Comparison of fixed-dose rosiglitazone/metformin combination therapy with sulphonylurea plus metformin in overweight individuals with Type 2 diabetes inadequately controlled on metformin alone.

AIM: This 52-week, randomized, double-blind, parallel-group study was designed to compare rosiglitazone/metformin fixed-dose combination therapy with combination sulphonylurea plus metformin therapy in overweight individuals with inadequately controlled type 2 diabetes mellitus. METHOD: Individuals with inadequate glycaemic control (HbA (1c)> or =7%) while on metformin monotherapy (> or =0.85 g/day) entered a 4-week run-in period during which they received metformin 2 g/day. At the end of the run-in, individuals with fasting plasma glucose > or =7.0 mmol/l were randomized to treatment with metformin (2 g/day) and either rosiglitazone (4 mg/day; RSG+MET [N=294]) or a sulphonylurea (glibenclamide 5 mg/day or gliclazide 80 mg/day; SU+MET [N=302]). Medications were up-titrated to maximum tolerated doses (rosiglitazone 8 mg, glibenclamide 15 mg or gliclazide 320 mg plus metformin 2 g/day) during the first 12 weeks of double-blind treatment. The primary efficacy end point was the change in HbA (1c) from baseline after 52 weeks of treatment. RESULTS: RSG+MET was non-inferior to SU+MET with respect to changes in HbA (1c) after one year of treatment (DeltaHbA (1c)= -0.78% and -0.86%, respectively; treatment difference =0.09%, 95% CI=-0.08, 0.25). The HbA (1c) reductions with RSG+MET, but not SU+MET, were accompanied by significant improvements in measures of beta-cell function including proinsulin:insulin ratio. The degree of beta-cell failure was significantly greater with SU+MET compared to RSG+MET as measured by the coefficient of failure (0.543 vs. 0.055 HbA (1c)%/year, respectively, p=0.0002). The proportion of individuals who experienced hypoglycaemic events was significantly (p<0.0001) lower with RSG+MET (6%) than with SU+MET (30%). Diastolic ambulatory blood pressure and cardiovascular biomarkers (high-sensitivity C-reactive protein and plasminogen activator inhibitor-1) were also reduced following one year of treatment with RSG+MET but not SU+MET. Both treatments were generally well tolerated. CONCLUSION: Fixed-dose combination therapy with rosiglitazone/metformin is non-inferior to sulphonylurea plus metformin combination therapy in reducing HbA (1c) over one year of treatment. Improvements in measures of beta-cell function suggest that the improvements in glycaemic control may be better maintained in long-term therapy with the rosiglitazone/metformin combination.     

Efficacy and safety of acarbose add-on therapy in the treatment of overweight patients with Type 2 diabetes inadequately controlled with metformin: a double-blind, placebo-controlled study

This 6-month, double-blind, placebo-controlled, randomised, parallel-group study investigated the potential of acarbose add-on therapy for improving the glycaemic control of overweight patients with Type 2 diabetes and was inadequately controlled with metformin monotherapy. Patients were randomised to receive acarbose titrated up to 100 mg three times daily (n=74) or placebo (n=78). All patients were receiving metformin 850 mg twice or thrice daily before the study and continued to receive this dose throughout the study. The mean difference in glycated haemoglobin (HbA(1c)) (+/-S.D.) from baseline to endpoint was -0.7+/-1.2% U in the acarbose intention-to-treat (ITT) group, compared with +0.2+/-1.3% in the placebo ITT group (P=0.0001). Significantly, more patients in the acarbose group were classified as 'responders', with an HbA(1c) at the end of treatment of less than 7.0% or a decrease by at least 15% relative to baseline (acarbose vs. placebo; 42 vs. 17%; P=0.002). The difference in fasting blood glucose level from baseline to endpoint was -1.0+/-2.8 (S.D.) mmol/l in the acarbose ITT group, compared with +1.3+/-2.8 mmol/l in the placebo ITT group (P=0.0001), and for 2-h postprandial blood glucose level -1.4+/-3.8 vs. +1.1+/-3.5 mmol/l (P=0.0001). In all, 60% of patients in the acarbose group and 33% in the placebo group had an adverse event considered to be possibly or probably related to drug therapy, leading to withdrawal by 15 and 3%, respectively. The results indicate that acarbose has potential clinical utility for improving glycaemic control in overweight patients with Type 2 diabetes inadequately controlled with metformin.     

