Once-weekly insulin efsitora alfa: Design and rationale for the QWINT phase 3 clinical development programme.

AIMS: Insulin efsitora alfa (efsitora) is a once-weekly basal insulin. This review describes the study design and rationale of the efsitora phase 3 Once Weekly (QW) Insulin Therapy (QWINT) clinical development programme, including the five trials, QWINT-1 through QWINT-5. MATERIALS AND METHODS: The five trials included insulin-naïve adults (QWINT-1 and -2) with type 2 diabetes (T2D), adults with T2D previously treated with basal insulin (QWINT-3 and -4), and QWINT-5 in adults with type 1 diabetes. All five trials were designed as multicentre, randomized, controlled, open-label, treat-to-target studies to investigate the efficacy and safety of efsitora versus active once-daily basal insulin comparators (insulin glargine U100 or insulin degludec U100). The primary objective of each trial is to compare the change in HbA1c from baseline to week 26 or 52 between efsitora and the active comparator. The key secondary objectives include change in fasting glucose, insulin dose and continuous glucose monitoring variables, and patient-reported outcome questionnaires. CONCLUSIONS: The QWINT development programme includes a racially and geographically diverse population to provide important information regarding the efficacy and safety of efsitora and its clinical management of people with diabetes.

Tirzepatide for the treatment of adults with type 2 diabetes: An endocrine perspective.

Tirzepatide is a novel glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GLP-1) receptor agonist approved in the United States as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes and under investigation for use in chronic weight management, major adverse cardiovascular events and the management of other conditions, including heart failure with preserved ejection fraction and obesity and non-cirrhotic non-alcoholic steatohepatitis. The Phase 3 SURPASS 1-5 clinical trial programme was designed to assess efficacy and safety of once-weekly subcutaneously injected tirzepatide (5, 10 and 15 mg), as monotherapy or combination therapy, across a broad spectrum of people with type 2 diabetes. Use of tirzepatide in clinical studies was associated with marked reductions of glycated haemoglobin (-1.87 to -2.59%, -20 to -28 mmol/mol) and body weight (-6.2 to -12.9 kg), as well as reductions in parameters commonly associated with heightened cardiometabolic risk such as blood pressure, visceral adiposity and circulating triglycerides. In SUPRASS-2, these reductions were greater than with the GLP-1 receptor agonist semaglutide 1 mg. Tirzepatide was well tolerated, with a low risk of hypoglycaemia when used without insulin or insulin secretagogues and showed a generally similar safety profile to the GLP-1 receptor agonist class. Accordingly, evidence from these clinical trials suggests that tirzepatide offers a new opportunity for the effective lowering of glycated haemoglobin and body weight in adults with type 2 diabetes.

Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial.

BACKGROUND: Despite advancements in care, many people with type 2 diabetes do not meet treatment goals; thus, development of new therapies is needed. We aimed to assess efficacy, safety, and tolerability of novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide monotherapy versus placebo in people with type 2 diabetes inadequately controlled by diet and exercise alone. METHODS: We did a 40-week, double-blind, randomised, placebo-controlled, phase 3 trial (SURPASS-1), at 52 medical research centres and hospitals in India, Japan, Mexico, and the USA. Adult participants (≥18 years) were included if they had type 2 diabetes inadequately controlled by diet and exercise alone and if they were naive to injectable diabetes therapy. Participants were randomly assigned (1:1:1:1) via computer-generated random sequence to once a week tirzepatide (5, 10, or 15 mg), or placebo. All participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) from baseline at 40 weeks. This study is registered with ClinicalTrials.gov, NCT03954834. FINDINGS: From June 3, 2019, to Oct 28, 2020, of 705 individuals assessed for eligibility, 478 (mean baseline HbA1c 7·9% [63 mmol/mol], age 54·1 years [SD 11·9], 231 [48%] women, diabetes duration 4·7 years, and body-mass index 31·9 kg/m2) were randomly assigned to tirzepatide 5 mg (n=121 [25%]), tirzepatide 10 mg (n=121 [25%]), tirzepatide 15 mg (n=121 [25%]), or placebo (n=115 [24%]). 66 (14%) participants discontinued the study drug and 50 (10%) discontinued the study prematurely. At 40 weeks, all tirzepatide doses were superior to placebo for changes from baseline in HbA1c, fasting serum glucose, bodyweight, and HbA1c targets of less than 7·0% (<53 mmol/mol) and less than 5·7% (<39 mmol/mol). Mean HbA1c decreased from baseline by 1·87% (20 mmol/mol) with tirzepatide 5 mg, 1·89% (21 mmol/mol) with tirzepatide 10 mg, and 2·07% (23 mmol/mol) with tirzepatide 15 mg versus +0·04% with placebo (+0·4 mmol/mol), resulting in estimated treatment differences versus placebo of -1·91% (-21 mmol/mol) with tirzepatide 5 mg, -1·93% (-21 mmol/mol) with tirzepatide 10 mg, and -2·11% (-23 mmol/mol) with tirzepatide 15 mg (all p<0·0001). More participants on tirzepatide than on placebo met HbA1c targets of less than 7·0% (<53 mmol/mol; 87-92% vs 20%) and 6·5% or less (≤48 mmol/mol; 81-86% vs 10%) and 31-52% of patients on tirzepatide versus 1% on placebo reached an HbA1c of less than 5·7% (<39 mmol/mol). Tirzepatide induced a dose-dependent bodyweight loss ranging from 7·0 to 9·5 kg. The most frequent adverse events with tirzepatide were mild to moderate and transient gastrointestinal events, including nausea (12-18% vs 6%), diarrhoea (12-14% vs 8%), and vomiting (2-6% vs 2%). No clinically significant (<54 mg/dL [<3 mmol/L]) or severe hypoglycaemia were reported with tirzepatide. One death occurred in the placebo group. INTERPRETATION: Tirzepatide showed robust improvements in glycaemic control and bodyweight, without increased risk of hypoglycaemia. The safety profile was consistent with GLP-1 receptor agonists, indicating a potential monotherapy use of tirzepatide for type 2 diabetes treatment. FUNDING: Eli Lilly and Company.

