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Diabetes mellitus (DM) is more common among people living with human immunodeficiency virus (PLWH) compared with healthy individuals. In a prospective multicenter study (N = 248), we identified normoglycemic (48.7%), prediabetic (44.4%), and diabetic (6.9%) PLWH. Glycosylated hemoglobin (HbA1c) and fasting blood glucose (FBG) sensitivity in defining dysglycemia was 96.8%, while addition of oral glucose tolerance test led to reclassification of only 4 patients. Inclusion of 93 additional PLWH with known DM enabled identification of multiple independent predictors of dysglycemia or diabetes: older age, higher body mass index, Ethiopian origin, HIV duration, lower integrase inhibitor exposure, and advanced disease at diagnosis. Shotgun metagenomic microbiome analysis revealed 4 species that were significantly expanded with hyperglycemia/hyperinsulinemia, and 2 species that were differentially more prevalent in prediabetic/diabetic PLWH. Collectively, we uncover multiple potential host and microbiome predictors of altered glycemic status in PLWH, while demonstrating that FBG and HbA1c likely suffice for diabetes screening. These potential diabetic predictors merit future prospective validation. [ABSTRACT FROM AUTHOR]

In the primary care setting providers have more tools available than ever before to impact positively obesity, diabetes, and their complications, such as renal and cardiac diseases. It is important to recognise what is available for treatment taking into account diabetes heterogeneity. For those who develop type 2 diabetes (T2DM), effective treatments are available that for the first time have shown a benefit in reducing mortality and macrovascular complications, in addition to the well‐established benefits of glucose control in reducing microvascular complications. Some of the newer medications for treating hyperglycaemia have also a positive impact in reducing heart failure (HF). Technological advances have also contributed to improving the quality of care in patients with diabetes. The use of technology, such as continuous glucose monitoring systems (CGM), has improved significantly glucose and glycated haemoglobin A1c (HbA1c) values, while limiting the frequency of hypoglycaemia. Other technological support derives from the use of predictive algorithms that need to be refined to help predict those subjects who are at great risk of developing the disease and/or its complications, or who may require care by other specialists. In this review we also provide recommendations for the optimal use of the new medications; sodium‐glucose co‐transporter‐2 inhibitors (SGLT2i) and Glucagon‐like peptide‐receptor agonists 1 (GLP1RA) in the primary care setting considering the relevance of these drugs for the management of T2DM also in its early stage. [ABSTRACT FROM AUTHOR]

Objective: In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk.Research Design and Methods: In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6 month to 4 year) or total (baseline to 4 year) eGFR slopes.Results: Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001).Conclusions: Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Aims  We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM). Methods and results  DECLARE–TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to <25), overweight (25 to <30), moderately obese (30 to <35), severely obese (35 to <40), and very-severely obese (≥40). Outcomes analysed were CV death, hospitalization for heart failure (HHF), renal-specific composite outcome, and atrial fibrillation or flutter (AF/AFL). Of 17 134 patients, 9.0% had a normal BMI, 31.5% were overweight, 32.4% were moderately, 17.2% severely, and 9.8% were very-severely obese. Higher BMI was associated with a higher adjusted risk of HHF and AF/AFL (hazard ratio 1.30 and 1.28, respectively, per 5 kg/m2; P  < 0.001 for all). Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percent difference: −1.9 to −2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m2) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients. Conclusions  In DECLARE–TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM. Clinical trial registration URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534. [ABSTRACT FROM AUTHOR]

Objective: Current guidelines recommend prescribing SGLT2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c.Research Design and Methods: In the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomly assigned to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population and with dapagliflozin versus placebo in HbA1c subgroups were studied by Cox regression models.Results: In the overall population, higher baseline HbA1c was associated with a higher risk of cardiovascular death or hospitalization for heart failure (HHF); major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and ischemic stroke; and cardiorenal outcomes (adjusted hazard ratios 1.12 [95% CI 1.06-1.19], 1.08 [1.04-1.13], and 1.17 [1.11-1.24] per 1% higher level, respectively). Elevated HbA1c was associated with a greater increased risk for MACE and cardiorenal outcomes in patients with multiple risk factors (MRF) than in established ASCVD (P-interaction = 0.0064 and 0.0093, respectively). Compared with placebo, dapagliflozin decreased the risk of cardiovascular death/HHF, HHF, and cardiorenal outcomes, with no heterogeneity by baseline HbA1c (P-interaction > 0.05).Conclusions: Higher HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c <7%. [ABSTRACT FROM AUTHOR]

Objective: The association of long‐term HbA1c variability with mortality has been previously suggested. However, the significance of HbA1c variability and trends in different age and HbA1c categories is unclear. Research Design and Methods: Data on patients with diabetes listed in the Israeli National Diabetes Registry during years 2012–2016 (observation period) were collected. Patients with >4 HbA1c measurements, type 1 diabetes, eGFR < 30mg/ml/min, persistent HbA1c < 6% or malignancy were excluded. Utilizing machine learning methods, patients were classified into clusters according to their HbA1c trend (increasing, stable, decreasing). Mortality risk during 2017–2019 was calculated in subgroups defined by age (35–54, 55–69, 70–89 years) and last HbA1c (≤7% and >7%) at end of observation period. Models were adjusted for demographic, clinical and laboratory measurements including HbA1c, standard deviation (SD) of HbA1c and HbA1c trend. Results: This historical cohort study included 293,314 patients. Increased HbA1c variability (high SD) during the observation period was an independent predictor of mortality in patients aged more than 55 years (p < 0.01). The HbA1c trend was another independent predictor of mortality. Patients with a decreasing versus stable HbA1c trend had a greater mortality risk; this association persisted in all age groups in patients with HbA1c > 7% at the end of the observation period (p = 0.02 in age 35–54; p < 0.01 in aged >55). Patients with an increasing versus stable HbA1c trend had a greater mortality risk only in the elderly group (>70), yet in both HbA1c categories (p < 0.01). Conclusions: HbA1c variability and trend are important determinants of mortality risk and should be considered when adjusting glycaemic targets. [ABSTRACT FROM AUTHOR]

