EMPA-REG OUTCOME Research Articles

Implications of the CANVAS Study in Reducing Cardiovascular Outcomes.

In recent years, Cardiovascular Outcome Event Trials (CVOTs) in type 2 diabetes mellitus (T2DM) have demonstrated that sodium glucose transporter 2 inhibitors (SGLT2i) could reduce major adverse cardiovascular events (MACE) and cardiovascular mortality independent of a glucose lowering mechanism. SGLT2i trials reported significant results that have generated biologically plausible theories with regard to the macrovascular benefit. In this review, we have summarized and discussed the results of the CANVAS program. The CANVAS program is unique as it is an analysis of two aggregated cohorts. The two cohorts were similar at baseline but had different durations of exposure to canagliflozin. It showed a 14% reduction in the primary MACE composite. However, the individual components of the MACE composite were not significantly different from placebo. Initial analysis also indicated a reno-protective effect. The results of the CANVAS program are similar overall yet different when compared to the EMPA-REG OUTCOMES trial, especially with regard to cardiovascular mortality and adverse event profile. This could possibly be due to the differences in the cardiovascular risk profile of the enrolled population in the two trials. Other possibilities include drug-specific effects and different mechanisms of lowering overall MACE. In addition, a brief comparison of CANVAS to the CVD-REAL indicates that the CANVAS trial results may apply to a larger, more generalized population than those in the CANVAS program.

Empagliflozin directly improves diastolic function in human heart failure.

Empagliflozin, a clinically used oral antidiabetic drug that inhibits the sodium-dependent glucose co-transporter 2, has recently been evaluated for its cardiovascular safety. Surprisingly, empagliflozin reduced mortality and hospitalization for heart failure (HF) compared to placebo. However, the underlying mechanisms remain unclear. Therefore, our study aims to investigate whether empagliflozin may cause direct pleiotropic effects on the myocardium. In order to assess possible direct myocardial effects of empagliflozin, we performed contractility experiments with in toto-isolated human systolic end-stage HF ventricular trabeculae. Empagliflozin significantly reduced diastolic tension, whereas systolic force was not changed. These results were confirmed in murine myocardium from diabetic and non-diabetic mice, suggesting independent effects from diabetic conditions. In human HF cardiomyocytes, empagliflozin did not influence calcium transient amplitude or diastolic calcium level. The mechanisms underlying the improved diastolic function were further elucidated by studying myocardial fibres from patients and rats with diastolic HF (HF with preserved ejection fraction, HFpEF). Empagliflozin beneficially reduced myofilament passive stiffness by enhancing phosphorylation levels of myofilament regulatory proteins. Intravenous injection of empagliflozin in anaesthetized HFpEF rats significantly improved diastolic function measured by echocardiography, while systolic contractility was unaffected. Empagliflozin causes direct pleiotropic effects on the myocardium by improving diastolic stiffness and hence diastolic function. These effects were independent of diabetic conditions. Since pharmacological therapy of diastolic dysfunction and HF is an unmet need, our results provide a rationale for new translational studies and might also contribute to the understanding of the EMPA-REG OUTCOME trial.

Empagliflozin and Kidney Function Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-REG OUTCOME Trial.

Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes. Participants (n=7020) were randomized (1:1:1) to empagliflozin 10 mg/d, empagliflozin 25 mg/d, or placebo added to standard of care. We calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline to week 4), chronic maintenance treatment (week 4 to last value on treatment), and post-treatment (last value on treatment to follow-up). Compared with placebo, empagliflozin was associated with uniform shifts in individual eGFR slopes across all periods. On treatment initiation, adjusted mean slope (eGFR change per week, ml/min per 1.73 m2) decreased with empagliflozin (-0.77; 95% confidence interval, -0.83 to -0.71; placebo: 0.01; 95% confidence interval, -0.08 to 0.10; P<0.001). However, annual mean slope (ml/min per 1.73 m2 per year) did not decline with empagliflozin during chronic treatment (empagliflozin: 0.23; 95% confidence interval, 0.05 to 0.40; placebo: -1.46; 95% confidence interval, -1.74 to -1.17; P<0.001). After drug cessation, the adjusted mean eGFR slope (ml/min per 1.73 m2 per week) increased and mean eGFR returned toward baseline level only in the empagliflozin group (0.56; 95% confidence interval, 0.49 to 0.62; placebo -0.02; 95% confidence interval, -0.12 to 0.08; P<0.001). Results were consistent across patient subgroups at higher CKD risk. The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function.