Report from the CVOT Summit 2021: new cardiovascular, renal, and glycemic outcomes.

The 7th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Renal, and Glycemic Outcomes, was held virtually on November 18-19, 2021. Pursuing the tradition of the previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed CVOTs. This year's focus was placed on the outcomes of EMPEROR-Preserved, FIGARO-DKD, AMPLITUDE-O, SURPASS 1-5, and STEP 1-5. Trial implications for diabetes and obesity management and the impact on new treatment algorithms were highlighted for endocrinologists, diabetologists, cardiologists, nephrologists, and general practitioners. Discussions evolved from outcome trials using SGLT2 inhibitors as therapy for heart failure, to CVOTs with nonsteroidal mineralocorticoid receptor antagonists and GLP-1 receptor agonists. Furthermore, trials for glycemic and overweight/obesity management, challenges in diabetes management in COVID-19, and novel guidelines and treatment strategies were discussed.Trial registration The 8th Cardiovascular Outcome Trial Summit will be held virtually on November 10-11, 2022 ( http://www.cvot.org ).

The Effect of Prestudy Insulin Therapy on Safety and Efficacy of Human Regular U-500 Insulin by Pump or Injection: A Posthoc Analysis.

OBJECTIVE: We conducted a posthoc analysis of the VIVID study (Safety and Efficacy of Human Regular U-500 Insulin Administered by Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Injections in Subjects With Type 2 Diabetes Mellitus: A Randomized, Open-Label, Parallel Clinical Trial), comparing 2 delivery methods of human regular U-500 insulin (U-500R), continuous subcutaneous insulin infusion (CSII) versus multiple daily injection (MDI), in type 2 diabetes requiring high insulin, to determine influence of prestudy insulin on glycemic outcomes. METHODS: We compared A1C, total daily insulin dose (TDD), weight, and hypoglycemia by subgroups of prestudy insulin (prestudy U-500R vs non-U-500R) and treatment (CSII vs MDI). RESULTS: At baseline, prestudy U-500R had higher TDD, higher body mass index, lower A1C and fasting plasma glucose, and higher rate of hypoglycemia compared to non-U-500R. Active titration of U-500R reduced A1C in both subgroups, with maximum benefit at 8 weeks. At 26 weeks, CSII provided the greatest reduction in A1C in both subgroups, with a greater reduction in non-U-500R. MDI provided an A1C reduction in both subgroups, with the greater reduction in non-U-500R. At 8 weeks, prestudy U-500R reached its lowest A1C; thereafter, A1C rebounded with MDI and remained stable with CSII. In non-U-500R, A1C continued to decrease to study end. In non-U-500R, hypoglycemia increased during active titration, but then decreased in the posttitration maintenance period. In both subgroups, TDD increased from baseline with MDI but not with CSII. Body weight increased in both subgroups but was greater in prestudy U-500R with CSII compared to MDI. CONCLUSION: Regardless of previous insulin, people on high-dose insulin could lower A1C with U-500R, with additional benefit from CSII. These results may provide guidance for use of U-500R in clinical practice.