Metformin-glibenclamide versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy

AIM: This double-blind study evaluated the efficacy and safety of metformin-glibenclamide tablets vs. metformin plus rosiglitazone therapy in patients with type 2 diabetes inadequately controlled on metformin monotherapy. SUBJECTS AND METHODS: After an open-label, metformin lead-in phase, 318 patients were randomly assigned to treatment based on metformin-glibenclamide 500/2.5 mg tablets (initial daily dose 1000/5 mg) or metformin 500 mg plus rosiglitazone 4 mg (initial daily dose 1000-2000 mg + 4 mg, depending on previous treatment) for 24 weeks. Doses were titrated to achieve the therapeutic glycaemic target. The primary efficacy variable was the change in HbA1C. RESULTS: At week 24, metformin-glibenclamide tablets resulted in significantly greater reductions in HbA1C (-1.5%) and fasting plasma glucose [-2.6 mmol/l (-46 mg/dl)] than metformin plus rosiglitazone [-1.1%, p < 0.001; -2 mmol/l (-36 mg/dl), p = 0.03]. More patients receiving metformin-glibenclamide attained HbA1C <7.0% than did those in the metformin plus rosiglitazone group (60 vs. 47%) and had fasting plasma glucose levels <7 mmol/l (<126 mg/dl) by week 24 (34 vs. 25%). Both treatments were well tolerated. Frequency of adverse gastrointestinal events was comparable between groups. Four per cent of patients receiving metformin-glibenclamide withdrew because of symptomatic hypoglycaemia contrasted with 3% of patients receiving metformin plus rosiglitazone who withdrew because of persistent hyperglycaemia. Hypoglycaemic events were mild or moderate in intensity and were easily self-managed. CONCLUSIONS: Metformin-glibenclamide tablets resulted in significantly greater reductions in HbA1C and fasting plasma glucose compared with metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy.     

Rosiglitazone RECORD study: glucose control outcomes at 18 months.

AIMS: To compare glucose control over 18 months between rosiglitazone oral combination therapy and combination metformin and sulphonylurea in people with Type 2 diabetes. METHODS: RECORD, a multicentre, parallel-group study of cardiovascular outcomes, enrolled people with an HbA(1c) of 7.1-9.0% on maximum doses of metformin or sulphonylurea. If on metformin they were randomized to add-on rosiglitazone or sulphonylurea (open label) and if on sulphonylurea to rosiglitazone or metformin. HbA(1c) was managed to < or = 7.0% by dose titration. A prospectively defined analysis of glycaemic control on the first 1122 participants is reported here, with a primary outcome assessed against a non-inferiority margin for HbA(1c) of 0.4%. RESULTS: At 18 months, HbA(1c) reduction on background metformin was similar with rosiglitazone and sulphonylurea [difference 0.07 (95% CI -0.09, 0.23)%], as was the change when rosiglitazone or metformin was added to sulphonylurea [0.06 (-0.09, 0.20)%]. At 6 months, the effect on HbA(1c) was greater with add-on sulphonylurea, but was similar whether sulphonylurea was added to rosiglitazone or metformin. Differences in fasting plasma glucose were not statistically significant at 18 months [rosiglitazone vs. sulphonylurea -0.36 (-0.74, 0.02) mmol/l, rosiglitazone vs. metformin -0.34 (-0.73, 0.05) mmol/l]. Increased homeostasis model assessment insulin sensitivity and reduced C-reactive protein were greater with rosiglitazone than metformin or sulphonylurea (all P < or = 0.001). Body weight was significantly increased with rosiglitazone compared with sulphonylurea [difference 1.2 (0.4, 2.0) kg, P = 0.003] and metformin [difference 4.3 (3.6, 5.1) kg, P < 0.001]. CONCLUSIONS: In people with diabetes, rosiglitazone in combination with metformin or sulphonylurea was demonstrated to be non-inferior to the standard combination of metformin + sulphonylurea in lowering HbA(1c) over 18 months, and produces greater improvements in C-reactive protein and basal insulin sensitivity but is also associated with greater weight gain.     

