Insulin Glargine In Patients Research Articles

Cost-utility analysis of once-weekly insulin icodec and once-daily insulin glargine in patients with type 2 diabetes receiving basal-bolus insulin therapy in China.

The purpose of this study is to explore the rational pricing range for the once-weekly administration of insulin icodec in the treatment of type 2 diabetes patients in China who have already received basal insulin therapy. The data foundation of this study originates from the ONWARDS 4 clinical trial and research materials on Chinese type 2 diabetes patients. By comprehensively applying cost-utility analysis methods and binary search techniques, the appropriate price positioning of insulin icodec was determined from the perspective of China's healthcare system. In the long-term treatment simulation, we found that insulin icodec and insulin glargine performed similarly in terms of quality-adjusted life years (QALYs), with 10.15 and 10.07 years, respectively. Although the annual cost of insulin icodec was initially assumed to be equivalent to that of insulin glargine, in-depth analysis revealed that insulin icodec may have higher cost-effectiveness potential. Further price sensitivity analysis indicated that the reasonable cost range of insulin icodec lies between $851.95 and $1358.25. After fine-tuning through univariate sensitivity analysis, this cost range was revised to $784.90 to $1145.96, a conclusion that was robustly validated in subsequent probabilistic sensitivity analysis and scenario simulations. The conclusion drawn from this study is that, with insulin glargine as the cost reference, the economic cost of insulin icodec for Chinese type 2 diabetes patients is expected to range from $784.90 to $1145.96, providing a reference basis for clinical decision-making and healthcare policy formulation.

The Impact of Adding Prandial Insulin to a Basal Based Regimen with Insulin Glargine in Type 2 Diabetic Patients.

Background: Type 2 diabetes (T2D) is a progressive disease that should be managed with insulin in case of oral glucose lowering drugs (OGLDs) failure. If basal insulin is not sufficient, rapid acting insulin will be added before the largest meal. We assessed the impact of adding one prandial insulin to a basal based regimen and insulin glargine in patients with type 2 diabetes to measure the percentage of subjects achieving the HbA1c target by the end of 24 weeks of treatment in routine clinical practice. Methods: This study was a 24-week observational study of patients with T2D not adequately controlled with OGLDs and basal insulin, for whom the physician had decided to initiate prandial insulin. The study endpoint was assessed at visit 1 (baseline), visit 2 at week 12 (±1 week) and visit 3 at week 24 (±1 week). The percentage of patients who achieved HbA1c targets was assessed at week 24. Statistical analyses were performed using IBM SPSS for Windows v 19 (IBM, Armonk, New York, USA). Logistic regression analysis was used to detect predicting factors of achieving the HbA1c target by week 24. P<0.05 was considered as significant level. Results : Four hundred and eighteen patients with a mean±SD age of 56.24±9.85 years and a mean±SD duration of diabetes of 12.50±7.16 years were included. The median total daily dose of basal insulin was 24 units, while prandial insulin was started with 6 (4, 10) U/day, titrating up to 10 (8, 18) U/day at week 24. The daily dose of prandial insulin was the only factor that could significantly predict achieving targeted HbA1c by week 24 [OR: 1.04; 95% CI: 1.007,1.079; p-value: 0.019]. At week 24, 96 (22.9%) subjects achieved the HbA1c target with one prandial insulin. Conclusion : The results of our study suggest that “basal plus therapy” can lead to good glycemic control with a low risk of hypoglycemia and weight gain in patients with type 2 diabetes.

Pancreatic Safety of Once-Weekly Dulaglutide in Chinese Patients with Type 2 Diabetes Mellitus: Subgroup Analysis by Potential Influencing Factors.