The relationship between HbA1c and hypoglycaemia in patients with diabetes treated with insulin degludec versus insulin glargine 100 units/mL.

AIM: Treat-to-target, randomized controlled trials have confirmed lower rates of hypoglycaemia at equivalent glycaemic control with insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) in patients with type 1 (T1D) or type 2 diabetes (T2D). Treat-to-target trials are designed to enable comparisons of safety and tolerability at a similar HbA1c level. In this post hoc analysis of the SWITCH 1 and 2 trials, we utilised a patient-level modelling approach to compare how glycaemic control might differ between basal insulins at a similar rate of hypoglycaemia. MATERIALS AND METHODS: Data for HbA1c and symptomatic hypoglycaemia from the SWITCH 1 and SWITCH 2 trials were analyzed separately for patients with type 1 diabetes and type 2 diabetes, respectively. The association between the individual patient-level risk of hypoglycaemia and HbA1c was investigated using a Poisson regression model and used to estimate potential differences in glycaemic control with degludec versus glargine U100, at the same rate of hypoglycaemia. RESULTS: Improvements in glycaemic control increased the incidence of hypoglycaemia with both basal insulins across diabetes types. Our analysis suggests that patients could achieve a mean HbA1c reduction of 0.70 [0.05; 2.20]95% CI (for type 1 diabetes) or 0.96 [0.39; 1.99]95% CI (for type 2 diabetes) percentage points (8 [1; 24]95% CI or 10 [4; 22]95% CI mmol/mol, respectively) further with degludec than with glargine U100 before incurring an equivalent risk of hypoglycaemia. CONCLUSION: Our findings suggest that patients in clinical practice may be able to achieve lower glycaemia targets with degludec versus glargine U100, before incurring an equivalent risk of hypoglycaemia.

Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS Program.

This study compared initiation of insulin and other antihyperglycaemic agents (AHAs) with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year, fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs. 16%), insulin (3% vs. 9%) or any non-insulin AHA (5% vs. 12%) (P < .001 for all); overall AHA initiation rates increased over time but were consistently lower with canagliflozin compared with placebo. During the study, the likelihood of initiating insulin was 2.7 times lower for participants treated with canagliflozin compared with placebo (hazard ratio, 0.37; 95% CI: 0.31, 0.43; P < .001). The time difference between 10% of patients in the canagliflozin and placebo groups being initiated on insulin from the beginning of the trial was about 2 years. Time to initiation of other AHAs, including metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sulphonylureas, was also delayed for canagliflozin versus placebo (P < .001 for each). Compared with placebo, canagliflozin delayed the need for initiation of other AHAs and delayed time to insulin therapy, an outcome that is important to many people with diabetes.

Lower rates of hypoglycaemia in older individuals with type 2 diabetes using insulin degludec versus insulin glargine U100: Results from SWITCH 2.

AIM: This study aimed to investigate the safety of insulin degludec (degludec) in relation to age and risk of hypoglycaemia post hoc in individuals with type 2 diabetes (T2D) (SWITCH 2 trial). METHODS: In this crossover study, individuals with T2D who were at risk of hypoglycaemia were randomized to double-blind treatment with degludec or insulin glargine 100 units/mL (glargine U100) ± oral antidiabetic drugs. After 32 weeks, patients crossed over to the other treatment. Primary endpoint was number of overall severe (positively adjudicated) or glucose-confirmed (plasma glucose <56 mg/dL; 3.1 mmol/L) symptomatic hypoglycaemia events during the two 16-week maintenance periods. RESULTS: For individuals ≤65 (n = 450) and >65 (n = 270) years, baseline median (range) duration of diabetes was 12 (1-40) vs 15 (1-54) years, mean HbA1c was 7.7% vs 7.4% and mean estimated glomerular filtration rate was 87.0 vs 63.7 mL/min/1.73 m2 , respectively. No significant differences in HbA1c reduction were seen in individuals ≤65 or >65 years. During both maintenance periods, treatment with degludec lowered rates of hypoglycaemia (overall/nocturnal symptomatic) vs those with glargine U100 in individuals ≤65 (31% vs 43%) and >65 (30% vs 41%) years. With degludec and glargine U100, respectively, six vs nine severe hypoglycaemic events occurred in individuals ≤65 years and four vs eight events occurred in those >65 years. Adverse event rates were 3.2 and 3.3 events/patient-year for individuals ≤65 years and were 3.5 and 4.1 events/patient-year for individuals >65 years with degludec and glargine U100, respectively. CONCLUSION: Treatment with degludec was safe and effective, with a frequency of hypoglycaemia lower than that with glargine U100 in both younger and older individuals (>65 years) with T2D.

