Rates Of Nocturnal Hypoglycemia Research Articles

Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial

Aims/hypothesisA head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin.MethodsThis randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m2. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0–5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period.ResultsOf the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300.Conclusions/interpretationThere was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300.Trial registrationClinicalTrials.gov NCT03078478FundingThis trial was funded by Novo Nordisk (Bagsvaerd, Denmark)

Insulin analogs versus human insulins for the management of diabetes: An evidence-based review

Insulin analogs are preferred by many physicians over human insulins in the management of Type 1 diabetes and in patients with Type 2 diabetes who require insulin. Insulin analogs have a pharmacological profile that is close to the normal physiological action of insulin. There is a notion among some clinicians that insulin analogs offer advantages over human insulins, including better glucose control, less hypoglycemia, and flexibility. A large number of clinical studies, along with systematic reviews, have compared insulin analogs to human insulins in regard to glucose control, rates of hypoglycemia, quality of life, and cost-effectiveness. For Type 1 diabetes, rapid-acting insulin analogs offer better glucose control and less rates of hypoglycemia compared to regular human insulin. Long-acting basal insulins result in less nocturnal hypoglycemia compared to neutral protamine Hagedorn (NPH) insulin but no difference in glucose control in patients with Type 1 diabetes. For patients with Type 2 diabetes, rapid-acting insulins offer no advantage for glucose control or rates of hypoglycemia when compared to regular insulin. There was only a reduction in rates of nocturnal hypoglycemia with no difference in glucose control with the use of basal insulin analogs compared to NPH insulin in Type 2 diabetes. The cost of insulin analogs is considerably higher than human insulins and favorable cost-effectiveness was only demonstrated with rapid-acting insulin analogs in Type 1 diabetes. The available evidence does not support the routine use of insulin analogs over human insulins. There are only few situations where insulin analogs have shown clear benefit over human insulin. In a large percentage of patients cost consideration and lack of better glucose control would favor the use of human insulins.

Fasting C-peptide, a biomarker for hypoglycaemia risk in insulin-naïve people with type 2 diabetes initiating basal insulin glargine 100 U/mL.

To examine the relationship between baseline fasting C-peptide (FCP) and outcomes in insulin-naïve people with type 2 diabetes initiating basal insulin glargine 100 U/mL (Gla-100). Post hoc pooled analysis of nine randomized, treat-to-target trials in patients with type 2 diabetes inadequately controlled on oral antihyperglycaemic drugs initiating once-daily Gla-100. Participants (n = 2165) were stratified at baseline according to FCP (≤0.40, >0.40-1.20, >1.20-2.00, >2.00 nmol/L). Glycaemic control, body weight, insulin dose and hypoglycaemia were determined at 24 weeks. At baseline low FCP levels were associated with longer known diabetes duration, lower body mass index and higher fasting plasma glucose (FPG). Following Gla-100 introduction, the mean HbA1c reduction at week 24 was similar in all four FCP groups, albeit fewer people in the lowest FCP group achieved HbA1c <7.0% versus FCP groups >0.40 nmol/L. By contrast, FPG reduction and proportion reaching FPG ≤5.6 mmol/L were greatest in the lowest FCP group, diminishing at higher FCP levels. Gla-100 dose at week 24 was lowest in the ≤0.40 nmol/L FCP group and highest in the >1.20 nmol/L FCP group. Incidence and event rate of overall, nocturnal and severe hypoglycaemia were higher at week 24 in groups with lower FCP levels. In multivariable regression analysis baseline FCP, concomitant sulphonylurea use and endpoint HbA1c were strong predictors of hypoglycaemia. FCP levels identified patients with type 2 diabetes experiencing different responses to basal insulin Gla-100. A low FCP identifies a markedly insulin-deficient, insulin-sensitive subgroup/phenotype with an enhanced risk of hypoglycaemia, which requires a low initial basal insulin dose, cautious titration and earlier addition of prandial glucose-lowering therapy.

Meta-Analysis and Cost-Effectiveness Analysis of Insulin Glargine 100 U/mL Versus Insulin Degludec for the Treatment of Type 2 Diabetes in China.

