Effect of metformin and insulin vs. placebo and insulin on whole body composition in overweight patients with type 2 diabetes: a randomized placebo-controlled trial.

Some studies indicate potential beneficial effects of metformin on body composition and bone. This trial compared metformin + insulin vs placebo + insulin. Metformin treatment had a small but positive effect on bone quality in the peripheral skeleton, reduced weight gain, and resulted in a more beneficial body composition compared with placebo in insulin-treated patients with type 2 diabetes. INTRODUCTION: Glucose-lowering medications affect body composition. We assessed the long-term effects of metformin compared with placebo on whole body bone and body composition measures in patients with type 2 diabetes mellitus. METHODS: This was a sub-study of the Copenhagen Insulin and Metformin Therapy trial, which was a double-blinded randomized placebo-controlled trial assessing 18-month treatment with metformin compared with placebo, in combination with different insulin regimens in patients with type 2 diabetes mellitus (T2DM). The sub-study evaluates the effects on bone mineral content (BMC), density (BMD), and body composition from whole body dual-energy X-ray absorptiometry (DXA) scans which were assessed at baseline and after 18 months. RESULTS: Metformin had a small, but positive, (p < 0.05) effect on subtotal, appendicular, and legs BMC and BMD compared with placebo. After adjustment for sex, age, vitamin D, smoking, BMI, T2DM duration, HbA1c, and insulin dose, the effects on appendicular BMC and BMD persisted (p < 0.05 for both). The changes in appendicular BMC and BMD corresponded approximately to a 0.7% and 0.5% increase in the metformin group and 0.4% and 0.4% decrease in the placebo group, respectively. These effects were mostly driven by an increase in BMC and BMD in the legs and a loss of BMC and BMD in the arms. During 18 months, all participants increased in weight, fat mass (FM), FM%, and lean mass (LM), but decreased in LM%. The metformin group increased less in weight (subtotal weight (weight-head) - 2.4 [- 3.5, - 1.4] kg, p value < 0.001) and FM (- 1.5 [- 2.3, - 0.8] kg, p value < 0.001) and decreased less in LM% (0.6 [0.2, 1.1] %, p value < 0.001) compared with the placebo group. CONCLUSION: Metformin treatment had a small positive effect on BMC and BMD in the peripheral skeleton and reduced weight gain compared with placebo in insulin-treated patients with T2DM.

The effect of metformin versus placebo in combination with insulin analogues on bone mineral density and trabecular bone score in patients with type 2 diabetes mellitus: a randomized placebo-controlled trial.

Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS) in patients with type 2 diabetes. Metformin had no significant effect on BMD in the spine and hip or TBS compared with a placebo. INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures despite a high bone mass. Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS). METHODS: This was a sub-study of a multicenter, randomized, 18-month placebo-controlled, double-blinded trial with metformin vs. placebo in combination with different insulin regimens (the Copenhagen Insulin and Metformin Therapy trial) in patients with T2DM. BMD in the spine and hip and TBS in the spine were assessed by dual-energy X-ray absorptiometry at baseline and after 18 months follow-up. RESULTS: Four hundred seven patients were included in this sub-study. There were no between-group differences in BMD or TBS. From baseline to 18 months, TBS decreased significantly in both groups (metformin group, - 0.041 [- 0.055, - 0.027]; placebo group - 0.046 [- 0.058, - 0.034]; both p < 0.001). BMD in the spine and total hip did not change significantly from baseline to 18 months. After adjustments for gender, age, vitamin D, smoking, BMI, duration of T2DM, HbA1c, and insulin dose, the TBS between-group differences increased but remained non-significant. HbA1c was negatively associated with TBS (p = 0.009) as was longer duration of diabetes, with the femoral neck BMD (p = 0.003). Body mass index had a positive effect on the hip and femoral neck BMD (p < 0.001, p = 0.045, respectively). CONCLUSIONS: Eighteen months of treatment with metformin had no significant effect on BMD in the spine and hip or TBS in patients with T2DM compared with a placebo. TBS decreased significantly in both groups. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00657943).

