al. Effect of empagliflozin monotherapy on postprandial glucose and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, 4-week study. Cardiovasc Diabetol 2015;14:11.
8. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care 2016;39:1115-22.
9. Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 2015;38:420-8.
10. Weir MR, Januszewicz A, Gilbert RE, et al. Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J Clin Hypertens 2014;16:875-82.
11. Rajasekeran H, Lytvyn Y, Cherney DZ. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int 2016;89:524-6.
12. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014;129:587-97.
13. Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2014;2:369-84.
14. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016. [Epub ahead of print]
15. Neeland IJ, Gupta S, Ayers CR, et al. Relation of regional fat distribution to left ventricular structure and function. Circ Cardiovasc Imaging 2013;6:800-7.
16. Neeland IJ, Turer AT, Ayers CR, et al. Body fat distribution and incident cardiovascular disease in obse adults. J Am Coll Cardiol 2015;65:2150-1.
17. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessmetn Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J 2013;166:217-23.
18. Tanaka A, Inoue T, Kitakaze M, et al. Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial. Cardiovasc Diabetol 2016;15:57.
19. Canagliflozin Advisory Committee Meeting presentation. January 10, 2013. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf.
20. Dapagliflozin Advisory Committee Meeting presentation. July 19, 2011. http://www.Fda.Gov/DOWNLOADS/ADVISORYCOMMITTEES/COMMITTEESMEETINGMATERIALS/DRUGS/ENDOCRINOLOGICANDMETABOLICDRUGSADVISORYCOMMITTEE/UCM262994.Pdf.
21. Sha S, Polidori D, Farrell K, et al. Pharmacodynamic differences between canagliflozin and dapagliflozin: results of a randomized, double-blind crossover study. Diabetes Obes Metab 2015;17:188-97.
22. Lapuerta P, Zambrowicz B, Strumph P, Sands A. Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor. Diab Vasc Dis Res 2015;12:101-10.

Keywords: Adiposity, Albuminuria, Arrhythmias, Cardiac, Benzhydryl Compounds, Biomarkers, Blood Pressure, Cardiac Output, Creatinine, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Diuretics, Erythropoietin, Fatty Acids, Nonesterified, Glucagon-Like Peptides, Glucose, Glucosides, Heart Failure, Heart Ventricles, Hematocrit, Glycated Hemoglobin A, Hyperglycemia, Hypertension, Hypoglycemia, Hypoglycemic Agents, Inflammation, Insulin, Juxtaglomerular Apparatus, Ketones, Lipid Metabolism, Monitoring, Ambulatory, Muscle Relaxation, Myocardial Infarction, Natriuresis, Plasma Volume, Oxidative Stress, Renal Insufficiency, Chronic, Renal Replacement Therapy, Sodium, Sodium-Glucose Transporter 2, Sympathetic Nervous System, Uric Acid, Vascular Resistance, Vascular Stiffness, Waist Circumference, Water-Electrolyte Balance, Weight Gain, Weight Loss, Metabolic Syndrome

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