A post-hoc pooled analysis to evaluate the risk of hypoglycaemia with insulin glargine 300 U/mL (Gla-300) versus 100 U/mL (Gla-100) over wider nocturnal windows in individuals with type 2 diabetes on a basal-only insulin regimen.

The EDITION trials in type 2 diabetes demonstrated comparable glycaemic control with less nocturnal and anytime (24-hour) hypoglycaemia for insulin glargine 300 U/mL (Gla-300) versus glargine 100 U/mL (Gla-100). However, the predefined nocturnal window (0:00-5:59 AM) may not be the most relevant for clinical practice. This post-hoc analysis compared expansions of the predefined nocturnal interval during basal insulin treatment without prandial insulin. Patient-level, 6-month data, pooled from the EDITION 2 and 3 trials and the EDITION JP 2 trial (N = 1922, basal insulin only) were analysed. Accompanying hypoglycaemia during treatment with Gla-300 was compared to that during treatment with Gla-100, using predefined (0:00-5:59 AM) and expanded (10:00 PM-5:59 AM, 0:00-7:59 AM, 10:00 PM to pre-breakfast SMPG) windows. Confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemic events were reported most frequently between 6:00 AM and 8:00 AM. Windows expanded beyond 6:00 AM included more events than other windows. The percentage of participants with at least one event was lower with Gla-300 than Gla-100 in all windows examined. Expanding the nocturnal interval allows better assessment of the risk of hypoglycaemia associated with basal insulin. The risk of nocturnal hypoglycaemia was consistently lower with Gla-300 versus Gla-100 using all four windows.

Day-to-day fasting self-monitored blood glucose variability is associated with risk of hypoglycaemia in insulin-treated patients with type 1 and type 2 diabetes: A post hoc analysis of the SWITCH Trials.

AIMS: To investigate the association between day-to-day fasting self-monitored blood glucose (SMBG) variability and risk of hypoglycaemia in type 1 (T1D) and type 2 diabetes (T2D), and to compare day-to-day fasting SMBG variability between treatments with insulin degludec (degludec) and insulin glargine 100 units/mL (glargine U100). MATERIALS AND METHODS: Data were retrieved from two double-blind, randomized, treat-to-target, two-period (32 weeks each) crossover trials of degludec vs glargine U100 in T1D (SWITCH 1, n = 501) and T2D (SWITCH 2, n = 720). Available fasting SMBGs were used to determine the standard deviation (SD) of day-to-day fasting SMBG variability for each patient and the treatment combination. The association between day-to-day fasting SMBG variability and overall symptomatic, nocturnal symptomatic and severe hypoglycaemia was analysed for the pooled population using linear regression, with fasting SMBG variability included as a three-level factor defined by population tertiles. Finally, day-to-day fasting SMBG variability was compared between treatments. RESULTS: Linear regression showed that day-to-day fasting SMBG variability was significantly associated with overall symptomatic, nocturnal symptomatic and severe hypoglycaemia risk in T1D and T2D (P < 0.05). Day-to-day fasting SMBG variability was significantly associated (P < 0.01) with all categories of hypoglycaemia risk, with the exception of severe hypoglycaemia in T2D when analysed within tertiles. Degludec was associated with 4% lower day-to-day fasting SMBG variability than glargine U100 in T1D (P = 0.0082) and with 10% lower day-to-day fasting SMBG variability in T2D (P < 0.0001). CONCLUSIONS: Higher day-to-day fasting SMBG variability is associated with an increased risk of overall symptomatic, nocturnal symptomatic and severe hypoglycaemia. Degludec has significantly lower day-to-day fasting SMBG variability vs glargine U100.

Practical Guidance on Effective Basal Insulin Titration for Primary Care Providers.

IN BRIEF Basal insulin therapy is well established for glycemic control in patients with diabetes but often is not optimally implemented, leading to poor clinical outcomes and adherence. Primary care providers can and should work together with other members of the diabetes care team to allow for effective titration of basal insulin that involves patients and their caregivers. Adequate guidance and monitoring during the titration process can minimize some of the adverse effects caused by basal insulin administration, while improving glycemic control in a timely manner.