The role of glucagon in the possible mechanism of cardiovascular mortality reduction in type 2 diabetes patients.

Type 2 diabetes (T2D) is one of the major public health issues worldwide. The main cause of mortality and morbidity among T2D patients are cardiovascular (CV) causes. Various antidiabetics are used in T2D treatment, but until recently they lacked clear evidence of the reduction in CV mortality and all-cause mortality as independent study end-points. The aim of this article was to present and critically evaluate potential mechanisms behind the remarkable results documented in trials with new antidiabetics for the treatment of T2D. Relevant data were collected using the MEDLINE, PubMed, EMBASE, Web of Science, Science Direct, and Scopus databases with the key words: "type 2 diabetes," "mortality," "glucagon," "empagliflozin," "liraglutide," "insulin" and "QTc." Searches were not limited to specific publication types or study designs. The EMPA-REG OUTCOME trial with empagliflozin and LEADER trial with liraglutide presented remarkable results regarding the reduction in mortality in T2D treatment. However, the potential mechanism for those beneficial effects is difficult to determine. It is not likely that improvements in classic CV risk factors are responsible for the observed effect. A potential mechanism may be caused by the elevation of postprandial (PP) glucagon concentrations that can be seen with an empagliflozin and liraglutide therapy, which could have beneficial effects considering the myocardial electrical stability in T2D patients. This hypothesis throws new light upon possible mechanisms of reduction in mortality in T2D patients.

PDB76 - COST-EFFECTIVENESS ANALYSIS OF EMPAGLIFLOZIN IN COMPARISON TO LIRAGLUTIDE BASED ON CARDIOVASCULAR OUTCOME TRIALS

In the cardiovascular outcome trials (CVOTs) EMPA-REG OUTCOME, and LEADER, empagliflozin (SGLT-2 inhibitor), and liraglutide (GLP-1) + standard of care (SoC) were compared to SoC (placebo arm in the trial) in patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD). This study assessed the cost-effectiveness of empagliflozin+SoC in comparison to liraglutide+SoC in patients with T2D and established CVD based on the respective CVOTs using the UK National Health Service (NHS) perspective. The IQVIA Core Diabetes Model (CDM) was calibrated to reproduce the clinical event rates observed in the EMPA-REG OUTCOME trial. Baseline characteristics and observed effects on physiological parameters (HbA1c, BMI, blood pressure, lipids) were used as inputs. Network meta-analysis provided the relative risks for cardiovascular outcomes with empagliflozin versus liraglutide. Microvascular outcomes were predicted by standard CDM risk equations. The relative treatment effect on the CVOTs was assumed for five years, the modelling horizon of the analysis. The CDM was populated with UK event costs and quality of life data taken from literature. Drug costs were from the British National Formulary and Monthly Index of Medical Specialities. Discounting of 3.5% was applied. Over a 5-year time horizon, CDM projected 2.608 and 2.506 QALY and 14,473GBP and 18,820GBP total costs for empagliflozin+SoC and liraglutide+SoC, respectively, making empagliflozin+SoC the dominant strategy. Projected mortality rate was 10.52% for empagliflozin+SoC and 13.26% for liraglutide+SoC. Myocardial infarction rate was comparable (6.10% vs. 6.14%), non-fatal stroke rate was higher (3.42% vs. 2.43%) and heart failure rate was lower in the empagliflozin arm (5.79% vs. 7.66%) compared to the liraglutide arm. One-way and probabilistic sensitivity analyses showed robustness of the results. Based on the results of the CVOTs, cost effectiveness analysis suggested that empagliflozin+SoC was dominant compared to liraglutide+SoC from the UK NHS perspective over a 5-year time horizon.

