Search

Severe insulin resistance syndromes result from primary insulin signaling defects, adipose tissue abnormalities or other complex syndromes. Mutations in TBC1D4lead to partial insulin signaling defects, characterized mainly by postprandial insulin resistance. We describe an individual with severe insulin-resistant diabetes unresponsive to multiple therapies, in whom exome and genome analyses identified a complex rearrangement in TBC1D4. The rearrangement was of the pattern DUP-TRP/INV-DUP, with mutational signatures suggestive of replicative repair and Alu-Alurecombination as the underlying mechanisms. TBC1D4encodes the TBC1D4/AS160 RabGTPase activating protein (RabGAP) involved in the translocation of glucose transporter 4 (GLUT4) from the cytosol to the cell membrane. Although the precise functional mechanism underlying insulin resistance in the proband is yet to be determined, this case provides further support for the link between TBC1D4and hereditary insulin-resistant diabetes.

IMPORTANCE: Dapagliflozin reduces the risk of hospitalizations for heart failure and the progression of chronic kidney disease in patients with and without type 2 diabetes (T2D), whereas the effects on reducing atherosclerotic events appear less clear. OBJECTIVE: To explore whether N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) levels can identify a subset of patients with T2D at higher risk and who might benefit more from dapagliflozin with regard to atherosclerotic events. DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of the DECLARE-TIMI 58 trial, a randomized clinical trial of dapagliflozin in patients with T2D and either multiple risk factors for atherosclerotic cardiovascular disease (ASCVD; approximately 60%) or established ASCVD (approximately 40%). All patients with available blood samples at randomization were included in these analyses. Data were collected from May 2013 to September 2018, and data were analyzed from May 2019 to June 2022. INTERVENTIONS: Dapagliflozin vs placebo. MAIN OUTCOMES AND MEASURES: Major adverse cardiovascular events (MACE), the composite of myocardial infarction, ischemic stroke, or cardiovascular death, which was one of dual primary outcomes of the main trial. RESULTS: Of 14 565 included patients, 9143 (62.8%) were male, and the mean (SD) age was 63.9 (6.8) years. When tested individually in a multivariable model for MACE risk, NT-proBNP and hsTnT were each significantly associated with the risk of MACE (adjusted hazard ratio [aHR] per 1 SD in log-transformed biomarker: NT-proBNP, 1.62; 95% CI, 1.49-1.76; hsTnT: 1.59; 95% CI, 1.46-1.74). The magnitude of the association was similar in patients with ASCVD (NT-proBNP: aHR, 1.60; 95% CI, 1.45-1.77; hsTnT: aHR, 1.62; 95% CI, 1.45-1.81) and multiple risk factors for ASCVD (NT-proBNP: aHR, 1.62; 95% CI, 1.40-1.88; hsTnT: aHR, 1.51; 95% CI, 1.29-1.77). Moreover, both biomarkers remained independently associated with MACE when both were included in the multivariable model (NT-proBNP: aHR, 1.46; 95% CI, 1.34-1.60; hsTnT: aHR, 1.39; 95% CI, 1.26-1.53). Modeled as a continuous variable, baseline biomarker levels did not modify the relative treatment effect of dapagliflozin vs placebo with MACE. However, the relative risk reduction numerically grew with higher biomarker levels, as did the baseline risk. Thus, MACE event rates were nominally lower in dapagliflozin-treated vs placebo-treated patients with biomarker concentrations in the top quartile (NT-proBNP: HR, 0.83; 95% CI, 0.71-0.97; absolute risk reduction [ARR], 2.4%; hsTnT: HR, 0.85; 95% CI, 0.72-0.99; ARR, 2.7%), whereas there was no significant treatment effect in patients with biomarkers levels in quartiles 1 to 3 (NT-proBNP: HR, 1.02; 95% CI, 0.88-1.18; ARR, 0%; hsTnT: HR, 0.97; 95% CI, 0.84-1.13; ARR, 0.2%). CONCLUSIONS AND RELEVANCE: In this study, NT-proBNP and hsTnT levels were associated with the risk for future cardiovascular events in both primary and secondary prevention patients with T2D. Both cardiac biomarkers were helpful to identify patients at very high risk for atherosclerotic events that may derive reduction in risk of MACE with dapagliflozin. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01730534

In people with type 2 diabetes at high risk of cardiovascular or kidney disease, sodium-glucose co-transporter 2 (SGLT2) inhibitors consistently reduce the risk of hospitalisations for heart failure. Less is known about their effects on hospitalisation from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease, which includes most of the global population of people with type 2 diabetes. We aimed to assess the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease.

