Search

AimTo investigate multiple risk factor target attainment in adults with diabetes mellitus (DM) for atherosclerotic cardiovascular disease (ASCVD) prevention and the predictors of such attainment in a contemporary DM registry.MethodsIn the US Diabetes Collaborative Registry we identified patients who were at target for glycated haemoglobin (HbA1c; < 53 mmol/mol (7%) or < 64 mmol/mol (8%) if with ASCVD), LDL cholesterol (< 2.6 mmol/L (100 mg/dL) or < 1.8 mmol/L (70 mg/dL) 1.8 if with ASCVD) and blood pressure (BP;

Aims: To investigate the effects of empagliflozin on measured glomerular filtration rate (mGFR), estimated plasma volume (PV) and estimated extracellular volume (ECV) in a cohort of patients with type 2 diabetes (T2D) and high risk of cardiovascular events. Materials and Methods: In this prespecified substudy of the randomized, placebo‐controlled SIMPLE trial, patients with T2D at high risk of cardiovascular events were allocated to either empagliflozin 25 mg or placebo once daily for 13 weeks. The prespecified outcome was between‐group change in mGFR, measured by the 51Cr‐EDTA method after 13 weeks; changes in estimated PV and estimated ECV were included. Results: From April 4, 2017 to May 11, 2020, 91 participants were randomized. Of these, 45 patients from the empagliflozin group and 45 patients from the placebo group were included in the intention‐to‐treat analysis. Treatment with empagliflozin reduced mGFR by −7.9 mL/min (95% confidence interval [CI] −11.1 to −4.7; P < 0.001), estimated ECV by −192.5 mL (95% CI −318.0 to −66.9; P = 0.003) and estimated PV by −128.9 mL (95% CI −218.0 to 39.8; P = 0.005) at Week 13. Conclusions: Treatment with empagliflozin for 13 weeks reduced mGFR, estimated ECV and estimated PV in patients with T2D and high risk of cardiovascular events. [ABSTRACT FROM AUTHOR]

Aim: To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants. Materials and methods: In SOUL, the effects of oral semaglutide, the first oral glucagon‐like peptide‐1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double‐blind, parallel‐group, placebo‐controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2). The primary outcome is time from randomization to first occurrence of a major adverse CV event (MACE; a composite of CV death, nonfatal myocardial infarction or nonfatal stroke). This event‐driven trial will continue until 1225 first adjudication‐confirmed MACEs have occurred. Enrolment has been completed. Results: Overall, 9650 participants were enrolled between June 17, 2019 and March 24, 2021 (men 71.1%, White ethnicity 68.9%, mean age 66.1 years, diabetes duration 15.4 years, body mass index 31.1 kg/m2, glycated haemoglobin 63.5 mmol/mol [8.0%]). The most frequently used antihyperglycaemic medications at baseline were metformin (75.7%), insulin and insulin analogues (50.5%), sulphonylureas (29.1%), sodium‐glucose cotransporter‐2 inhibitors (26.7%) and dipeptidyl peptidase‐4 inhibitors (23.0%). At randomization, 70.7% of participants had CAD, 42.3% had CKD, 21.1% had cerebrovascular disease and 15.7% had symptomatic PAD (categories not mutually exclusive). Prevalent heart failure was reported in 23.0% of participants. Conclusion: SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD. [ABSTRACT FROM AUTHOR]

Objective: Ectopic accumulation of cardiac adipose tissue volume (CAT) has been associated with cardiac remodelling and cardiac dysfunction in type 2 diabetes and may be a future therapeutic target. In this substudy from the SIMPLE‐trial, we investigated short‐term empagliflozin therapy's effects on CAT in patients with type 2 diabetes. Research design and Methods: Between 4 April 2017 and 11 May 2020, we randomized 90 patients with type 2 diabetes and established or high risk of cardiovascular disease to 25 mg empagliflozin or placebo for 13 weeks. The substudy focused on change in CAT evaluated by images acquired during 82Rubidium‐positron emissions tomography/computed tomography. The analysis included 78 patients who had at least one scan. Furthermore, we report on the relation to the concurrent effects on left ventricular mass, end‐diastolic volume and end‐systolic volume, body composition and glucometabolic status. Results: Mean ± SD baseline CAT was 258.5 ± 117.9 ml. Empagliflozin reduced CAT after 13 weeks by 12.41 ml [95% CI (−23.83 to −0.99), p =.034] as compared with placebo. Similarly, left ventricular mass [−5.16 g, 95% CI (−8.80 to −1.52), p =.006], end‐diastolic volume and end‐systolic volume decreased with empagliflozin. In addition, significant improvements were observed in body composition, with reduced total fat mass, and in measures of glucose and lipid metabolism. However, no correlation was observed between changes in CAT and changes in cardiac parameters and change in CAT appeared mediated primarily by concurrent change in weight. Conclusions: Empagliflozin provides an early reduction of CAT; however, no association was observed with concurrent changes in cardiac volumetrics. [ABSTRACT FROM AUTHOR]

Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors are now seen as an integral part of therapy in type 2 diabetes to control not only blood glucose but to improve cardiovascular and kidney outcomes. Diabetic ketoacidosis (DKA) is an uncommon but serious complication of type 2 diabetes, which has a high case fatality rate. The absolute risk of DKA in large, prospective randomized clinical trials in people with type 2 diabetes using SGLT2 inhibitors has been low, although the relative risk is higher in those assigned to SGLT2 inhibitors compared with placebo. In those without diabetes but prescribed SGLT2 inhibitors for heart failure or chronic kidney disease, the risk of DKA is similar to placebo. Over the course of the COVID‐19 pandemic, cases of DKA have also been reported in cases of COVID‐19 hospitalizations. Consensus guidelines have recommended that SGLT2 inhibitors should be avoided in cases of serious illness and suggest they are not recommended for routine in‐hospital use. However, recent data suggest potential beneficial effects of SGLT2 inhibitors in the setting of acute illness with COVID‐19 with no increase in adverse events and low rates of DKA, which were non‐severe. Given the low rates of DKA in cardiovascular outcome trials and in hospitalized patients with type 2 diabetes, the potential for SGLT2 inhibitors not being re‐initiated following discharge and their cardiovascular and kidney benefits, we believe the practice of routine 'sick day' guidance should be re‐examined based on current evidence with a call for further research in this area. Furthermore, high‐quality trials of initiation of SGLT2 inhibitors in people admitted to hospital with cardiovascular disease or kidney disease, and trials of continuation of SGLT2 inhibitors in people, with careful monitoring of DKA should be conducted. These should be further supplemented with large observational studies. [ABSTRACT FROM AUTHOR]

Aims: Pioglitazone is a potent insulin‐sensitizing drug with anti‐atherosclerotic properties, but adverse effects have limited its use. We assessed the benefits and risks of lower versus higher doses of pioglitazone taken by participants in the Insulin Resistance Intervention in Stroke Trial. Materials and Methods: Efficacy [myocardial infarction (MI) or recurrent stroke] new‐onset diabetes) and adverse outcomes (oedema, weight gain, heart failure and bone fracture) were examined for subjects assigned to pioglitazone or placebo within strata defined by mode dose of study drug taken (i.e. the dose taken on most days in the study). Results: Among the 1938 patients randomized to pioglitazone, the mode dose was <15 mg/day in 546 participants, 15 mg/day in 128, 30 mg/day in 89, and 45 mg/day in 1175. There was no significant effect on stroke/MI or new‐onset diabetes with <15 mg/day. For 15 mg/30 mg/day pooled, the adjusted hazard ratios (95% CI) for stroke/MI were 0.48 (0.30, 0.76; p =.002) and 0.74 (0.69, 0.94) for 45 mg/day. For new‐onset diabetes, the adjusted hazard ratios were 0.34 (0.15, 0.81; p =.001) and 0.31 (0.59, 0.94; p =.001) respectively. For oedema, weight gain and heart failure, the risk estimates for pioglitazone were lower for subjects taking <45 mg daily. For fractures, the increased risk with pioglitazone was similar across all dose strata. Conclusions: Lower doses of pioglitazone appear to confer much of the benefit with less adverse effects than the full dose. Further study is needed to confirm these findings so that clinicians may optimize dosing of this secondary prevention strategy in patients with stroke. [ABSTRACT FROM AUTHOR]