PDB63 - COST-EFFECTIVENESS ANALYSIS OF EMPAGLIFLOZIN TREATMENT IN PATIENTS WITH TYPE 2 DIABETES AND CHRONIC HEART FAILURE BASED ON SUBGROUP OF EMPA-REG OUTCOME IN THE UNITED KINGDOM

In type 2 diabetes (T2D) patients with established CV disease, empagliflozin reduced heart failure hospitalizations (HHF) and CV death compared to SoC, regardless of HF at baseline. Given the poor outcomes and economic burden of these comorbidities, we investigated the cost-effectiveness of empagliflozin on top of SoC in T2D patients with HF at baseline over a lifelong time horizon from a UK perspective. Discrete event simulation economic model was developed to project CV events including HHF, CV death, and kidney outcomes for EMPA-REG OUTCOME T2D patients with HF at baseline. Respective risk equations were derived using event-free survival curves with time-dependent covariates. Model validity was assessed by comparing predicted and observed outcomes at three years. UK unit costs of complications and QoL data were obtained from literature. The drug costs were from the British National Formulary and Monthly Index of Medical Specialties. Outcomes included event rates per 100 patient-years (PYs), life years (LYs), costs, and quality-adjusted life years (QALYs). Patients on empagliflozin were projected to experience fewer events of 1st HHF (3.64 vs 4.61 per 100 PY) and recurrent HHF (2.78 vs 4.92 per 100 PY), CV deaths (6.07 vs 7.37 per 100 PY), and non-fatal MI (2.67 vs 3.31 per 100 PY), but higher event rate for non-fatal stroke (2.57 vs 1.54 per 100 PY), compared to SoC. Treatment with empagliflozin projected 1.22 LYs and 0.65 QALYs gained. Incremental Cost-Effectiveness Ratio (ICER) for empagliflozin compared with SoC was £434/QALY. Probabilistic sensitivity analyses suggested that the probability of empagliflozin being cost-effective in patients with T2D and HF at a threshold of £20,000/QALY was 89%. Based on results of EMPA-REG OUTCOME, this cost effectiveness analysis suggests that empagliflozin on top of SoC is a cost-effective treatment option for patients with T2D and chronic HF from the UK NHS perspective.

Empagliflozin Reduces Mortality and Hospitalization for Heart Failure in Patients with Type 2 Diabetes and Peripheral Artery Disease: A Sub-Analysis of the EMPA-REG OUTCOME Trial

Empagliflozin Reduces Mortality and Hospitalization for Heart Failure in Patients with Type 2 Diabetes and Peripheral Artery Disease: A Sub-Analysis of the EMPA-REG OUTCOME Trial

Empagliflozin Reduces Mortality in Patients with Type 2 Diabetes and a History of Left Ventricular Hypertrophy: A Sub-Analysis of the EMPA-REG OUTCOME Trial

Empagliflozin Reduces Mortality in Patients with Type 2 Diabetes and a History of Left Ventricular Hypertrophy: A Sub-Analysis of the EMPA-REG OUTCOME Trial

PDB71 - ASSESSING THE RELATIVE COST-EFFECTIVENESS OF EMPAGLIFLOZIN AND CANAGLIFLOZIN FOR THE TREATMENT OF TYPE 2 DIABETES PATIENTS WITH EXISTING CARDIOVASCULAR DISEASE IN THE UK

