Paul Norwood

Effect of Insulin Glargine Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients With Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial

IMPORTANCE Achieving glycemic control remains a challenge for patients with type 2 diabetes, even with insulin therapy. OBJECTIVE To assess whether a fixed ratio of insulin degludec/liraglutide was noninferior to continued titration of insulin glargine in patients with uncontrolled type 2 diabetes treated with insulin glargine and metformin. DESIGN, SETTING, AND PARTICIPANTS Phase 3, multinational, multicenter, 26-week, randomized, open-label, 2-group, treat-to-target trial conducted at 75 centers in 10 countries from September 2013 to November 2014 among 557 patients with uncontrolled diabetes treated with glargine (20-50 U) and metformin (≥1500 mg/d) with glycated hemoglobin (HbA1c) levels of 7% to 10% and a body mass index of 40 or lower. INTERVENTIONS 1:1 randomization to degludec/liraglutide (n = 278; maximum dose, 50 U of degludec/1.8 mg of liraglutide) or glargine (n = 279; no maximum dose), with twice-weekly titration to a glucose target of 72 to 90 mg/dL. MAIN OUTCOMES AND MEASURES Primary outcome measure was change in HbA1c level after 26 weeks, with a noninferiority margin of 0.3% (upper bound of 95% CI, <0.3%). If noninferiority of degludec/liraglutide was achieved, secondary end points were tested for statistical superiority and included change in HbA1c level, change in body weight, and rate of confirmed hypoglycemic episodes. RESULTS Among 557 randomized patients (mean: age, 58.8 years; women, 49.7%), 92.5% of patients completed the trial and provided data at 26 weeks. Baseline HbA1c level was 8.4% for the degludec/liraglutide group and 8.2% for the glargine group. HbA1c level reduction was greater with degludec/liraglutide vs glargine (-1.81% for the degludec/liraglutide group vs -1.13% for the glargine group; estimated treatment difference [ETD], -0.59% [95% CI, -0.74% to -0.45%]), meeting criteria for noninferiority (P < .001), and also meeting criteria for statistical superiority (P < .001). Treatment with degludec/liraglutide was also associated with weight loss compared with weight gain with glargine (-1.4 kg for degludec/liraglutide vs 1.8 kg for glargine; ETD, -3.20 kg [95% CI, -3.77 to -2.64],P < .001) and fewer confirmed hypoglycemic episodes (episodes/patient-year exposure, 2.23 for degludec/liraglutide vs 5.05 for glargine; estimated rate ratio, 0.43 [95% CI, 0.30 to 0.61],P < .001). Overall and serious adverse event rates were similar in the 2 groups, except for more nonserious gastrointestinal adverse events reported with degludec/liraglutide (adverse events, 79 for degludec/liraglutide vs 18 for glargine). CONCLUSIONS AND RELEVANCE Among patients with uncontrolled type 2 diabetes taking glargine and metformin, treatment with degludec/liraglutide compared with up-titration of glargine resulted in noninferior HbA1c levels, with secondary analyses indicating greater HbA1c level reduction after 26 weeks of treatment. Further studies are needed to assess longer-term efficacy and safety. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01952145.