Aims: Empagliflozin treatment reduced liver fat in small type 2 diabetes cohorts. This post‐hoc study evaluated effects of empagliflozin on risk for non‐alcoholic fatty liver disease‐related steatosis and fibrosis, as well as the relationship between risk categories and cardiorenal outcomes in the randomized, placebo‐controlled EMPA‐REG OUTCOME trial. Materials and methods: EMPA‐REG OUTCOME treated 7020 people with type 2 diabetes and cardiovascular disease with 10/25 mg/day empagliflozin or placebo. For this analysis, the Dallas steatosis index, hepatic steatosis index, non‐alcoholic fatty liver disease fibrosis score and Fibrosis‐4 score were calculated to assess steatosis and fibrosis risk. Changes from baseline in scores were examined by mixed model repeated measures and their associations with cardiorenal outcomes and mortality by Cox regression. Results: At baseline, 73% and 84% of participants had high steatosis risk by Dallas steatosis index and hepatic steatosis index, whereas 23% and 4% had a high risk of advanced fibrosis by non‐alcoholic fatty liver disease fibrosis score and Fibrosis‐4 score. Percentages of people at high steatosis risk slightly decreased with empagliflozin only, whereas empagliflozin did not improve percentages of individuals at high fibrosis risk over time compared with placebo. The high risk of advanced fibrosis at baseline related to higher risk for cardiovascular events. Effects of empagliflozin on cardiorenal and all‐cause mortality outcomes were consistent across all risk groups. Conclusions: Empagliflozin may reduce steatosis but not fibrosis risk in individuals with type 2 diabetes and cardiovascular disease. The improvements in cardiorenal outcomes and mortality associated with empagliflozin therapy appear to be independent of steatosis and fibrosis risk. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of empagliflozin on uric acid (UA) levels, antigout medication and gout episodes in the EMPA‐REG OUTCOME trial (NCT01131676). Materials and methods: A total of 7020 patients with type 2 diabetes (T2D) were randomized to either empagliflozin (10 or 25 mg) or placebo. The effects of empagliflozin versus placebo on UA concentration were assessed using mixed linear models. A composite outcome of new prescription of antigout medication or gout episode was studied with Cox proportional hazards models. Results: Empagliflozin reduced serum UA levels versus placebo: week 52 adjusted mean treatment difference = −0.37 (95% confidence interval [CI] −0.42, −0.31) mg/dL; this was more pronounced in patients with baseline UA ≥ 7.0 mg/dL versus <7.0 mg/dL: week 52 adjusted mean treatment difference = −0.56 (95% CI −0.68, −0.43) and −0.30 (95% CI −0.37, −0.24) mg/dL, respectively. Among 6607 patients not taking antigout medications at baseline, 5.2% had a gout episode or initiated antigout treatment versus 3.6% in the placebo and empagliflozin groups, respectively: hazard ratio 0.67 (95% CI 0.53, 0.85; P = 0.001). Both components of the composite outcome contributed to the reduction with empagliflozin in the composite. Risk reduction was similar with both empagliflozin doses. Conclusions: Empagliflozin reduced UA levels and the composite of gout episodes or prescription of antigout medication. These clinically important findings expand the utility of empagliflozin as a potential antigout treatment in patients with T2D, beyond its well‐established cardio‐renal benefits. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effects of empagliflozin versus placebo on subsequent insulin initiation or dosing changes in a large cardiovascular outcomes trial. Materials and Methods: In EMPA‐REG OUTCOME, 7020 patients with type 2 diabetes and cardiovascular disease received empagliflozin 10 mg, 25 mg, or placebo. Median follow‐up was 3.1 years. After 12 weeks of treatment, changes in background antihyperglycaemic therapy were permitted. Among insulin‐naïve patients, we assessed the effects of pooled empagliflozin arms versus placebo on time to initiation of insulin. Among insulin‐treated patients, we assessed effects on time to an increase or decrease in insulin dose of more than 20%. Results: In 3633 (52%) participants not treated with insulin at baseline, empagliflozin reduced new use of insulin versus placebo by 60% (7.1% vs. 16.4%; adjusted HR 0.40 [95% CI 0.32‐0.49]; P <.0001). In 3387 (48%) patients using insulin at baseline, empagliflozin reduced the need for a greater than 20% insulin dose increase by 58% (14.4% vs. 29.3%; adjusted HR 0.42 [95% CI 0.36‐0.49]; P <.0001) and increased the proportion achieving sustained greater than 20% insulin dose reductions without subsequent increases in HbA1c compared with placebo (9.2% vs. 4.9%; adjusted HR 1.87 [95% CI: 1.39‐2.51]; P <.0001). Sensitivity analyses confirmed consistent findings when insulin dose changes of more than 10% or more than 30% were considered. Conclusions: In patients with type 2 diabetes and cardiovascular disease, empagliflozin markedly and durably delays insulin initiation and substantial increases in insulin dose, while facilitating sustained reductions in insulin requirements over time. [ABSTRACT FROM AUTHOR]

Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular death or worsening heart failure (HF), and improve symptom burden, physical function and quality of life in patients with HF and reduced ejection fraction. The mechanisms of the HF benefits of SGLT2 inhibitors, however, remain unclear. In this substudy of the DEFINE‐HF trial, patients randomized to dapagliflozin or placebo had lung fluid volumes (LFVs) measured by remote dieletric sensing at baseline and after 12 weeks of therapy. A significantly greater proportion of dapagliflozin‐treated patients (as compared with placebo) experienced improvement in LFVs and fewer dapagliflozin‐treated patients had no change or deterioration in LFVs after 12 weeks of treatment. To our knowledge, this is the first study to suggest a direct effect of dapagliflozin (or any SGLT2 inhibitor) on more effective "decongestion", contributing in a meaningful way to the ongoing debate regarding the mechanisms of SGLT2 inhibitor HF benefits. [ABSTRACT FROM AUTHOR]

Aim: To determine the relationship between polyvascular disease and risk of hospitalization for heart failure (HHF) and cardiovascular (CV) death in the EMPA‐REG OUTCOME population, and the relationship of kidney dysfunction co‐existent with polyvascular disease on CV/heart failure (HF) outcomes. Materials and Methods: Patients with type 2 diabetes and atherosclerotic CV (ASCVD) received empagliflozin 10, 25 mg or placebo. Post hoc, subgroups were analyzed by one versus two or more vascular beds, and the estimated glomerular filtration rate ([eGFR] < vs. ≥60 mL/min/1.73 m2) at baseline. The empagliflozin arms were pooled. Time to CV death, HHF, CV death (excluding fatal stroke) or HHF, all‐cause mortality (ACM) and 3‐point major adverse CV events (3P‐MACE) were assessed using multivariable Cox regression models. Results: Baseline characteristics (N = 6959) within subgroups were balanced between treatment groups. In the placebo group, two or more versus one vascular bed increased HHF risk (1.59 [95% confidence interval 1.02, 2.49]), CV death (2.17 [1.52, 3.09]), CV death/HHF (1.79 [1.32, 2.43]), ACM (1.95 [1.44, 2.64]) and 3P‐MACE (1.76 [1.36, 2.27]). Hazard ratios for those with polyvascular disease/kidney dysfunction (vs. 1 vascular bed/eGFR ≥60 mL/min/1.73 m2) were HHF 2.80 (1.46, 5.36), CV death 3.10 (1.87, 5.13), CV death/HHF 2.71 (1.74, 4.23), ACM 2.59 (1.67, 4.02) and 3P‐MACE 2.62 (1.82, 3.77). Empagliflozin reduced the risk of all outcomes across subgroups. Conclusions: Polyvascular disease with/without kidney dysfunction markedly increases the risk of HF/CV events. Empagliflozin consistently reduces risk, regardless of vascular bed and kidney function status. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association of different categories of baseline cardio‐metabolic risk factors on the treatment effects of empagliflozin 10 and 25 mg when added as second‐line therapy to metformin in patients with type 2 diabetes (T2D). Materials and Methods: Patients aged 18 years or older with HbA1c 7.0%‐10.0% were included. Analysis of covariance compared change from baseline to weeks 24 and 76 in HbA1c, body weight (BW) and systolic blood pressure (SBP) by respective baseline categories (HbA1c <8.5/≥8.5%; BW <80/80‐90/>90 kg, SBP <130/130‐140/>140 mmHg). Analyses were also conducted with a model using continuous covariates of cardio‐metabolic factors. Results: In total, 637 patients (56.7% males; mean [SD] age 55.7 [9.9] years, HbA1c 7.9% [0.9%], BW 81.2 [18.8] kg, SBP 129.4 [14.6] mmHg) received one or more dose of either empagliflozin 10 mg (n = 217) or 25 mg (n = 213), or placebo (n = 207). At both time points, empagliflozin 10/25 mg versus placebo significantly (P <.0001) reduced HbA1c and BW, with greater reductions in HbA1c at higher baseline HbA1c (P interaction week 24/76 categorical and continuous models:.0290/.1431 and.0004/.0042, respectively) and in BW (P interaction.1340/.0012 and.0202/<.0001, respectively). Both empagliflozin doses also significantly lowered SBP versus placebo at both time points, with similar efficacy by subgroups of baseline SBP. Adverse events were consistent with the established empagliflozin safety profile across treatment groups. Conclusions: Empagliflozin, as add‐on to metformin, decreases HbA1c and BW, particularly in patients with higher HbA1c and BW baseline values, and effectively lowers SBP. [ABSTRACT FROM AUTHOR]