IntroductionIn the randomized, open-label, parallel-arm, active-controlled phase III AWARD-CHN2 trial, once-weekly dulaglutide plus concomitant oral antihyperglycemic medications (OAMs) improved HbA1c over 26 weeks compared with once-daily insulin glargine in patients with type 2 diabetes mellitus (T2DM). This post-hoc subgroup analysis of AWARD-CHN2 investigated the pancreatic safety of dulaglutide in Chinese patients with T2DM, stratified by potential influencing factors.MethodsChanges in pancreatic enzyme (pancreatic amylase, total amylase, and lipase) levels over 26 weeks were assessed and stratified by patient age (< 60, ≥ 60 years), sex (female, male), duration of diabetes (< 10, ≥ 10 years), baseline weight (< 70, ≥ 70 kg), BMI (< 25, ≥ 25 kg/m2), HbA1c (< 8.5, ≥ 8.5%), triglycerides (< 2.3, ≥ 2.3 mmol/L), and concomitant OAMs (metformin, sulfonylurea, metformin plus sulfonylurea).ResultsA total of 203 Chinese patients with T2DM were included in this post-hoc analysis. Pancreatic enzyme levels increased within the normal range from baseline to Week 26, and no pancreatitis events were confirmed by independent adjudication. Least-squares mean increase in pancreatic amylase (U/L) from baseline to Week 26 was comparable across all subgroups with no statistically (all P-values > 0.05) or clinically significant between-group differences for age (< 60 years: 5.34; ≥ 60 years: 6.71), sex (female: 5.85; male: 5.66), duration of diabetes (< 10 years: 6.15; ≥ 10 years: 4.85), weight (< 70 kg: 6.19; ≥ 70 kg: 5.39), BMI (< 25 kg/m2: 5.92; ≥ 25 kg/m2: 5.61), HbA1c (< 8.5%: 6.82; ≥ 8.5%: 4.08), triglycerides (< 2.3 mmol/L: 4.94; ≥ 2.3 mmol/L: 8.04), and concomitant OAMs (metformin: 5.68; sulfonylurea: 5.44; metformin plus sulfonylurea: 5.87). Similar results were observed for total amylase and lipase.ConclusionIn Chinese patients with T2DM receiving dulaglutide 1.5 mg in AWARD-CHN2, elevations of pancreatic enzymes over 26 weeks were within the normal range and were neither associated with pancreatitis nor baseline factors, which suggests the clinical use of dulaglutide in Chinese patients with T2DM is not associated with pancreatic safety issues.Clinical Trial registrationNCT01648582.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01139-2.

Similar immunogenicity profiles between the proposed biosimilar MYL-1501D and reference insulin glargine in patients with diabetes mellitus: the phase 3 INSTRIDE 1 and INSTRIDE 2 studies

BackgroundMYL-1501D is a proposed biosimilar to insulin glargine. The noninferiority of MYL-1501D was demonstrated in patients with type 1 diabetes and type 2 diabetes in 2 phase 3 trials. Immunogenicity of MYL-1501D and reference insulin glargine was examined in both studies.MethodsINSTRIDE 1 and INSTRIDE 2 were multicenter, open-label, randomized, parallel-group studies. In INSTRIDE 1, patients with type 1 diabetes received MYL-1501D or insulin glargine over a 52-week period. In INSTRIDE 2, patients with type 2 diabetes treated with oral antidiabetic drugs, insulin naive or not, received MYL-1501D or reference insulin glargine over a 24-week period. Incidence rates and change from baseline in relative levels of antidrug antibodies (ADA) and anti–host cell protein (anti-HCP) antibodies in both treatment groups were determined by a radioimmunoprecipitation assay and a bridging immunoassay, respectively. Results were analyzed using a mixed-effects model (INSTRIDE 1) or a nonparametric Wilcoxon rank sum test (INSTRIDE 2).ResultsTotal enrollment was 558 patients in INSTRIDE 1 and 560 patients in INSTRIDE 2. The incidence of total and cross-reactive ADA was comparable between treatment groups in INSTRIDE 1 and INSTRIDE 2 (P > 0.05 for both). A similar proportion of patients had anti-HCP antibodies in both treatment groups in INSTRIDE 1 at week 52 (MYL-1501D, 93.9 %; reference insulin glargine, 89.6 %; P = 0.213) and in INSTRIDE 2 at week 24 (MYL-1501D, 87.3 %; reference insulin glargine, 86.9 %; P > 0.999).ConclusionsIn INSTRIDE 1 and INSTRIDE 2, similar immunogenicity profiles were observed for MYL-1501D and reference insulin glargine in patients with type 1 diabetes and type 2 diabetes, respectively.Trial registrationClinicalTrials.gov, INSTRIDE 1 (NCT02227862; date of registration, August 28, 2014); INSTRIDE 2 (NCT02227875; date of registration, August 28, 2014).

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.