The contribution of metformin to glycaemic control in patients with Type 2 diabetes mellitus receiving combination therapy with insulin

Combination therapy of oral hypoglycaemic agents and insulin is a therapeutic option for those who have deterioration in glycaemic control. We examined the contribution of metformin by withdrawing it from Type 2 diabetic patients who had been stabilised on combination therapy. Fifty-one subjects with Type 2 diabetes and secondary oral hypoglycaemic agent failure were studied in a randomised, open and parallel study. In the first phase of 36 weeks, subjects were stabilised on combined therapy of sulphonylureas and nocturnal insulin, with or without metformin. During the second phase, metformin was withdrawn. The primary variables for efficacy were HbA(1c), fasting plasma glucose and 3-point capillary blood glucose profiles. After stabilisation with combination therapy, those subjects on metformin used less insulin to maintain glycaemic control (13.7+/-6.8 vs. 23.0+/-9.4 U/day, P=0.001) and had lower HbA(1c) values (8.13+/-0.89 vs. 9.05+/-1.30%, P=0.003) compared with those not given metformin. Withdrawal of metformin therapy caused deterioration in HbA(1c) (P=0.001). This study confirms that metformin plays an important role in the success of the combination therapy. The rational use of metformin and sulphonylurea together with insulin will help to improve metabolic control in Type 2 diabetes patients who have secondary drug failure.     

Long-term effects of pioglitazone and metformin on insulin sensitivity in patients with Type 2 diabetes mellitus.

AIM: Despite their comparable glycaemic effects in patients with Type 2 diabetes mellitus (T2DM), pioglitazone and metformin may have different effects on insulin sensitivity because they have different mechanisms of action. We studied the changes in insulin sensitivity, as assessed by the Quantitative Insulin Sensitivity Check Index (QUICKI), in patients with T2DM who used metformin or pioglitazone as monotherapy or in combination therapy with sulphonylurea. METHODS: Data in this report are from two multicentre, randomized, double-blind, double-dummy studies conducted in Europe (monotherapy) or in Europe and Canada (combination therapy study). Patients were randomized to 52 weeks of treatment consisting of a 12-week forced titration period and a 40-week maintenance period. HbA(1c), fasting plasma glucose (FPG) and fasting serum insulin (FSI) were quantified from a single blood sample at weeks 0, 8, 16, 24, 32, 42 and 52. Insulin sensitivity was assessed with QUICKI, which is calculated from FSI and fasting blood glucose (FBG) concentrations using the formula 1/(log(10) FSI + log(10) FBG). Time course effects of the treatments were compared by repeated measures analysis of covariance. RESULTS: As monotherapy, pioglitazone and metformin increased QUICKI compared with baseline (baseline vs. end point [mean +/- sem]; pioglitazone [0.303 +/- 0.001 vs. 0.321 +/- 0.001; P < 0.001] and metformin [0.304 +/- 0.001 vs. 0.315 +/- 0.001; P < 0.001]). Pioglitazone increased insulin sensitivity more than metformin from week 4 through week 52. There were significant increases in QUICKI from baseline in both combination therapy groups (baseline vs. end point; pioglitazone + sulphonylurea [0.305 +/- 0.001 vs. 0.319 +/- 0.001; P < 0.001] and metformin + sulphonylurea [0.306 +/- 0.001 vs. 0.317 +/- 0.001; P < 0.001]). Overall, pioglitazone + sulphonylurea significantly increased insulin sensitivity more than metformin + sulphonylurea. CONCLUSION: Pioglitazone differed from metformin in its effects on insulin sensitivity despite both drugs having comparable glycaemic effects.     

