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Basal insulin therapy does not stop loss of β-cell function, which is the hallmark of type 2 diabetes mellitus, and thus diabetes control inevitably deteriorates. Insulin degludec is a new, ultra-longacting basal insulin. We aimed to assess efficacy and safety of insulin degludec compared with insulin glargine in patients with type 2 diabetes mellitus. In this 52 week, phase 3, open-label, treat-to-target, non-inferiority trial, undertaken at 123 sites in 12 countries, we enrolled adults (aged ≥18 years) with type 2 diabetes mellitus and a glycated haemoglobin (HbA1c) of 7·0–10·0% after 3 months or more of any insulin regimen (with or without oral antidiabetic drugs). We randomly allocated eligible participants in a 3:1 ratio to receive once-daily subcutaneous insulin degludec or glargine, stratified by previous insulin regimen, via a central interactive response system. Basal insulin was titrated to a target plasma glucose concentration of 3·9–<5·0 mmol/L self-measured before breakfast. The primary outcome was non-inferiority of degludec to glargine measured by change in HbA1c from baseline to week 52 (non-inferiority limit of 0·4%) by ANOVA in the full analysis set. We assessed rates of hypoglycaemia in all treated patients. This study is registered with ClinicalTrials.gov, number NCT00972283. 744 (99%) of 755 participants randomly allocated degludec and 248 (99%) of 251 allocated glargine were included in the full analysis set (mean age 58·9 years [SD 9·3], diabetes duration 13·5 years [7·3], HbA1c 8·3% [0·8], and fasting plasma glucose 9·2 mmol/L [3·1]); 618 (82%) and 211 (84%) participants completed the trial. After 1 year, HbA1c decreased by 1·1% in the degludec group and 1·2% in the glargine group (estimated treatment difference [degludec–glargine] 0·08%, 95% CI −0·05 to 0·21), confirming non-inferiority. Rates of overall confirmed hypoglycaemia (plasma glucose <3·1 mmol/L or severe episodes requiring assistance) were lower with degludec than glargine (11·1 vs 13·6 episodes per patient-year of exposure; estimated rate ratio 0·82, 95% CI 0·69 to 0·99; p=0·0359), as were rates of nocturnal confirmed hypoglycaemia (1·4 vs 1·8 episodes per patient-year of exposure; 0·75, 0·58 to 0·99; p=0·0399). Rates of severe hypoglycaemia seemed similar (0·06 vs 0·05 episodes per patient-year of exposure for degludec and glargine) but were too low for assessment of differences. Rates of other adverse events did not differ between groups. A policy of suboptimum diabetes control to reduce the risk of hypoglycaemia and its consequences in advanced type 2 diabetes mellitus might be unwarranted with newer basal insulins such as degludec, which are associated with lower risks of hypoglycaemia than insulin glargine. Novo Nordisk.

Anti-Diabetes and Anti-Obesity Medications: Effects on Weight in People With Diabetes Priscilla Hollander , MD Abstract In Brief Choosing medications for people with diabetes involves consideration of a number of factors, including effects on weight. Improvements in glucose control are often linked to weight gain, but this does not have to be the inevitable result of diabetes treatment. Adding a drug that either promotes weight-loss or is weight neutral to one that promotes weight gain and providing medical nutrition therapy can be considered. Footnotes Priscilla Hollander, MD, is medical director at the Baylor University Medical Center Ruth Collins Diabetes Center in Dallas, Texas. Note of disclosure: Dr. Hollander has recieved honoraria for speaking engagements from Merck, Pfizer, and Sanofi-Aventis and has served on advisory boards for these companies and for Roche Pharmaceuticals, all of which manufacture pharmaceutical products for the treatment of diabetes. American Diabetes Association

