Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a novel insulin-independent therapy for type 2 diabetes mellitus (T2DM). By inhibiting renal glucose re-absorption, they improve glycaemic control and have beneficial effects on weight and blood pressure. Current guidance states that any new diabetes medication must be shown not to unacceptably increase cardiovascular risk. The landmark EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial demonstrated that treatment with the SGLT2 inhibitor empagliflozin compared with placebo showed a significant reduction in the risk of major cardiovascular end points and hospitalisation for heart failure for patients with T2DM and existing cardiovascular disease. A positive impact on several renal outcomes was also demonstrated in secondary analysis. These milestone results are set to have significant implications on prescribing practice in T2DM, with potential benefits for many patients with existing cardiovascular disease.
In normal human physiology, the kidneys filter approximately 180 g of glucose daily.1 The majority is re-absorbed into the circulation via sodium-glucose co-transporter (SGLT) proteins in the renal proximal convoluted tubule. SGLT2 has the predominant role absorbing approximately 90% of glucose with the remaining 10% absorbed by SGLT1.2 SGLTs transport sodium and glucose into proximal tubule epithelial cells using the sodium gradient created by Na+/K+ ATPase pumps at the basolateral cell membrane. Glucose is then transported passively by glucose transporter 2 (GLUT2) along its concentration gradient into the interstitium and on to the peritubular capillaries. By inhibiting this process, SGLT2 inhibitors reduce renal glucose re-absorption, increase urinary glucose excretion and reduce serum glucose concentration. The three SGLT2 inhibitors licensed for use in the UK are outlined in table 1.3
SGLT2 inhibitors are generally well tolerated and carry a low risk of hypoglycaemia.4 The glycosuria caused by SGLT2 inhibition causes net calorie loss and has a modest diuretic and natriuretic effect. Consequently, they cause weight loss and a reduction in systolic blood pressure of around 4 mmHg.1,4 Additionally, glycosuria leads to the most common side effect of genital infection.1 There have been case reports of diabetic ketoacidosis (DKA), including euglycaemic ketoacidosis, in type 2 diabetic patients taking SGLT2 inhibitors.5 While the overall incidence is felt to be low, this is an area of ongoing interest.
SGLT2 inhibitors are recommended by the National Institute for Health and Care Excellence (NICE) for the management of T2DM as dual therapy in combination with metformin if a sulphonylurea is contraindicated/not tolerated or if a patient is at significant risk of hypoglycaemia.6-8 Canagliflozin and empagliflozin are also recommended as triple therapy alongside metformin and either a sulphonylurea or pioglitazone, and additionally in combination with insulin with or without other glucose-lowering therapies. Dapagliflozin is currently not recommended as triple therapy (unless as part of a clinical trial) or in combination with pioglitazone.6
This randomised, double-blind, placebo-controlled trial assessed the cardiovascular safety of empagliflozin in patients with T2DM and established cardiovascular disease.9 There were 7,020 patients from 590 centres across 42 countries randomised to empagliflozin 10 mg or 25 mg daily or placebo in a 1:1:1 ratio with a median follow-up of 3.1 years. Patients were required to have a previous history of at least one of the following atherosclerotic diagnoses: previous myocardial infarction, single- or multi-vessel coronary artery disease, unstable angina (more than two months prior to consent), previous stroke or peripheral arterial disease. Mean baseline HbA1c(%) was 8.08 ± 0.84 in the placebo group and 8.07 ± 0.85 in the pooled empagliflozin group. The cohort had significant cardiovascular risk at baseline including an estimated glomerular filtration rate (eGFR) 30 to 59 ml/min/1.73 m2 in 25.5% of patients and heart failure in 10% of patients.
The primary outcome was major adverse cardiovascular events (MACE: a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) analysed in the pooled empagliflozin group compared with placebo. The risk of the primary end point was significantly reduced in the empagliflozin group compared with the placebo group (10.5% vs. 12.1%; hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.74 to 0.99; p=0.04 for superiority). Compared with placebo, empagliflozin also resulted in a significant reduction in the risk of cardiovascular death (3.7% vs. 5.9%; HR 0.62; 95% CI 0.49 to 0.77; p<0.001), all-cause mortality (5.7% vs. 8.3%; HR 0.68; 95% CI 0.57 to 0.82; p<0.001) and hospitalisation for heart failure (2.7% vs. 4.1%; HR 0.65; 95% CI 0.50 to 0.85; p=0.002). There were no significant between group differences for nonfatal myocardial infarction, nonfatal stroke and a key secondary outcome comprising the primary end point and hospitalisation for unstable angina. Results were similar for both doses of empagliflozin. Overall numbers of adverse events were similar between groups. As anticipated, there was a significant increase in genital infections in the empagliflozin group (6.4% vs. 1.8%). An increase in urosepsis was also demonstrated with empagliflozin (0.4% vs. 0.1%). DKA occurred in four patients in the empagliflozin group (0.1%) and one patient in the placebo group (<0.1%).
The effect of empagliflozin on progression of chronic kidney disease in the EMPA-REG OUTCOME cohort was examined as part of a pre-specified secondary objective.10 The primary end point, defined as ‘incident or worsening nephropathy’, comprised of progression to macroalbuminuria, doubling of serum creatinine level, initiation of renal-replacement therapy or death from renal disease. Empagliflozin was associated with a significant reduction in the risk of a primary end point event compared with placebo (12.7% vs. 18.8%; HR 0.61; 95% CI 0.53 to 0.70; p<0.001). Rates of adverse events including acute kidney injury were similar in the empagliflozin and placebo groups, regardless of renal function at baseline.