This study aimed to determine the relative cost-effectiveness of the sodium-glucose co-transporter-2 (SGLT-2) inhibitors empagliflozin and canagliflozin for the treatment of UK patients with type 2 diabetes (T2D) and established cardiovascular (CV) disease. A published model was used to simulate the treatment of T2D based on the UKPDS risk equations. This was used to extrapolate the clinical outcomes of the EMPA-REG OUTCOME and CANVAS trials for empagliflozin and canagliflozin, respectively, and compare the long-term economic impact from the UK NHS perspective. Hazard ratios (HRs) derived by Bucher indirect treatment comparison were used to simulate rates of the following clinical events: non-fatal myocardial infarction (MI), non-fatal stroke, hospitalisation for heart failure, CV-related mortality, progression of albuminuria, and a composite renal outcome. Adverse events included amputation, bone fracture, genital infection and renal injury. In the base case, HRs for non-significant outcomes were set to 1; absolute HRs were tested in a sensitivity analysis. Quality of life was captured via a baseline utility value, with permanent decrements associated with each event experienced. Treatment and disease management costs were derived from published sources. A lifetime horizon was used, with costs and QALYs discounted at 3.5%pa. In the base case analysis, each patient receiving empagliflozin was predicted to gain 0.99 life years (undiscounted) and 0.43 QALYs (discounted) versus canagliflozin. The predicted gain in life years resulted in a net incremental cost of £585 per patient over the horizon modelled; nevertheless, due to quality of life gains, an incremental cost-effectiveness ratio (ICER) of £1,376/QALY versus canagliflozin was estimated. Sensitivity analyses demonstrated that the ICER was relatively insensitive to varying key model parameters (remained <£8,000/QALY). Empagliflozin is expected to be cost-effective versus canagliflozin for the treatment of UK patients with T2D and established CV disease. This conclusion appears robust in various sensitivity analyses.

PDB62 - COST-EFFECTIVENESS ANALYSIS OF EMPAGLIFLOZIN IN JAPAN BASED ON RESULTS FROM THE SUBGROUP ANALYSIS OF ASIAN PATIENTS IN THE EMPA-REG OUTCOME TRIAL

We assessed the cost-effectiveness of empagliflozin in Japan based on the Asian subgroup analysis of the EMPA-REG OUTCOME trial. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of cardiovascular (CV) and renal events in patients with type 2 diabetes and established CV disease. Cost-effectiveness analysis based on the overall population of the EMPA-REG OUTCOME trial was reported previously by using lifetime discrete event simulation model. The same modeling frame was adapted to evaluate the cost-effectiveness of treatment with empagliflozin added to standard of care (SoC) compared to SoC in Japan. The time to relevant clinical events and the hazard ratios were derived from an Asian subgroup analysis of the EMPA-REG OUTCOME trial. The costs for each event were estimated from Japanese medical claims data. Direct medical cost, life expectancy and quality-adjusted life years (QALYs) were calculated from a payers’ perspective. Treatment with empagliflozin was estimated to increase life expectancy by 3.9 year and 2.1 QALYs while total cost increased by 814,764 yen (6,267 € at an exchange rate of 1 €=130 yen) compared to treatment with SoC. The incremental cost-effectiveness ratio (ICER) was 384,636 yen/QALY (2,959 €/QALY). In the sensitivity analysis, there was no case which was in excess of the reference value of ICER in the pilot introduction for price revision in Japan, 5 million yen/QALY (38,462 €/QALY). Based on the Asian subgroup analysis of the EMPA-REG OUTCOME trial, our results suggest that empagliflozin is highly cost-effective compared with SoC in Japan.