Aim: To explore the cardiovascular (CV) and kidney effects of empagliflozin in patients with different clinical phenotypes of diabetic kidney disease (DKD) (i.e. with the presence or absence of overt albuminuria) participating in the EMPA‐REG OUTCOME trial. Materials and methods: EMPA‐REG OUTCOME randomized participants (1:1:1) to empagliflozin 10 mg, 25 mg or placebo, added to standard of care. Post hoc, patients with different clinical phenotypes of DKD at baseline were categorized in three subgroups: (a) overt DKD (overt albuminuria [urinary albumin‐to‐creatinine ratio of >300 mg/g] with any estimated glomerular filtration rate [eGFR]; n = 769); (b) non‐overt DKD (kidney impairment [eGFR < 60 mL/min/1.73 m2] without overt albuminuria [urinary albumin‐to‐creatinine ratio of ≤300 mg/g]; n = 1290); and (c) 'all others' (eGFR ≥ 60 mL/min/1.73 m2 without overt albuminuria; n = 4893). Analyses included CV (death, hospitalization for heart failure, all‐cause hospitalization) and selected kidney outcomes, change in eGFR and kidney safety. Cox proportional hazards models assessed the consistency of treatment effect across subgroups. Results: Empagliflozin significantly reduced the risk of CV and kidney outcomes across all subgroups (P‐values for interaction >.05), consistent with the overall trial population findings. Empagliflozin also significantly reduced the yearly loss of eGFR, assessed by chronic slopes, in all subgroups. The adverse event profile of empagliflozin was similar across all subgroups. Conclusions: Empagliflozin may improve CV and kidney outcomes and slow the progression of kidney disease in type 2 diabetes patients with DKD, irrespective of its clinical form, both with or without the presence of overt albuminuria. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association of the Thrombolysis In Myocardial Infarction (TIMI) Risk Score for Heart Failure in Diabetes (TRS‐HFDM) with mortality using data from the EMPA‐REG OUTCOME trial. Materials and Methods: In EMPA‐REG OUTCOME, patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease (N = 7020) received the sodium‐glucose co‐transporter‐2 inhibitor, empagliflozin, 10 or 25 mg or placebo. Post hoc, patients were stratified into risk categories (low‐intermediate, high, very‐high risk scores) using baseline TRS‐HFDM. Cox regression analyses evaluated the association of TRS‐HFDM categories with all‐cause mortality (ACM), CV death, hospitalization for heart failure (HHF) and CV death (excluding fatal stroke) or HHF, and whether empagliflozin reduced the risk of CV outcomes across these risk categories. Results: In placebo patients, increasing risk category was associated with a higher risk of ACM, CV death, and HHF. Empagliflozin reduced the risk of ACM (low‐intermediate HR 0.68 [95% CI 0.48, 0.97] and very‐high 0.69 [0.52, 0.91]), CV death (0.75 [0.48, 1.18] and 0.56 [0.41, 0.78]), HHF (0.53 [0.28, 1.01] and 0.67 [0.48, 0.96]), and CV death or HHF (0.69 [0.46, 1.03]) and (0.64 [0.49, 0.82]) across all risk categories versus placebo. Higher absolute risk reductions (ARRs) were observed for CV death in the very‐high versus low‐intermediate category (P = 0.01). Conclusions: Applied to EMPA‐REG OUTCOME, higher TRS‐HFDM was associated with increased HHF and mortality risk. Empagliflozin reduced CV outcomes across TRS‐HFDM categories. Higher ARRs were associated with higher risk scores. [ABSTRACT FROM AUTHOR]