Objective: This trial compared the efficacy and safety profiles of the insulin analogues detemir and glargine as the basal insulin component of a basal-bolus regimen in patients with type 2 diabetes mellitus (T2DM) who were being treated with oral antidiabetic drugs (OADs) or insulin with or without OADs. Methods: This was a multinational, 52-week, openlabel, parallel-group, noninferiority, treat-to-target trial. Patients with a diagnosis of T2DM for ≥12 months who had been receiving an OAD or insulin, with or without OADs, for >4 months were randomized in a 2:1 ratio to receive detemir or glargine. According to the approved labeling, detemir could be administered once or twice daily, and glargine was administered once daily. Insulin aspart was given at mealtimes. Insulin secretagogues and a-glucosidase inhibitors were discontinued at study entry, and existing OADs were continued. Doses of detemir and glargine were titrated to achieve a prebreakfast (and predinner for detemir administered twice daily) plasma glucose target of ≤6.0 mmol/L. Patients monitored their plasma glucose levels before breakfast and dinner on the 3 days before each of 13 scheduled visits, recorded their insulin doses on 1 of these 3 days, and recorded their 10-point self-monitored plasma glucose (SMPG) at baseline and after 24 and 52 weeks. The primary efficacy end point was glycosylated hemoglobin (HbA1c) at 52 weeks; secondary efficacy end points included changes in fasting plasma glucose (FPG), postprandial plasma glucose, insulin doses, and weight change at 52 weeks. Safety end points included the frequency of hypoglycemia and adverse events (AEs). Results: The intention-to-treat population included 319 patients (58.0% male, 42.0% female; 78.4% white; mean age, 58 years; mean weight, 92.8 kg; mean duration of diabetes, 13.6 years). At study entry, 46.1% of patients were receiving insulin and ≥1 OAD, 35.4 were receiving insulin only, and 18.5% were receiving ≥1 OAD only. At 52 weeks, there was no significant difference between detemir and glargine in terms of mean HbA1c (7.19% and 7.03%, respectively; mean difference, 0.17% [95% CI, -0.07 to 0.40]) or the mean decrease in HbAlc from baseline (-1.52% and -1.68%). The reduction in HbA1c was not significantly affected by whether detemir was administered once or twice daily. There were no significant differences between groups in terms of mean FPG (7.05 and 6.68 mmol/L) or the mean change in FPG from baseline (-2.56 and -2.92 mmol/L; mean difference, 0.36; 95% CI, -0.26 to 0.99). The overall shape of the 10-point SMPG profiles was not significantly different between groups. Mean weight gain at 52 weeks was significantly lower with detemir than with glargine (2.8 vs 3.8 kg; mean difference, -1.04; 95% CI, -2.08 to -0.01; P < 0.05). Doses of basal and prandial insulins at the end of the study were not significantly different between groups. Major hypoglycemic episodes were reported by 4.7% and 5.7% of patients in the respective treatment groups. There was no significant difference in the risk of hypoglycemia between groups. The proportion of patients with AEs and the number of AEs per patient were comparable between groups (185/214 patients [86.4%] reporting 743 AEs and 88/105 patients [83.8%] reporting 377 AEs). Conclusions: when used as indicated as part of a basal-bolus regimen in patients with T2DM who had previously received other insulin and/or OAD regimens, detemir was noninferior to glargine in its effects on overall glycemic control. Both basal insulins were associated with clinically relevant reductions in hyperglycemia. Both were well tolerated, with no significant difference in the frequency of hypoglycemia or AEs.

The risk for developing type 2 diabetes (T2DM) is greater among obese individuals. Following onset of the disease, patients with T2DM become more likely to be afflicted with diabetic micro- and macrovascular complications. Decreasing body weight has been shown to lower glycosylated hemoglobin and improve other metabolic parameters in patients with T2DM. Medications used to lower blood glucose may increase body weight in patients with T2DM and this has been repeatedly shown to be the case for conventional, human insulin formulations. Insulin detemir is a neutral, soluble, long-acting insulin analog in which threonine-30 of the insulin B-chain is deleted, and the C-terminal lysine is acetylated with myristic acid, a C14 fatty acid chain. Insulin detemir binds to albumin, a property that enhances its pharmacokinetic/ pharmacodynamic profile. Results from clinical trials have demonstrated that treatment with insulin detemir is associated with less weight gain than either insulin glargine or neutral protamine Hagedorn insulin. There are many potential reasons for the lower weight gain observed among patients treated with insulin detemir, including lower risk for hypoglycemia and therefore decreased defensive eating due to concern about this adverse event, along with other effects that may be related to the albumin binding of this insulin that may account for lower within-patient variability and consistent action. These might include faster transport across the blood-brain barrier, induction of satiety signaling in the brain, and preferential inhibition of hepatic glucose production versus peripheral glucose uptake. Experiments in diabetic rats have also indicated that insulin detemir increases adiponectin levels, which is associated with both weight loss and decreased eating. Keywords: basal insulin, body mass index, detemir, insulin analog, satiety