IMPORTANCE: Dapagliflozin was shown to reduce the cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes. However, data are limited on the relationship of the effect and safety with the concurrent use of CV medications in patients with type 2 diabetes. OBJECTIVE: To assess whether the cardiorenal efficacy and safety of dapagliflozin were consistent with and without background use of CV medications commonly used for heart failure (HF) and kidney disease in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: This study is a prespecified secondary analysis of DECLARE-TIMI 58, which was a randomized trial of dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and either atherosclerotic disease or multiple risk factors for CV disease. Patients were stratified by baseline use of the following CV medications: angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEI/ARBs), β-blockers, diuretics, and mineralocorticoid receptor antagonists (MRAs). The study was conducted from May 2013 to September 2018, and data were evaluated for this analysis from February 2021 to May 2022. INTERVENTIONS: Dapagliflozin or placebo. MAIN OUTCOMES AND MEASURES: The outcomes of interest were the composite of CV death or hospitalization for HF (HHF), HHF alone, and a kidney-specific composite outcome (persistent ≥40% decrease in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney-related death). RESULTS: Among 17 160 patients, 13 950 (81%) used ACEI/ARBs, 9030 (53%) used β-blockers, 6205 (36%) used diuretics, and 762 (4%) used MRAs at baseline. Changes in blood pressure and eGFR at 48 months with dapagliflozin compared with placebo did not differ regardless of concurrent therapy (placebo-corrected change, −1.6 mm Hg [95% CI, −4.2 to 1.0] to −2.6 mm Hg [95% CI, −3.3 to −2.9]; P > .05 for each interaction). Dapagliflozin consistently reduced the risk of CV death/HHF, HHF alone, and the kidney-specific composite outcome regardless of background use of selected medications (hazard ratio [HR] range: HR, 0.50; 95% CI, 0.39-0.63; to HR, 0.82; 95% CI, 0.72-0.95; P > .05 for each interaction). In patients receiving ACEI/ARBs + β-blockers + diuretics (n = 4243), dapagliflozin reduced the risk of CV death/HHF and of the kidney-specific outcome by 24% (HR, 0.76; 95% CI, 0.62-0.93) and 38% (HR, 0.62; 95% CI, 0.44-0.87), respectively. There were no significant treatment interactions with the concomitant CV medications for adverse events of volume depletion, acute kidney injury, or hyperkalemia (range: HR, 0.12; 95% CI, 0.02-0.99; to HR, 1.04; 95% CI, 0.83-1.32; P > .05 for each interaction). CONCLUSIONS AND RELEVANCE: Dapagliflozin consistently reduced the risk of CV and kidney outcomes irrespective of background use of various CV medications without any treatment interaction for key safety events. These data show the clinical benefit and safety of dapagliflozin in a broad range of patients with type 2 diabetes regardless of background therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01730534

IMPORTANCE: Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown. OBJECTIVE: To assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR). DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (<60 vs ≥60 mL/min/1.73 m2), urinary albumin to creatinine ratio (UACR; <30 vs ≥30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018. INTERVENTIONS: Dapagliflozin vs placebo. MAIN OUTCOMES AND MEASURES: The dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF. RESULTS: At baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, −0.5%; 1 marker, −1.0%; and 2 markers, −8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher. CONCLUSIONS AND RELEVANCE: The effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01730534

Supplemental Digital Content is available in the text.

The association of inpatient glucose measurements with amputations in patients admitted with acute diabetic foot has not been described.

Supplemental Digital Content is available in the text.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown beneficial effects on renal outcomes mainly in patients with established atherosclerotic cardiovascular disease. Here we report analyses of renal outcomes with the SGLT2 inhibitor dapagliflozin in the DECLARE–TIMI 58 cardiovascular outcomes trial, which included patients with type 2 diabetes both with and without established atherosclerotic cardiovascular disease and mostly with preserved renal function.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined.