To evaluate the efficacy and safety as well as the long-term cost-effectiveness of insulin glargine 100 U/mL (IGlar) versus insulin degludec (IDeg) for the treatment of type 2 diabetes mellitus (T2DM) from the Chinese healthcare system perspective. A systematic search of English and Chinese electronic databases for randomized controlled trials (RCTs) comparing IGlar with IDeg for the treatment of T2DM was performed, followed by a meta-analysis to compare the efficacy and safety of IGlar versus IDeg. The CORE Diabetes Model was used to estimate lifetime costs, quality-adjusted life years (QALYs) gained, and cost-effectiveness of IGlar versus IDeg. One-way and probabilistic sensitivity analyses were conducted to assess the underlying parameter uncertainty. Six RCTs were included in the meta-analysis. The IGlar group showed a statistically significant decrease in glycated hemoglobin (HbA1c) from baseline compared to the IDeg group (mean difference [MD] 0.08%, 95% confidence interval [CI] 0.01-0.14%, P = 0.02). Body mass index (BMI) control was numerically better in the IGlar group than in the IDeg group (MD 0.07kg/m2, 95% CI - 0.01 to 0.14kg/m2, P = 0.08). In terms of hypoglycemia, the incidence of non-severe overall hypoglycemia was comparable between the IDeg and IGlar patient groups (P > 0.05), while the incidence of non-severe nocturnal hypoglycemia (relative risk [RR 0.79], 95% CI 0.70-0.90, P < 0.01) and the event rates of non-severe overall (RR 0.91, 95% CI 0.85-0.97, P < 0.01) and non-severe nocturnal hypoglycemia (RR 0.91, 95% CI 0.85-0.97, P < 0.01) were lower in the IDeg group. The incidences and event rates of both severe overall and nocturnal hypoglycemia were similar for the two groups (P > 0.05). The cost-effectiveness analysis showed that IGlar is the dominant treatment option compared with IDeg, with a lifetime savings of 1004 Chinese yuan in direct medical costs and a net gain of 0.015 QALYs per patient. Both one-way and probabilistic sensitivity analyses confirmed the robustness of the results. IGlar is a cost-saving option with incremental effectiveness compared with IDeg for the treatment of T2DM in China. Sanofi China.

Lilly Insulin Glargine Versus Lantus® in Insulin-Naïve and Insulin-Treated Adults with Type 2 Diabetes: A Randomized, Controlled Trial (ELEMENT 5).

IntroductionThis study compared the efficacy and safety of similar U-100 insulin glargine products, namely, Lilly insulin glargine (LY IGlar; Basaglar®) and the reference insulin glargine product (IGlar; Lantus®), used once daily in combination with oral antihyperglycemic medications (OAMs) in adults with type 2 diabetes (T2D).MethodsELEMENT 5 was a phase III, randomized, multinational, open-label, treat-to-target, 24-week trial. Participants were insulin naïve (glycated hemoglobin [HbA1c] ≥ 7.0% to ≤ 11.0%) or on basal insulin (IGlar, neutral protamine Hagedorn or insulin detemir; HbA1c ≤ 11.0%) and taking ≥ 2 OAMs. The primary objective was to show that LY IGlar is noninferior to IGlar in terms of HbA1c reduction (0.4% noninferiority margin).ResultsThe study population (N = 493) was predominantly Asian (48%) or White (46%), with similar baseline characteristics between arms (P > 0.05). At 24 weeks, LY IGlar was noninferior to IGlar in terms of change in HbA1c level from baseline (− 1.25 vs. − 1.22%, respectively; least squares mean difference − 0.04%; 95% confidence interval − 0.22%, 0.15%). Other 24-week efficacy and safety results were also similar between treatments (P > 0.05), including insulin dose; percentage of patients having HbA1c of < 7% and ≤ 6.5%; overall rate and incidence of total, nocturnal, and severe hypoglycemia; adverse events; insulin antibody response; and weight gain. Daily mean 7-point self-monitored blood glucose reduction was similar between treatments at 24 weeks, with no differences at any time point except premorning-meal (fasting) blood glucose (LY IGlar − 2.37 mmol/L; IGlar − 2.69 mmol/L; P = 0.007).ConclusionOverall, LY IGlar and IGlar combined with OAMs provided similar glucose control and safety findings in this T2D population, which included a greater proportion of Asian patients and had broader background basal insulin experience than a previously studied T2D population.Trial RegistrationClinicalTrials.gov identifier, NCT02302716.FundingEli Lilly and Company and Boehringer Ingelheim.Plain Language SummaryPlain language summary available for this article.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0549-3) contains supplementary material, which is available to authorized users.