Prevention of Heart Failure in Patients with Diabetes: Role of Diabetes Medications

Type 2 diabetes mellitus (DM) is a major risk factor for the development of heart failure (HF). In patients with DM, preventing HF using diabetes medications should be an imperative for primary care physicians and cardiologists alike. Prior studies with DPP-IV inhibitors, thiazolidinediones (TZDs), and GLP-1 agonists have demonstrated either a neutral effect on HF or increased HF hospitalizations. Two recent large-scale randomized controlled trials (RCTs), EMPA-REG OUTCOME and CANVAS, compared sodium glucose transporter-2 inhibitor (SGLT-2i) to placebo. Use of SGLT-2i led to a substantial reduction in HF events and hospitalizations in patients with DM, with or without history of HF. Use of SGLT-2i therapy has been shown to reduce HF in patients with DM.

EMPAGLIFLOZIN REDUCES MORTALITY AND HOSPITALIZATION FOR HEART FAILURE IN PATIENTS WITH OR WITHOUT A HISTORY OF MYOCARDIAL INFARCTION OR STROKE AT BASELINE

In the EMPA-REG OUTCOME trial, empagliflozin added to standard of care reduced cardiovascular (CV) death by 38% (HR 0.62 [95% CI 0.49, 0.77]), all-cause mortality by 32% (HR 0.68 [95% CI 0.57, 0.82]) and hospitalization for heart failure (HHF) by 35% (HR 0.65 [95% CI 0.50, 0.85]) vs placebo in

Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials.

This review examines recent randomized controlled cardiovascular (CV) outcome trials of glucose-lowering therapies in type 2 diabetes and their impact on the treatment of patients with type 2 diabetes. The trials were designed to comply with regulatory requirements to confirm that major adverse cardiac events (MACE) are not detrimentally affected by such therapies. Trials involving dipeptidyl peptidase-4 (DPP-4) inhibitors did not alter a composite MACE outcome comprising CV deaths, non-fatal myocardial infarction and non-fatal stroke; however, the possibility that some members of this class might incur a small increased risk or worsening of heart failure cannot be excluded. Some studies on glucagon-like peptide-1 receptor agonists (liraglutide: LEADER trial; semaglutide: SUSTAIN-6 trial) found significant benefits for MACE, while treatment with sodium-glucose co-transporter-2 inhibitors (empagliflozin: EMPA-REG OUTCOME trial; canagliflozin: CANVAS trial) also significantly reduced MACE and reduced hospitalization for heart failure. Comparisons among trials are complicated by variance in the populations recruited, particularly CV status at randomization, and differences in trial design, data collection and analyses. A large proportion of patients recruited into these trials have previously experienced adverse CV events; thus, the therapies are mostly assessing secondary prevention of a further event. This contrasts with the overall type 2 diabetes population receiving glucose-lowering therapies, of whom the majority will not have had MACE and will be regarded as primary prevention. Overall, the trials provide reassuring evidence that new glucose-lowering medications do not adversely affect CV events and some of these agents may offer CV protection.

Decrease of cardiovascular risk in patients with type 2 diabetes: review of the common strategies and clinical studies

Military Medical Academy of S.M. Kirov, Saint-Petersburg, Russia&#x0D; Recent clinical trials about the cardiovascular safety of empagliflozin and liraglutide demonstrated a convincing lowering effect on mortality from cardiovascular causes among the patients with type 2 diabetes. These findings resulted in many questions about why this phenomenon was seen in two drugs with widely different mechanisms of functioning. It is important to note that the glucose-lowering effect was moderate, although a feature seen in both empagliflozin and liraglutide was their ability to increase insulin sensitivity. In many fundamental studies, this feature was associated with a reduction of cardiovascular risks. Insulin resistance, which has always been a pathophysiological base for the development of cardiovascular disease in patients with type 2 diabetes, is a topic for this report. Different methods to manage insulin resistance, including lifestyle changes, drug treatment and metabolic surgery, are discussed. Furthermore, the most common features of glucose-lowering drugs are analysed, including protective effects for cardiovascular outcomes in patients with type 2 diabetes presented in randomised clinical trials. Studies include the United Kingdom Prospective Diabetes Study (UKPDS), PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive), Insulin Resistance Intervention After Stroke (IRIS), Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) and the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME). The current study shows that the potential to reduce the risk of cardiovascular disease is determined not only by effective lowering of glucose but also by the ability to lower insulin resistance, which causes a paradigm shift in the management of type 2 diabetes.