Objective: Heart failure (HF) is an impactful complication of type 2 diabetes mellitus (T2DM). We aimed to develop and validate a risk score for hospitalization for HF (HHF) incorporating biomarkers and clinical factor(s) in patients with T2DM.Research Design and Methods: We derived a risk score for HHF using clinical data, high-sensitivity troponin T (hsTnT), and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) from 6,106 placebo-treated patients with T2DM in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using Cox regression. The strongest indicators of HHF risk were included in the score using integer weights. The score was externally validated in 7,251 placebo-treated patients in DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58). The effect of dapagliflozin on HHF was assessed by risk category in DECLARE-TIMI 58.Results: The strongest indicators of HHF risk were NT-proBNP, prior HF, and hsTnT (each P < 0.001). A risk score using these three variables identified a gradient of HHF risk (P-trend <0.001) in the derivation and validation cohorts, with C-indices of 0.87 (95% CI, 0.84-0.89) and 0.84 (0.81-0.86), respectively. Whereas there was no significant effect of dapagliflozin versus placebo on HHF in the low-risk group (hazard ratio [HR] 0.98 [95% CI 0.50-1.92]), dapagliflozin significantly reduced HHF in the intermediate-, high-, and very-high-risk groups (HR 0.64 [0.43-0.95], 0.63 [0.43-0.94], and 0.72 [0.54-0.96], respectively). Correspondingly, absolute risk reductions (95% CI) increased across these latter 3 groups: 1.0% (0.0-1.9), 3.0% (0.7-5.3), and 4.4% (-0.2 to 8.9) (P-trend <0.001).Conclusions: We developed and validated a risk score for HHF in T2DM that incorporated NT-proBNP, prior HF, and hsTnT. The risk score identifies patients at higher risk of HHF who derive greater absolute benefit from dapagliflozin. [ABSTRACT FROM AUTHOR]

Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk.Research Design and Methods: DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death.Results: Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to <30 mg/g, 4,030 (23.93%) with 30-300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35-1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, Pinteraction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, Pinteraction = 0.480).Conclusions: In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Objective: International guidelines propose prescribing sodium-glucose cotransporter 2 (SGLT2) inhibitors to patients with type 2 diabetes (T2D) as secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) or for primary prevention of cardiovascular events in high-risk patients with multiple risk factors (MRF) for ASCVD. The current analyses expand on the cardiovascular renal and metabolic effects of SGLT2 inhibitors in MRF patients.Research Design and Methods: In DECLARE-TIMI 58, 17,160 patients with T2D and MRF (59.4%) or established ASCVD (40.6%) were randomized to dapagliflozin versus placebo; patients were followed for a median of 4.2 years. The cardiovascular and renal outcomes in the MRF cohort were studied across clinically relevant subgroups for treatment effect and subgroup-based treatment interaction.Results: Among patients with MRF, the reduction with dapagliflozin in risk of cardiovascular death or hospitalization for heart failure (CVD/HHF) (hazard ratio [HR] 0.84, 95% CI 0.67-1.04) and the renal-specific outcome (HR 0.51, 95% CI 0.37-0.69) did not differ from that for patients with ASCVD (Pinteraction 0.99 and 0.72, respectively). The effect on CVD/HHF was entirely driven by a reduction in HHF (HR 0.64, 95% CI 0.46-0.88). The benefits of dapagliflozin on HHF and on the renal-specific outcome, among the subset with MRF, were directionally consistent across clinically relevant subgroups. At 48 months, HbA1c, weight, systolic blood pressure, and urinary albumin-to-creatinine ratio were lower with dapagliflozin versus placebo and estimated glomerular filtration rate was higher (P < 0.001).Conclusions: In patients with T2D and MRF, dapagliflozin reduced the risk of HHF and adverse renal outcomes regardless of baseline characteristics. These analyses support the benefit of dapagliflozin for important outcomes in a broad primary prevention population. [ABSTRACT FROM AUTHOR]

Aim: To undertake a cost‐effectiveness analysis of dapagliflozin in treating high‐risk patients with type 2 diabetes mellitus (T2DM), using both directly observed events in the DECLARE‐TIMI 58 trial and surrogate risk factors to predict endpoints not captured within the trial. Methods: An established T2DM model was adapted to integrate survival curves derived from the DECLARE‐TIMI 58 trial, and extrapolated over a lifetime for all‐cause mortality, hospitalization for heart failure, stroke, myocardial infarction, hospitalization for unstable angina, and end‐stage kidney disease. The economic analysis considered the overall DECLARE trial population, as well as reported patient subgroups. Total and incremental costs, life‐years and quality‐adjusted life‐years associated with dapagliflozin versus placebo were estimated from the perspective of the UK healthcare payer. Results: In the UK setting, treatment with dapagliflozin compared to placebo was estimated to be dominant, with an expected increase in quality‐adjusted life‐years from 10.43 to 10.48 (+0.06) and a reduction in lifetime total costs from £39 451 to £36 899 (−£2552). Across all patient subgroups, dapagliflozin was estimated to be dominant, with the greatest absolute benefit in the prior heart failure subgroup (incremental lifetime costs −£4150 and quality‐adjusted life‐years +0.11). Conclusions: The results of this study demonstrate that dapagliflozin compared to placebo appears to be cost‐effective, when considering evidence reported from the DECLARE‐TIMI 58 trial, at established UK willingness‐to‐pay thresholds. The findings highlight the potential of dapagliflozin to have a meaningful impact in reducing the economic burden of T2DM and its associated complications across a broad T2DM population. [ABSTRACT FROM AUTHOR]