Immunogenicity and Efficacy of Insulin Glargine Biosimilar Ezelin versus Originator Insulin Glargine in Patients with Type 2 Diabetes.

PurposeTo compare the immunogenicity and efficacy of insulin glargine biosimilar Ezelin (EZL) versus originator insulin glargine Lantus (LAN) as a reference basal insulin in patients with type 2 diabetes (T2D).Patients and MethodsThis was a randomized, multicenter, open-label, 24-week study in insulin-naïve patients with T2D, with HbA1c of >7.0%. We randomly assigned 133 eligible patients to receive either EZL or LAN. Baseline characteristics, including insulin autoantibody (IAA), zinc transporter 8 (ZnT8) antibody, HbA1C, fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (2hPPG), AST, ALT, BUN, eGFR, and oral antidiabetic drugs, were obtained before starting insulin treatment. After starting treatment, insulin dose was titrated to achieve FPG target along with oral antidiabetic drugs. Patients were given home glucometer and assisted to record plasma glucose measurement and adverse event (AE). Every month, patients came to the diabetes clinic and performed a regular physical examination and intensifying treatment if needed. Out of the 133 randomized patients, only 122 completed the study and can be examined for their IAA and ZnT8 after 6 months of treatment. The study was registered in clinicaltrials.gov, NCT03352674.ResultsThere is a similar proportion of patients with changes of IAA from baseline: 1 out of 58 (1.7%) patients receiving EZL versus 1 out of 64 (1.6%) patients receiving LAN (p = 1.000). One patient in the EZL group (1.7%) versus none in the LAN group experienced a change of ZnT8 antibody from baseline. Similar glucose control in EZL versus LAN was determined by the change in HbA1c, FPG, and 2hPPG (−2.0%, −67.46 mg/dL, and −76.51 mg/dL in the EZL group versus −1.7%, −58.11 mg/dL, and −70.03 mg/dL in the LAN group). There were six events of documented hypoglycemia in the EZL group versus five events in the LAN group. No patients experienced diabetic ketoacidosis during the study.ConclusionOverall, insulin glargine biosimilar EZL and originator insulin glargine LAN have shown a similar immunogenicity profile, as well as efficacy in providing glucose control and safety findings in T2D populations.

PDB6 Cost-Effectiveness of Liraglutide Versus Insulin Glargine, BOTH in Combination with Metformin for Patients with Type 2 Diabetes in China

To evaluate the long-term cost-effectiveness of liraglutide compared with insulin glargine in patients with type 2 diabetes mellitus (T2DM) insufficiently controlled on metformin monotherapy from China’s health care system perspective.

949-P: Dulaglutide Improves Kidney Fibrosis Biomarker Levels in Patients with Type 2 Diabetes and Moderate-to-Severe Chronic Kidney Disease

The AWARD-7 clinical trial demonstrated that once-weekly dulaglutide slowed the decline in estimated glomerular filtration rate (eGFR) and decreased urine albumin/creatinine ratio compared to insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (CKD). Lower levels of urinary C3M, a marker for type III collagen degradation, and increased level of plasma PRO-C6, a marker for type VI collagen formation, have been reported to correlate with CKD progression and lower eGFR. This exploratory analysis evaluated changes in urinary C3M and plasma PRO-C6 in response to treatment with dulaglutide 1.5 mg compared to insulin glargine in AWARD-7. At baseline, urinary C3M and serum PRO-C6 levels were comparable between the dulaglutide 1.5 mg and insulin glargine groups. At week 26 and 52 of treatment, urinary C3M levels were significantly higher and serum PRO-C6 levels were significantly lower in the dulaglutide 1.5 mg group compared with insulin glargine group, respectively (Table). In conclusion, dulaglutide was associated with decreased levels of biomarkers for type VI collagen formation and increased type III collagen degradation, suggesting a potential effect to reduce kidney fibrosis. These anti-fibrotic effects could be a potential mechanism for the beneficial effects observed with dulaglutide treatment on CKD in type 2 diabetes. Disclosure K.R. Tuttle: Consultant; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Goldfinch Bio, Novo Nordisk Inc. J.M. Wilson: Employee; Self; Lilly Diabetes. Y. Lin: None. H. Qian: Employee; Self; Eli Lilly and Company. K. Kelly-Boruff: Employee; Self; Eli Lilly and Company. F. Genovese: None. M.A. Karsdal: Stock/Shareholder; Self; Nordic Bioscience. K.L. Duffin: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Pfizer Inc. F.T. Botros: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company