Comparing effects of insulin analogues and human insulin on nocturnal glycaemia in hypoglycaemia-prone people with Type 1 diabetes.

AIMS: To assess the difference between analogue and human insulin with regard to nocturnal glucose profiles and risk of hypoglycaemia in people with recurrent severe hypoglycaemia. METHODS: A total of 72 people [46 men, mean ± sd age 54 ± 12 years, mean ± sd HbA1c 65 ± 12 mmol/mol (8.1 ± 1.1%), mean ± sd duration of diabetes 30 ± 14 years], who participated in a 2-year randomized, crossover trial of basal-bolus therapy with insulin detemir/insulin aspart or human NPH insulin/human regular insulin (the HypoAna trial) were studied for 2 nights during each treatment. Venous blood was drawn hourly during sleep. Primary endpoints were nocturnal glucose profiles and occurrence of hypoglycaemia (blood glucose ≤ 3.9 mmol/l). RESULTS: During insulin analogue treatment, the mean nocturnal plasma glucose level was significantly higher than during treatment with human insulin (10.6 vs 8.1 mmol/l). The fasting plasma glucose level was similar between the treatments. Nocturnal hypoglycaemia was registered during 41/101 nights (41%) in the human insulin arm and 19/117 nights (16%) in the insulin analogue arm, corresponding to a hazard ratio of 0.26 (95% CI 0.14 to 0.45; P < 0.0001) with insulin analogue. CONCLUSIONS: Treatment with insulin analogue reduces the occurrence of nocturnal hypoglycaemia assessed by nocturnal glucose profiles in people with Type 1 diabetes prone to severe hypoglycaemia. Nocturnal glucose profiles provide a more comprehensive assessment of clinical benefit of insulin regimens as compared to conventional recording of hypoglycaemia.

Study rationale and design of the CIMT trial: the Copenhagen Insulin and Metformin Therapy trial.

BACKGROUND: Patients with type 2 diabetes (T2DM) have an increased mortality rate primarily because of macrovascular disease. Where T2DM patients cannot be managed sufficiently through diet, exercise and peroral antidiabetic drugs, that is when haemoglobin A1c (HbA1c) is above 7.0%, it is yet unknown whether a combination of metformin and insulin analogues is superior to insulin analogues alone. Nor is it known which insulin analogue regimen is the optimal. OBJECTIVE: The primary objective of this trial is to evaluate the effect of an 18-month treatment with metformin vs. placebo in combination with one of three insulin analogue regimens, the primary outcome measure being carotid intima-media thickness (CIMT) in T2DM patients. DESIGN: A randomized, stratified, multicentre trial having a 2 x 3 factorial design. The metformin part is double masked and placebo controlled. The insulin treatment is open. The intervention period is 18 months. PATIENT POPULATION: Nine hundred and fifty patients with T2DM and HbA1c > or = 7.5% on treatment with oral hypoglycaemic agents or on insulin treatment and deemed able, by the investigator, to manage once-daily insulin therapy with a long-acting insulin analogue. RANDOMIZATION: Central randomization stratified for age (above 65 years), previous insulin treatment and treatment centre. INTERVENTIONS: Metformin 1 g x two times daily vs. placebo (approximately 475 patients vs. 475 patients) in combination with insulin detemir before bedtime (approximately 315 patients) or biphasic insulin aspart 30 before dinner with the possibility to increase to two or three injections daily (approximately 315 patients) or insulin aspart before the main meals (three times daily) and insulin detemir before bedtime (approximately 315 patients). Intervention follows a treat-to-target principle in all six arms aiming for an HbA1c < or = 7.0%. OUTCOME MEASURES: Primary outcome measure is the change in CIMT from baseline to 18 months. Secondary outcome measures comprises the composite outcome of death, acute myocardial infarction, stroke or amputation assessed by an adjudication committee blinded to intervention, other cardiovascular clinical outcomes, average postprandial glucose increment from 0 to 18 months, hypoglycaemia and any inadvertent medical episodes. In addition, change in plaque formation in the carotids, HbA1c, cardiovascular biomarkers, body composition, progression of microvascular complications and quality of life will be assessed as tertiary outcome measures. TIME SCHEDULE: Patient enrolment started May 2008. Follow-up is expected to finish in March 2011. CONCLUSION: CIMT is designed to provide evidence as to whether metformin is advantageous even during insulin treatment and to provide evidence regarding which insulin analogue regimen is most advantageous with regard to cardiovascular disease.