A Novel Testosterone 2% Gel for the Treatment of Hypogonadal Males

Testosterone replacement therapy (TRT) can improve the symptoms, signs, and well being of hypogonadal men by restoring serum testosterone concentrations to physiologic levels. This multicenter, open-label noncomparative trial of men with hypogonadism evaluated the pharmacokinetic profile and safety of a novel testosterone 2% gel (Fortesta™ Gel), administered once daily to the front and inner thighs at starting doses of 40 mg/d. The metered-dose delivery system allowed dose adjustments in 10-mg increments between 10 and 70 mg/d. Of the 149 patients enrolled, 138 patients (92.6%) completed the study and 129 patients (86.6%) were included in the efficacy analysis. On day 90, mean testosterone concentration (C(avg) [0-24 hours] ± SD) was 438.6 ± 162.5 ng/dL. Overall, 100 (77.5%) patients achieved serum total testosterone concentrations within the normal physiologic range (≥ 300 and ≤ 1140 ng/dL). On day 90, mean testosterone C(max) (± SD) was 827.6 ± 356.5 ng/dL. On day 90, a total of 122 patients (94.6%) had C(max) levels of 1500 ng/dL or less and 2 patients (1.6%) had values between 1800 and 2500 ng/dL. Similar results for C(avg) (0-24 hours) and C(max) were observed on day 35. All enrolled patients were included in the safety analysis. Testosterone 2% gel was generally well tolerated, with the most common adverse events (AE) being mild and moderate skin reactions. There were no serious AEs related to testosterone 2% gel. Once-daily testosterone 2% gel restored levels of testosterone in more than 75% of patients, with low risk of supraphysiologic testosterone levels. Patients may find this a suitable option for TRT because of its application site and low volume.

Placebo‐controlled, randomized trial of the addition of once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide to titrated daily insulin glargine in patients with type 2 diabetes (AWARD‐9)

To compare the addition of weekly dulaglutide vs the addition of placebo to titrated glargine in patients with type 2 diabetes (T2D) with sub‐optimum glycated haemoglobin (HbA1c) concentration.

Safety of exenatide once weekly in patients with type 2 diabetes mellitus treated with a thiazolidinedione alone or in combination with metformin for 2 years.

BACKGROUND Patients with type 2 diabetes mellitus are routinely treated with combinations of glucose-lowering agents. The adverse event (AE) profile and effects on glycemic control have not been assessed for the glucagon-like peptide-1 receptor agonist exenatide once weekly in combination with a thiazolidinedione (TZD) with or without metformin. OBJECTIVE This study was conducted to examine the long-term safety profile and changes in glycemic control and weight for exenatide once weekly with TZD with or without metformin in patients with type 2 diabetes mellitus over 2 years. METHODS In this single-arm, open-label trial with treatment up to 104 or 117 weeks, patients received 2 mg exenatide once weekly while continuing treatment with a TZD with or without metformin. Patients were either exenatide-naïve before this study or had previously received exenatide twice daily, which was discontinued on initiating exenatide once weekly. Patients were on a stable dosage of TZD (rosiglitazone or pioglitazone) and, if applicable, metformin. Treatment-emergent AEs were defined as those first occurring or worsening post baseline. Descriptive statistics were used for absolute and change-from-baseline data, and a one-sample t test for within-group change in glycosylated hemoglobin (HbA(1c)). RESULTS Of 134 patients in the intent-to-treat population (baseline mean [SD] HbA(1c),7.2% [1.0%]), 44 were exenatide-naïve (baseline HbA(1c), 7.8% [1.0%]) and 90 switched from exenatide twice daily (baseline HbA(1c), 7.0% [0.8%]). Of intent-to-treat patients, 106 (79%) completed the final treatment visit (week 104 or week 117). The most common AEs were nausea (17% of patients) and injection-site nodule (12% of patients). Serious AEs were reported in 14% of patients and 5% withdrew because of a treatment-emergent AE. No identifiable pattern of serious AEs was observed. There were 4 reports of edema and no reports of heart failure. No major hypoglycemia was reported; minor hypoglycemia was reported in 4% of patients. Exenatide-naïve patients experienced mean (SE) HbA(1c) reductions of -0.7% (0.2%) and weight reductions of -2.7 (0.8) kg, whereas patients with prior exposure to exenatide twice daily experienced a reduction of -0.4% (0.1%) in HbA(1c) and no change in weight. CONCLUSIONS Adverse events over 2 years were consistent with the reported safety profiles of exenatide once weekly and TZDs. Exenatide-naïve patients experienced improvements in HbA(1c) and weight, while patients with the benefit of prior exenatide therapy experienced an additional reduction from baseline in HbA(1c) and no additional change in weight after 2 years. ClinicalTrials.gov identifier: NCT00753896.

Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial

Abstract Context Combination therapy with insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is important for treating type 2 diabetes (T2D). This trial assesses the efficacy and safety of semaglutide, a GLP-1RA, as an add-on to basal insulin. Objective To demonstrate the superiority of semaglutide vs placebo on glycemic control as an add-on to basal insulin in patients with T2D. Design Phase 3a, double-blind, placebo-controlled, 30-week trial. Setting This study included 90 sites in five countries. Patients We studied 397 patients with uncontrolled T2D receiving stable therapy with basal insulin with or without metformin. Interventions Subcutaneous semaglutide 0.5 or 1.0 mg once weekly or volume-matched placebo. Main Outcome Measures Primary endpoint was change in glycated Hb (HbA1c) from baseline to week 30. Confirmatory secondary endpoint was change in body weight from baseline to week 30. Results At week 30, mean HbA1c reductions [mean baseline value, 8.4% (67.9 mmol/mol)] with semaglutide 0.5 and 1.0 mg were 1.4% (15.8 mmol/mol) and 1.8% (20.2 mmol/mol) vs 0.1% (1.0 mmol/mol) with placebo [estimated treatment difference (ETD) vs placebo, –1.35 (14.8 mmol/mol); 95% CI, –1.61 to –1.10 and ETD, –1.75% (19.2 mmol/mol); 95% CI, –2.01 to –1.50; both P < 0.0001]. Severe or blood glucose–confirmed hypoglycemic episodes were reported in 11 patients (17 events) and 14 patients (25 events) with semaglutide 0.5 and 1.0 mg, respectively, vs seven patients (13 events) with placebo (estimated rate ratio vs placebo, 2.08; 95% CI, 0.67 to 6.51 and estimated rate ratio vs placebo, 2.41; 95% CI, 0.84 to 6.96 for 0.5 and 1.0 mg; both P = nonsignificant). Mean body weight decreased with semaglutide 0.5 and 1.0 mg vs placebo from baseline to end of treatment: 3.7, 6.4, and 1.4 kg (ETD, –2.31; 95% CI, –3.33 to –1.29 and ETD, –5.06; 95% CI, –6.08 to –4.04 kg; both P < 0.0001). Premature treatment discontinuation due to adverse events was higher for semaglutide 0.5 and 1.0 mg vs placebo (4.5%, 6.1%, and 0.8%), mainly due to gastrointestinal disorders. Conclusions Semaglutide, added to basal insulin, significantly reduced HbA1c and body weight in patients with uncontrolled T2D vs placebo.

Testosterone 2% Gel Can Normalize Testosterone Concentrations in Men with Low Testosterone Regardless of Body Mass Index

INTRODUCTION Little is known about the effect of body mass index (BMI) on the efficacy and safety of testosterone therapy in hypogonadal men. A prior noncomparative trial demonstrated that testosterone 2% gel restored testosterone levels in hypogonadal men and was generally well tolerated. AIM This post hoc analysis evaluated the influence of BMI on the pharmacokinetics of testosterone therapy in men with low testosterone. METHODS Men (N = 149) aged 18-75 applied testosterone 2% gel to the front and inner thigh once daily for 90 days. Starting dose was 40 mg/day, which could be adjusted at days 14, 35, and 60. Patients were split into categories depending on baseline BMI: Tertile 1 (≤ 29.1 kg/m(2)), Tertile 2 (29.2-32.4 kg/m(2)), and Tertile 3 (>32.4 kg/m(2)). MAIN OUTCOME MEASURES Efficacy end points were average serum total testosterone concentrations over 24 hours and maximum serum testosterone concentrations at day 90. Adverse events were recorded. RESULTS The efficacy analysis included 129 men with low testosterone (mean age 52.9, 54.0, and 54.2 years for Tertiles 1, 2, and 3, respectively) defined as serum testosterone <250-300 ng/dL. Baseline testosterone levels were comparable across BMI tertiles. After 90 days of treatment with testosterone 2% gel (≥ 40 mg/day), 79.1%, 79.5%, and 73.8% of patients in Tertiles 1, 2, and 3, respectively, achieved serum testosterone concentrations in the physiologic range (i.e., ≥ 300 to ≤ 1,140 ng/dL). The mean average daily dose at day 90 was higher in participants in Tertiles 3 vs. 2 (P = 0.039) and Tertiles 3 vs. 1 (P = 0.010). The gel was generally well tolerated, with skin reactions the most commonly reported adverse event (16.1%; n = 24). CONCLUSIONS In this study, daily application of testosterone 2% gel was effective at returning serum testosterone to physiologic levels in men with low testosterone and high BMI, although required dose was affected by BMI.