The cardiovascular safety of dapagliflozin was recently examined in a meta-analysis of 21 clinical trials.11 Cardiovascular events from five phase 2b studies of 12 to 24 weeks duration and 16 phase 3 studies of up to 208 weeks duration were adjudicated by an independent committee. In total, 9,339 patients with T2DM were included: 5,936 had received dapagliflozin in doses ranging from 2.5 to 10 mg over a total of 6,668 patient-years; while 3,403 patients had received control (placebo or comparator treatment) over 3,882 patient-years. At baseline, 3,214 patients (34.4%) had a history of cardiovascular disease (coronary artery disease, cerebrovascular disease, peripheral vascular disease or congestive heart failure). In the overall population, the composite MACE outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and unstable angina) occurred in 95 (1.6%) patients receiving dapagliflozin and 81 (2.4%) patients receiving control (HR 0.787; 95% CI 0.579 to 1.070). In the subgroup of patients with cardiovascular disease at baseline, there were 67 (3.6%) events in the dapagliflozin group compared with 61 (4.5%) events in the control group (HR 0.806; 95% CI 0.562 to 1.156).
Although not significantly different, these results are compatible with the reductions in cardiovascular events that were seen with empagliflozin in EMPA-REG OUTCOME and will be formally tested in the DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events) trial. Cohort data for canagliflozin has been presented to the Food and Drugs Administration (FDA) but is not yet published.
The mechanisms through which empagliflozin may exert a cardioprotective effect are uncertain. Given the early divergence between groups in the EMPA-REG cohort for heart failure hospitalisation and mortality (observed at three months onwards), the dramatic improvement in these outcomes and the lack of significant reduction in nonfatal myocardial infarction and stroke, explanations other than impact on atherosclerosis and established benefits on HbA1c, weight and blood pressure have been sought.12 The EMPA-REG OUTCOME investigators speculate on a multi-factorial aetiology including changes in cardiac function, arterial stiffness, cardiorenal effects and reduction in albuminuria and uric acid levels.9 It has been hypothesised that treatment with SGLT2 inhibitors encourages oxidation of beta-hydroxybutyrate in preference to fatty acids during metabolism in the heart, as well as other organs.12 In rat heart models, this results in reduced oxygen consumption and improved work efficiency at a mitochondrial level.13 Furthermore, the increase in haematocrit caused by SGLT2 inhibitors is likely to increase oxygen delivery to tissues.12 This mechanism may work in synergy with the shift in metabolism towards beta-hydroxybutyrate.12 Others have suggested that by improving renal sodium and glucose handling, SGLT2 inhibition offers several haemodynamic benefits including reduced pre- and afterload, reduced myocardial oxygen demand and potential improvements in cardiac systolic and diastolic function.14
Further trials are ongoing to determine if SGLT2 inhibitors exhibit a class effect on cardiovascular and renal outcomes in T2DM. CANVAS (CANagliflozin cardioVascular Assessment Study),15 involving canagliflozin, and DECLARE-TIMI 58,16 involving dapagliflozin, are two large double-blind, placebo-controlled trials in patients with T2DM and increased cardiovascular risk with a primary composite end point of MACE. Completion of follow-up is anticipated in 2017 and 2019, respectively. Renal outcomes provide the focus for two further placebo-controlled trials involving canagliflozin. CANVAS-R will examine the progression of albuminuria in T2DM, with MACE as a secondary end point,17 while CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) will assess progression of renal impairment and incidence of renal or cardiovascular death in patients with existing renal impairment.18 These trials are expected to complete follow-up in 2017 and 2019, respectively (table 2).
In light of the striking improvements in cardiovascular outcomes seen in the EMPA-REG OUTCOME trial, the ability of non-diabetic patients with heart failure to benefit from SGLT2 inhibition has been hypothesised. It has been announced that clinical trials investigating the impact of empagliflozin and dapagliflozin therapy on patients with chronic heart failure are planned in the near future.19,20 These trials will involve patients with and without T2DM and will focus on heart failure with reduced and preserved ejection fraction.
Conflict of interest
GM has received payments for lectures or advisory boards from Astra Zeneca, Boehringer Ingelheim, and Janssen. MF has received payment for lectures and advisory boards from Astra Zeneca, Boehringer Ingelheim, and Janssen.
The first article in this series on dipeptidyl peptidase-4 (DPP-4) inhibitors was published in our last issue Br J Cardiol 2017;24:17-20 (doi: 10.5837/bjc.2017.001)
- Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce blood glucose levels by impairing renal glucose reabsorption
- Empagliflozin was associated with a significant reduction in major adverse cardiovascular events and heart failure hospitalisation in a large, double-blind, placebo-controlled trial involving patients with type 2 diabetes and cardiovascular disease
- Cardiovascular outcome trials involving canagliflozin and dapagliflozin are expected to report in 2017 and 2019, respectively
- The potential for SGLT2 inhibitors to benefit patients with chronic heart failure, both with and without diabetes, is under investigation
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