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Aim: To investigate risk factors associated with kidney disorders in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk. Methods: In DEVOTE, a cardiovascular outcomes trial, 7637 patients were randomised to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100), with standard of care. In these exploratory post hoc analyses, serious adverse event reports were searched using Standardised MedDRA® Queries related to chronic kidney disease (CKD) or acute kidney injury (AKI). Baseline predictors of CKD, AKI and change in estimated glomerular filtration rate (eGFR) were identified using stepwise selection and Cox or linear regression. Results: Over 2 years, eGFR (mL/min/1.73 m2) decline was small and similar between treatments (degludec: 2.70; glargine U100: 2.92). Overall, 97 and 208 patients experienced CKD and AKI events, respectively. A history of heart failure was a risk factor for CKD (hazard ratio [HR] 1.97 [95% confidence interval [CI] 1.41; 2.75]) and AKI (HR 2.28 [95% CI 1.64; 3.17]). A history of hepatic impairment was a significant predictor of CKD (HR 3.28 [95% CI 2.12; 5.07]) and change in eGFR (estimate: −8.59 [95% CI −10.20; −7.00]). Conclusion: Our findings indicate that traditional, non-modifiable risk factors for kidney disorders apply to insulin-treated patients with T2D at high CV risk. Trial registration: NCT01959529 (ClinicalTrials.gov).

Aims The ability to differentiate patient populations with type 2 diabetes at high risk of severe hypoglycaemia could impact clinical decision making. The aim of this study was to develop a risk score, using patient characteristics, that could differentiate between populations with higher and lower 2‐year risk of severe hypoglycaemia among individuals at increased risk of cardiovascular disease. Materials and methods Two models were developed for the risk score based on data from the DEVOTE cardiovascular outcomes trials. The first, a data‐driven machine‐learning model, used stepwise regression with bidirectional elimination to identify risk factors for severe hypoglycaemia. The second, a risk score based on known clinical risk factors accessible in clinical practice identified from the data‐driven model, included: insulin treatment regimen; diabetes duration; sex; age; and glycated haemoglobin, all at baseline. Both the data‐driven model and simple risk score were evaluated for discrimination, calibration and generalizability using data from DEVOTE, and were validated against the external LEADER cardiovascular outcomes trial dataset. Results Both the data‐driven model and the simple risk score discriminated between patients at higher and lower hypoglycaemia risk, and performed similarly well based on the time‐dependent area under the curve index (0.63 and 0.66, respectively) over a 2‐year time horizon. Conclusions Both the data‐driven model and the simple hypoglycaemia risk score were able to discriminate between patients at higher and lower risk of severe hypoglycaemia, the latter doing so using easily accessible clinical data. The implementation of such a tool (http://www.hyporiskscore.com/) may facilitate improved recognition of, and education about, severe hypoglycaemia risk, potentially improving patient care.

Aims To undertake a post‐hoc analysis, utilizing a hypoglycaemia risk score based on DEVOTE trial data, to investigate if a high risk of severe hypoglycaemia was associated with an increased risk of cardiovascular events, and whether reduced rates of severe hypoglycaemia in patients identified as having the highest risk affected the risk of cardiovascular outcomes. Materials and Methods The DEVOTE population was divided into quartiles according to patients' individual hypoglycaemia risk scores. For each quartile, the observed incidence and rate of severe hypoglycaemia, major adverse cardiovascular event (MACE) and all‐cause mortality were determined to investigate whether those with the highest risk of hypoglycaemia were also at the greatest risk of MACE and all‐cause mortality. In addition, treatment differences within each risk quartile [insulin degludec (degludec) vs. insulin glargine 100 units/mL (glargine U100)] in terms of severe hypoglycaemia, MACE and all‐cause mortality were investigated. Results Patients with the highest risk scores had the highest rates of severe hypoglycaemia, MACE and all‐cause mortality. Treatment ratios between degludec and glargine U100 in the highest risk quartile were 95% confidence interval (CI) 0.56 (0.39; 0.80) (severe hypoglycaemia), 95% CI 0.76 (0.58; 0.99) (MACE) and 95% CI 0.77 (0.55; 1.07) (all‐cause mortality). Conclusions The risk score demonstrated that a high risk of severe hypoglycaemia was associated with a high incidence of MACE and all‐cause mortality and that, in this high‐risk group, those treated with degludec had a lower incidence of MACE. These observations support the hypothesis that hypoglycaemia is a risk factor for cardiovascular events.