In the EMPA‐REG OUTCOME trial, we explored the association between pre‐randomization uric acid level tertile (<309.30 μmol/L; 309.30 to <387.21 μmol/L; ≥387.21 μmol/L) and cardiovascular (CV) death, hospitalization for heart failure (HHF), HHF or CV death, all‐cause mortality, three‐point major adverse CV events (MACE), and incident or worsening nephropathy. Patients with type 2 diabetes and CV disease received empagliflozin or placebo. The median baseline plasma uric acid level was 344.98 μmol/L, and patients' baseline characteristics were mainly balanced across tertiles. Baseline uric acid levels were associated with cardio‐renal outcomes: in the placebo group, for the highest versus lowest tertile, the multivariable hazard ratios for three‐point MACE, HHF or CV death, and incident or worsening nephropathy were 1.22 (95% confidence interval [CI] 0.89–1.67; P = 0.2088), 1.51 (95% CI 1.02–2.23; P = 0.0396) and 1.77 (95% CI 1.33–2.34; P < 0.0001), respectively. When tested as a continuous variable, baseline uric acid was associated with all outcomes in the placebo group. Empagliflozin improved all cardio‐renal outcomes across tertiles, with all interaction P values >0.05. Further investigation of these relationships is required. [ABSTRACT FROM AUTHOR]

Aims: In the EMPA‐REG OUTCOME® trial, the sodium‐glucose cotransporter 2 inhibitor empagliflozin when given in addition to standard care improved cardiovascular (CV) and renal outcomes, and reduced mortality. Trial participants were on a variety of glucose‐lowering therapies at baseline, some of which could potentially affect CV risk. This analysis investigated whether the use of background diabetes therapy affected the risk of CV death, hospitalizations for heart failure, and progression of chronic kidney disease, among patients treated with empagliflozin. Materials and methods: Patients meeting inclusion and exclusion criteria were randomized to placebo, empagliflozin 10 mg or empagliflozin 25 mg; glucose‐lowering therapy was to remain unchanged for 12 weeks and then adjusted to achieve glycaemic control according to local guidelines. Differences in risk of cardio‐renal outcomes between empagliflozin and placebo by baseline use of metformin, sulphonylurea (SU) and insulin were assessed using a Cox proportional hazards model. Results: Of 7020 eligible patients, 74% were receiving metformin, 43% SU and 48% insulin at baseline (each alone or in combination); the most common regimens were metformin plus SU (20%) and metformin plus insulin (20%). Empagliflozin reduced the risk of CV death irrespective of the use of: metformin [with: hazard ratio (HR) 0.71 (95% confidence interval, CI, 0.54–0.94); without: 0.46 (0.32–0.68); Pinteraction= 0.07]; SU [with: HR 0.64 (0.44–0.92); without: 0.61 (0.46–0.81); Pinteraction = 0.85]; or insulin [with: HR 0.63 (0.46–0.85); without: 0.61 (0.44–0.85); Pinteraction = 0.92]. Reductions in three‐point major adverse CV events, hospitalizations for heart failure, and all‐cause mortality were consistent across subgroups of baseline therapies. Empagliflozin reduced the risks of incident or worsening nephropathy versus placebo irrespective of the use of SU or insulin at baseline (Pinteraction > 0.05), but there was a greater reduction in this risk for patients not using metformin [HR 0.47 (95% CI 0.37–0.59)] versus those using metformin [HR 0.68 (95% CI 0.58–0.79)] at baseline (Pinteraction = 0.01). Conclusions: The addition of empagliflozin to antihyperglycaemic regimens of patients with type 2 diabetes and CV disease consistently reduced their risks of adverse CV outcomes and mortality irrespective of baseline use of metformin, SU or insulin. For chronic kidney disease progression, there may be a larger benefit from empagliflozin in those patients who are not using metformin. [ABSTRACT FROM AUTHOR]

