Assessing reproducibility and utility of clustering of patients with type 2 diabetes and established CV disease (SAVOR -TIMI 53 trial)

Objective To assess the reproducibility and clinical utility of clustering-based subtyping of patients with type 2 diabetes (T2D) and established cardiovascular (CV) disease. Methods The cardiovascular outcome trial SAVOR-TIMI 53 (n = 16,492) was used. Analyses focused on T2D patients with established CV disease. Unsupervised machine learning technique called “k-means clustering” was used to divide patients into subtypes. K-means clustering including HbA1c, age of diagnosis, BMI, HOMA2-IR and HOMA2-B was used to assign clusters to the following diabetes subtypes: severe insulin deficient diabetes (SIDD); severe insulin-resistant diabetes (SIRD); mild obesity-related diabetes (MOD); mild age-related diabetes (MARD). We refer these subtypes as “clustering-based diabetes subtypes”. A simulation study using randomly generated data was conducted to understand how correlations between the above variables influence the formation of the cluster-based diabetes subtypes. The predictive utility of clustering-based diabetes subtypes for CV events (3-point MACE), renal function reduction (eGFR decrease >30%) and diabetic disease progression (introduction of additional anti-diabetic medication) were compared with conventional risk scores. Hazard ratios (HR) were estimated by Cox-proportional hazard models. Results In the SAVOR-TIMI 53 trial based dataset, the percentage of the clustering-based T2D subtypes were; SIDD (18%), SIRD (17%), MOD (29%), MARD (37%). Using the simulated dataset, the diabetes subtypes could be largely reproduced from a log-normal distribution when including known correlations between variables. The predictive utility of clustering-based diabetic subtypes on CV events, renal function reduction, and diabetic disease progression did not show an advantage compared to conventional risk scores. Conclusions The consistent reproduction of four clustering-based T2D subtypes can be explained by the correlations between the variables used for clustering. Subtypes of T2D based on clustering had limited advantage compared to conventional risk scores to predict clinical outcome in patients with T2D and established CV disease.

Glycemic efficacy and safety of the SGLT2 inhibitor ertugliflozin in patients with type 2 diabetes and stage 3 chronic kidney disease: an analysis from the VERTIS CV randomized trial

IntroductionHere we report the glycemic efficacy and safety of ertugliflozin in patients in the VERTIS CV cardiovascular outcome trial with chronic kidney disease (CKD) stage 3.Research design and methodsPrespecified and post-hoc analyses were performed in patients with an estimated glomerular filtration rate (eGFR) 30–<60 mL/min/1.73 m2 at screening. The primary endpoint was glycemic efficacy at week 18. Longer term glycemic efficacy and changes in body weight, systolic blood pressure (SBP), and eGFR were also evaluated.ResultsAmong 8246 patients in VERTIS CV, 1776 patients had CKD stage 3; 1319 patients had CKD stage 3A (eGFR 45–<60 mL/min/1.73 m2); 457 patients had CKD stage 3B (eGFR 30–<45 mL/min/1.73 m2). Week 18 least squares (LS)-mean (95% CI) placebo-adjusted changes from baseline in glycated hemoglobin (HbA1c) for 5 mg and 15 mg ertugliflozin were −0.27% (−0.37% to –0.17%) and −0.28% (−0.38% to –0.17%), respectively, for CKD stage 3 overall and −0.27% (−0.38% to –0.15%) and −0.31% (−0.43% to –0.19%), respectively, for CKD stage 3A (all p<0.001). For CKD stage 3B, the reduction in HbA1c for 5 mg ertugliflozin was −0.28% (−0.47% to –0.08%) (p=0.006) and for 15 mg ertugliflozin was −0.19% (−0.39% to 0.01%) (p=0.064). LS-mean placebo-adjusted reductions in body weight (range: −1.32 to −1.95 kg) and SBP (range: −2.42 to −3.41 mm Hg) were observed across CKD stage 3 categories with ertugliflozin. After an initial dip, eGFR remained above or near baseline with ertugliflozin treatment. The incidence of overall adverse events (AEs), symptomatic hypoglycemia, hypovolemia, and kidney-related AEs did not differ between ertugliflozin and placebo across CKD stage 3 subgroups.ConclusionsIn VERTIS CV patients with CKD stage 3A, ertugliflozin resulted in reductions in HbA1c, body weight and SBP, maintenance of eGFR, and was generally well tolerated. Results in the CKD stage 3B subgroup were generally similar except for an attenuated HbA1c response with the 15 mg dose.Trial registration numberNCT01986881.