Reduced parietooccipital white matter glutamine measured by proton magnetic resonance spectroscopy in treated graves' disease patients.

CONTEXT: Graves' disease is an autoimmune disease of the thyroid gland. Patients often have affective and cognitive complaints, whether these disappear after treatment remains disputed. OBJECTIVE: Our objective was to evaluate cerebral biochemistry in acute and treated Graves' disease. DESIGN: We conducted a prospective study, investigating volunteers once and patients before and 1 yr after treatment. SETTING: The study was performed at a radiology department, a memory disorder clinic, and two endocrinology clinics. PATIENTS AND OTHER PARTICIPANTS: Of 53 consecutively referred, newly diagnosed, and untreated patients with Graves' thyrotoxicosis, 27 patients (34 +/- 8 yr) and 33 matched volunteers were included. INTERVENTIONS: Patients were treated with thionamide. MAIN OUTCOME MEASURES: We assessed brain metabolite concentrations. METHODS: Proton magnetic resonance spectroscopy of the brain and a battery of biochemical, affective, and cognitive tests were used. RESULTS: Previously reported findings of reduced choline and myo-inositol in acute Graves' disease were confirmed and reversibility was demonstrated. Parieto-occipital white matter glutamine was and remained significantly reduced (P < 0.01). Acute phase parieto-occipital white matter total choline correlated significantly (r = -0.57; P < 0.01) with impaired thyroid function. Pretreatment total T(3) predicted posttreatment occipital gray matter glutamine (r = -0.52; P < 0.01). Occipital gray matter total choline (r = -0.53; P < 0.01) and parietooccipital white matter glutamate (r = -0.54; P < 0.01) correlated with initial values of selected attention and concentration cognitive scores and predicted them at follow-up. CONCLUSIONS: The persistent reduction of glutamine in white matter, the decreasing glutamate in occipital gray matter, and the correlation with severity of the initial disease as well as with attention and concentration cognitive scores indicated that there was a persistent and possibly progressive disturbance of the glutamate glutamine cycling in Graves' disease.

Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic B-cell function and arginine-stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus.

AIMS: To assess the effect of liraglutide, a once-daily human glucagon-like peptide-1 analogue on pancreatic B-cell function. methods: Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First- and second-phase insulin release were measured by means of the insulin-modified frequently sampled intravenous glucose tolerance test. Arginine-stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin-modified frequently sampled intravenous glucose tolerance test. RESULTS: The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first-phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second-phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine-stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity. CONCLUSIONS: Fourteen weeks of treatment with liraglutide showed improvements in first- and second-phase insulin secretion, together with improvements in arginine-stimulated insulin secretion during hyperglycaemia.

Effect of insulin analogues on frequency of non-severe hypoglycaemia in patients with type 1 diabetes prone to severe hypoglycaemia: The HypoAna trial.