Once-weekly dulaglutide versus insulin glargine in the early control of fasting serum glucose and HbA1c

AimsTo determine the early benefit:risk balance of dulaglutide versus insulin glargine in patients with type 2 diabetes mellitus (T2DM). MethodsThis post hoc analysis used data from a randomized, open-label study (AWARD-2; modified intention-to-treat group) in which suboptimally controlled metformin + glimepiride-treated patients received dulaglutide 1.5 mg (n = 273) or insulin glargine (n = 262). Two composite endpoints were used: for weeks 2–20, fasting serum glucose (FSG) <130 mg/dL (<7.2 mmol/L) without hypoglycemia (blood glucose ≤70 mg/dL [≤3.9 mmol/L] or severe hypoglycemia); at week 26, patients with glycated hemoglobin (HbA1c) <7.0% (<53.0 mmol/mol) or reduction from baseline ≥1.0% (≥10.9 mmol/mol), no hypoglycemia (as defined above) and no weight gain. Odds ratios (ORs) were generated using logistic regression analysis. ResultsThe probability of reaching the FSG target without hypoglycemia was higher with dulaglutide than with insulin glargine at weeks 4 (OR 1.78; 95% confidence interval [CI] 1.22–2.60) and 8 (OR 1.69; 95% CI 1.15–2.48). The proportion of patients achieving the 26-week endpoint was higher with dulaglutide (37.4% vs. 10.3%; OR 5.28; 95% CI 3.28–8.48). ConclusionsDulaglutide's balanced efficacy-to-safety profile compares favorably with that of insulin glargine and is apparent soon after treatment initiation and after 6 months of therapy.

Efficacy of exenatide and insulin glargine on nonalcoholic fatty liver disease in patients with type 2 diabetes.

The aim of this study was to investigate the efficacy of exenatide and insulin glargine in patients with newly diagnosed type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). We performed a 24-week randomized controlled multicentre clinical trial. Seventy-six patients were randomly assigned 1:1 to receive exenatide or insulin glargine treatment. The endpoints included changes in liver fat content (LFC), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) measured by magnetic resonance spectroscopy, blood glucose, liver enzymes, lipid profile, body weight, and Fibrosis-4 index (FIB-4). LFC, VAT, SAT, and FIB-4 were significantly reduced after exenatide treatment (ΔLFC, -17.55 ± 12.93%; ΔVAT, -43.57 ± 68.20 cm2 ; ΔSAT, -28.44 ± 51.48 cm2 ; ΔFIB-4, -0.10 ± 0.26; all P < .05). In comparison, only LFC (ΔLFC, -10.49 ± 11.38%; P < .05), and not VAT, SAT, or FIB-4 index (all P > .05), was reduced after insulin glargine treatment. Moreover, exenatide treatment resulted in greater reductions in alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transpeptidase (GGT) than insulin glargine (P < 0.05). The body weight, waist circumference, postprandial plasma glucose, and low-density lipoprotein cholesterol (LDL-C) in the exenatide group also presented greater reductions than the insulin glargine group (P < .05). The proportion of adverse events were comparable between the two groups. Both exenatide and insulin glargine reduced LFC in patients with drug-naive T2DM and NAFLD; however, exenatide showed greater reductions in body weight, visceral fat area, liver enzymes, FIB-4, postprandial plasma glucose, and LDL-C.

Cost-Utility Analysis of Saxagliptin/Dapagliflozin Versus Gliclazide and Insulin Glargine: Economic Implications of the Outcomes of the CVD-Real Studies I and II.