Rates of hypoglycaemia are lower in patients treated with insulin degludec/liraglutide (IDegLira) than with IDeg or insulin glargine regardless of the hypoglycaemia definition used

To re‐analyse, using a series of alternative hypoglycaemia definitions, the data from 2 trials, DUAL I and V, in which the once‐daily, fixed ratio combination of insulin degludec/liraglutide (IDegLira) was compared with basal insulin therapy.

23. Insulin Degludec/Liraglutide (IDegLira) Is Superior to Insulin Glargine (IG) in A1c Reduction, Risk of Hypoglycemia, and Weight Change: DUAL V Study (166-OR)

SamenvattingThis 26-week, open-label trial compared the efficacy and safety of IDegLira vs. IG in subjects with type 2 diabetes uncontrolled on IG (20-50U). Adults (n = 557, A1c 7-10%) were randomized to either once-daily IDegLira or continued IG uptitration, both + metformin. Initial doses were 16 dose steps (16U IDeg + 0.6 mg Lira) for IDegLira (maximum 50 dose steps) and pre-trial dose for IG (mean 32U; no maximum). Fasting self-measured blood glucose titration target was 71-90 mg/dL for both arms. Mean A1c decreased from 8.4 to 6.6% (IDegLira) and from 8.2 to 7.1% (IG) (p < 0.001). Mean fasting plasma glucose decreased similarly in both arms from 160 to 110 mg/dL. Weight decreased from 88.3 to 86.9kg (IDegLira) and increased from 87.3 to 89.1 kg (IG) (p < 0.001). More subjects achieved the composite endpoints with IDegLira vs. IG. IDegLira was insulin sparing; mean 26-week dose was 41 dose steps (IDegLira) and 66U (IG) (p < 0.001). Rates of confirmed and nocturnal hypoglycemia were significantly lower with IDegLira vs. IG. Overall and serious adverse event rates were similar in both arms. Trial completion numbers were 90% (IDegLira) vs. 95% (IG). IDegLira was superior to IG in A1c reduction, risk of hypoglycemia and weight change. IDegLira offers clinical advantages over IG in intensifying therapy while minimising insulin dose requirements, in subjects uncontrolled on IG.

Inhaled insulin: a clinical perspective with emphasis on EXUBERA®

There is a Type 2 diabetes epidemic; however, unfortunately, even though insulin is an effective therapy, it is mostly used late and as a last resort. Type 1 diabetics find it difficult to administer extra insulin injections when needed owing to the inconvenience and, although most cope well, many dislike injecting themselves so frequently. The newly approved EXUBERA® inhaled insulin should help counteract the resistance of patients and physicians in instituting insulin in the Type 2 diabetic, and the Type 1 diabetic can take more than 1000 fewer injections per year, making their diabetes easier to live with. Pulmonary function tests have demonstrated clinically insignificant changes after years of monitoring. The increases of insulin antibodies found in those who use inhaled insulin have not affected diabetes control. Side effects of inhaled insulin are insignificantly different from injectable insulin except for a couple of mild coughs after an inhalation, which decrease quickly with time. The two dosage forms of EXUBERA insulin are 1 and 3 mg (equivalent to approximately 3 and 8 U of U-100 insulin, respectively), are adaptable to most regimens for both types of diabetes, and inhaled insulin is preferred by a significant majority of patients. Inhaled insulin should be cost effective if it allows earlier institution in the Type 2 diabetic thus improving diabetic control and lowering the expensive complications of diabetes.