Effect of Insulin Degludec Versus Insulin Glargine U100 on Hypoglycemia in Hispanic Patients With Type 2 Diabetes: Results From the SWITCH 2 Trial.

IN BRIEF Hispanic patients with type 2 diabetes have poorer glycemic control and are at higher risk of severe diabetes complications and mortality than non-Hispanic white patients. This post hoc analysis investigated the safety and efficacy of insulin degludec versus insulin glargine 100 units/mL (glargine U100) in the Hispanic patient subpopulation from the SWITCH 2 trial. In Hispanic patients, hypoglycemia was consistently lower and nocturnal hypoglycemia was significantly lower with degludec versus glargine U100 at similar levels of glycemic control. Overall, results in Hispanic patients in SWITCH 2 were consistent with those in non-Hispanic patients.

Development of predictive risk models for major adverse cardiovascular events among patients with type 2 diabetes mellitus using health insurance claims data.

BACKGROUND: There exist several predictive risk models for cardiovascular disease (CVD), including some developed specifically for patients with type 2 diabetes mellitus (T2DM). However, the models developed for a diabetic population are based on information derived from medical records or laboratory results, which are not typically available to entities like payers or quality of care organizations. The objective of this study is to develop and validate models predicting the risk of cardiovascular events in patients with T2DM based on medical insurance claims data. METHODS: Patients with T2DM aged 50 years or older were identified from the Optum™ Integrated Real World Evidence Electronic Health Records and Claims de-identified database (10/01/2006-09/30/2016). Risk factors were assessed over a 12-month baseline period and cardiovascular events were monitored from the end of the baseline period until end of data availability, continuous enrollment, or death. Risk models were developed using logistic regressions separately for patients with and without prior CVD, and for each outcome: (1) major adverse cardiovascular events (MACE; i.e., non-fatal myocardial infarction, non-fatal stroke, CVD-related death); (2) any MACE, hospitalization for unstable angina, or hospitalization for congestive heart failure; (3) CVD-related death. Models were developed and validated on 70% and 30% of the sample, respectively. Model performance was assessed using C-statistics. RESULTS: A total of 181,619 patients were identified, including 136,544 (75.2%) without prior CVD and 45,075 (24.8%) with a history of CVD. Age, diabetes-related hospitalizations, prior CVD diagnoses and chronic pulmonary disease were the most important predictors across all models. C-statistics ranged from 0.70 to 0.81, indicating that the models performed well. The additional inclusion of risk factors derived from pharmacy claims (e.g., use of antihypertensive, and use of antihyperglycemic) or from medical records and laboratory measures (e.g., hemoglobin A1c, urine albumin to creatinine ratio) only marginally improved the performance of the models. CONCLUSION: The claims-based models developed could reliably predict the risk of cardiovascular events in T2DM patients, without requiring pharmacy claims or laboratory measures. These models could be relevant for providers and payers and help implement approaches to prevent cardiovascular events in high-risk diabetic patients.

Efficacy and tolerability of the new autoinjected suspension of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes.

AIMS: To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready-to-use autoinjector with a Miglyol diluent (exenatide QWS-AI). This study compared the efficacy and safety of exenatide QWS-AI with the first-in-class glucagon-like peptide-1 receptor agonist exenatide twice daily (BID). MATERIALS AND METHODS: This randomized, open-label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose-lowering medication randomized patients 3:2 to either exenatide QWS-AI (2 mg) or exenatide BID (10 µg) for 28 weeks. The primary outcome was the 28-week change in glycated haemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments. RESULTS: A total of 375 patients (mean HbA1c, 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m2 ; diabetes duration, 8.5 years) received either exenatide QWS-AI (n = 229) or exenatide BID (n = 146); HbA1c was reduced by -1.4% and -1.0%, respectively (least-squares mean difference, -0.37%; P = .0072). More patients achieved HbA1c <7.0% with exenatide QWS-AI (49.3%) than with exenatide BID (43.2%; P = .225). Body weight was reduced in both groups (P = .37 for difference). Gastrointestinal adverse events (AEs) were reported in 22.7% (exenatide QWS-AI) and 35.6% (exenatide BID) of patients; fewer patients in the exenatide QWS-AI group withdrew because of AEs than in the exenatide BID group. Minor hypoglycaemia occurred most often with concomitant sulfonylurea use. CONCLUSIONS: Exenatide QWS-AI was associated with a greater reduction in HbA1c, similar weight loss and a favorable gastrointestinal AE profile compared with exenatide BID.