Diabetes treatment cost represents an ever-growing problem. The adoption of new drugs in therapy, although they can guarantee an improvement in patient’s quality of life, can meet obstacles when it involves an increase in costs. We decided to compare the costs and benefits of the new saxagliptin and dapagliflozin combination versus traditional therapies. Bodyweight loss and the sharp reduction in hypoglycemic episodes were the 2 main clinical outcomes that emerged from registered studies of saxagliptin and dapagliflozin compared with the sulfonylureas. These results, combined with the good cardiovascular risk profile, led to develop a cost-utility analysis. We aimed to show the economic value of this new association therapy. We carried out a cost-utility analysis from the Italian National Healthcare System (NHS) perspective, focused on direct costs related to the treatment and management of main diabetes complications. Utility scores adopted have been measured based on the patient’s perception of weight changes. In light of the better durability profile of saxagliptin/dapagliflozin compared with gliclazide, we also considered a simulation scenario to assess the impact on costs of switching to basal insulin, starting from gliclazide and the fixed combination, respectively, and based on the related probabilities to switch. To assess the robustness of the results, a 1-way sensitivity analysis was performed by changing the main parameters by ±20%. Furthermore, the sensitivity of the results was tested considering the addition of a percent discount, because the purchase costs of drugs are usually subject to hidden discounts. We calculated the total direct annual cost per patient of saxagliptin/dapagliflozin versus gliclazide and insulin glargine for patients with type 2 diabetes mellitus not achieving glycemic control on metformin plus saxagliptin alone, dapagliflozin alone, or gliclazide at a lower dosage. Total treatment costs have been obtained adding the direct cost of the drug, needles, glycemic self-monitoring, hypoglycemic events, cardiovascular complications, and effect on consumption of other drugs. The total direct cost of saxagliptin/dapagliflozin fixed dose combination was €414.62 higher than gliclazide (€1.067.72 vs €653.10), and greater than basal insulin, with a difference of €166.99 (€1067.72 vs €900.72). Despite the higher annual direct total cost, the additional cost per quality-adjusted life year (QALY) gained, compared with gliclazide, has been €11 517, and €4639, when compared with insulin glargine in the base-case scenario, and the robustness of the results has been shown in the sensitivity analysis. The results of our cost-utility analysis, expressed as incremental cost-effectiveness ratios, were fully compliant with the threshold adopted for Italy. Then, saxagliptin/dapagliflozin can be considered a cost-effective oral hypoglycemic agent. The positive effect of this drug on the quality of life, induced by the bodyweight loss, has allowed this outcome, despite the higher annual cost per patient, mainly determined by the drug purchase cost.

Exenatide twice-daily does not affect renal function or albuminuria compared to titrated insulin glargine in patients with type 2 diabetes mellitus: A post-hoc analysis of a 52-week randomised trial

AimsTo compare the effects of long-term treatment with the GLP-1RA exenatide twice-daily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients. MethodsWe post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean ± SD age 60 ± 8 years, HbA1c 7.5 ± 0.9%, eGFR 86 ± 16 mL/min/1.73 m2, median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44–1.29] mg/mmol) randomised to exenatide 10 µg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albumin-excretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out. ResultsHbA1c-reductions were similar with exenatide (mean ± SEM −0.80 ± 0.10%) and iGlar (−0.79 ± 0.14%; treatment-difference 0.02%; 95% CI −0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P < 0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (−3.9 ± 2.1 mL/min/1.73 m2; P = 0.069) and iGlar (−2.7 ± 1.2 mL/min/1.73 m2; P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (−5.4 kg; 2.9–7.9; P < 0.001), but did not affect blood pressure, lipids or plasma uric acid. ConclusionsAmong T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar.Trial registration:ClinicalTrials.gov ID: NCT00097500.

Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE subanalysis (DEVOTE 10).

AimTo 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 MethodsPatients 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.ResultsAt 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.ConclusionsUse 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.

Developing, Planning and Conducting an Interim Analysis: Lessons From the DEVOTE Cardiovascular Outcomes Trial (Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events).

In 2013, a randomized, double-blind, active comparator-controlled, event-driven cardiovascular outcomes trial (DEVOTE) was initiated to compare the cardiovascular safety of insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes at high risk of cardiovascular events. The FDA agreed that an interim analysis could form the basis for an early regulatory approval. We report here the operational model developed to support the DEVOTE interim analysis and the results. The interim analysis model was designed to reduce the risk of any confidentiality breaches. The Data Access Management Plan comprehensively described the interim analysis operational processes and procedures to maintain the integrity of the ongoing trial while the interim analysis was conducted, submitted, and acted upon by the FDA, and also until completion of the full trial. Most importantly, those who were unblinded to the interim results were limited to a team of 14 members. A total of 150 first major adverse cardiovascular events were recorded at cut-off for the interim analysis. The estimated hazard ratio was 0.92 (95% CI 0.67, 1.27) and non-inferiority to glargine U100 was confirmed as the upper bound of the confidence interval was below 1.8, as prespecified. Based on these results, the FDA approved the use of degludec and degludec/insulin aspart (IDegAsp) in the United States in 2015 before trial completion. The DEVOTE interim analysis succeeded as a model by which to conduct an interim analysis and submit confidential data for regulatory review and action while continuing the trial to address a primary hypothesis.