Glycemic control using inhaled, dry-powder insulin plus a single injection of long-acting insulin was compared with a conventional regimen in patients with type 2 diabetes, which was previously managed with at least two daily insulin injections. Patients were randomized to 6 months' treatment with either premeal inhaled insulin plus a bedtime dose of Ultralente (n = 149) or at least two daily injections of subcutaneous insulin (mixed regular/NPH insulin; n = 150). The primary efficacy end point was the change in HbA1c from baseline to the end of study. HbA1c decreased similarly in the inhaled (-0.7%) and subcutaneous (-0.6%) insulin groups (adjusted treatment group difference: -0.07%, 95% CI -0.32 to 0.17). HbA1c < 7.0% was achieved in more patients receiving inhaled (46.9%) than subcutaneous (31.7%) insulin (odds ratio 2.27, 95% CI 1.24-4.14). Overall hypoglycemia (events per subject-month) was slightly lower in the inhaled (1.4 events) than in the subcutaneous (1.6 events) insulin group (risk ratio 0.89, 95% CI 0.82-0.97), with no difference in severe events. Other adverse events, with the exception of increased cough in the inhaled insulin group, were similar. No difference in pulmonary function testing was seen. Further studies are underway to assess tolerability in the longer term. Insulin antibody binding increased more in the inhaled insulin group. Treatment satisfaction was greater in the inhaled insulin group. Inhaled insulin appears to be effective, well tolerated, and well accepted in patients with type 2 diabetes and provides glycemic control comparable to a conventional subcutaneous regimen.

OBJECTIVE: To examine the efficacy and safety of rimonabant, a selective cannabinoid receptor type-1 antagonist, in patients with type 2 diabetes receiving insulin monotherapy. RESEARCH DESIGN AND METHODS: Patients (n = 368; A1C ≥7%) were randomized to 20 mg/day rimonabant or placebo in this 48-week, double-blind, placebo-controlled multicenter trial. Change in baseline A1C to week 48 (primary outcome) and changes in body weight, waist circumference, and lipid levels (secondary outcomes) were assessed. RESULTS: Rimonabant significantly reduced baseline A1C versus placebo (-0.89 vs. -0.24%; P < 0.0001), and significantly greater improvements were observed in cardiometabolic risk factors. More rimonabant patients achieved >10% reduction in mean total daily insulin dose versus placebo (P = 0.0012), and fewer required rescue medication (P < 0.0001). Hypoglycemia, nausea, dizziness, anxiety, and depression were more frequent with rimonabant. CONCLUSIONS: Rimonabant improved glycemic control and cardiometabolic risk factors in patients with type 2 diabetes receiving insulin.

Mealtime amylin replacement with the human amylin analog pramlintide, as an adjunct to mealtime insulin replacement, reduces postprandial glucose excursions in patients with type 2 diabetes. The aim of the present study was to assess the long-term efficacy and safety of pramlintide in this patient population. In a 52-week, double-blind, placebo-controlled, parallel-group, multicenter study, 656 patients with type 2 diabetes (age 57 +/- 10 years, diabetes duration 12 +/- 7 years, BMI 34.0 +/- 7.0 kg/m(2), HbA(1c) 9.1 +/- 1.2%, mean +/- SD) treated with insulin (alone or in combination with sulfonylureas and/or metformin) were randomized to receive additional preprandial subcutaneous injections of either placebo or pramlintide (60 micro g TID, 90 microg BID, or 120 microg BID). Treatment with pramlintide 120 micro g BID led to a sustained reduction from baseline in HbA(1c) (-0.68 and -0.62% at weeks 26 and 52, respectively), which was significantly greater than that seen with placebo (P < 0.05). The proportion of patients achieving an HbA(1c) <8% was approximately twofold greater with pramlintide (120 microg BID) than with placebo (46 vs. 28%, P < 0.05). The glycemic improvement with pramlintide 120 micro g BID was accompanied by a mean weight loss (-1.4 kg vs. +0.7 kg with placebo at week 52, P < 0.05) and occurred without an overall increase in the severe hypoglycemia event rate. The most common adverse event associated with pramlintide use was transient, mild-to-moderate nausea. Mealtime amylin replacement with pramlintide 120 microg BID, as an adjunct to insulin therapy, improves long-term glycemic and weight control in patients with type 2 diabetes.

Type 2 diabetes mellitus (T2DM) can substantially decrease quality of life (QOL). This study examined the effects on QOL-relevant psychosocial measures of a widely available commercial weight loss program enhanced for individuals with T2DM. A year-long multi-site randomized clinical trial compared the Weight Watchers (WW) approach, supplemented with phone and email counseling with a certified diabetes educator (CDE), to brief standard diabetes nutrition counseling and education (Standard Care; SC). Participants were 400 women and 163 men (N=279 WW; 284 SC) with T2DM [mean (±SD) HbA1c 8.32±1%; BMI=37.1±5.7kg/m2; age=55.1 ± 9.1years]. Psychosocial outcomes were assessed at baseline, month 6, and month 12 using a diabetes specific psychosocial measure (Diabetes Distress Scale [DDS]), Impact of Weight on Quality of Life-Lite scale (IWQOL), a generic QOL measure (SF-36), and a depression screen (PHQ-9). WW participants showed significantly greater improvements than did SC participants on all DDS subscales and total score and on IWQOL total score and physical function, sex life and work domains (all ps<.05). There was no significant treatment effect on SF-36 scores or PHQ-9. WW enhanced for individuals with T2DM was superior to SC in improving psychosocial outcomes most specific to T2DM and obesity. Available commercial WL programs, combined with scalable complementary program-specific diabetes counseling, may have benefits that extend to diabetes-related distress and weight-relevant QOL.