Glycaemic control and hypoglycaemia in people with type 2 diabetes switching from twice-daily basal insulin to once-daily insulin glargine 300 U/mL or insulin glargine 100 U/mL (EDITION 1 and EDITION 2 subgroup analysis).

In this post hoc analysis we compared glycaemic control and hypoglycaemia between insulin glargine 300 U/mL (Gla-300) and glargine 100 U/mL (Gla-100) administered once daily in people with type 2 diabetes (T2DM) from the EDITION 1 (basal plus mealtime insulin) and EDITION 2 (basal insulin plus oral antihyperglycaemic drugs) trials who were previously receiving twice-daily insulin. At randomization, 16.9% and 20.0% of people in EDITION 1 and 2, respectively, were receiving twice-daily basal insulin. Glycated haemoglobin change from baseline to Month 6 was similar over 6 months with Gla-300 or Gla-100 (least squares mean difference -0.01%; 95% confidence interval [CI] -0.27 to 0.24] in EDITION 1 and 0.16%; 95% CI -0.25 to 0.57, in EDITION 2). Participants previously receiving twice-daily insulin in EDITION 1 had a lower risk of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia with Gla-300 vs Gla-100 at night (00:00-05:59 hours), but not at any time (24 hours); in EDITION 2 the risk was reduced at night and any time (24 hours). In conclusion, Gla-300 provided similar glycaemic control with less hypoglycaemia compared with Gla-100 in people with T2DM switching from twice-daily to once-daily basal insulin.

HBA1C CONTROL AND COST-EFFECTIVENESS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS INITIATED ON CANAGLIFLOZIN OR A GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONIST IN A REAL-WORLD SETTING.

OBJECTIVE: To compare glycated hemoglobin (HbA1c) control and medication costs between patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin 300 mg (CANA) or a glucagon-like peptide 1 receptor agonist (GLP-1 RA) in a real-world setting. METHODS: Adults with T2DM newly initiated on CANA or a GLP-1 RA (index date) were identified from IQVIA™ Real-World Data Electronic Medical Records U.S. database (March 29, 2012-April 30, 2016). Inverse probability of treatment weighting accounted for differences in baseline characteristics. HbA1c levels at 3-month intervals were compared using generalized estimating equations. Medication costs used wholesale acquisition costs. RESULTS: For both cohorts (CANA: n = 11,435; GLP-1 RA: n = 11,582), HbA1c levels decreased at 3 months postindex and remained lower through 30 months. Absolute changes in mean HbA1c from index to 3 months postindex for CANA and GLP-1 RA were -1.16% and -1.21% (patients with baseline HbA1c ≥7% [53 mmol/mol]); -1.54% and -1.51% (patients with baseline HbA1c ≥8% [64 mmol/mol]); and -2.13% and -1.99% (patients with baseline HbA1c ≥9% [75 mmol/mol]), respectively. Postindex, CANA patients with baseline HbA1c ≥7% had similar HbA1c levels at each interval versus GLP-1 RA patients, except 9 months (mean HbA1c, 7.75% [61 mmol/mol] vs. 7.86% [62 mmol/mol]; P = .0305). CANA patients with baseline HbA1c ≥8% and ≥9% had consistently lower HbA1c numerically versus GLP-1 RA patients and statistically lower HbA1c at 9 (baseline HbA1c ≥8% or ≥9%), 27, and 30 months (baseline HbA1c ≥9%). Continuous 12-month medication cost $3,326 less for CANA versus GLP-1 RA. CONCLUSION: This retrospective study demonstrated a similar evolution of HbA1c levels among CANA and GLP-1 RA patients in a real-world setting. Lower medication costs suggest CANA is economically dominant over GLP-1 RA (similar effectiveness, lower cost). ABBREVIATIONS: AHA = antihyperglycemic agent BMI = body mass index CANA = canagliflozin 300 mg DCSI = diabetes complications severity index eGFR = estimated glomerular filtration rate EMR = electronic medical record GLP-1 RA = glucagon-like peptide 1 receptor agonist HbA1c = glycated hemoglobin ICD-9-CM = International Classification of Diseases-Ninth Revision-Clinical Modification ICD-10-CM = International Classification of Diseases-Tenth Revision-Clinical Modification IPTW = inverse probability of treatment weighting ITT = intent-to-treat MPR = medication possession ratio PDC = proportion of days covered PS = propensity score PSM = propensity score matching Quan-CCI = Quan-Charlson comorbidity index SGLT2 = sodium-glucose cotransporter 2 T2DM = type 2 diabetes mellitus WAC = wholesale acquisition cost.