Efficacy and safety of adding single dose insulin glargine in patients with type 2 diabetes uncontrolled by oral hypoglycemic drugs

Abstract:&#x0D; Unfortunately, a Significant number of type 2 diabetic patients on oral hypoglycemic agents are not achieving the desired and recommended target of glycemic control in terms of reduction of HbA1c and fasting plasma glucose, this is largely because most of them are reluctant to use insulin injections for many reasons, mainly the painful injection, fear of hypoglycemia or inability to adapt to a complex regimen of multiple insulin injections. it has been recommended by many diabetes associations ( the American diabetes association(ADA) and the European association for the study of diabetes(EASD) ), in their algorithm of management of hyperglycemia in patients with uncontrolled diabetes (HbA1c &lt; 7 %) to add a basal ( long acting) insulin to their oral drug regimen as a more simple initial step of adding insulin that is acceptable by most patients and capable of achieving target glycemic levels. insulin glargine is the preferred long acting insulin analogue for its pharmacodynamic properties (peakless action profile with low incidence of hypoglycemia and longer duration of action) , furthermore, its pen formulary makes it less painful than conventional human insulin syringe injections.

Dapagliflozin plus Saxagliptin Shows Noninferior A1C Reduction vs. Insulin Glargine in Patients with Type 2 Diabetes Inadequately Controlled by Metformin With or Without Sulfonylurea

This international, multicenter, randomized, open-label phase 3b trial (NCT02551874) evaluated the efficacy and safety of dapagliflozin (DAPA) 10 mg/day plus saxagliptin (SAXA) 5 mg/day vs. titrated insulin glargine (INS) in patients with type 2 diabetes (T2D) poorly controlled by metformin (MET) ≥1500 mg/day ± sulfonylurea (SU) ≥50% maximum dose (A1C levels 8-12%). The primary end point was change in A1C from baseline to week 24; DAPA + SAXA was tested for non-inferiority vs. INS. Secondary end points were: change in body weight; proportions of patients a) with hypoglycemia, b) achieving A1C &amp;lt;7% without hypoglycemia, c) achieving A1C &amp;lt;7% at week 24; and change in 24-hour glucose at week 2 assessed by continuous glucose monitoring. Mean±SD baseline data were age 55.5±9.6 years; A1C 9.1±1.0%; BMI 32.2±5.3 kg/m2, and were similar in both arms. DAPA + SAXA resulted in non-inferior reductions in A1C without weight gain, reductions in mean 24-hour glucose, and was associated with a lower prevalence of hypoglycemia and a greater proportion of patients achieving A1C &amp;lt;7% without hypoglycemia vs. INS (Table); there were no additional safety concerns. DAPA + SAXA therapy resulted in similar glycemic control, prevented weight gain and reduced risk of hypoglycemia compared with titrated INS in patients with T2D poorly controlled by MET ± SU. Disclosure T. Vilsbøll: None. E. Ekholm: None. E.K. Johnsson: Employee; Self; AstraZeneca. N. Dronamraju: None. S. Jabbour: None. M. Lind: Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eli Lilly and Company. Advisory Panel; Self; MSD K.K.. Research Support; Self; Pfizer Inc.. Consultant; Self; Medtronic.