Rosiglitazone: safety and efficacy in combination with insulin in poorly controlled type 2 diabetes mellitus patients treated with insulin alone

AIMS: To assess the safety and efficacy of rosiglitazone and insulin treatment in combination in poorly controlled insulin-treated type 2 diabetes mellitus (T2DM) patient. METHOD: In this prospective, open-labelled, nonrandomised study, rosiglitazone was added to the insulin therapy in T2DM patients with baseline HbA1c>or=7.5%. Patients were followed for 12 months. Insulin dosage was adjusted as necessary. RESULTS: Insulin and rosiglitazone combination was used in 53 patients (29 male, 24 female) for 12 months. Baseline vs. 12-month results shown as mean+/-S.D.: HbA1c reduction 1.53% (9.82+/-1.12 vs. 8.29+/-1.45, P=.0001), insulin dosage reduction 10 U (74+/-34 vs. 64+/-34 U), percentage insulin dose reduction 13.53%, and weight gain 1.0 kg only (84+/-19.93 vs. 85+/-25.73 kg, P=.1). Systolic blood pressure 144+/-22.9 vs. 134+/-15.8 mm Hg (P=.03), total cholesterol 6.18+/-4.15 vs. 4.75+/-2.71 micromol/L, triglyceride 2.62+/-1.49 vs. 2.07+/-1.44 micromol/L, and HDL cholesterol 1.43+/-0.71 vs. 1.63+/-0.36 micromol/L (P=.02). Alanine transaminase actually reduced significantly from 26+/-22 to 19+/-9 IU/L (P=.001). Improved glycaemic control was associated with favourable reduction in cardiovascular risk factors. Rosiglitazone was discontinued only in nine patients (weight gain-4, no improvement noticed-4, ankle swelling-1). No hepatotoxicity was observed. CONCLUSION: Rosiglitazone+insulin combination is safe and effective in inadequately controlled insulin-treated T2DM patients.     

Effect of pioglitazone in combination with insulin therapy on glycaemic control, insulin dose requirement and lipid profile in patients with type 2 diabetes previously poorly controlled with combination therapy

AIM: The aim of this randomized placebo-controlled study was to evaluate the safety and efficacy of pioglitazone administered alone or in combination with metformin in reducing insulin dosage requirements for improved glycaemic control in patients with type 2 diabetes previously poorly controlled with combination therapy. METHODS: In this multicentre, double-blind study, 222 patients with haemoglobin A1c (HbA(1c))>8.0% at screening treated with combination therapy initially were given titrated insulin therapy (to fasting plasma glucose <140 mg/dl) and then were randomly assigned to 20-week treatment with pioglitazone or placebo in combination with insulin, with or without concurrent metformin therapy. More than 98% of patients were taking metformin prior to and during the study. RESULTS: Pioglitazone significantly reduced (p < 0.05) insulin dose requirements 2 weeks after treatment initiation. At study end relative to baseline, pioglitazone reduced daily insulin dosages by 12.0 units (p < 0.001), a 21.5% (12.0/55.8 units at baseline) group mean average reduction. Relative to placebo, pioglitazone reduced daily insulin dosages by 12.7 units [95% confidence interval [CI]: -17.5, -8.0], while improving mean HbA(1c) levels [adjusted mean HbA(1c) change: pioglitazone, -1.6% vs. placebo, -1.4% (not statistically different)]. Pioglitazone also significantly increased high-density lipoprotein cholesterol levels [adjusted mean difference: +4.5 (95% CI: 2.6-6.5) mg/dl], decreased triglyceride levels [-43.9 (-69.2, -18.6) mg/dl], shifted low-density lipoprotein (LDL) particle concentrations from small [pattern B, -13.6% (-17.7%, -9.5%)] to large [pattern A, +15.1% (10.8%, 19.5%)] and increased mean LDL particle size [+3.8 (2.6, 4.9) A]. More pioglitazone-treated patients experienced oedema (9.0 vs. 4.5%) and weight gain (9.1 vs. 2.7%) than placebo patients. CONCLUSIONS: Pioglitazone in combination with insulin therapy improved glycaemic control, reduced insulin dose requirements and improved lipid profiles in patients with type 2 diabetes previously poorly controlled with combination therapy.     