Cardiovascular Outcomes Trials Update: Insights from the DEVOTE Trial.

The DEVOTE study compared the cardiovascular safety of two basal insulins, degludec, and glargine U100 in patients with type 2 diabetes (T2D) at high risk for cardiovascular disease (CVD). In this review, we summarize the results of DEVOTE and provide a clinical perspective. DEVOTE was a phase 3b, multicenter, international, treat-to-target, double-blind, event-driven trial. Patients with T2D > 50years of age with prior CVD or > 60years of age with CVD risk factors were randomly assigned to receive either degludec (n= 3818) or insulin glargine U100 (n= 3819) and were followed until at least 633 positively adjudicated major adverse cardiovascular events (MACE; cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) accrued. At baseline, the mean age of the subjects was 65.0years, the mean duration of diabetes was 16.4years, and the mean HbA1c was 8.4 ± 1.7%. After a median follow-up of 2years, HbA1c had decreased to 7.5 ± 1.2% in each group. Degludec was non-inferior to insulin glargine U100 with respect to the primary MACE outcome (hazard ratio 0.91; 95% CI 0.78-1.06). Significantly, lower rates of severe hypoglycemia and nocturnal severe hypoglycemia were observed with degludec compared to glargine U100 (rate ratios of 0.60; 95% CI 0.48-0.76 and 0.47; 95% CI 0.31 to 0.73, respectively). DEVOTE demonstrated that the cardiovascular safety of degludec was comparable to that of insulin glargine U100 in patients with T2D at high risk for CVD. Additionally, degludec was superior to insulin glargine U100 with respect to the risk for severe hypoglycemia. These results suggest that degludec might be preferred in patients at risk for severe hypoglycemia, including the elderly, those with CVD and/or those with chronic kidney disease.

Effectiveness and safety of insulin glargine versus detemir analysis in patients with type 1 diabetes: systematic review and meta-analysis.

Diabetes mellitus type 1 (DM1) is an autoimmune disease characterized by metabolic destruction of pancreatic cells responsible for insulin production, with treatment based on replacing insulin. Long-acting insulin analogs are indicated for patients with DM1 who exhibit important oscillations of their daily glycemia, despite its higher cost. Our study objective was to evaluate the effectiveness and safety of two long-acting insulins, insulin glargine and detemir, in treating patients with DM1. We undertook a systematic review with meta-analysis of observational studies (cohort and registry) available in the databases and the gray literature, and a complementary search in the Diabetes Care journal. Outcomes assessed were: glycated hemoglobin concentration; fasting plasma or capillary glucose; occurrence of episodes of severe hypoglycemia and occurrence of nocturnal hypoglycemia. The assessment of methodological quality was performed using the Newcastle score. The meta-analyses were performed on software Review Manager® 5.2. Out of 705 publications, 8 cohort studies were included. The quality of these studies was classified as high. In the meta-analysis, results regarding episodes of severe hypoglycemia (p = 0.02) and fasting glucose (p = 0.01) were in favor of detemir. The glycated hemoglobin (p = 0.49; I2 = 89) showed high heterogeneity and no statistically significant difference between the two. The meta-analysis of total insulin dose favored glargine (p = 0.006; I2 = 75). The rates of nocturnal hypoglycemia (NH) were evaluated only for one study and showed a significant reduction of NH after therapy with detemir, (p < 0.0001). Although some outcomes were favorable to detemir insulin analog, it has not been possible to identify important differences of effectiveness and safety between the two analogs. These results can help in the current debate on the inclusion of long-acting analogs on the list of reimbursed medicines in Brazil, especially with the recent introduction of an insulin glargine biosimilar at a considerably lower price.