Treatment Effects of Once-Weekly Dulaglutide vs. Insulin Glargine in Patients with Different Baseline Glycemic Patterns (Based on High/Low Fasting or High/Low Postprandial Glucose)—A Post-Hoc Analysis of the AWARD-2 Clinical Trial

Insulin glargine (Glar) exerts its action primarily through a decrease in fasting plasma glucose (FPG), whereas dulaglutide (DU), a once-weekly GLP-1RA, targets both fasting and postprandial glucose (PPG). This post-hoc analysis of the AWARD-2 study assessed the efficacy of DU vs. Glar in patients with type 2 diabetes with different glycemic patterns at baseline determined by self-monitoring of blood glucose (fasting glucose [FG] vs. PPG). Patients were categorized into 4 groups based on combinations of low and high FG and PPG, with median baseline values of FG (151 mg/dL) and PPG (182 mg/dL) being used as threshold for low and high, respectively. Analyses were conducted using analysis of covariance. DU showed a statistically significantly greater reduction in A1c compared with Glar for all of the subgroups, except for low FG/high PPG, where the numerical difference was in favor of DU but did not reach statistical significance (Table). Total hypoglycemia was numerically lower for DU vs. Glar in all subgroups. DU showed efficacy on A1c reductions across different baseline glycemic patterns vs. Glar (with the exception of low FG/high PPG), indicating a clinical benefit of targeting both FG and PPG, irrespective of the baseline glycemic phenotype. Disclosure F. Giorgino: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim GmbH. Research Support; Self; Eli Lilly and Company, Johnson &amp; Johnson Services, Inc.. Consultant; Self; MedImmune, Merck Sharp &amp; Dohme Corp., Roche Diabetes Care Health and Digital Solutions, Sanofi. Research Support; Self; Takeda Development Centre Europe Ltd. M. Yu: Employee; Self; Eli Lilly and Company. A. Haupt: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Z. Milicevic: Employee; Self; Eli Lilly and Company. L. Garcia-Perez: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial

Many antihyperglycaemic drugs, including insulin, are primarily cleared by the kidneys, restricting treatment options for patients with kidney disease. Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist that is not cleared by the kidneys, and confers a lower risk of hypoglycaemia than does insulin. We assessed the efficacy and safety of dulaglutide in patients with type 2 diabetes and moderate-to-severe chronic kidney disease. AWARD-7 was a multicentre, open-label trial done at 99 sites in nine countries. Eligible patients were adults with type 2 diabetes and moderate-to-severe chronic kidney disease (stages 3-4), with an HbA1c of 7·5-10·5%, and who were being treated with insulin or insulin plus an oral antihyperglycaemic drug and were taking a maximum tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Participants were randomly assigned (1:1:1) by use of a computer-generated random sequence with an interactive response system to once-weekly injectable dulaglutide 1·5 mg, once-weekly dulaglutide 0·75 mg, or daily insulin glargine as basal therapy, all in combination with insulin lispro, for 52 weeks. Insulin glargine and lispro doses were titrated as per an adjustment algorithm; dulaglutide doses were masked to participants and investigators. The primary outcome was HbA1c at 26 weeks, with a 0·4% non-inferiority margin. Secondary outcomes included estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). The primary analysis population was all randomly assigned patients who received at least one dose of study treatment and had at least one post-randomisation HbA1c measurement. The safety population was all patients who received at least one dose of study treatment and had any post-dose data. This study is registered with ClinicalTrials.gov, number NCT01621178. Between Aug 15, 2012, and Nov 30, 2015, 577 patients were randomly assigned, 193 to dulaglutide 1·5 mg, 190 to dulaglutide 0·75 mg, and 194 to insulin glargine. The effects on HbA1c change at 26 weeks of dulaglutide 1·5 mg and 0·75 mg were non-inferior to those of insulin glargine (least squares mean [LSM] -1·2% [SE 0·1] with dulaglutide 1·5 mg [183 patients]; -1·1% [0·1] with dulaglutide 0·75 mg [180 patients]; -1·1% [0·1] with insulin glargine [186 patients]; one-sided p≤0·0001 for both dulaglutide doses vs insulin glargine). The differences in HbA1c concentration at 26 weeks between dulaglutide and insulin glargine treatments were LSM difference -0·05% (95% CI -0·26 to 0·15, p<0·0001) with dulaglutide 1·5 mg and 0·02% (-0·18 to -0·22, p=0·0001) with dulaglutide 0·75 mg. HbA1c-lowering effects persisted to 52 weeks (LSM -1·1% [SE 0·1] with dulaglutide 1·5 mg; -1·1% [0·1] with dulaglutide 0·75 mg; -1·0% [0·1] with insulin glargine). At 52 weeks, eGFR was higher with dulaglutide 1·5 mg (Chronic Kidney Disease Epidemiology Collaboration equation by cystatin C geometric LSM 34·0 mL/min per 1·73 m2 [SE 0·7]; p=0·005 vs insulin glargine) and dulaglutide 0·75 mg (33·8 mL/min per 1·73 m2 [0·7]; p=0·009 vs insulin glargine) than with insulin glargine (31·3 mL/min per 1·73 m2 [0·7]). At 52 weeks, the effects of dulaglutide 1·5 mg and 0·75 mg on UACR reduction were not significantly different from that of insulin glargine (LSM -22·5% [95% CI -35·1 to -7·5] with dulaglutide 1·5 mg; -20·1% [-33·1 to -4·6] with dulaglutide 0·75 mg; -13·0% [-27·1 to 3·9] with insulin glargine). Proportions of patients with any serious adverse events were similar across groups (20% [38 of 192] with dulaglutide 1·5 mg, 24% [45 of 190] with dulaglutide 0·75 mg, and 27% [52 of 194] with insulin glargine). Dulaglutide was associated with higher rates of nausea (20% [38 of 192] with dulaglutide 1·5 mg and 14% [27 of 190] with 0·75 mg, vs 5% [nine of 194] with insulin glargine) and diarrhoea (17% [33 of 192] with dulaglutide 1·5 mg and 16% [30 of 190] with 0·75 mg, vs 7% [14 of 194] with insulin glargine) and lower rates of symptomatic hypoglycaemia (4·4 events per patient per year with dulaglutide 1·5 mg and 4·3 with dulaglutide 0·75 mg, vs 9·6 with insulin glargine). End-stage renal disease occurred in 38 participants: eight (4%) of 192 with dulaglutide 1·5 mg, 14 (7%) of 190 with dulaglutide 0·75 mg, and 16 (8%) of 194 with insulin glargine. In patients with type 2 diabetes and moderate-to-severe chronic kidney disease, once-weekly dulaglutide produced glycaemic control similar to that achieved with insulin glargine, with reduced decline in eGFR. Dulaglutide seems to be safe to use to achieve glycaemic control in patients with moderate-to-severe chronic kidney disease. Eli Lilly and Company.