Tackling obesity during the COVID-19 pandemic Obesity in patients younger than 60 years is a risk factor for COVID-19 hospital admission. Keywords: COVID-19; diabetes; obesity; pre-diabetes EN COVID-19 diabetes obesity pre-diabetes 1 5 5 03/19/21 20210301 NES 210301 INTRODUCTION Most people contracting coronavirus disease 2019 (COVID-19) develop a non-serious disease with some remaining entirely asymptomatic. Obesity predisposes to the risk of higher mortality in young COVID-19 patients. [Extracted from the article]

Aim: To assess the associations between baseline glucose‐lowering agents (GLAs) and cardiorenal outcomes with dapagliflozin versus placebo in the DECLARE‐TIMI 58 study. Materials and methods: DECLARE‐TIMI 58 assessed the cardiorenal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. This post hoc analysis elaborates the efficacy and safety outcomes by baseline GLA for treatment effect and GLA‐based treatment interaction. Results: At baseline, 14 068 patients (82.0%) used metformin, 7322 (42.7%) sulphonylureas, 2888 (16.8%) dipeptidyl peptidase‐4 inhibitors, 750 (4.4%) glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and 7013 (40.9%) insulin. Dapagliflozin reduced the composite of cardiovascular death (CVD) and hospitalization for heart failure (HHF) versus placebo regardless of baseline GLA, with greater benefit in the small group of patients with baseline use of GLP‐1 RAs (HR [95% CI] 0.37 [0.18, 0.78] vs. 0.86 [0.75, 0.98] in GLP‐1 RA users vs. non‐users, Pinteraction =.03). The overall HR for major adverse cardiovascular events (CVD, myocardial infarction or ischaemic stroke) was 0.93 (95% CI 0.84, 1.03) with dapagliflozin versus placebo, with no interaction by baseline GLA (Pinteraction >.05). The renal‐specific outcome was reduced with dapagliflozin versus placebo in the overall cohort (HR [95%CI] 0.53[0.43‐0.66]), with no interaction by baseline GLA (Pinteraction >.05). All of these outcomes were similar in those with versus those without baseline metformin use. Conclusions: The effects of dapagliflozin on cardiorenal outcomes were generally consistent regardless of baseline GLA, with consistent benefits regardless of baseline metformin use. The potential clinical benefit of combining sodium‐glucose co‐transporter‐2 inhibitors with GLP‐1 RAs, given some evidence of cardiovascular risk reduction with both classes, should be explored further. [ABSTRACT FROM AUTHOR]

Hypoglycaemia is common in patients with type 1 diabetes and type 2 diabetes and constitutes a major limiting factor in achieving glycaemic control among people with diabetes. While hypoglycaemia is defined as a blood glucose level under 70 mg/dL (3.9 mmol/L), symptoms may occur at higher blood glucose levels in individuals with poor glycaemic control. Severe hypoglycaemia is defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions to assure neurologic recovery. Hypoglycaemia is the most important safety outcome in clinical studies of glucose lowering agents. The American Diabetes Association Standards of Medical Care recommends that a management protocol for hypoglycaemia should be designed and implemented by every hospital, along with a clear prevention and treatment plan. A tailored approach, using clinical and pathophysiologic disease stratification, can help individualize glycaemic goals and promote new therapies to improve quality of life of patients. Data from recent large clinical trials reported low risk of hypoglycaemic events with the use of newer anti-diabetic drugs. Increased hypoglycaemia risk is observed with the use of insulin and/or sulphonylureas. Vulnerable patients with T2D at dual risk of severe hypoglycaemia and cardiovascular outcomes show features of "frailty." Many of such patients may be better treated by the use of GLP-1 receptor agonists or SGLT2 inhibitors rather than insulin. Continuous glucose monitoring (CGM) should be considered for all individuals with increased risk for hypoglycaemia, impaired hypoglycaemia awareness, frequent nocturnal hypoglycaemia and with history of severe hypoglycaemia. Patients with impaired awareness of hypoglycaemia benefit from real-time CGM. The diabetes educator is an invaluable resource and can devote the time needed to thoroughly educate the individual to reduce the risk of hypoglycaemia and integrate the information within the entire construct of diabetes self-management. Conversations about hypoglycaemia facilitated by a healthcare professional may reduce the burden and fear of hypoglycaemia among patients with diabetes and their family members. Optimizing insulin doses and carbohydrate intake, in addition to a short warm up before or after the physical activity sessions may help avoiding hypoglycaemia. Several therapeutic considerations are important to reduce hypoglycaemia risk during pregnancy including administration of rapid-acting insulin analogues rather than human insulin, pre-conception initiation of insulin analogues, and immediate postpartum insulin dose reduction. [ABSTRACT FROM AUTHOR]