Hypoglycemia with Mealtime Fast-Acting Insulin Aspart vs. Insulin Aspart Across Two Large Type 1 Diabetes Trials

Hypoglycemia is a ubiquitous challenge with insulin treatment in type 1 diabetes (T1D), with nocturnal episodes of particular concern. Severe (as defined by the ADA) or blood glucose-confirmed (&amp;lt;56 mg/dL [3.1 mmol/L]) hypoglycemia was investigated across two double-blind, treat-to-target, randomized trials assessing the efficacy and safety of mealtime fast-acting insulin aspart (FA) vs. insulin aspart (IAsp) by multiple daily injections in adults with T1D: a 52-week trial in combination with insulin detemir (onset 1; n=761), and a 26-week trial in combination with insulin degludec (onset 8; n=684). FA was confirmed to be non-inferior to IAsp regarding change from baseline in A1C in both trials, with a statistically significantly greater A1C reduction with FA in onset 1. Importantly, nocturnal hypoglycemia rates were consistently lower with FA vs. IAsp in both trials (pooled estimated treatment rate ratio [ETR] 0.84 [95% CI 0.72;0.98]; p=0.02) (Figure), while no significant difference was observed for overall (pooled ETR 0.94 [95% CI: 0.85;1.05]) and diurnal hypoglycemia (pooled ETR 0.96 [95% 0.86;1.07])(Figure) with some heterogeneity across trials. In summary, analysis across two large trials supports the safety of mealtime FA, with lower rates of nocturnal hypoglycemia with FA vs. IAsp. ClinicalTrials.gov: NCT01831765; NCT02500706. Disclosure C. De Block: None. A. Carlson: Advisory Panel; Self; Sanofi, Insulet Corporation. Consultant; Self; Merck &amp; Co., Inc.. Research Support; Self; Medtronic, Novo Nordisk A/S. L. Rose: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Member of Association of Statutory Health Insurance Physicians. T. Gondolf: Employee; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Chr. Hansen A/S. A. Gorst-Rasmussen: Employee; Self; Novo Nordisk A/S. W. Lane: Advisory Panel; Self; Novo Nordisk A/S, Insulet Corporation, Intarcia Therapeutics, Inc., Sanofi. Research Support; Self; Novo Nordisk A/S, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Sanofi, Dexcom, Inc.. Speaker's Bureau; Self; Novo Nordisk A/S, Insulet Corporation.

Human Regular U-500 Insulin via Continuous Subcutaneous Insulin Infusion vs. Multiple Daily Injections in Adults with T2D—The VIVID Study—All Randomized Population

VIVID is the first prospective randomized controlled trial evaluating CSII (using an investigational Omnipod U-500™ Insulin Management System) vs. MDI (TID) with U-500R (Humulin® R U-500). This was a 26-week, open-label, multicenter, parallel study in adults with T2D on high dose insulin (201-600 units/day) with or without other antihyperglycemic agents (NCT02561078). We present results for the all randomized population (N=420); results for the primary population (excluding participants on concomitant GLP-1 RAs or SGLT2 inhibitors) are reported separately. Baseline characteristics were similar between arms. Without adjusting for multiplicity, CSII demonstrated significantly greater reduction in A1C and FPG at a lower total daily dose vs. MDI at 26 weeks. Also, a higher percentage of participants on CSII reached A1C targets &amp;lt;7.0%, &amp;lt;7.5%, and &amp;lt;8.0%. Severe hypoglycemia rates were low. Other hypoglycemia rates were similar (documented symptomatic) or higher (nocturnal) for CSII vs. MDI. Weight gain was similar (Table). In the all randomized population, U-500R via CSII demonstrated greater efficacy at a lower dose with a higher nocturnal hypoglycemia rate vs. MDI. CSII with U-500R may be a viable option for patients with T2D on high dose insulin. Individualized dose titration will be important for safely achieving glycemic targets. Disclosure G. Grunberger: Research Support; Self; Medtronic MiniMed, Inc., Novo Nordisk Inc.. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Janssen Pharmaceuticals, Inc.. A. Bhargava: None. T.T. Ly: Employee; Self; Insulet Corporation. H. Zisser: Employee; Self; Verily Life Sciences LLC.. Stock/Shareholder; Self; Verily Life Sciences LLC. L. Ilag: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J.K. Malone: Employee; Self; Eli Lilly and Company. S. Zhang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. J. Johnson: Employee; Self; Eli Lilly and Company.