The Effect of Dapagliflozin on Albuminuria in DECLARE-TIMI 58

<b>Objective: </b>Sodium glucose co-transporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the DECLARE-TIMI 58 cardiovascular outcome trial, which included populations with lower cardiorenal risk. <p><b>Methods:</b> 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-creatinine ratio (UACR) was tested at baseline, 6-months, 12-months and yearly thereafter. Change in UACR over time was measured as a continuous and categorical variable (≤15; >15 to<30; ≥30-≤300; >300 mg/g), by treatment arm. Composite cardiorenal outcome was ≥40% sustained-decline in eGFR to <60 mL/min/1.73m², end-stage kidney disease, cardiovascular- or renal-death; specific renal outcome included all except cardiovascular-death.</p> <p><b>Results:</b> Baseline UACR was available for 16,843 (98.15%) participants; 9,067 (53.83%) with ≤15 mg/g; 2,577 (15.30%) with <15->30 mg/g; 4,030 (23.93%) with 30-300 mg/g; and 1,169 (6.94%) with >300 mg/g. Measured as continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared to placebo, across all UACR and eGFR categories (all p<0.0001). Sustained-confirmed ≥1 category improvement in UACR was more common in dapagliflozin vs. placebo [HR=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, P_int=0.033); renal-specific outcome was reduced for all UACR subgroups (p<0.05, P_int=0.480).</p> <p><b>Conclusion: </b>In DECLARE-TIMI 58, dapagliflozin demonstrated a favourable 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. </p>

The Effect of Dapagliflozin on Albuminuria in DECLARE-TIMI 58

<b>Objective: </b>Sodium glucose co-transporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the DECLARE-TIMI 58 cardiovascular outcome trial, which included populations with lower cardiorenal risk. <p><b>Methods:</b> 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-creatinine ratio (UACR) was tested at baseline, 6-months, 12-months and yearly thereafter. Change in UACR over time was measured as a continuous and categorical variable (≤15; >15 to<30; ≥30-≤300; >300 mg/g), by treatment arm. Composite cardiorenal outcome was ≥40% sustained-decline in eGFR to <60 mL/min/1.73m², end-stage kidney disease, cardiovascular- or renal-death; specific renal outcome included all except cardiovascular-death.</p> <p><b>Results:</b> Baseline UACR was available for 16,843 (98.15%) participants; 9,067 (53.83%) with ≤15 mg/g; 2,577 (15.30%) with <15->30 mg/g; 4,030 (23.93%) with 30-300 mg/g; and 1,169 (6.94%) with >300 mg/g. Measured as continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared to placebo, across all UACR and eGFR categories (all p<0.0001). Sustained-confirmed ≥1 category improvement in UACR was more common in dapagliflozin vs. placebo [HR=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, P_int=0.033); renal-specific outcome was reduced for all UACR subgroups (p<0.05, P_int=0.480).</p> <p><b>Conclusion: </b>In DECLARE-TIMI 58, dapagliflozin demonstrated a favourable 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. </p>

The Effect of Dapagliflozin on Albuminuria in DECLARE-TIMI 58

<b>Objective: </b>Sodium glucose co-transporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the DECLARE-TIMI 58 cardiovascular outcome trial, which included populations with lower cardiorenal risk. <p><b>Methods:</b> 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-creatinine ratio (UACR) was tested at baseline, 6-months, 12-months and yearly thereafter. Change in UACR over time was measured as a continuous and categorical variable (≤15; >15 to<30; ≥30-≤300; >300 mg/g), by treatment arm. Composite cardiorenal outcome was ≥40% sustained-decline in eGFR to <60 mL/min/1.73m², end-stage kidney disease, cardiovascular- or renal-death; specific renal outcome included all except cardiovascular-death.</p> <p><b>Results:</b> Baseline UACR was available for 16,843 (98.15%) participants; 9,067 (53.83%) with ≤15 mg/g; 2,577 (15.30%) with <15->30 mg/g; 4,030 (23.93%) with 30-300 mg/g; and 1,169 (6.94%) with >300 mg/g. Measured as continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared to placebo, across all UACR and eGFR categories (all p<0.0001). Sustained-confirmed ≥1 category improvement in UACR was more common in dapagliflozin vs. placebo [HR=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, P_int=0.033); renal-specific outcome was reduced for all UACR subgroups (p<0.05, P_int=0.480).</p> <p><b>Conclusion: </b>In DECLARE-TIMI 58, dapagliflozin demonstrated a favourable 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. </p>

The Effect of Dapagliflozin on Albuminuria in DECLARE-TIMI 58

<b>Objective: </b>Sodium glucose co-transporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the DECLARE-TIMI 58 cardiovascular outcome trial, which included populations with lower cardiorenal risk. <p><b>Methods:</b> 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-creatinine ratio (UACR) was tested at baseline, 6-months, 12-months and yearly thereafter. Change in UACR over time was measured as a continuous and categorical variable (≤15; >15 to<30; ≥30-≤300; >300 mg/g), by treatment arm. Composite cardiorenal outcome was ≥40% sustained-decline in eGFR to <60 mL/min/1.73m², end-stage kidney disease, cardiovascular- or renal-death; specific renal outcome included all except cardiovascular-death.</p> <p><b>Results:</b> Baseline UACR was available for 16,843 (98.15%) participants; 9,067 (53.83%) with ≤15 mg/g; 2,577 (15.30%) with <15->30 mg/g; 4,030 (23.93%) with 30-300 mg/g; and 1,169 (6.94%) with >300 mg/g. Measured as continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared to placebo, across all UACR and eGFR categories (all p<0.0001). Sustained-confirmed ≥1 category improvement in UACR was more common in dapagliflozin vs. placebo [HR=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, P_int=0.033); renal-specific outcome was reduced for all UACR subgroups (p<0.05, P_int=0.480).</p> <p><b>Conclusion: </b>In DECLARE-TIMI 58, dapagliflozin demonstrated a favourable 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. </p>