Aims: To evaluate comprehensively the safety of dapagliflozin in patients with type 2 diabetes (T2DM), with emphasis placed on potential safety concerns related to the sodium‐glucose co‐transporter‐2 inhibitor class. Methods: In the Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58 (DECLARE‐TIMI 58) study, 17 160 patients with T2DM were randomized to dapagliflozin or placebo and followed for a median of 4.2 years. Safety was evaluated in 17 143 patients receiving at least one dose of study drug. Results: Acute kidney injury occurred less frequently with dapagliflozin, and adverse events suggestive of volume depletion were balanced between treatment groups, both irrespective of baseline estimated glomerular filtration rate, blood pressure, diuretic or loop diuretic use (interaction P values >0.05). Fractures and malignancies were balanced between the groups, irrespective of sex, diabetes duration or smoking (interaction P values >0.05) and fewer cases of bladder cancer occurred in the dapagliflozin versus the placebo group. Diabetic ketoacidosis was very rare, but more frequent with dapagliflozin versus placebo (27 vs. 12 patients with events; P = 0.02), yet signs, symptoms and contributing factors were similar in the two groups. Major hypoglycaemia occurred less frequently with dapagliflozin versus placebo, regardless of baseline use of either insulin or sulphonylureas (interaction P values >0.05). There were more adverse events of genital infections leading to discontinuation of study drug in the dapagliflozin versus the placebo group, but serious genital infections were few and balanced between treatment groups. Urinary tract infections, acute pyelonephritis and urosepsis were also balanced between treatment groups. Conclusions: Dapagliflozin was well tolerated. The long duration and large number of patient‐years in DECLARE‐TIMI 58 comprehensively addressed previous safety questions, confirming the robust safety profile of dapagliflozin. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether the cardiovascular and renal benefits observed with dapagliflozin in the DECLARE‐TIMI 58 trial are also observed in patients with short and long‐standing diabetes. Materials and Methods: This post hoc analysis studied the dual primary efficacy endpoints, a composite of cardiovascular death or hospitalization for heart failure (CVD/HHF) and major adverse cardiovascular events (MACE; CVD, myocardial infarction [MI], ischaemic stroke) by diabetes duration. Results: Of the 17 160 patients, 3836 had diabetes duration of ≤5 years, 4731 >5‐10 years, 3952 >10‐15 years, 2433 >15‐20 years and 2206 >20 years. Dapagliflozin reduced the risk of CVD/HHF by a similar amount across diabetes duration subgroups, ranging from HR 0.79 (0.58‐1.06) in patients with diabetes duration of ≤5 years to 0.75 (0.55‐1.03) in those patients with diabetes duration of >20 years (interaction trend P‐value 0.76). Hazard ratios (HRs) for MACE ranged from 1.08 (0.87‐1.35) in patients with diabetes duration of ≤5 years to 0.67 (0.52‐0.86) in those patients with diabetes duration of >20 years (interaction trend P‐value 0.004). This was driven by greater reductions in the risk of MI and ischaemic stroke with dapagliflozin in patients with long‐standing diabetes (interaction trend P‐values 0.019 and 0.015, respectively). The duration‐based MACE heterogeneity was apparent in those with or without a history of prior MI and in those with multiple risk factors. The renal‐specific outcome was reduced with dapagliflozin with HRs ranging from 0.79 (0.47‐1.34) in patients with diabetes duration of ≤5 years to 0.42 (0.25‐0.72) in those patients with diabetes duration of >20 years (interaction trend P‐value 0.084). Conclusions: Dapagliflozin reduced the risk of CVD/HHF consistently, regardless of diabetes duration, whereas the treatment effect for MACE differed by duration subgroups, with significant reductions with dapagliflozin in patients with long‐standing diabetes. [ABSTRACT FROM AUTHOR]

Aim: To assess the possible risk of acute kidney injury (AKI) with the use of sodium‐glucose co‐transporter‐2 inhibitors (SGLT2‐i) as well as changes in estimated glomerular filtration rate (eGFR), hospitalizations and mortality in a real‐world setting. Materials and methods: Included in this historical cohort study were patients with type 2 diabetes in a large health organization in Israel who initiated therapy with SGLT2‐i or dipeptidyl peptidase‐4 inhibitors (DPP‐4i) during 1 April 2015 to 30 June 2017. We collected data on serum creatinine measurements taken between 180 days prior to and 24 weeks after therapy initiation. Study endpoints included ≥30% reduction in eGFR, hospitalization with AKI, any hospitalization and all‐cause mortality. Results: Overall 6418 and 5604 patients initiated SGLT2‐i and DPP‐4i, respectively. Baseline mean (SD) eGFR was higher among the SGLT2‐i group compared with the DPP‐4i group (88.3 [17.4] and 82.8 [23.7], respectively) but were similar when stratifying by chronic kidney disease (CKD) stages. The adjusted odds ratio (OR) (95% confidence interval [CI]) for ≥30% reduction in eGFR with SGLT2‐i versus DPP4‐i was 0.70 (0.49‐1.00) and ORs ranged from 1.97 (0.62‐6.26) to 0.45 (0.21‐0.99) in patients with baseline eGFR 30 to 45 and ≥90 mL/min/1.73 m2, respectively. Risks of AKI (OR = 0.47, 95% CI 0.27‐0.80), hospitalization (OR = 0.66, 95% CI 0.56‐0.78) or all‐cause mortality (OR = 0.43, 95% CI 0.20‐0.95) were lower in patients initiating SGLT2‐i versus DPP‐4i. Conclusions: This real‐world data analysis supports reassuring findings from previous randomized clinical trials showing no increased AKI risk among SGLT2‐i users. Nevertheless, because of the more prominent decrease in eGFR in patients with moderate CKD, cautious use of SGLT2‐i in patients with reduced eGFR is advised. [ABSTRACT FROM AUTHOR]