Multinational Consensus: Insulin Initiation with Insulin Degludec/Aspart (IDegAsp).

Insulin degludec/aspart (IDegAsp) is the first soluble insulin co-formulation, combining a long-acting insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp). In type 2 diabetes patients with oral antidiabetes agent (OAD) inadequacy, insulin initiation with IDegAsp once daily provides superior long-term glycemic control compared to insulin glargine, with similar fasting plasma glucose (FPG) and insulin doses, and numerically lower rates of overall and nocturnal hypoglycemia. Furthermore, in patients with uncontrolled type 2 diabetes previously treated with insulins, IDegAsp twice daily effectively improves glycated hemoglobin and FPG, with fewer hypoglycemic episodes versus premix insulins and basal bolus therapy. In patients with type 1 diabetes mellitus, IDegAsp once daily with two doses of IAsp is a convenient, yet effective, regimen as compared to the conventional 4-5 injection-based basal bolus therapy. IDegAsp is an appropriate and reasonable option for initiation of insulin therapy in both type 1 and type 2 diabetes.

New Medications for the Treatment of Diabetes.

New Medications for the Treatment of Diabetes.

Efficacy and Safety of Insulin Degludec versus Insulin Glargine: A Systematic Review and Meta-Analysis of Fifteen Clinical Trials.

Aims Insulin degludec (IDeg) and insulin glargine (IGlar) are both proved to be effective in diabetes. This study aimed to assess the effects and safety of IDeg versus IGlar. Methods A systematic literature search was conducted using the PubMed, EMBASE, and Cochrane Library electronic databases to identify all randomized controlled trials (RCTs). Results Fifteen RCTs were identified. The combined data showed that the decrease in the glycosylated hemoglobin (HbA1c) level was slightly different, and the proportion of patients who achieved HbA1c < 7% was similar between the IDeg and IGlar groups. Further, a statistically significant decrease in the fasting plasma glucose level was observed in the IDeg group as compared to the IGlar group. In patients with T2DM, IDeg was associated with lower rates of overall hypoglycemia. Nocturnal hypoglycemia was significantly lower in the case of IDeg than in the case of IGlar in both T1DM and T2DM patients. No statistically significant differences were observed between the groups. Conclusions Compared with IGlar, IDeg is associated with equivalent glycemic control and a statistically significantly lower rate of nocturnal hypoglycemia in patients with T1DM and T2DM. In T2DM patients, IDeg also provides better results in terms of overall hypoglycemia.

Original paper: Efficacy and safety analysis of insulin degludec/insulin aspart compared with biphasic insulin aspart 30: A phase 3, multicentre, international, open-label, randomised, treat-to-target trial in patients with type 2 diabetes fasting during Ramadan

AimsTo compare the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) and biphasic insulin aspart 30 (BIAsp 30) before, during and after Ramadan in patients with type 2 diabetes mellitus (T2DM) who fasted during Ramadan. MethodsIn this multinational, randomised, treat-to-target trial, patients with T2DM who intended to fast and were on basal, pre- or self-mixed insulin ± oral antidiabetic drugs for ≥90 days were randomised (1:1) to IDegAsp twice daily (BID) or BIAsp 30 BID. Treatment period included pre-Ramadan treatment initiation (with insulin titration for 8–20 weeks), Ramadan (4 weeks) and post-Ramadan (4 weeks). Insulin doses were reduced by 30–50% for the pre-dawn meal (suhur) on the first day of Ramadan, and readjusted to the pre-Ramadan levels at the end of Ramadan. Hypoglycaemia was analysed as overall (severe or plasma glucose <3.1 mmol/L [56 mg/dL]), nocturnal (00:01–05:59) or severe (requiring assistance of another person). ResultsDuring the treatment period, IDegAsp (n = 131) had significantly lower overall and nocturnal hypoglycaemia rates with similar glycaemic efficacy, versus BIAsp 30 (n = 132). During Ramadan, despite achieving significantly lower pre-iftar (meal at sunset) self-measured plasma glucose (estimated treatment difference: −0.54 mmol/L [−1.02; −0.07]95% CI, p = .0247; post hoc) with similar overall glycaemic efficacy, IDegAsp showed significantly lower overall and nocturnal hypoglycaemia rates versus BIAsp 30. ConclusionsIDegAsp is a suitable therapeutic agent for patients who need insulin for sustained glucose control before, during and after Ramadan fasting, with a significantly lower risk of hypoglycaemia, versus BIAsp 30, an existing premixed insulin analogue.

Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes

Hypoglycemia, a serious risk for insulin-treated patients with type 2 diabetes, negatively affects glycemic control. 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. 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. 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. 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. 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. 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. clinicaltrials.gov Identifier: NCT02030600.

Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes

Hypoglycemia, common in patients with type 1 diabetes, is a major barrier to achieving good glycemic control. Severe hypoglycemia can lead to coma or death. To determine whether insulin degludec is noninferior or superior to insulin glargine U100 in reducing the rate of symptomatic hypoglycemic episodes. Double-blind, randomized, crossover noninferiority trial involving 501 adults with at least 1 hypoglycemia risk factor treated at 84 US and 6 Polish centers (January 2014-January 12, 2016) for two 32-week treatment periods, each with a 16-week titration and a 16-week maintenance period. Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 249) or to receive insulin glargine U100 followed by insulin degludec (n = 252) and randomized 1:1 to morning or evening dosing within each treatment sequence. The primary end point was the rate of overall severe or blood glucose-confirmed (<56 mg/dL) symptomatic hypoglycemic episodes during the maintenance period. Secondary end points included the rate of nocturnal symptomatic hypoglycemic episodes and proportion of patients with severe hypoglycemia during the maintenance period. The noninferiority criterion for the primary end point and for the secondary end point of nocturnal hypoglycemia was defined as an upper limit of the 2-sided 95% CI for a rate ratio of 1.10 or lower; if noninferiority was established, 2-sided statistical testing for superiority was conducted. Of the 501 patients randomized (mean age, 45.9 years; 53.7% men), 395 (78.8%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia were 2200.9 episodes per 100 person-years' exposure (PYE) in the insulin degludec group vs 2462.7 episodes per 100 PYE in the insulin glargine U100 group for a rate ratio (RR) of 0.89 (95% CI, 0.85-0.94; P < .001 for noninferiority; P < .001 for superiority; rate difference, -130.31 episodes per 100 PYE; 95% CI, -193.5 to -67.16). The rates of nocturnal symptomatic hypoglycemia were 277.1 per 100 PYE in the insulin degludec group vs 428.6 episodes per 100 PYE in the insulin glargine U100 group, for an RR of 0.64 (95% CI, 0.56-0.73; P < .001 for noninferiority; P < .001 for superiority; rate difference, -61.94 episodes per 100 PYE; 95% CI, -83.85 to -40.03). A lower proportion of patients in the insulin degludec than in the insulin glargine U100 group experienced severe hypoglycemia during the maintenance period (10.3%, 95% CI, 7.3%-13.3% vs 17.1%, 95% CI, 13.4%-20.8%, respectively; McNemar P = .002; risk difference, -6.8%; 95% CI, -10.8% to -2.7%). Among patients with type 1 diabetes and at least 1 risk factor for hypoglycemia, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemic episodes. clinicaltrials.gov Identifier: NCT02034513.

United States experience of insulin degludec alone or in combination for type 1 and type 2 diabetes.

Insulin degludec has been the product of a sophisticated and systematic biochemical engineering program which began with the release of insulin detemir. The goal was to produce a long-lasting basal insulin with low individual variability. Certainly, this goal has been achieved. Degludec has a duration of action approaching twice that of glargine. Another advantage of degludec is in its lack of unpredictable copolymerization of added aspart. In several studies, degludec has shown lower rates of nocturnal hypoglycemia than glargine. Degludec can be administered flexibly with a very flat insulin concentration curve at any time of day. Initial US Food and Drug Administration concerns about a possible increase in cardiac events in degludec-treated patients have been allayed by the results of a study targeting individuals with high cardiac risk. Degludec is now marketed in the US competing with glargine. Despite the long duration of action of degludec, attempted administration three times weekly resulted in less effective lowering of glycated hemoglobin and an increased incidence of hypoglycemia compared to daily glargine. Conversely the coformulation of degludec and liraglutide has proven very successful in reducing glycated hemoglobin levels with less hypoglycemia and less weight gain than with degludec alone and with less gastrointestinal symptoms than with liraglutide alone. A large study comparing glargine insulin and degludec in patients with increased cardiac risk is now ongoing. This study may or may not prove superiority of one or the other insulin, but, with the coming of biosimilar glargine insulin, cost factors may be dominant in determining which basal insulin is to be used. Nonetheless, the coformulation with liraglutide will likely insure the future of degludec insulin in the treatment of type 2 diabetes.