Introduction:Circulating cardiovascular (CV) biomarkers, including N-terminal pro-B type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT), are associated with risk of heart failure (HF) events in patients (pts) with type 2 diabetes (T2D). Less is known about the prognostic significance of changes in these biomarkers over time or the early effects of the SGLT2i dapagliflozin (dapa) on these markers.Methods:DECLARE-TIMI 58 was a randomized, placebo-controlled trial of dapa in 17,160 pts with T2D (median f/u = 4.2y). NT-proBNP & hsTnT (Roche) were measured at baseline & 6 mo. The outcome of interest was CV death (CVD) or hosp for HF (HHF). Outcome analyses were performed from a landmark of the 6-mo study visit with pts categorized by change in each biomarker over the first 6 mo. Hazard ratios were adjusted for baseline biomarker value, randomized treatment, age, sex, race, smoking, eGFR, prior HF, BMI, T2D duration, insulin use, CAD, prior MI, ischemic stroke, PAD, dyslipidemia, & hypertension. Linear mixed models were used to assess the effect of dapa on log-transformed NT-proBNP & hsTnT.Results:Serial NT-proBNP & hsTnT values were available in 13,459 pts (78%). Among pts allocated to placebo (n=6,698), NT-proBNP was more dynamic than hsTnT (≥20% change from baseline in 71% vs. 33% of pts; p<0.001). In the full cohort, independent of randomized treatment, there was a stepwise graded relationship between change in NT-proBNP & hsTnT and risk of CVD/HHF, whereby increases in either biomarker were associated with higher risk and decreases in either biomarker were associated with lower risk (p-trend for adj-HR <0.001 for each). Considered together, changes in the 2 markers were complementary (Fig; p<0.001). Dapa significantly reduced NT-proBNP (relative LS mean change, -6% [-4% to -8%]; p<0.001) but not hsTnT (0% [-1% to +1%]; p=0.92) over 6 mo.Conclusions:Early changes in hsTnT & NT-proBNP are associated with subsequent risk of CVD/HHF in pts with T2D.

Background:In the DECLARE-TIMI 58 trial, involving patients with type 2 diabetes at high cardiovascular (CV) risk, dapagliflozin reduced the risk for heart failure hospitalization and adverse kidney outcomes, compared to placebo. Whether dapagliflozin lowers the risks for the broader outcome of adverse event (AE)-related hospital admissions is unknown.Methods:The DECLARE-TIMI 58 trial randomized 17,160 subjects with type 2 diabetes and a high risk for or established CV disease, to receive dapagliflozin or placebo (1:1). Dapagliflozin effect on AE-related hospital admissions was assessed overall and by baseline cardiovascular and kidney subgroups. Investigator reported system organ class classification was used to evaluate dapagliflozin's effects on admissions due to different etiologies.Results:Over a median follow up of 4.2 years, dapagliflozin reduced the risk of AE-related hospital admissions by 11% (32.4% vs. 35.4% of participants, HR 0.89 [95% CI 0.85, 0.94]; p<0.0001). The reduction in AE-related hospital admissions was consistent across baseline cardiovascular and kidney subgroups (p-interaction≥0.30) (Figure). Dapagliflozin reduced the risk for admissions due to cardiac disorders (HR 0.91 [95% CI 0.84,0.995] p=0.0387), renal or urinary disorders (0.61 [0.49, 0.77] p<0.0001), and other non-cardiac, non-renal etiologies (0.89 [0.84,0.95] p=0.0001).Conclusion:Dapagliflozin reduced the risk for AE-related hospital admissions, including non-cardiac and non-renal hospitalizations, in patients with type 2 diabetes. These findings have implications for patients' quality of life and overall type 2 diabetes-attributed healthcare burden.

ABSTRACTIntroduction: DPP-4 inhibitors are a class of compounds used for the treatment of type 2 diabetes. The drugs inhibit the degradation of GLP-1, thus amplifying the incretin effect. They have moderate glycemic efficacy, a low propensity of causing hypoglycaemia and are weight neutral. The drugs are often used as second line therapy after metformin.Areas covered: This review summarizes the available compounds in the market and discusses the novel compounds that are currently under development. Several large cardiovascular outcome trials with some of the compounds have been completed, and their results and implications are considered. Fixed dose combination pills are currently the main focus of research and the contribution of these to the care of patients with diabetes is further discussed.Expert opinion: The DPP-4 inhibitors have been a successful class in drug development for diabetes. Taken orally and available as fixed dose combinations with metformin or with SGLT-2 inhibitors, they have reached a large market share of over 7 billion dollars. Other than retagliptin, it does not appear that any additional compound will be launched soon. Currently, the main focus is on the development of additional fixed dose combinations with SGLT-2 inhibitors, but the success of these combinations remains to be seen.