Effect of Orlistat in Overweight and Obese Patients With Type 2 Diabetes Treated With Metformin John M. Miles , MD , Lawrence Leiter , MD , Priscilla Hollander , MD, PHD , Thomas Wadden , PHD , James W. Anderson , MD , Michael Doyle , MD , John Foreyt , PHD , Louis Aronne , MD and Samuel Klein , MD From the Lipid and Diabetes Research Center, St. Lukes Hospital, Kansas City, Missouri Abstract OBJECTIVE —The purpose of this study was to assess the effect of orlistat, a gastrointestinal lipase inhibitor, on body weight, glycemic control, and cardiovascular risk factors in metformin-treated type 2 diabetic patients. RESEARCH DESIGN AND METHODS —A 1-year multicenter, randomized, double-blind, placebo-controlled trial of 120 mg orlistat t.i.d. ( n = 249) or placebo ( n = 254) combined with a reduced-calorie diet was conducted in overweight and obese patients with suboptimal control of type 2 diabetes. RESULTS —After 1 year of treatment, mean (±SE) weight loss was greater in the orlistat than in the placebo group (−4.6 ± 0.3% vs. −1.7 ± 0.3% of baseline wt, P < 0.001). Orlistat treatment caused a greater improvement in glycemic control than placebo, as evidenced by a greater reduction in serum HbA 1c , adjusted for changes in metformin and sulfonylurea therapy (−0.90 ± 0.08 vs. −0.61 ± 0.08, P = 0.014); a greater proportion of patients achieving decreases in HbA 1c of ≥0.5 and ≥1.0% (both P < 0.01); and a greater reduction in fasting serum glucose (−2.0 ± 0.2 vs. −0.7 ± 0.2 mmol/l, P = 0.001). Compared with the placebo group, patients treated with orlistat also had greater decreases in total cholesterol, LDL cholesterol, and systolic blood pressure (all P < 0.05). Although more subjects treated with orlistat experienced gastrointestinal side effects than placebo (83 vs. 62%, P < 0.05), more subjects in the placebo group withdrew prematurely from the study than in the orlistat group (44 vs. 35%, P < 0.05). CONCLUSIONS —Orlistat is a useful adjunctive treatment for producing weight loss and improving glycemic control, serum lipid levels, and blood pressure in obese patients with type 2 diabetes who are being treated with metformin. UKPDS, U.K. Prospective Diabetes Study Footnotes Address correspondence and reprint requests to John M. Miles, MD, Division of Endocrinology and Metabolism, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. E-mail: miles.john{at}mayo.edu . Received for publication 13 August 2001 and accepted in revised form 5 April 2002. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. DIABETES CARE

OBJECTIVE:--This is a randomized, placebo-controlled study of the weight-loss efficacy and safety of a controlled-release (CR) formulation of topiramate in overweight and obese patients with type 2 diabetes treated with diet and exercise alone or in combination with metformin. RESEARCH DESIGN AND METHODS--Patients with type 2 diabetes, BMI >=27 kg/m², A1C >6.5 and <11.0%, treated with diet and exercise alone or in combination with metformin monotherapy were enrolled. Patients were randomized to placebo or topiramate CR titrated up to 175 mg/day. Treatment consisted of a 7-week titration phase followed by a 9-week maintenance phase. RESULTS:--A total of 111 subjects were randomized and analyzed. By the end of week 16, patients in the placebo and topiramate groups lost 2.5 and 6.0 kg, which represented 2.3 and 5.8%, respectively, of their baseline body weight (P < 0.001 vs. placebo). A1C improved from a baseline of 7.4% in the placebo and 7.6% in the topiramate groups to 7.1 and 6.7%, respectively, representing a 0.4 and 0.9% reduction from baseline, respectively (P < 0.001 vs. placebo). Topiramate also significantly reduced blood pressure and urinary albumin excretion. Adverse events were predominantly neuropsychiatric or central and peripheral nervous system related. CONCLUSIONS:--Topiramate CR treatment produced significant weight loss and meaningful improvements in A1C and blood pressure in obese patients with type 2 diabetes treated with diet and exercise or in combination with metformin. However, the central nervous system and psychiatric adverse event profile of topiramate CR makes it unsuitable for the treatment of obesity and diabetes.