Extended-release naltrexone/bupropion is safe and effective among subjects with type 2 diabetes already taking incretin agents: a post-hoc analysis of the LIGHT trial

Background Extended-release naltrexone/bupropion (NB) is indicated for chronic weight management. Incretin agents are recommended for patients with type 2 diabetes. This analysis looked at the add-on of NB to incretins to see if weight loss could occur in patients already stabilized on incretin agents. Methods This was a post-hoc analysis of NB vs. placebo (PL) among subjects with type 2 diabetes stable on an incretin agent prior to randomization in a double-blind, PL-controlled cardiovascular outcome trial (N = 1317). Results Over 1 year, mean weight loss was significantly greater among NB patients vs. PL among those taking DPP-4i (mean absolute difference 4.6% [p < 0.0001]) and those taking GLP-1RAs (mean absolute difference 5.2%, p < 0.0001). Proportions of subjects achieving 5% weight loss were significantly greater for NB vs. PL at weeks 26 and 52 among those taking DPP-4is or GLP-1RAs. There were no significant differences in effectiveness observed between NB + DPP-4i and NB + GLP-1RA or between PL + DPP-4i and PL + GLP-1RA in any of the analyses. Serious adverse events were reported by 9.1% and 11.1% for PL + DPP-4i and PL + GLP-1RA, respectively, and 13.3% and 12.4% of NB + DPP-4i and NB + GLP-1RA, respectively. Conclusion NB appears to be effective in reducing weight in patients with T2DM and obesity/overweight who are taking DPP-4ihibitors or GLP-1RA. The SAE rates in all arms of this analysis were lower than have been reported in other cardiovascular outcome trials in type 2 diabetes.

Transposition of cardiovascular outcome trial effects to the real-world population of patients with type 2 diabetes

Background Transferring results obtained in cardiovascular outcome trials (CVOTs) to the real-world setting is challenging. We herein transposed CVOT results to the population of patients with type 2 diabetes (T2D) seen in routine clinical practice and who may receive the medications tested in CVOTs. Methods We implemented the post-stratification approach based on aggregate data of CVOTs and individual data of a target population of diabetic outpatients. We used stratum-specific estimates available from CVOTs to calculate expected effect size for the target population by weighting the average of the stratum-specific treatment effects according to proportions of a given characteristic in the target population. Data are presented as hazard ratio (HR) and 95% confidence intervals. Results Compared to the target population (n = 139,708), the CVOT population (n = 95,816) was younger and had a two to threefold greater prevalence of cardiovascular disease. EMPA-REG was the CVOT with the largest variety of details on stratum-specific effects, followed by TECOS, whereas DECLARE and PIONEER-6 had more limited stratum-specific information. The post-stratification HR estimate for 3 point major adverse cardiovascular event (MACE) based on EMPA-REG was 0.88 (0.74–1.03) in the target population, compared to 0.86 (0.74–0.99) in the trial. The HR estimate based on LEADER was 0.88 (0.77–0.99) in the target population compared to 0.87 (0.78–0.97) in the trial. Consistent results were obtained for SUSTAIN-6, EXSCEL, PIONEER-6 and DECLARE. The effect of DPP-4 inhibitors observed in CVOTs remained neutral in the target population. Conclusions Based on CVOT stratum-specific effects, cardiovascular protective actions of glucose lowering medications tested in CVOTs are transferrable to a much different real-world population of patients with T2D.

Series: Cardiovascular outcome trials for diabetes drugs Degludec and DEVOTE

DEVOTE (Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardio-vascular Events) was an FDA-mandated cardiovascular outcome trial and was the first – and at present the only – completed trial comparing two insulins. DEVOTE compared insulin degludec and insulin glargine (U100) in 7,637 people with type 2 diabetes with established cardiovascular disease, chronic kidney disease, or both, and older diabetic patients with increased cardiovascular risk. DEVOTE demonstrated non-inferiority for major cardiovascular events (MACE), a composite of death from cardiovascular causes, non-fatal myocardial infarction and non-fatal stroke, with a pre-specified non-inferiority margin of 1.3. At 24 months the mean HbA1c was similar in the two groups. Mean fasting plasma glucose was significantly lower in the degludec group than in the glargine group, and pre-specified severe hypoglycaemia was also significantly lower in the degludec group. DEVOTE satisfied the FDA cardiovascular safety requirements for new antidiabetic therapies.