SummaryBackground Rimonabant, a selective cannabinoid type 1 receptor blocker, reduces bodyweight and improves cardiovascular and metabolic risk factors in non-diabetic overweight or obese patients. The aim of the RIODiabetes trial was to assess the efficacy and safety of rimonabant in overweight or obese patients with type 2 diabetes that was inadequately controlled by metformin or sulphonylureas. Methods 1047 overweight or obese type 2 diabetes patients (body-mass index 27-40 kg/m 2 ) with a haemoglobin A 1c (HbA 1c ) concentration of 6•5-10•0% (mean 7•3% [SD 0•9] at baseline) already on metformin or sulphonylurea monotherapy were given a mild hypocaloric diet and advice for increased physical activity, and randomly assigned placebo (n=348), 5 mg/day rimonabant (360) or 20 mg/day rimonabant (339) for 1 year. Two individuals in the 5 mg/day group did not receive double-blind treatment and were thus not included in the final analysis. The primary endpoint was weight change from baseline after 1 year of treatment. Analyses were done on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov, number NCT00029848. Findings 692 patients completed the 1 year follow-up; numbers in each group after 1 year were much the same. Rimonabant was generally well tolerated. The incidence of adverse events that led to discontinuation was slightly greater in the 20 mg/day rimonabant group, mainly due to depressed mood disorders, nausea, and dizziness. Interpretation These data indicate that 20 mg/day rimonabant, in combination with diet and exercise, can produce a clinically meaningful reduction in bodyweight and improve HbA 1c and a number of cardiovascular and metabolic risk factors in overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas.

Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.

OBJECTIVE—Safety and efficacy of biphasic insulin aspart 70/30 (BIAsp 70/30, prebreakfast and presupper) were compared with once-daily insulin glargine in type 2 diabetic subjects inadequately controlled on oral antidiabetic drugs (OADs). RESEARCH DESIGN AND METHODS—This 28-week parallel-group study randomized 233 insulin-naive patients with HbA1c values ≥8.0% on >1,000 mg/day metformin alone or in combination with other OADs. Metformin was adjusted up to 2,550 mg/day before insulin therapy was initiated with 5–6 units BIAsp 70/30 twice daily or 10–12 units glargine at bedtime and titrated to target blood glucose (80–110 mg/dl) by algorithm-directed titration. RESULTS—A total of 209 subjects completed the study. At study end, the mean HbA1c value was lower in the BIAsp 70/30 group than in the glargine group (6.91 ± 1.17 vs. 7.41 ± 1.24%, P < 0.01). The HbA1c reduction was greater in the BIAsp 70/30 group than in the glargine group (−2.79 ± 0.11 vs. −2.36 ± 0.11%, respectively; P < 0.01), especially for subjects with baseline HbA1c >8.5% (−3.13 ± 1.63 vs. −2.60 ± 1.50%, respectively; P < 0.05). More BIAsp 70/30–treated subjects reached target HbA1c values than glargine-treated subjects (HbA1c ≤6.5%: 42 vs. 28%, P < 0.05; HbA1c <7.0%: 66 vs. 40%, P < 0.001). Minor hypoglycemia (episodes/year) was greater in the BIAsp 70/30 group than in the glargine group (3.4 ± 6.6 and 0.7 ± 2.0, respectively; P < 0.05). Weight gain and daily insulin dose at study end were greater for BIAsp 70/30–treated subjects than for glargine-treated subjects (weight gain: 5.4 ± 4.8 vs. 3.5 ± 4.5 kg, P < 0.01; insulin dose: 78.5 ± 39.5 and 51.3 ± 26.7 units/day, respectively). CONCLUSIONS—In subjects with type 2 diabetes poorly controlled on OADs, initiating insulin therapy with twice-daily BIAsp 70/30 was more effective in achieving HbA1c targets than once-daily glargine, especially in subjects with HbA1c >8.5%.

OBJECTIVETo assess the efficacy and safety of 32 mg naltrexone sustained-release (SR)/360 mg bupropion SR (NB) in overweight/obese individuals with type 2 diabetes with or without background oral antidiabetes drugs.RESEARCH DESIGN AND METHODSThis was a 56-week, double-blind, placebo-controlled study in which 505 patients received standardized lifestyle intervention and were randomized 2:1 to NB or placebo. Coprimary end points were percent weight change and achievement of ≥5% weight loss. Secondary end points included achievement of HbA1c <7% (53 mmol/mol), achievement of weight loss ≥10%, and change in HbA1c, waist circumference, fasting blood glucose, and lipids.RESULTSIn the modified intent-to-treat population (54% female, 80% Caucasian, and mean age 54 years, weight 106 kg, BMI 37 kg/m2, and HbA1c 8.0% [64 mmol/mol]), NB resulted in significantly greater weight reduction (−5.0 vs. −1.8%; P < 0.001) and proportion of patients achieving ≥5% weight loss (44.5 vs. 18.9%, P < 0.001) compared with placebo. NB also resulted in significantly greater HbA1c reduction (−0.6 vs. −0.1% [6.6 vs. 1.1 mmol/mol]; P < 0.001), percent of patients achieving HbA1c <7% (53 mmol/mol) (44.1 vs. 26.3%; P < 0.001), and improvement in triglycerides and HDL cholesterol compared with placebo. NB was associated with higher incidence of nausea (42.3 vs. 7.1%), constipation (17.7 vs. 7.1%), and vomiting (18.3 vs. 3.6%). No difference was observed between groups in the incidence of depression, suicidal ideation, or hypoglycemia.CONCLUSIONSNB therapy in overweight/obese patients with type 2 diabetes induced weight loss, which was associated with improvements in glycemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes.