The Favorable Effect of Empagliflozin on Erectile Function in an Experimental Model of Type 2 Diabetes

IntroductionFollowing the results of the EMPA-REG Outcome trial, we hypothesized that empagliflozin, a highly potent and specific sodium/glucose cotransporteur 2 inhibitor, could improve type 2 diabetes mellitus (T2DM)-associated erectile dysfunction (ED), a highly prevalent complication of T2DM, very often coexisting with cardiovascular complications and considered as a prognostic factor of cardiovascular disease in men with diabetes. AimTo investigate the effects of chronic treatment with empagliflozin on ED in a T2DM rat model in the presence or absence of sildenafil. MethodsMale Goto-Kakizaki (GK), a model of T2DM, and age-matched Wistar rats received placebo or empagliflozin treatment at 25.3 ± 0.9 mg/kg/d for 4 weeks. Then, the in vivo effect of empagliflozin on erectile function was assessed by electrical stimulation of the cavernous nerve at different frequencies under anesthesia in the presence or absence of acute intravenous injection of sildenafil. Endothelium-dependent, -independent, and nitrergic relaxations of cavernosal strips from the rats were studied. Main Outcome MeasuresBody weight, food consumption, metabolic parameters, plasma inflammation biomarkers, and in vivo erectile responses elicited by electrical stimulation of the cavernous nerve in empagliflozin-treated and untreated GK rats and control Wistar rats were assessed and followed by concentration or frequency response curves to endothelium-dependent, -independent, and nitrergic relaxations of cavernosal strips from these rats. ResultsChronic empagliflozin followed by acute sildenafil significantly improved erectile responses in adult GK rats (n = 12–15/group). Ratios of intracavernous pressure and area under the curve/mean arterial pressure during the electrical stimulation were significantly increased in empagliflozin-treated vs untreated GK rats. Nitrergic relaxations of cavernosal strips from GK rats were significantly increased with empagliflozin compared with placebo. Moreover, the effect of sildenafil on erectile function was not altered by empagliflozin treatment. Clinical ImplicationsEmpagliflozin may benefit T2DM patient with ED. Strengths & LimitationsThe mechanism(s) by which empagliflozin shows favorable effect on erectile function in GK rats needs to be further elucidated. ConclusionEmpagliflozin shows favorable effect on erectile function in diabetic GK rats mediated by an improvement of nitrergic relaxation of erectile tissue. Whether this favorable effect on ED in the experimental context of T2DM is due to better glycemic control or to another effect of empagliflozin deserves further investigation.Assaly R, Gorny D, Compagnie S, et al. The Favorable Effect of Empagliflozin on Erectile Function in an Experimental Model of Type 2 Diabetes. J Sex Med 2018;15:1224–1234.

Antihyperglycemic agents as novel natriuretic therapies in diabetic kidney disease.

While sodium-glucose cotransporter-2 (SGLT2) inhibitors have been used for the routine management of type 2 diabetes for several years, it is perhaps their natriuretic effects that are most important clinically. This natriuresis activates tubuloglomerular feedback, resulting in reduced glomerular hypertension and proteinuria, leading to renal protective effects in the EMPA-REG OUTCOME and CANVAS Program trials. In the cardiovascular system, it is likely that plasma volume contraction due to natriuresis in response to SGLT2 inhibition is at least in part responsible for the reduction in the risk of heart failure observed in these trials. We compare this mechanism of action with other antidiabetics. Importantly, other diuretic classes, including thiazide and loop diuretics, have not resulted in such robust clinical benefits in patients with type 2 diabetes, possibly because these older agents do not influence intraglomerular pressure directly. In contrast, SGLT2 inhibitors do have important physiological similarities with carbonic anhydrase inhibitors, which also act proximally, and have been shown to activate tubuloglomerular feedback.