Patient-level meta-analysis of efficacy and hypoglycaemia in people with type 2 diabetes initiating insulin glargine 100U/mL or neutral protamine Hagedorn insulin analysed according to concomitant oral antidiabetes therapy.

Evaluate efficacy and hypoglycaemia according to concomitant oral antidiabetes drug (OAD) in people with type 2 diabetes initiating insulin glargine 100U/mL (Gla-100) or neutral protamine Hagedorn (NPH) insulin once daily. Four studies (target fasting plasma glucose [FPG] ⩽100mg/dL [⩽5.6mmol/L]; duration ⩾24weeks) were included. Standardised data from 2091 subjects (Gla-100, n=1024; NPH insulin, n=1067) were analysed. Endpoints included glycated haemoglobin (HbA1c) and FPG change, glycaemic target achievement, hypoglycaemia, weight change, and insulin dose. Mean HbA1c and FPG reductions were similar with Gla-100 and NPH insulin regardless of concomitant OAD (P=0.184 and P=0.553, respectively) and similar proportions of subjects achieved HbA1c <7.0% (P=0.603). There was a trend for more subjects treated with Gla-100 achieving FPG ⩽100mg/dL versus NPH insulin (relative risk [RR] 1.09 [95% confidence interval (CI) 0.97-1.23]; P=0.135). Plasma glucose confirmed (<70mg/dL) overall and nocturnal hypoglycaemia incidences and rates were lower with Gla-100 versus NPH insulin (overall RR 0.93 [95% CI 0.87-1.00]; P=0.041; nocturnal RR 0.73 [95% CI 0.65-0.83]; P<0.001). After 24weeks, weight gain and insulin doses were higher with Gla-100 versus NPH insulin (2.7kg vs 2.3kg, P=0.009 and 0.42U/kg vs 0.39U/kg; P=0.003, respectively). Insulin doses were higher when either insulin was added to sulfonylurea alone. Pooled results from treat-to-target trials in insulin-naïve people with type 2 diabetes demonstrate a significantly lower overall and nocturnal hypoglycaemia risk across different plasma glucose definitions with Gla-100 versus NPH insulin at similar glycaemic control. OAD therapy co-administered with Gla-100 or NPH insulin impacts glycaemic control and overall nocturnal hypoglycaemia risk.

Insulin degludec/insulin aspart vs biphasic insulin aspart 30 twice daily in Japanese patients with type 2 diabetes: A randomized controlled trial

Aims/IntroductionInsulin degludec/insulin aspart (IDegAsp) is a soluble combination of insulin degludec (70%) and insulin aspart (30%). The present exploratory trial investigated the safety of switching unit‐to‐unit from twice‐daily basal or pre‐mix insulin to twice‐daily IDegAsp in Japanese patients with type 2 diabetes.Materials and MethodsIn this 6‐week, open‐label, parallel‐group, controlled trial, 66 participants were randomized (1:1) to receive either IDegAsp or biphasic insulin aspart 30 (BIAsp 30) twice daily at the same total daily dose as pre‐trial insulin. During the trial, insulin doses were adjusted according to a pre‐specified algorithm to achieve pre‐breakfast and pre‐dinner plasma glucose of 4.4–7.2 mmol/L.ResultsNo severe hypoglycemic episodes occurred. There were no statistically significant differences in rates of confirmed hypoglycemia (rate ratio IDegAsp/BIAsp 30: 0.63, 95% confidence interval: 0.31–1.30) and confirmed nocturnal hypoglycemia (rate ratio: 0.49, 95% confidence interval: 0.10–2.38) for IDegAsp vs BIAsp 30. The hypoglycemia rate for IDegAsp was constant over the 6 weeks of treatment. IDegAsp and BIAsp 30 were both safe and well tolerated. Reduction in fasting plasma glucose was statistically significantly greater for IDegAsp than for BIAsp 30 (estimated treatment difference, IDegAsp‐BIAsp 30: −1.6 mmol/L, 95% confidence interval: −2.4 to −0.8). The apparent decrease in mean postprandial plasma glucose increment (IDegAsp: 4.2–3.8 mmol/L; BIAsp 30: 4.5–2.8 mmol/L) was not statistically significantly different between treatments (estimated treatment difference: 1.0 mmol/L, 95% confidence interval: −0.1 to 2.2).ConclusionsSwitching unit‐to‐unit from basal or pre‐mix insulin to IDegAsp seems not to be associated with any concerns related to hypoglycemia or general safety in Japanese patients with type 2 diabetes.