Introduction The associations of chronic kidney disease (CKD) severity, cardiovascular disease (CVD), and insulin with the risks of major adverse cardiovascular events (MACE), mortality, and severe hypoglycemia in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk are not known. This secondary, pooled analysis of data from the DEVOTE trial examined whether baseline glomerular filtration rate (GFR) categories were associated with a higher risk of these outcomes. Methods DEVOTE was a treat-to-target, double-blind trial involving 7637 patients with T2D at high CV risk who were randomized to once-daily treatment with either insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). Patients with estimated GFR data at baseline (n = 7522) were analyzed following stratification into four GFR categories. Results The risks of MACE, CV death, and all-cause mortality increased with worsening baseline GFR category (P

Aim To compare the associations between concomitant liraglutide use versus no liraglutide use and the risk of major adverse cardiovascular events (MACE) and all-cause mortality among patients receiving basal insulin (either insulin degludec [degludec] or insulin glargine 100 units/mL [glargine U100]) in the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE). Materials and methods Patients with type 2 diabetes and high cardiovascular risk were randomized 1:1 to degludec or glargine U100. Hazard ratios for MACE/mortality were calculated using a Cox regression model adjusted for treatment and time-varying liraglutide use at any time during the trial, without interaction. Sensitivity analyses were adjusted for baseline covariates including, but not limited to, age, sex, smoking and prior cardiovascular disease. Results At baseline, 436/7637 (5.7%) patients were treated with liraglutide; after baseline, 187/7637 (2.4%) started and 210/7637 (2.7%) stopped liraglutide. Mean liraglutide exposure from randomization was 530.2 days. Liraglutide use versus no liraglutide use was associated with significantly lower hazard rates for MACE [0.62 (0.41; 0.92)95%CI ] and all-cause mortality [0.50 (0.29; 0.88)95%CI ]. There was no significant difference in the rate of severe hypoglycaemia with versus without liraglutide use. Multiple sensitivity analyses yielded similar results. Conclusions Use of liraglutide was associated with significantly lower risk of MACE and death in patients with type 2 diabetes and high cardiovascular risk using basal insulin.

Introduction: The aim of this study was to evaluate the short-term cost-utility of insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) for the treatment of type 2 diabetes in the basal–bolus subgroup of the head-to-head cardiovascular (CV) outcome trial, DEVOTE. Methods: A cost-utility analysis was conducted over a 2-year time horizon using a decision analytic model to compare costs in patients receiving once daily degludec or glargine U100, both as part of a basal–bolus regimen, in addition to standard care. Clinical outcomes and patient characteristics were taken exclusively from DEVOTE, whilst health-related quality of life utilities and UK-specific costs (expressed in 2016 GBP) were obtained from the literature. The analysis was conducted from the perspective of the National Health Service. Results: Degludec was associated with mean cost savings of GBP 28.78 per patient relative to glargine U100 in patients with type 2 diabetes at high CV risk. Cost savings were driven by the reduction in risk of diabetes-related complications with degludec, which offset the higher treatment costs relative to glargine U100. Degludec was associated with a mean improvement of 0.0064 quality-adjusted life-years (QALYs) compared with glargine U100, with improvements driven predominantly by lower rates of severe hypoglycemia with degludec versus glargine U100. Improvements in quality-adjusted life expectancy combined with cost neutrality resulted in degludec being dominant over glargine U100. Sensitivity analyses demonstrated that the incremental cost-utility ratio was stable to variations in the majority of model inputs. Conclusion: The present short-term modeling analysis found that for the basal–bolus subgroup of patients in DEVOTE, with a high risk of CV events, degludec was cost neutral (no additional costs) compared with glargine U100 over a 2-year time horizon in the UK setting. Furthermore, there were QALY gains with degludec, particularly due to the reduction in the risk of severe hypoglycemia. Funding: Novo Nordisk A/S. Trial Registration: ClinicalTrials.gov identifier, NCT01959529.

Aims: The aim of this study was to describe the risks of cardiovascular (CV) events and severe hypoglycaemia with insulin degludec (degludec) vs insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes (T2D) aged 65 years or older. Materials and methods: A total of 7637 patients in the DEVOTE trial, a treat-to-target, randomized, double-blind trial evaluating the CV safety of degludec vs glargine U100, were divided into three age groups (50-64 years, n = 3682; 65-74 years, n = 3136; ≥75 years, n = 819). Outcomes by overall age group and randomized treatment differences were analysed for major adverse cardiovascular events (MACE), all-cause mortality, severe hypoglycaemia and serious adverse events (SAEs). Results: Patients with increasing age had higher risks of CV death, all-cause mortality and SAEs, and there were non-significant trends towards higher risks of MACE and severe hypoglycaemia. Treatment effects on the risk of MACE, all-cause mortality, severe hypoglycaemia and SAEs were consistent across age groups, based on the non-significant interactions between treatment and age with regard to these outcomes. Conclusions: There were higher risks of CV death, all-cause mortality and SAEs, and trends towards higher risks of MACE and severe hypoglycaemia with increasing age after adjusting for baseline differences. The effects across age groups of degludec vs glargine U100 on MACE, all-cause mortality and severe hypoglycaemia were comparable, suggesting that the risk of MACE, as well as all-cause mortality, is similar and the risk of severe hypoglycaemia is lower with degludec regardless of age. Evidence is conclusive only until 74 years of age.