Rosiglitazone in Type 2 diabetes mellitus: an evaluation in British Indo-Asian patients.

AIMS: To evaluate the effectiveness of rosiglitazone in reducing hyperglycaemia in patients with Type 2 diabetes mellitus (DM) of Indo-Asian origin taking concurrent sulphonylurea therapy. METHODS: A randomized, double-blind, placebo-controlled study of 26 weeks' duration at 31 primary and secondary care centres in areas of the UK with a high Indo-Asian population, including 177 patients aged 28-78 years. Rosiglitazone 8 mg/day or matching placebo was added to existing sulphonylurea therapy. The primary endpoint was change from baseline in glycosylated haemoglobin A1c (HbA1c) at week 26. RESULTS: The mean changes in HbA1c were -1.16% with rosiglitazone (baseline 9.21%) and +0.26% with placebo (baseline 9.06%) (treatment difference P < 0.001; 95% confidence interval (CI) -1.81, -1.08). HbA1c fell below 8% in 55% and 19% of patients, respectively (treatment difference P < 0.001; 95% CI 0.22, 0.51). The greatest improvements occurred in patients whose glycaemic control was initially poor. Improvements in homeostasis model assessment of insulin sensitivity and pancreatic beta-cell function with rosiglitazone were not accompanied by a change in plasma insulin or C-peptide after 26 weeks. Free fatty acids fell by 0.09 mmol/l with rosiglitazone and increased by 0.03 mmol/l with placebo (treatment difference P < 0.001; 95% CI -0.19, -0.07). CONCLUSION: Rosiglitazone improved insulin sensitivity, pancreatic beta-cell function, and glycaemic control in Indo-Asian patients with Type 2 DM who are at greater risk of the complications of Type 2 DM than other ethnic groups.     

Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes

Objective: To evaluate the efficacy and tolerability of sitagliptin when added to insulin therapy alone or in combination with metformin in patients with type 2 diabetes. Methods: After a 2 week placebo run‐in period, eligible patients inadequately controlled on long‐acting, intermediate‐acting or premixed insulin (HbA1c ≥ 7.5% and ≤ 11%), were randomised 1:1 to the addition of once‐daily sitagliptin 100 mg or matching placebo over a 24‐week study period. The study capped the proportion of randomised patients on insulin plus metformin at 75%. Further, the study capped the proportion of randomised patients on premixed insulin at 25%. The metformin dose and the insulin dose were to remain stable throughout the study. The primary endpoint was HbA1c change from baseline at week 24. Results: Mean baseline characteristics were similar between the sitagliptin (n = 322) and placebo (n = 319) groups, including HbA1c (8.7 vs. 8.6%), diabetes duration (13 vs. 12 years), body mass index (31.4 vs. 31.4 kg/m²), and total daily insulin dose (51 vs. 52 IU), respectively. At 24 weeks, the addition of sitagliptin significantly (p < 0.001) reduced HbA1c by 0.6% compared with placebo (0.0%). A greater proportion of patients achieved an HbA1c level < 7% while randomised to sitagliptin as compared with placebo (13 vs. 5% respectively; p < 0.001). Similar HbA1c reductions were observed in the patient strata defined by insulin type (long‐acting and intermediate‐acting insulins or premixed insulins) and by baseline metformin treatment. The addition of sitagliptin significantly (p < 0.001) reduced fasting plasma glucose by 15.0 mg/dl (0.8 mmol/l) and 2‐h postmeal glucose by 36.1 mg/dl (2.0 mmol/l) relative to placebo. A higher incidence of adverse experiences was reported with sitagliptin (52%) compared with placebo (43%), due mainly to the increased incidence of hypoglycaemia (sitagliptin, 16% vs. placebo, 8%). The number of hypoglycaemic events meeting the protocol‐specified criteria for severity was low with sitagliptin (n = 2) and placebo (n = 1). No significant change from baseline in body weight was observed in either group. Conclusion: In this 24‐week study, the addition of sitagliptin to ongoing, stable‐dose insulin therapy with or without concomitant metformin improved glycaemic control and was generally well tolerated in patients with type 2 diabetes.     