ABSTRACTIntroduction:The safety of agents used to treat type 2 diabetes (T2D), a chronic disease requiring life-long intervention, is of particular interest. Saxagliptin is a potent and selective DPP-4 inhibitor that has emerged as a therapeutic option for T2D.Areas covered:Its safety was assessed in a development program of 20 phase 2/3 randomized clinical trials and in SAVOR-TIMI 53 trial that evaluated the cardiovascular outcomes. In order to capture any further safety signals, mainly in the long-term, a post-marketing safety surveillance is ongoing. This paper discusses the tolerability and safety profile of the agent, including cardiovascular, renal, pancreatic, hepatic and bone adverse events.Expert opinion:Saxagliptin is a safe therapeutic option for patients with T2D, with low risk of hypoglycemia and good tolerability. It demonstrated cardiovascular safety (including in patients with pre-existing cardiovascular disease and/or HF) and safety with respect to all-cause mortality and adverse events of special interest. In SAVOR-TIMI53, saxagliptin was associated with an unexpected increased risk of HF hospitalization, mainly in the first 12 months; a mechanistic explanation for this has not been found. Further research needs to elucidate the effect of antidiabetic drugs on the heart, by including biomarkers and echocardiographic sub-studies within large outcome trials.

Insulin is a common treatment option for many patients with type 2 diabetes, and is generally used late in the natural history of the disease. Its injectable delivery mode, propensity for weight gain and hypoglycaemia, and the paucity of trials assessing the risk-to-safety ratio of early insulin use are major shortcomings associated with its use in patients with type 2 diabetes. Development of new insulins—such as insulin analogues, including long-acting and short-acting insulins—now provide alternative treatment options to human insulin. These novel insulin formulations and innovative insulin delivery methods, such as oral or inhaled insulin, have been developed with the aim to reduce insulin-associated hypoglycaemia, lower intraindividual pharmacokinetic and pharmacodynamic variability, and improve imitation of physiological insulin release. Availability of newer glucose-lowering drugs (such as glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose co-transporter-2 inhibitors) also offers the opportunity for combination treatment; the results of the first trials in this area of research suggest that such treatment might lead to use of reduced insulin doses, less weight gain, and fewer hypoglycaemic episodes than insulin treatment alone. These and future developments will hopefully offer better opportunities for individualisation of insulin treatment for patients with type 2 diabetes.

Introduction:The dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are novel oral hypoglycemic drugs which have been in clinical use for the past 7 years. The drugs are safe, weight neutral and widely prescribed. There are currently eight gliptins registered worldwide with several more in advanced stages of development.Areas covered:The place of the gliptins in the treatment algorithm of type 2 diabetes is discussed as well as unique features of the individual drugs. The gliptins may possess cardiovascular protective effects and their administration may promote β-cell survival; claims currently being evaluated in clinical and preclinical studies. The global market revenues and future prospects of the gliptins are discussed and the gliptins in Phases II and III of development are reviewed.Expert opinion:The gliptins are an optional second-line therapy after metformin; they are generally well tolerated with low risk of hypoglycemia. The various compounds differ with respect to their pharmacokinetic and pharmacodynamic properties; however, their clinical efficacy appears to be similar. The clinical differences between the various compounds stem from effects other than hypoglycemic effects, their safety and side effects profile. The currently registered compounds appear to have maximized the clinical potential of DPP-4 inhibition, and the new compounds in the companies' pipelines seem to be as effective as the ones presently in use. There are two gliptins in advanced stages of development which will be registered for once-weekly dosing, possibly increasing patient adherence to therapy. Several individual gliptins are being evaluated for treatment in diabetes subpopulations such as type 1 patients or adolescents.

SGLT2 inhibitors (SGLT2i) are effective in the management of diabetes and in reducing adverse cardiovascular and renal outcomes. Randomized clinical trials demonstrated safety and tolerability in older adults. Adverse effects associated with SGLT2i are impacted by patient frailty, comorbidities, and concomitant medication use and, therefore, must be thoroughly evaluated before initiating treatment. The risk of volume depletion, hypoglycemia, genital infections, and diabetic ketoacidosis can be minimized by appropriate patient selection, patient education, and early symptom recognition. Limited data exists regarding the risk of urinary tract infections, fractures, and amputations in the elderly treated with SGLT2i and routine monitoring is recommended.