Sodium glucose cotransporter 2 (SGLT2) inhibitors have been approved for the treatment of type 2 diabetes mellitus since 2012. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Cardiovascular outcomes according to urinary albumin and kidney disease in patients with type 2 diabetes at high cardiovascular risk: observations from the SAVOR-TIMI 53 trial. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. [Extracted from the article]

Aim: To describe the baseline characteristics of participants randomized in the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE‐TIMI 58) trial, the pivotal study conducted to assess cardiovascular (CV) outcomes with dapagliflozin. Methods: The DECLARE‐TIMI 58 trial will analyse 17 160 patients with type 2 diabetes randomized to treatment with dapagliflozin (10 mg/d) or matching placebo. We analysed their baseline characteristics. Results: The participants’ mean ± SD age was 63.8 ± 6.8 years, 62.6% were male, and their mean ± SD diabetes duration was 11.8 ± 7.8 years, glycated haemoglobin 8.3% ± 1.2% (67 mmol/mol ± 9.7 mmol/mol) and body mass index 32.1 ± 6.0 kg/m2. Randomization included 6971 (40.6%) patients with atherosclerotic CV disease (CVD), and 10 189 (59.4%) patients with multiple risk factors (MRF) for CVD (defined as men age ≥ 55 years or women ≥60 years, with at least one of dyslipidaemia, hypertension or smoking). Patients with CVD compared with patients with MRF were younger (62.5 ± 8.1 vs 64.7 ± 5.6 years), more frequently male (72.1% vs 56.1%), less often used metformin (74.6% vs 81.2%), more often used insulin (44.2% vs 36.4%), and more frequently used statins, aspirin, clopidogrel and β‐blockers (82.2%, 71.1%, 24.7% and 66.6% vs 63.7%, 39.1%, 1.5% and 32.3%, respectively). Conclusion: The DECLARE‐TIMI 58 trial is expected to provide conclusive data on the effect of treatment with dapagliflozin in addition to standard of care, on CV outcomes in a broad patient population with type 2 diabetes and CVD or MRF for CVD. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Improved risk assessment for patients with type 2 diabetes and elevated cardiovascular (CV) risk is needed. The Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS 2°P) predicts a gradient of risk in patients with prior myocardial infarction (MI) but has not been evaluated in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: CV event rates were compared by baseline TRS 2°P in 16,488 patients enrolled in SAVORTIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53)with type 2 diabetes and high CV risk or established CV disease. Calibration was tested in the diabetes cohort from the REACH (REduction of Atherothrombosis for Continued Health) Registry. RESULTS: TRS 2°P revealed a robust risk gradient for the composite of CV death, MI, and ischemic stroke in the full trial population, with 2-year event rates of 0.9% in the lowestand 19.8% in the highest-risk groups (Ptrend < 0.001). A clear risk gradient was present within the subgroups of all coronary artery disease (CAD), CAD without prior MI, CAD with priorMI, peripheral artery disease, and prior stroke (Ptrend < 0.001 for each), with consistent risk relationships across subgroups. The C-statistic (0.71 for CV death and 0.66 for the composite end point) was consistent in each subgroup. There was close calibration with the type 2 diabetes cohort from the REACH Registry (goodness-of-fit P = 0.78). CONCLUSIONS: The expanded TRS 2°P provides a practical and well-calibrated risk prediction tool for patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to assess the clinical implications of calculating an individualized HbA1c target using a recently published algorithm in a real-life clinical setting.Methods: General practitioners (GPs) from the Spanish Society of Family Medicine Diabetes Expert Group were invited to participate in the study. Each GP selected a random sample of patients with diabetes from his or her practice and submitted their demographic and clinical data for analysis. Individualized glycaemic targets were calculated according to the algorithm. Predictors of good glycaemic control were studied. The rate of patients attaining their individualized glycaemic target or the uniform target of HbA1c  < 7.0% was calculated.Results: Forty GPs included 408 patients in the study. Of the 8 parameters included in the algorithm, "comorbidities," "risk of hypoglycaemia from treatment," and "diabetes duration" had the greatest impact on determining the individualized glycaemic target. Number of glucose-lowering agents and adherence were independently associated with glycaemic control. Overall, 60.5% of patients had good glycaemic control per individualized target, and 56.1% were well controlled per the uniform target of HbA1c  < 7.0% (P = .20). However, 12.8% (23 of 246) of the patients with HbA1c  ≥ 7.0% were adequately controlled per individualized target, and 2.6% (6 of 162) of the patients with HbA1c  < 7.0% were uncontrolled since their individualized target was lower.Conclusions: In a real-life clinical setting, applying individualized targets did not change the overall rate of patients with good glycaemic control yet led to reclassification of 7.1% (29 of 408) of the patients. More studies are needed to validate these results in different populations. [ABSTRACT FROM AUTHOR]