Saxagliptin added to TZD provided statistically significant improvements in key parameters of glycemic control vs. TZD monotherapy and was generally well tolerated.

OBJECTIVE -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.RESEARCH DESIGN AND METHODS -In a 52-week, double-blind, placebocontrolled, parallel-group, multicenter study, 656 patients with type 2 diabetes (age 57 Ϯ 10 years, diabetes duration 12 Ϯ 7 years, BMI 34.0 Ϯ 7.0 kg/m 2 , HbA 1c 9.1 Ϯ 1.2%, mean Ϯ 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 g TID, 90 g BID, or 120 g BID).RESULTS -Treatment with pramlintide 120 g BID led to a sustained reduction from baseline in HbA 1c (Ϫ0.68 and Ϫ0.62% at weeks 26 and 52, respectively), which was significantly greater than that seen with placebo (P Ͻ 0.05). The proportion of patients achieving an HbA 1c Ͻ8% was approximately twofold greater with pramlintide (120 g BID) than with placebo (46 vs. 28%, P Ͻ 0.05). The glycemic improvement with pramlintide 120 g BID was accompanied by a mean weight loss (Ϫ1.4 kg vs. ϩ0.7 kg with placebo at week 52, P Ͻ 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.CONCLUSIONS -Mealtime amylin replacement with pramlintide 120 g BID, as an adjunct to insulin therapy, improves long-term glycemic and weight control in patients with type 2 diabetes. Diabetes Care 26:784 -790, 2003

Objective:This study investigated the efficacy and safety of insulin degludec (IDeg) once daily (OD), varying injection timing day to day in subjects with type 1 diabetes.Research Design and Methods:This 26-week, open-label, treat-to-target, noninferiority trial compared IDeg forced flexible (Forced-Flex) OD (given in a fixed schedule with a minimum 8 and maximum 40 hours between doses) with IDeg or insulin glargine (IGlar) given at the same time daily OD. In the 26-week extension, all IDeg subjects were transferred to a free-flexible (Free-Flex) regimen, which allowed any-time-of-day dosing, and compared with subjects continued on IGlar.Results:After 26 treatment weeks, mean glycosylated hemoglobin was reduced with IDeg Forced- Flex (−0.40%), IDeg (−0.41%), and IGlar (−0.58%). IDeg Forced-Flex noninferiority was achieved. Fasting plasma glucose reductions were similar with IDeg Forced-Flex and IGlar but greater with IDeg (−2.54 mmol/L) than IDeg Forced-Flex (−1.28 mmol/L) (P = .021). At week 52, IDeg Free-Flex subjects had similar glycosylated hemoglobin but greater fasting plasma glucose reductions than IGlar subjects (−1.07 mmol/L) (P = .005). Confirmed hypoglycemia rates (plasma glucose <3.1 mmol/L or severe hypoglycemia) were similar at weeks 26 and 52. Nocturnal confirmed hypoglycemia was lower with IDeg Forced-Flex vs IDeg (37%; P = .003) and IGlar (40%; P = .001) at week 26 and 25% lower with IDeg Free-Flex vs IGlar (P = .026) at week 52.Conclusions:IDeg can be administered OD at any time of day, with injection timing varied without compromising glycemic control or safety vs same-time-daily IDeg or IGlar. This may improve basal insulin adherence by allowing injection-time adjustment according to individual needs.

OBJECTIVE -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.RESEARCH DESIGN AND METHODS -Patients were randomized to 6 months' treatment with either premeal inhaled insulin plus a bedtime dose of Ultralente (n ϭ 149) or at least two daily injections of subcutaneous insulin (mixed regular/NPH insulin; n ϭ 150). The primary efficacy end point was the change in HbA 1c from baseline to the end of study.RESULTS -HbA 1c decreased similarly in the inhaled (Ϫ0.7%) and subcutaneous (Ϫ0.6%) insulin groups (adjusted treatment group difference: Ϫ0.07%, 95% CI Ϫ0.32 to 0.17). HbA 1c Ͻ7.0% 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.CONCLUSIONS -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.