AIM: Insulin analogues reduce the risk of hypoglycaemia compared with human insulin in patients with type 1 diabetes (T1D) and minor hypoglycaemia problems. The HypoAna trial showed that, in patients with recurrent severe hypoglycaemia, treatment based on insulin analogues reduces the risk of severe hypoglycaemia. The present study aims to assess whether this also applies to non-severe hypoglycaemia events during the day and at night. METHODS: This 2-year investigator-initiated multicentre, prospective, randomized, open, blinded endpoint (PROBE) trial involved patients with T1D and at least two episodes of severe hypoglycaemia during the previous year. Using a balanced crossover design, patients were randomized to basal-bolus therapy based on analogue (detemir/aspart) or human (NPH/regular) insulins. A total of 114 participants were included. Endpoints were the number of severe hypoglycaemic events and non-severe events, including documented symptomatic and asymptomatic episodes occurring during the day and at night (ClinicalTrials.gov number: NCT00346996). RESULTS: Analogue-based treatment resulted in a 6% (2-10%; P=0.0025) overall relative risk reduction of non-severe hypoglycaemia. This was due to a 39% (32-46%; P<0.0001) reduction of non-severe nocturnal hypoglycaemia, seen for both symptomatic (48% [36-57%]; P<0.0001) and asymptomatic (28% [14-39%]; P=0.0004) nocturnal hypoglycaemia episodes. No clinically significant differences in hypoglycaemia occurrence were observed between the insulin regimens during the day. The time needed to treat one patient with insulin analogues to avoid one episode (TNT1) of non-severe nocturnal hypoglycaemia was approximately 3 months. CONCLUSION: In T1D patients prone to severe hypoglycaemia, treatment with analogue insulin reduced the risk of non-severe nocturnal hypoglycaemia compared with human insulin.

Sildenafil in the treatment of erectile dysfunction in men with diabetes: demand, efficacy and patient satisfaction.

The objective of this study is to describe the eligibility, consumption, efficacy and patient satisfaction when treating men with diabetes with Sildenafil. The study is a prospective, self-reported, flexible-dose study. In total, 45 patients with diabetes (type 1 or 2), complaining of erectile dysfunction, were treated with Sildenafil over a 12-week period. Efficacy was assessed using a patientlog, a general satisfaction questionnaire and the International Index of Erectile Function (IIEF). Of 326 men, 192 reported erectile dysfunction, 79 did not fulfil the criteria for Sildenafil treatment and 49 declined to participate. In the group of 33 (age 45-75 y, mean+/-s.d.: 58.1+/-7.2) completing the study, erectile function was significantly improved (P < 0.0001). A total of 12 patients (36.4%) experienced no treatment effect at all. Eligibility and desire for treatment was low. Sildenafil is far from being a 'cure all' in the treatment of ED in diabetes.

Comparison of the soluble basal insulin analog insulin detemir with NPH insulin: a randomized open crossover trial in type 1 diabetic subjects on basal-bolus therapy.

OBJECTIVE: Insulin detemir (NN304) is a soluble basal insulin analog developed to cover basal insulin requirements. This trial aimed to compare the blood glucose-lowering effect of insulin detemir with that of NPH insulin (NPH) and to evaluate the two treatments with regard to intrasubject variation of fasting blood glucose, incidence of hypoglycemia, dose requirements, and safety. RESEARCH DESIGN AND METHODS: This multicenter open randomized crossover trial in 59 type 1 diabetic subjects comprised a 2-week run-in period on a basal-bolus regimen with NPH insulin once daily, followed by two 6-week periods of optimized basal-bolus therapy with either once-daily insulin detemir or NPH insulin. RESULTS: The area under the curve, in the time interval 23:00-8:00, derived from 24-h serum glucose profiles, was not statistically significantly different for the two treatment periods (insulin detemir:NPH ratio 89.2:83.5, P = 0.59). The intrasubject variation in fasting blood glucose during the last 4 days of treatment was lower for insulin detemir compared with NPH (P < 0.001). Mean dose requirements of insulin detemir were 2.35 times higher (95% CI 2.22-2.48) compared with NPH. During the last week of treatment, fewer subjects experienced hypoglycemic episodes on insulin detemir (60%) compared with NPH treatment (77%) (P = 0.049). CONCLUSIONS: Insulin detemir was as effective as NPH in maintaining glycemic control when administered at a higher molar dose. The results indicate that insulin detemir may provide more predictable fasting blood glucose with lower intrasubject variation and reduced risk of hypoglycemia compared with NPH.