Objectives: To evaluate the cost-effectiveness of insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) in basal–bolus regimens for patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk based on the DEVOTE CV outcomes trial. Methods: A microsimulation model, informed by clinical outcomes from the subgroup of patients using basal–bolus insulin therapy in DEVOTE (NCT01959529) and by the UKPDS Outcomes Model 2 risk equations, was used to model direct costs (2018 GBP) and effectiveness outcomes [quality-adjusted life years (QALYs)] with degludec versus glargine U100 over a 40-year time horizon. The model captured the development of eight diabetes-related complications, death, severe hypoglycemia and insulin dosing. This analysis was conducted from the perspective of National Health Service (NHS) England. Results: Treatment with degludec versus glargine U100 in basal–bolus regimens was associated with improved clinical outcomes at a higher cost per patient [incremental cost effectiveness ratio (ICER): £14,956 GBP/QALY]. Degludec remained cost effective versus glargine U100 in all exploratory sensitivity analyses, with ICERs below the widely accepted willingness-to-pay threshold, although the result was most sensitive to assumptions regarding the persistence of treatment effects. Conclusions: Our long-term modeling analysis suggested that degludec was cost effective (from the perspective of NHS England) versus glargine U100 in basal–bolus regimens for patients with T2D at high CV risk. Our findings raise important questions regarding how to model the health economics of diabetes therapies.

Introduction: The associations of chronic kidney disease (CKD) severity, cardiovascular disease (CVD), and insulin with the risks of major adverse cardiovascular events (MACE), mortality, and severe hypoglycemia in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk are not known. This secondary, pooled analysis of data from the DEVOTE trial examined whether baseline glomerular filtration rate (GFR) categories were associated with a higher risk of these outcomes. Methods: DEVOTE was a treat-to-target, double-blind trial involving 7637 patients with T2D at high CV risk who were randomized to once-daily treatment with either insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). Patients with estimated GFR data at baseline (n = 7522) were analyzed following stratification into four GFR categories. Results: The risks of MACE, CV death, and all-cause mortality increased with worsening baseline GFR category (P < 0.05), with a trend towards higher rates of severe hypoglycemia. Patients with prior CVD, CKD (estimated GFR < 60 mL/min/m2), or both were at higher risk of MACE, CV death, and all-cause mortality. Only CKD was associated with a higher rate of severe hypoglycemia, and the risk of MACE was higher in patients with CVD than in those with CKD (P = 0.0003). There were no significant interactions between randomized treatment and GFR category. Conclusion: The risks of MACE, CV death, and all-cause mortality were higher with lower baseline GFR and with prior CVD, CKD, or both. The relative effects of degludec versus glargine U100 on outcomes were consistent across baseline GFR categories, suggesting that the lower rate of severe hypoglycemia associated with degludec use versus glargine U100 use was independent of baseline GFR category. Funding: Novo Nordisk.

Aim: To compare the associations between concomitant liraglutide use versus no liraglutide use and the risk of major adverse cardiovascular events (MACE) and all-cause mortality among patients receiving basal insulin (either insulin degludec [degludec] or insulin glargine 100 units/mL [glargine U100]) in the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE). Materials and Methods: Patients with type 2 diabetes and high cardiovascular risk were randomized 1:1 to degludec or glargine U100. Hazard ratios for MACE/mortality were calculated using a Cox regression model adjusted for treatment and time-varying liraglutide use at any time during the trial, without interaction. Sensitivity analyses were adjusted for baseline covariates including, but not limited to, age, sex, smoking and prior cardiovascular disease. Results: At baseline, 436/7637 (5.7%) patients were treated with liraglutide; after baseline, 187/7637 (2.4%) started and 210/7637 (2.7%) stopped liraglutide. Mean liraglutide exposure from randomization was 530.2 days. Liraglutide use versus no liraglutide use was associated with significantly lower hazard rates for MACE [0.62 (0.41; 0.92)95%CI] and all-cause mortality [0.50 (0.29; 0.88)95%CI]. There was no significant difference in the rate of severe hypoglycaemia with versus without liraglutide use. Multiple sensitivity analyses yielded similar results. Conclusions: Use of liraglutide was associated with significantly lower risk of MACE and death in patients with type 2 diabetes and high cardiovascular risk using basal insulin.