Improved glycaemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients.

AIM: To compare the effect of glimepiride in combination with metformin with monotherapy of each drug on glycaemic control in Type 2 diabetic patients. DESIGN AND METHODS: Randomized, double-blind, double-dummy, parallel-group multicentre study conducted in France. Type 2 diabetic patients aged 35-70 years inadequately controlled by metformin monotherapy 2550 mg daily for at least 4 weeks were randomized to either metformin, glimepiride or metformin and glimepiride. RESULTS: Three hundred and seventy-two patients aged 56 +/- 8 years were treated for 5 months. Combination treatment was significantly more efficient in controlling HbA1c (% change + 0.07 +/- 1.20 for metformin, + 0.27 +/- 1.10 for glimepiride, -0.74 +/- 0.96 for combination treatment, P < 0.001), fasting blood glucose (FBG) (mmol/l change + 0.8 +/- 0.4 for metformin, + 0.7 +/- 3.1 for glimepiride and -1.8 +/- 2.2 for combination treatment, P < 0.001) and post-prandial blood glucose (PPBG) (mmol/l change + 1.1 +/- 5.9 for metformin, + 0.1 +/- 5.1 for glimepiride and -2.6 +/- 3.9 for combination treatment, P < 0.001) than either glimepiride or metformin alone. There was no significant difference between metformin or glimepiride monotherapy with respect to the change in HbA1c or FBG; however, glimepiride was significantly more effective than metformin in reducing PPBG. The incidence of symptomatic hypoglycaemia was higher in the combination group than in either monotherapy group (P = 0.039). CONCLUSIONS: Addition of glimepiride to metformin in Type 2 diabetic patients inadequately controlled by metformin alone resulted in superior glycaemic control compared with glimepiride or metformin monotherapy.     

Saxagliptin add‐on therapy in Chinese patients with type 2 diabetes inadequately controlled by insulin with or without metformin: Results from the SUPER study,a randomized,double‐blind,placebo‐controlled trial

This prospective, multicentre, phase III study (NCT02104804) evaluated the efficacy and safety of saxagliptin add‐on therapy in Chinese patients with type 2 diabetes inadequately controlled by insulin ± metformin. Patients with glycated haemoglobin (HbA1c) 7.5% to 10.5% and fasting plasma glucose (FPG) <15 mmol/L (270 mg/dL) on stable insulin therapy (20‐150 U/d) were randomized (1:1) to saxagliptin 5 mg once daily (N = 232) or placebo (N = 230) for 24 weeks, stratified by metformin use. The primary efficacy measure was change in HbA1c. Saxagliptin treatment resulted in a greater adjusted mean change in HbA1c from baseline to week 24 than placebo (?0.58%; P < .001), irrespective of metformin use, and a greater mean change in FPG (0.9 mmol/L [?15.9 mg/dL]; P < .001). More patients achieved HbA1c <7% with saxagliptin (11.4%) than with placebo (3.5%, P = .002). Adverse events and incidence of hypoglycaemia were similar in both groups. Overall, add‐on saxagliptin 5 mg once daily significantly improved glycaemic control without increasing hypoglycaemia risk and was well tolerated in Chinese patients with type 2 diabetes inadequately controlled by insulin (± metformin).     

Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial

PURPOSE: To assess the efficacy and safety of adding rosiglitazone to an established regimen of glyburide/metformin in patients with type 2 diabetes who had not achieved adequate glycemic control (glycosylated hemoglobin [HbA1C] levels >7.0% and < or =10.0%). METHODS: Following an open-label, lead-in phase to optimize the dosing of glyburide/metformin tablets, 365 patients randomly received additive therapy comprising rosiglitazone (4 mg once daily) or placebo for 24 weeks. Based on glycemic response, rosiglitazone dose was maintained or increased to 4 mg twice daily. Glyburide/metformin dose was maintained or reduced by 2.5/500 mg for symptomatic hypoglycemia. The primary endpoint was the change in HbA1C level from baseline to week 24. The proportions of patients achieving HbA1C levels <7% and a fasting plasma glucose level <126 mg/dL were also assessed. RESULTS: After 24 weeks, therapy with glyburide/metformin plus rosiglitazone resulted in a greater reduction in HbA1C levels (-1.0%, P<0.001) compared with combination therapy that included placebo, and in a larger proportion of patients (42% vs. 14%) who attained levels <7%. The difference in fasting plasma glucose levels between groups was -48 mg/dL (P<0.001), favoring glyburide/metformin plus rosiglitazone. The adverse event profile in the rosiglitazone-treated group included mild-to-moderate edema (8%), hypoglycemia (22%), and weight gain of 3 kg. No patient experienced hypoglycemia requiring third-party assistance. CONCLUSION: In patients with inadequate glycemic control despite established glyburide/metformin therapy, the addition of rosiglitazone improves glycemic control, allowing more patients to achieve an HbA1C level <7% and perhaps delaying the need for insulin treatment.     

Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with Type 2 diabetes.

AIMS: To compare the glycaemic control of an insulin lispro mixture (25% insulin lispro and 75% NPL) twice daily in combination with metformin to that of once-daily insulin glargine plus metformin in patients with Type 2 diabetes inadequately controlled with intermediate insulin, or insulin plus oral agent(s) combination therapy. RESEARCH DESIGN AND METHODS: Ninety-seven patients were randomized in a multicentre, open-label, 32-week crossover study. Primary variables evaluated: haemoglobin A1c (A1c), 2-h post-prandial blood glucose (BG), hypoglycaemia rate (episodes/patient/30 days), incidence (% patients experiencing > or = 1 episode) of overall and nocturnal hypoglycaemia. RESULTS: At endpoint, A1c was lower with the insulin lispro mixture plus metformin compared with glargine plus metformin (7.54% +/- 0.87% vs. 8.14% +/- 1.03%, P < 0.001). Change in A1c from baseline to endpoint was greater with the insulin lispro mixture plus metformin (-1.00% vs. -0.42%; P < 0.001). Two-hour post-prandial BG was lower after morning, midday, and evening meals (P < 0.001) during treatment with the insulin lispro mixture plus metformin. The fasting BG values were lower with glargine plus metformin (P = 0.007). Despite lower BG at 03.00 hours (P < 0.01), patients treated with the insulin lispro mixture plus metformin had a lower rate of nocturnal hypoglycaemia (0.14 +/- 0.49 vs. 0.34 +/- 0.85 episodes/patient/30 days; P = 0.002), although the overall hypoglycaemia rate was not different between treatments (0.61 +/- 1.41 vs. 0.44 +/- 1.07 episodes/patient/30 days; P = 0.477). CONCLUSION: In patients with Type 2 diabetes and inadequate glucose control while on insulin or insulin and oral agent(s) combination therapy, treatment with a twice-daily insulin lispro mixture plus metformin, which targets both post-prandial and pre-meal BG, provided clinically significant improvements in A1c, significantly reduced post-prandial BG after each meal, and reduced nocturnal hypoglycaemia as compared with once-daily glargine plus metformin, a treatment that targets fasting BG.     