Clinical Pharmacokinetics and Pharmacodynamics of Insulin Glargine 300U/mL.

Concentrated insulin analogs have recently been approved and are available for clinical use in the management of diabetes mellitus. One new product is insulin glargine U-300 (Sanofi), a basal concentrated insulin of 300U/mL. Several studies have been conducted and completed evaluating blood samples for the pharmacokinetics of insulin glargine U-300 and euglycemic clamp procedures for the pharmacodynamics. This concentrated insulin has a low within-day variability and high day-to-day reproducibility, allowing for a more constant and prolonged duration of action, compared with insulin glargine U-100 (100U/mL). Insulin glargine U-300 is equally effective, when compared with insulin glargine U-100 for glycemic control in patients with type 1 and 2 diabetes mellitus. Insulin glargine U-300 has a similar efficacy profile to insulin glargine U-100 for glycemic control, yet with lower rates of nocturnal and severe hypoglycemia. Insulin glargine U-300 can be considered an acceptable basal insulin for patients with type 1 and 2 diabetes mellitus, and it has a potential role among patients who are naïve to insulin therapy or require titration of basal insulin. Titration of insulin glargine U-300 would result in less volume and a lower risk of hypoglycemia, compared with insulin glargine U-100. This article evaluates and summarizes the pharmacokinetics and pharmacodynamics of insulin glargine U-300, for patients with type 1 or 2 diabetes mellitus, and summarizes its application to clinical practice.

Basal insulin peglispro: Overview of a novel long-acting insulin with reduced peripheral effect resulting in a hepato-preferential action.

Basal insulin peglispro (BIL) is a novel basal insulin with a flat, prolonged activity profile. BIL has been demonstrated in a dog model, in healthy men and in patients with type 1 diabetes (T1D) to have significant hepato-preferential action resulting from reduced peripheral activity. In the IMAGINE-Phase 3 clinical trial program, more than 6000 patients were included, of whom ~3900 received BIL. Of the 7 pivotal IMAGINE trials, 3 studies were double-blinded and 3 were in T1D patients. BIL consistently demonstrated a greater HbA1c reduction, less glycaemic variability and a clinically relevant reduction in the rates of nocturnal hypoglycaemia across comparator [glargine and isophane insulin (NPH)] studies. Trials using basal/bolus regimens had higher rates of total hypoglycaemia with BIL due to higher rates of daytime hypoglycaemia. Severe hypoglycaemia rates were similar to comparator among both patients with T1D or type 2 diabetes (T2D). T1D patients lost weight compared with glargine (GL). Patients with T2D tended to gain less weight with BIL than with glargine. Compared to glargine, BIL was associated with higher liver fat, triglycerides and alanine aminotransferase (ALT) levels, including a higher frequency of elevation of ALT ≥3 times the upper limit of normal, but without severe, acute drug-induced liver injury. Injection site reactions, primarily lipohypertrophy, were more frequent with BIL. In conclusion, BIL demonstrated better glycaemic control with reduced glucose variability and nocturnal hypoglycaemia but higher triglycerides, ALT and liver fat relative to conventional comparator insulin. The hepato-preferential action of BIL with reduced peripheral activity may account for these findings.