P5334Effect of empagliflozin on cardiovascular events including recurrent events in the EMPA-REG OUTCOME trial

P5334Effect of empagliflozin on cardiovascular events including recurrent events in the EMPA-REG OUTCOME trial

P1876Empagliflozin reduces mortality in patients with type 2 diabetes and a history of left ventricular hypertrophy: a sub-analysis of the EMPA-REG OUTCOME trial

P1876Empagliflozin reduces mortality in patients with type 2 diabetes and a history of left ventricular hypertrophy: a sub-analysis of the EMPA-REG OUTCOME trial

The safety of empagliflozin plus metformin for the treatment of type 2 diabetes

ABSTRACTIntroduction: Metformin is the first-line glucose-lowering medication in type 2 diabetes mellitus (T2DM), but it generally requires soon or later the addition of a second-line therapy, among which a sodium-glucose cotransporter type 2 (SGLT-2) inhibitor, to reach and maintain adequate glucose control.Areas covered: This narrative review provides an analysis of both efficacy and safety of a dual therapy combining metformin and empagliflozin, a SGLT-2 inhibitor that has proven its’ potential to reduce major cardiovascular (CV) events, mortality, and renal outcomes in patients with T2DM and established CV disease. Pharmacokinetic studies showed the absence of drug–drug interactions and demonstrate bioequivalence between fixed-dose combination (FDC) and individual tablets of empagliflozin and metformin. Focus will be put on the use of this dual therapy in special populations.Expert opinion: The addition of empagliflozin to metformin therapy improves glucose control, with a minimal risk of hypoglycemia, while reducing body weight and arterial blood pressure. EMPA-REG OUTCOME showed that this combined therapy may be used in patients with established CV disease or heart failure. However, caution may be required in fragile elderly patients and in patients with severe impaired renal function. Further post-marketing surveillance is recommended to demonstrate long-term safety. FDC may improve adherence.

Empagliflozin is associated with improvements in liver enzymes potentially consistent with reductions in liver fat: results from randomised trials including the EMPA-REG OUTCOME\xae trial

Aims/hypothesisIn addition to beneficial effects on glycaemia and cardiovascular death, empagliflozin improves adiposity indices. We investigated the effect of empagliflozin on aminotransferases (correlates of liver fat) in individuals with type 2 diabetes.MethodsChanges from baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assessed in the EMPA-REG OUTCOME® trial (n = 7020), pooled data from four 24-week placebo-controlled trials (n = 2477) and a trial of empagliflozin vs glimepiride over 104 weeks (n = 1545). Analyses were performed using data from all participants and by tertiles of baseline aminotransferases.ResultsIn the EMPA-REG OUTCOME® trial, mean ± SE changes from baseline ALT at week 28 were −2.96 ± 0.18 and −0.73 ± 0.25 U/l with empagliflozin and placebo, respectively (adjusted mean difference: −2.22 [95% CI −2.83, −1.62]; p < 0.0001). Reductions in ALT were greatest in the highest ALT tertile (placebo-adjusted mean difference at week 28: −4.36 U/l [95% CI −5.51, −3.21]; p < 0.0001). The adjusted mean difference in change in ALT was −3.15 U/l (95% CI −4.11, −2.18) with empagliflozin vs placebo at week 24 in pooled 24-week data, and −4.88 U/l (95% CI −6.68, −3.09) with empagliflozin vs glimepiride at week 28. ALT reductions were largely independent of changes in weight or HbA1c. AST changes showed similar patterns to ALT, but the reductions were considerably lower.Conclusions/interpretationThese highly consistent results suggest that empagliflozin reduces aminotransferases in individuals with type 2 diabetes, in a pattern (reductions in ALT>AST) that is potentially consistent with a reduction in liver fat, especially when ALT levels are high.