In 2008, the US Food and Drug Administration (FDA) issued a guidance to industry statement concerning evaluation of the cardiovascular (CV) safety of new antihyperglycaemic therapies for type 2 diabetes. Fifteen CV outcome trials assessing three novel classes of antihyperglycaemic therapies, DPP‐4 inhibitors, GLP‐1 receptor agonists and SGLT‐2 inhibitors, were completed by the end of 2018 and several others are ongoing. In addition, one comparative insulin trial also has been completed. None of these trials reported an increase in risk for major adverse CV events (MACE), and six agents have demonstrated CV benefits. This experience has led to the first FDA‐approved indications for antihyperglycaemic medications to reduce the risk of CV death (empagliflozin) and to reduce the risk of MACE (liraglutide, canagliflozin), both indications specific to patients with established atherosclerotic cardiovascular disease (ASCVD). Because of the aggregate results from dedicated CV outcomes trials conducted in response to the FDA guidance statement, the contemporary paradigm for treatment of patients with type 2 diabetes has evolved substantially. However, the guidance has substantially increased the cost of developing new medications to address this important disease that afflicts hundreds of millions of adults worldwide, with reduction in quality of life as well as in life expectancy. The cost burden of drug development of medications proven effective that may directly impact cost to patients and to their insurers might be alleviated by modifications to the present guidance statement. These include areas of trial design, aspects of trial operation, expansion of composite outcomes to include broader component CV outcomes and continued evolution of analytic methodology. The guidance statement will benefit from consideration of a number of modifications to support continued innovation and, of course, the safety of marketed medications for type 2 diabetes. However, the requirement to assess each new antihyperglycaemic medication in at least one large‐scale standard randomized clinical outcomes trial should remain, so that clinicians can be reassured about the favourable efficacy/safety profiles of the medications they prescribe. [ABSTRACT FROM AUTHOR]

The sodium glucose co‐transporter‐2 inhibitor dapagliflozin has been shown to decrease urinary albumin‐to‐creatinine ratio (UACR). This effect, however, varies among individual patients. In this study, we assessed the baseline characteristics and concurrent changes in other cardiovascular risk markers that might be associated with UACR response to dapagliflozin. A pooled analysis of 11 phase 3 randomized, controlled clinical trials was performed. UACR change from baseline after 24 weeks treatment with dapagliflozin 10 mg/d in 531 patients with type 2 diabetes and UACR ≥30 mg/g at baseline was determined. UACR response was defined as >30% reduction from baseline at 24 weeks, whereas UACR non‐response was defined as ≤30% reduction at 24 weeks. A total of 288 (54%) patients were classified as responders and 243 (46%) as non‐responders. At 24 weeks, the UACR‐adjusted mean change from baseline was −71.2% and 25.9% in responders and non‐responders, respectively. Baseline characteristics were similar between both groups. Changes in HbA1c and body weight were comparable across groups. Responders showed a numerically larger reduction in estimated glomerular filtration rate and systolic blood pressure versus non‐responders. UACR reduction to dapagliflozin is an individual characteristic that cannot be predicted by baseline clinical features or changes in metabolic variables. Whether UACR response would improve long‐term renal and cardiovascular outcomes remains to be determined. [ABSTRACT FROM AUTHOR]

Aims: Randomized controlled trials have reported an association between pioglitazone and reduced incidence of stroke in type 2 diabetic (T2DM) and insulin‐resistant populations. We investigated this association within a real‐world database. Materials and methods: T2DM patients who initiated pioglitazone between 2000 and 2012 were extracted from the Clinical Practice Research Datalink (CPRD), a UK routine data source. Two non‐exposed control cohorts were matched according to age, gender, HbA1c, diabetes duration, stroke history, co‐morbidities and prior T2DM regimen. Control cohort‐1 comprised patients initiating a new T2DM therapy as their respective case initiated pioglitazone. Control cohort‐2 maintained the same T2DM regimen as their respective case prior to the case initiating pioglitazone. Primary outcome was incident stroke; other outcomes included mortality, length of hospital stay and stroke recurrence. Results: A total of 4234 patients initiating pioglitazone were matched to controls in cohort‐1 and 3604 in cohort‐2. For the primary outcome there were significantly reduced hazard ratios (HRs) for cases: controls. For cohort 1, the HR was 0.666 (95% CI, 0.466‐0.952) during the therapy period and was 0.750 (0.612‐0.919) over the entire observation period; for cohort 2, respective HRs were 0.516 (0.336‐0.794) and 0.773 (0.611‐0.978). There was no significant difference in 30‐day mortality rate or rate of recurrent stroke. For stroke events that required hospitalization, there was a significant difference in length of stay for patients discharged to usual residence (median, 3.0 days vs 7.0 days; P = .008) for control cohort‐2 while undergoing treatment. Conclusions: In support of evidence from 2 large randomized trials, these observational data show that pioglitazone has a potent effect in reducing stroke events in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]