Hypoglycaemia is a well-known risk associated with the use of sulphonylureas and insulin, often limiting achievement of glycaemic goals. Recognizing the precipitants and recurrence patterns of hypoglycaemic events, particularly major events, is therefore clinically important. The SAVOR-TIMI-53 trial was a cardiovascular outcome study of 16 492 patients allocated to saxagliptin vs placebo added to conventional care for a median of 2.1 years. Hypoglycaemic events were a prespecified outcome in the study and were defined as a symptomatic episode that recovered with carbohydrates or any recorded blood glucose <3.0 mmol/l (<54 mg/ dL). A major event was defined as one that required third-party assistance. Analysis of the features of the first hypoglycaemic event for each patient showed that a precipitant for the event was recognized by fewer than half of the patients, with the precipitant most often being a missed meal. In 40% of patients reporting major hypoglycaemic events, no precipitating factor was recognized, and in >60%, no previous hypoglycaemic event was reported during the timespan of the study, underscoring the lack of predictability of such an event. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes (T2D) is high and it is associated with poor prognosis. Hepatic steatosis results as a consequence of excessive hepatic lipid accumulation which correlates with insulin resistance and lipotoxicity, with subsequent oxidative stress, inflammation, apoptosis and fibrosis. Areas covered: This article presents the main pathophysiologic mechanisms and currently available drugs evaluated for their therapeutic effects on NAFLD/nonalcoholic steatohepatitis (NASH) and drugs under development that target relevant pathogenetic pathways. However, to date there is no particular drug approved for treatment of NAFLD in patients with T2D. Expert commentary: Early recognition and intervention are essential to ameliorate disease progression. Specific recommendations are still needed for NAFLD/NASH screening and diagnosis and therapeutic algorithm in patients with T2D. Lifestyle optimization with significant weight loss is a key intervention in patients with NAFLD and T2D. Pioglitazone, liraglutide, vitamin E, OCA and pentoxifylline have proven some histological improvements in NASH and omega 3-PUFAs were shown to decrease liver fat, but no specific recommendation can be made for treatment of NASH. Perhaps a combination of agents that target different pathogenic pathways are needed to better control disease progression, but more robust evidence for these agents is still needed. [ABSTRACT FROM PUBLISHER]

Many patients with type 2 diabetes fail to achieve adequate glucose control despite escalation of treatment and combinations of multiple therapies including insulin. Patients with long-standing type 2 diabetes often suffer from the combination of severe insulin deficiency in addition to insulin resistance, thereby requiring high doses of insulin delivered in multiple injections to attain adequate glycemic control. Insulin-pump therapy was first introduced in the 1970s as an approach to mimic physiological insulin delivery and attain normal glucose in patients with type 1 diabetes. The recent years have seen an increase in the use of this technology for patients with type 2 diabetes. This article summarizes the clinical studies evaluating insulin pump use in patients with type 2 diabetes and discusses the benefits and shortcomings of pump therapy in this population. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is a progressive disorder characterized by increasing hyperglycemia and the need to gradually intensify therapy in order to achieve and maintain glycemic control. Early initiation of combination therapy has been proposed as an approach to achieve glycemic goals earlier and delay the deterioration of glycemic control and with possible better preservation of β-cell function. We discuss in this article the pros and cons of this approach, focusing on individuals with HbA1c at diagnosis of 7.5-9.0%, where difference of opinion still exists on management. Initial combination therapy is proposed to lead to better and faster achievement of glycemic targets versus monotherapy and to impede clinical inertia and may possibly slow the deterioration of β-cell function. However, treating patients with sequential therapy is proposed to allow one to fully assess the efficacy and risk-to-benefit ratio of each drug as it is added. Furthermore, there is no evidence to support that rapid addition and titration of medications according to the glycemic profile achieved are inferior to initial combination therapy if glycemic targets are attained in a timely manner. Initial combination therapy is argued to postpone clinical inertia to the next decision point but does not eliminate it. Additionally, it may have been the agents chosen and not the timing of their initiation that led to improved β-cell function in the studies of initial combination therapy, and there are no data currently comparing use of the same drugs initiated simultaneously or sequentially. Heightened awareness of providers, individualization of therapy and setting, and reaching glycemic targets remain the mainstays of care. [ABSTRACT FROM AUTHOR]

Objective: To analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study.Research Design and Methods: Patients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement <54 mg/dL) or major hypoglycemia (requiring extended assistance) and patient characteristics overall and by treatment allocation were studied.Results: At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c ≤7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia.Conclusions: The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy. [ABSTRACT FROM AUTHOR]