Safety and Efficacy of Insulin Degludec/Liraglutide (IDegLira) and Insulin Glargine U100/Lixisenatide (iGlarLixi), Two Novel Co-Formulations of a Basal Insulin and a Glucagon-Like Peptide-1 Receptor Agonist, in Patients With Diabetes Not Adequately Controlled on Oral Antidiabetic Medications.

IN BRIEF Novel co-formulations of basal insulin analogs and glucagon-like peptide-1 (GLP-1) receptor agonists have provided new options for patients with type 2 diabetes who are not reaching recommended glycemic targets. The components of currently available co-formulations (insulin degludec/ liraglutide [IDegLira,] and insulin glargine U100/lixisenatide [iGlarLixi]) act synergistically to address multiple pathophysiologic defects while minimizing the side effects associated with either component when used alone. In Europe, these products are approved for use in patients on regimens of one or more oral antidiabetic drugs; in the United States, they are indicated for use as an adjunct to diet and exercise in patients with type 2 diabetes inadequately controlled with either basal insulin or their respective GLP-1 receptor agonist component. This article reviews key clinical trials in which these products were initiated in insulin-naive patients and describes how they can be safely and effectively titrated in clinical practice.

Consistent findings in glycaemic control, body weight and hypoglycaemia with iGlarLixi (insulin glargine/lixisenatide titratable fixed-ratio combination) vs insulin glargine across baseline HbA1c, BMI and diabetes duration categories in the LixiLan-L trial.

AIMS: To assess the impact of baseline characteristics on clinical outcomes in the LixiLan-L trial, a randomized open-label trial designed to evaluate the efficacy and safety of iGlarLixi, a novel fixed-ratio combination of insulin glargine 100 U (iGlar) plus lixisenatide, in comparison with iGlar over 30 weeks in a population of patients with type 2 diabetes mellitus (T2DM) inadequately controlled on a previous regimen of basal insulin alone or in combination with 1 or 2 oral glucose-lowering drugs. MATERIALS AND METHODS: In this exploratory analysis of LixiLan-L (N = 736), efficacy outcomes were assessed within population subgroups derived from the following baseline characteristics: glycated haemoglobin [HbA1c; <8%, ≥8% (<64, ≥64 mmol/mol)]; duration of T2DM (<10, ≥10 years); body mass index (<30, ≥30 kg/m2 ). Furthermore, the incidence of symptomatic hypoglycaemia with plasma glucose ≤3.9 mmol/L (≤70 mg/dL) was also analysed according to the same subgroups. RESULTS: Compared with the iGlar treatment group, patients treated with iGlarLixi showed consistently greater reductions in HbA1c during the treatment period, with higher percentages of patients achieving the HbA1c target level of <7% (<53 mmol/mol) in all of the subpopulations tested (P < .0001 for all), having consistent mitigation of body weight gain and with no major differences in the incidence of hypoglycaemia. CONCLUSIONS: iGlarLixi consistently improved glycaemic control compared with iGlar in all baseline characteristic subgroups of patients with T2DM inadequately controlled with insulin, including difficult-to-treat subgroups of patients with long duration of diabetes, obesity and high HbA1c. Clinical trial number: NCT02058160 (clinicaltrials.gov).

Quality measure and weight loss assessment in patients with type 2 diabetes mellitus treated with canagliflozin or dipeptidyl peptidase-4 inhibitors.