Similar Intrapatient Blood Glucose Variability with LY2963016 and Lantus® Insulin Glargine in Patients with Type 1 (T1D) or Type 2 Diabetes, Including a Japanese T1D Subpopulation.

IntroductionLY2963016 insulin glargine (LY IGlar) and Lantus® (IGlar), both with identical primary amino acid sequences, were compared in two phase 3 studies for intrapatient blood glucose variability.MethodsELEMENT-1 was a 52-week study in patients with type 1 diabetes (T1D), which included Japanese patients, and ELEMENT-2 was a 24-week study in non-Japanese patients with type 2 diabetes (T2D). In ELEMENT-1, 535 patients with T1D were evaluable (268 LY IGlar and 267 IGlar). Of these, 100 were Japanese patients (49 LY IGlar and 51 IGlar). In ELEMENT-2, 756 patients with T2D were evaluable (376 LY IGlar and 380 IGlar). We evaluated and compared intrapatient blood glucose variability of LY IGlar and IGlar in these studies from three different perspectives: intrapatient between-day fasting blood glucose variability, intrapatient between-day daily mean blood glucose variability, and intrapatient within-day blood glucose variability.ResultsOverall, evaluations of all three indices showed that intrapatient blood glucose variability was similar between LY IGlar and IGlar throughout the study periods both in the overall populations of patients with T1D and T2D and also in the subgroup of Japanese patients with T1D.ConclusionIntrapatient blood glucose variability between LY IGlar and IGlar was shown to be similar in patients with T1D or T2D.Clinical Trial RegistrationNCT01421147 (ELEMENT-1) and NCT01421459 (ELEMENT-2).FundingEli Lilly and Company (Indianapolis, IN, USA); Boehringer-Ingelheim (Ridgefield, CT, USA); Eli Lilly Japan K.K. (Kobe, Japan) and Nippon Boehringer Ingelheim Co., Ltd. (Tokyo, Japan).

Abstract #263 Twice Daily Insulin Glargine for Patients with Uncontrolled Type 2 Diabetes

Abstract #263 Twice Daily Insulin Glargine for Patients with Uncontrolled Type 2 Diabetes