Objective: Observations over the past few years have demonstrated the need to adjust glycemic targets based on parameters pertaining to individual patient characteristics and comorbidities. However, the weight and value given to each parameter will clearly vary depending on the experience of the provider, the characteristics of the patient, and the specific clinical situation.Research Design and Methods: To determine if there is current consensus on a global level with regard to identifying these parameters and their relative importance, we conducted a survey among 244 key worldwide opinion-leading diabetologists. Initially, the physicians were to rank the factors they take into consideration when setting their patients' glycemic target according to their relative importance. Subsequently, six clinical vignettes were presented, and the experts were requested to suggest an appropriate glycemic target. The survey results were used to formulate an algorithm according to which an estimate of the patient's glycemic target based on individualized parameters can be computed. Three additional clinical cases were submitted to a new set of experts for validation of the algorithm.Results: A total of 151 (61.9%) experts responded to the survey. The parameters "life expectancy" and "risk of hypoglycemia from treatment" were considered to be the most important. "Resources" and "disease duration" ranked the lowest. An algorithm was constructed based on survey results. It was validated by presenting three new cases to 57 leading diabetologists who suggested glycemic targets that were similar to those calculated by the algorithm.Conclusions: The resultant suggested algorithm is an additional decision-making tool offered to the clinician to supplement clinical decision making when considering a glycemic target for the individual patient with diabetes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Dapagliflozin improved heart failure and kidney outcomes in patients with type 2 diabetes (T2DM) with or at high risk for atherosclerotic cardiovascular disease in the DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58). Here, the aim was to analyze the efficacy and safety of dapagliflozin stratified according to baseline systolic blood pressure (SBP).Methods: The DECLARE-TIMI 58 trial randomly assigned patients with T2DM and either previous atherosclerotic cardiovascular disease or atherosclerotic cardiovascular disease risk factors to dapagliflozin or placebo. Patients were categorized by baseline SBP levels: <120, 120 to 129, 130 to 139, 140 to 159, and ≥160 mm Hg (normal, elevated, stage 1, stage 2, and severe hypertension, respectively). Efficacy outcomes of interest were hospitalization for heart failure and a renal-specific composite outcome (sustained decrease in estimated glomerular filtration rate by 40%, progression to end-stage renal disease, or renal death). Safety outcomes included symptoms of volume depletion, lower extremity amputations, and acute kidney injury.Results: The trial comprised 17 160 patients; mean age, 64.0±6.8 years; 37.4% women; median duration of T2DM, 11 years; 40.6% with prevalent cardiovascular disease. Overall, dapagliflozin reduced SBP by 2.4 mm Hg (95% CI, 1.9-2.9; P<0.0001) compared with placebo at 48 months. The beneficial effects of dapagliflozin on hospitalization for heart failure and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (Pinteractions=0.28 and 0.52, respectively). Among normotensive patients, the hazard ratios were 0.66 (95% CI, 0.42-1.05) and 0.39 (95% CI, 0.19-0.78), respectively, for hospitalization for heart failure and the renal-specific outcome. Events of volume depletion, amputation, and acute kidney injury did not differ with dapagliflozin overall or within any baseline SBP group.Conclusions: In patients with T2DM with or at high atherosclerotic cardiovascular disease risk, dapagliflozin reduced risk for hospitalization for heart failure and renal outcomes regardless of baseline SBP, with no difference in adverse events of interest at any level of baseline SBP. These results indicate that dapagliflozin provides cardiorenal benefits in patients with T2DM at high atherosclerotic cardiovascular disease risk independent of baseline blood pressure.Registration: URL: https://www.Clinicaltrials: gov; Unique identifier: NCT01730534. [ABSTRACT FROM AUTHOR]

Background: Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular complications. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk for hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes mellitus. An increased risk of amputation has been observed with canagliflozin in 1 previous trial. We examined cardiovascular and kidney efficacy and the risk of limb-related events in patients with and without PAD in an exploratory analysis.Methods: A total of 17 160 patients with type 2 diabetes mellitus, including 1025 (6%) with PAD, were randomized. Key efficacy outcomes were MACE (cardiovascular [CV] death, myocardial infarction, stroke), CV death/HHF, and progression of kidney disease. Amputations, peripheral revascularization, and limb ischemic adverse events were site-reported and categorized by a blinded reviewer.Results: Patients in the placebo arm with PAD versus those without tended to have higher adjusted risk of CV death, myocardial infarction, or stroke (adjusted hazard ratio [HR], 1.23 [95% CI, 0.97-1.56], P=0.094) and significantly higher adjusted risk of CV death/HHF (adjusted HR, 1.60 [95% CI, 1.21-2.12], P=0.0010) and progression of kidney disease (adjusted HR, 1.51 [95% CI, 1.13 - 2.03], P=0.0058), and limb adverse events (adjusted HR, 8.37, P<0.001). The relative risk reductions with dapagliflozin for CV death/HHF (HR, 0.86, PAD; HR, 0.82, no-PAD; P-interaction=0.79) and progression of kidney disease (HR, 0.78, PAD; HR, 0.76, no-PAD; P-interaction=0.84) were consistent regardless of PAD. There were 560 patients who had at least 1 limb ischemic event, 454 patients with at least 1 peripheral revascularization, and 236 patients with at least 1 amputation, with a total of 407 amputations reported. Overall, there were no significant differences in any limb outcome with dapagliflozin versus placebo including limb ischemic adverse events (HR, 1.07 [95% CI, 0.90-1.26]) and amputation (HR, 1.09 [95% CI, 0.84-1.40]), with no significant interactions by a history of PAD versus not (P-interactions=0.30 and 0.093, respectively).Conclusions: Patients with versus without PAD are at a higher risk of CV death of CV death, HHF, and kidney outcomes, and have a consistent benefits for CV death/HHF and progression of kidney disease with dapagliflozin. Patients with PAD had a higher risk of limb events, with no consistent pattern of incremental risk observed with dapagliflozin. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01730534. [ABSTRACT FROM AUTHOR]