BACKGROUND: Achieving control of glycated hemoglobin (HbA1c), blood pressure (BP), and body weight (BW) remains a challenge for most patients with type 2 diabetes mellitus (T2DM). In clinical trials, canagliflozin (CANA), an inhibitor of sodium-glucose co-transporter 2, has shown significant improvement compared to some dipeptidyl peptidase-4 (DPP-4) inhibitors in the achievement of such quality measures. This study used recent electronic medical records (EMR) data to assess quality measure achievement of HbA1C, BP, and BW loss in patients treated with CANA versus DPP-4 inhibitors. METHODS: Adult patients with ≥1 T2DM diagnosis and ≥12 months of clinical activity (baseline) before first CANA or DPP-4 prescription (index) were identified in the QuintilesIMS Health Real-World Data EMRs-US database (03/29/2012-10/30/2015). Patients were observed from the index to last encounter. Inverse probability of treatment weighting (IPTW) was used to adjust for observed baseline confounders between groups. Kaplan-Meier (KM) rates and Cox proportional hazard models were used to compare achievement of HbA1c < 7% (among patients <65 years old), HbA1c < 8%, systolic BP < 140 mmHg, diastolic BP < 90 mmHg, and BW loss ≥ 5% among patients not meeting these respective targets at baseline. RESULTS: A total of 10,702 CANA and 17,679 DPP-4 patients were selected. IPTW resulted in balanced baseline demographic, comorbidity, and disease characteristics (CANA: N = 13,793, mean age: 59.0 years; DPP-4: N = 14,588, mean age: 58.9 years). Up until 24 months post-index, CANA patients were more likely to reach an HbA1c < 7% (hazard ratio [HR] = 1.10, P = 0.007, KM rates: 42.8% vs. 40.3%), an HbA1c < 8% (HR = 1.16, P < 0.001, KM rates: 63.7% vs. 60.0%), and a BW loss ≥ 5% (HR = 1.46, P < 0.001, KM rates: 55.2% vs. 46.2%), compared to DPP-4 patients. Up until 12 months post-index, CANA patients were more likely to reach a systolic BP < 140 mmHg (HR = 1.07, P = 0.04, KM rates: 87.8% vs. 83.9%). but not a diastolic BP < 90 mmHg (HR = 0.95, P = 0.361), compared to DPP-4 patients. CONCLUSIONS: This retrospective study of EMR data covering up to 30 months after CANA approval (March 2013) suggests that patients initiated on CANA were more likely to reach HbA1c, systolic BP, and weight loss objectives specified by general diabetes care guidelines than patients initiated on DPP-4 inhibitors.

Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial.

IMPORTANCE: Hypoglycemia, a serious risk for insulin-treated patients with type 2 diabetes, negatively affects glycemic control. OBJECTIVE: To test whether treatment with basal insulin degludec is associated with a lower rate of hypoglycemia compared with insulin glargine U100 in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, treat-to-target crossover trial including two 32-week treatment periods, each with a 16-week titration period and a 16-week maintenance period. The trial was conducted at 152 US centers between January 2014 and December 2015 in 721 adults with type 2 diabetes and at least 1 hypoglycemia risk factor who were previously treated with basal insulin with or without oral antidiabetic drugs. INTERVENTIONS: Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 361) or to receive insulin glargine U100 followed by insulin degludec (n = 360) and randomized 1:1 to morning or evening dosing within each treatment sequence. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of overall symptomatic hypoglycemic episodes (severe or blood glucose confirmed [<56 mg/dL]) during the maintenance period. Secondary end points were the rate of nocturnal symptomatic hypoglycemic episodes (severe or blood glucose confirmed, occurring between 12:01 am and 5:59 am) and the proportion of patients with severe hypoglycemia during the maintenance period. RESULTS: Of the 721 patients randomized (mean [SD] age, 61.4 [10.5] years; 53.1% male), 580 (80.4%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were 185.6 vs 265.4 episodes per 100 patient-years of exposure (PYE) (rate ratio = 0.70 [95% CI, 0.61-0.80]; P < .001; difference, -23.66 episodes/100 PYE [95% CI, -33.98 to -13.33]), and the proportions of patients with hypoglycemic episodes were 22.5% vs 31.6% (difference, -9.1% [95% CI, -13.1% to -5.0%]). The rates of nocturnal symptomatic hypoglycemia with insulin degludec vs insulin glargine U100 were 55.2 vs 93.6 episodes/100 PYE (rate ratio = 0.58 [95% CI, 0.46-0.74]; P < .001; difference, -7.41 episodes/100 PYE [95% CI, -11.98 to -2.85]), and the proportions of patients with hypoglycemic episodes were 9.7% vs 14.7% (difference, -5.1% [95% CI, -8.1% to -2.0%]). The proportions of patients experiencing severe hypoglycemia during the maintenance period were 1.6% (95% CI, 0.6%-2.7%) for insulin degludec vs 2.4% (95% CI, 1.1%-3.7%) for insulin glargine U100 (McNemar P = .35; risk difference, -0.8% [95% CI, -2.2% to 0.5%]). Statistically significant reductions in overall and nocturnal symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were also seen for the full treatment period. CONCLUSIONS AND RELEVANCE: Among patients with type 2 diabetes treated with insulin and with at least 1 hypoglycemia risk factor, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02030600.