Introduction:SGLT2 inhibitors reduce cardiovascular (CV) risk in a broad range of patients including those with and without type 2 diabetes mellitus (DM). In addition, non-glycemic effects modify parameters that define metabolic syndrome (MetS) such as weight, BP, and lipid profile. In this context, we investigated the effects of dapagliflozin on key components of MetS and the association with outcomes.Methods:17,160 patients with DM were randomized to dapagliflozin or placebo in DECLARE-TIMI 58. Since all had DM, MetS was classified using a modification of IDF criteria requiring BMI ≥30 kg/m2and ≥1 of the following: triglycerides ≥150 mg/dL, HDL-C <40 in men or <50 mg/dL in women, SBP ≥130 or DBP ≥85 mmHg. Classification of MetS and its subcomponents were tracked at baseline and follow-up visits (6-48 months). An analysis adjusted for baseline characteristics and treatment was performed to assess the association of MetS with key outcomes.Results:At baseline, 53% had MetS. On adjusted analysis, MetS was predictive of CV death or hospitalization for heart failure (CVD/HHF) (HR 1.28, 95%CI 1.11-1.47, p<0.001), HHF (HR 1.62, 95%CI 1.33-1.97, p<0.001), and MI (HR 1.22, 95%CI 1.05-1.4, p=0.008). From 6 to 48 months, there was a lower prevalence of MetS in the dapagliflozin arm (47.9% vs. 52.5%, p<0.001, Figure 1), as well as lower prevalence of BMI ≥30 kg/m2(54.9% vs. 58.0%), low HDL-C (38.7% vs. 42.6%), and elevated BP (58.2% vs. 65.7%) with p<0.001 for each. In the dapagliflozin arm, there were lower odds of progression to MetS (10.5% vs. 13.5%; OR 0.76, 95%CI 0.64-0.89, p<0.001) and, in those with MetS at baseline, higher odds of regression (24.6% vs. 18.3%; OR 1.45, 95%CI 1.29-1.64, p<0.001) at 48 months.Conclusions:The presence of MetS is prognostically important in patients with DM. Dapagliflozin led to significant early and sustained changes in the likelihood of MetS.

Introduction:Women remain underrepresented in clinical trials and at high risk for CV events in type 2 DM (T2DM). The SGLT-2 inhibitor dapagliflozin (DAPA) reduces CV death or HF hospitalizations (CVD/HHF) in T2DM, but the relative benefit in women versus men is undefined.Methods:DECLARE-TIMI 58 randomized 17,160 patients with T2DM with or at risk for atherosclerotic disease to DAPA or placebo (median f/up 4.2y). The dual efficacy outcomes were the composite of CVD/HHF and CV death, MI or ischemic stroke (MACE). Cox models were stratified by sex. The prespecified renal-specific outcome was a ?40% drop in eGFR to <60 ml/min/1.73m2, new ESRD, or renal death. Reported safety events were those leading to drug discontinuation or serious adverse events (SAEs).Results:At baseline, women (n=6422, 37%) tended to be older, have a higher BMI, higher HbA1c and longer duration of T2DM than men, but were on fewer antihyperglycemic meds and less likely to have established CV disease. DAPA reduced CVD/HHF by 16% in women (HR 0.84, 0.66-1.07) and 17% in men (HR 0.83, 0.71-0.96; P int=0.90; Fig). The HRs for MACE with DAPA were similar in women (HR 0.93, 95% CI 0.77-1.12) and men (HR 0.93, 0.83-1.05; P int=0.99). Renal-specific events were reduced by 50% in women (HR 0.50, 0.35-0.70) and 45% in men (HR 0.55, 0.42-0.73; P int=0.64). Treatment emergent SAEs were less common in DAPA than placebo-treated patients in both women (29.3% vs 31.5%) and men (36.9% vs 39.0%; P int=0.78). Urinary tract infections were similar in DAPA vs placebo (women: 2.2% vs 2.1%; men: 1.0% vs 1.2%; P int=0.30), but genital infections were more common with DAPA in both women (1.0% vs 0.1%) and men (0.8% vs 0.1%; P int=0.93).Conclusions:Antihyperglycemic drugs are used less frequently in women than men, despite longer duration of DM and higher HbA1c. The SGLT-2 inhibitor DAPA offers comparable CV benefit and safety profiles in both women and men. These findings lend support to the use of SGLT-2 inhibitors in women with T2DM.

The latest findings from the EMPA-REG OUTCOME trial show a 34% reduction in hospitalization for heart failure or cardiovascular death in patients receiving empagliflozin, a sodium/glucose cotransporter 2 (SGLT2) inhibitor, compared with placebo. These outstanding results call for discussion of the clinical implications, and in-depth studies of the mechanisms of action of SGLT2 inhibitors.