Background: Metformin is first-line therapy for type 2 diabetes mellitus, although its effects on the cardiovascular system are unproved.Methods: In this post hoc analysis, patients in SAVOR-TIMI 53 (Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) with baseline biomarker samples (n=12 156) were classified as ever versus never taking metformin during the trial period. Associations between metformin exposure and outcomes were estimated with inverse probability of treatment weighting Cox modeling for the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, as well as cardiovascular death and all-cause mortality, with biomarkers included as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models.Results: Of the 12 156 patients with baseline biomarker samples, 8971 (74%) had metformin exposure, 1611 (13%) had prior heart failure, and 1332 (11%) had at least moderate chronic kidney disease (estimated glomerular filtration rate ≤45 mL·min-1·1.73 m-2). Metformin use was associated with no difference in risk for the composite end point (hazard ratio for inverse probability of treatment weighting, 0.92 [95% CI, 0.76-1.11]) but lower risk of all-cause mortality (hazard ratio for inverse probability of treatment weighting, 0.75 [95% CI, 0.59-0.95]). There was no significant relationship between metformin use and these end points in patients with prior heart failure or moderate to severe chronic kidney disease.Conclusions: In a cohort of 12 156 patients with type 2 diabetes mellitus and high cardiovascular risk, metformin use was associated with lower rates of all-cause mortality, including after adjustment for clinical variables and biomarkers, but not lower rates of the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease.Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01107886. [ABSTRACT FROM AUTHOR]

Background: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown.Methods: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality.Results: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66-1.17]) and those without HF (HR, 0.88 [95% CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86-1.10]; P for interaction=0.016).Conclusions: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF.Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534. [ABSTRACT FROM AUTHOR]

Background: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy.Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest.Results: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72-0.99; P=0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88-1.13; P=0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81-1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65-1.00; P=0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72-1.00; P=0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010).Conclusions: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI.Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534. [ABSTRACT FROM AUTHOR]

Background: Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as 2 new classes of antihyperglycemic agents that also reduce cardiovascular risk. The relative benefits in patients with and without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs remain undefined.Methods: We performed a systematic review and trial-level meta-analysis of GLP1-RA and SGLT2i cardiovascular outcomes trials using the PubMed and EMBASE databases (Excerpta Medica Database). The primary outcomes were the composite of myocardial infarction, stroke, and cardiovascular death (MACE); hospitalization for heart failure; and progression of kidney disease.Results: In total, data from 8 trials and 77 242 patients, 42 920 (55.6%) in GLP1-RA trials, and 34 322 (44.4%) in SGLT2i trials, were included. Both drug classes reduced MACE in a similar magnitude with GLP1-RA reducing the risk by 12% (hazard ratio [HR], 0.88; 95% CI, 0.84-0.94; P<0.001) and SGLT2i by 11% (HR, 0.89; 95% CI, 0.83-0.96; P=0.001). For both drug classes, this treatment effect was restricted to a 14% reduction in those with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.80-0.93; P=0.002), whereas no effect was seen in patients without established atherosclerotic cardiovascular disease (HR, 1.01; 95% CI, 0.87-1.19; P=0.81; P interaction, 0.028). SGLT2i reduced hospitalization for heart failure by 31% (HR, 0.69; 95% CI, 0.61-0.79; P<0.001), whereas GLP1-RA did not have a significant effect (HR, 0.93; 95% CI, 0.83-1.04; P=0.20). Both GLP1-RA (HR, 0.82; 95% CI, 0.75-0.89; P<0.001) and SGLT2i (HR, 0.62; 95% CI, 0.58-0.67; P<0.001) reduced the risk of progression of kidney disease including macroalbuminuria, but only SGLT2i reduced the risk of worsening estimated glomerular filtration rate, end-stage kidney disease, or renal death (HR, 0.55; 95% CI, 0.48-0.64; P<0.001).Conclusions: In trials reported to date, GLP1-RA and SGLT2i reduce atherosclerotic MACE to a similar degree in patients with established atherosclerotic cardiovascular disease, whereas SGLT2i have a more marked effect on preventing hospitalization for heart failure and progression of kidney disease. Their distinct clinical benefit profiles should be considered in the decision-making process when treating patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Currently available short-acting insulin analogs have slower absorption compared with endogenous insulin occasionally resulting in immediate postprandial hyperglycemia. Intradermal (ID) injection facilitates faster drug absorption and may result in improved insulin pharmacokinetics.Methods: Seventeen patients with type 2 diabetes were included in this single-center, pilot, open-label crossover study. Patients received 0.2 U/kg Insulin aspart ID injections using a MicronJet (MJ) needle and subcutaneous (SC) injections, using a conventional needle in a crossover design. Thirteen patients were studied under fasting conditions and four before a standard meal test. The pharmacokinetic/pharmacodynamic (PK/PD) profile, as well as the safety and tolerability of injections, was compared.Results: Fourteen patients completed the study per-protocol. ID versus SC injection demonstrated significantly shorter Tmax (median 35 vs. 87.5 min [P < 0.001]), while the Cmax did not significantly differ (median 80 vs. 55 μU/mL [P = 0.085]). Median insulin area under the curve (AUC; 360 min) did not differ between the groups (9914 vs. 10,936 μU/mL/min [p = 0.077]), yet 0-60 min insulin AUC was higher with ID versus SC injection (mean ± SD 3821 ± 1429 vs. 2534 ± 737 μU/mL/min [p = 0.01]) and 4-6 h AUC was lower with ID versus SC injection (mean ± SD 2054 ± 858 vs. 2929 ± 1412 μU/mL/min [p = 0.02]). The relative bioavailability of the ID versus the SC insulin (AUCID/AUCSC) was similar (median 0.91 [95% confidence interval 0.73-1.27]).Conclusions: ID insulin injection delivered through an MJ needle demonstrated superior PK profile compared with conventional SC administration, including shorter Tmax and higher early and lower late exposure in patients with type 2 diabetes. This may help achieve better insulin coverage of meals and lower postprandial glucose excursions. [ABSTRACT FROM AUTHOR]