Continuing metformin when starting insulin in patients with Type 2 diabetes: a double-blind randomized placebo-controlled trial.

AIMS: To test the effect of continuing metformin on weight gain and glycaemic control in patients with poorly controlled Type 2 diabetes who need to start insulin. METHODS: Patients with Type 2 diabetes on maximum tolerated oral agents referred for insulin conversion were recruited from hospital diabetes clinics into a double-blind randomized placebo-controlled trial. The 183 participants received metformin or placebo, titrated up to 2 g a day or maximum tolerated dose, with insulin started according to local practice. The main outcome measures were weight change over 12 months, HbA1c, insulin dose, frequency of hypoglycaemia, treatment satisfaction, and well-being. RESULTS: Over 12 months, metformin was associated with less weight gain than placebo [mean 6.1 kg vs. 7.6 kg; adjusted difference 1.5 kg (95% confidence interval 0.2-2.9); P=0.02], a greater reduction in HbA1c[1.5% vs. 1.3%; adjusted difference 0.5% (0.1-0.9); P=0.02] and a lower insulin requirement [62 units vs. 86; adjusted difference 25 units (15-34); P<0.001], but also more hypoglycaemia [relative risk of any episode 1.24 (1.02-1.1); P=0.03]. Treatment satisfaction improved more in patients on metformin than on placebo (P<0.001), as did the positive well-being score (P=0.02). CONCLUSIONS: Metformin decreases weight gain, lowers insulin requirement, and improves glycaemic control, and should be continued in patients with Type 2 diabetes who transfer to insulin.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin

AIM: To assess the efficacy and safety of a 24-week treatment with sitagliptin, a highly selective once-daily oral dipeptidyl peptidase-4 (DPP-4) inhibitor, in patients with type 2 diabetes who had inadequate glycaemic control [glycosylated haemoglobin (HbA(1c)) >or=7.5% and or=4 mg/day) monotherapy and 229 were on glimepiride (>or=4 mg/day) plus metformin (>or=1,500 mg/day) combination therapy. Patients exceeding pre-specified glycaemic thresholds during the double-blind treatment period were provided open-label rescue therapy (pioglitazone) until study end. The primary efficacy analysis evaluated the change in HbA(1c) from baseline to Week 24. Secondary efficacy endpoints included fasting plasma glucose (FPG), 2-h post-meal glucose and lipid measurements. RESULTS: Mean baseline HbA(1c) was 8.34% in the sitagliptin and placebo groups. After 24 weeks, sitagliptin reduced HbA(1c) by 0.74% (p < 0.001) relative to placebo. In the subset of patients on glimepiride plus metformin, sitagliptin reduced HbA(1c) by 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on glimepiride alone. The addition of sitagliptin reduced FPG by 20.1 mg/dl (p < 0.001) and increased homeostasis model assessment-beta, a marker of beta-cell function, by 12% (p < 0.05) relative to placebo. In patients who underwent a meal tolerance test (n = 134), sitagliptin decreased 2-h post-prandial glucose (PPG) by 36.1 mg/dl (p < 0.001) relative to placebo. The addition of sitagliptin was generally well tolerated, although there was a higher incidence of overall (60 vs. 47%) and drug-related adverse experiences (AEs) (15 vs. 7%) in the sitagliptin group than in the placebo group. This was largely because of a higher incidence of hypoglycaemia AEs (12 vs. 2%, respectively) in the sitagliptin group compared with the placebo group. Body weight modestly increased with sitagliptin relative to placebo (+0.8 vs. -0.4 kg; p < 0.001). CONCLUSIONS: Sitagliptin 100 mg once daily significantly improved glycaemic control and beta-cell function in patients with type 2 diabetes who had inadequate glycaemic control with glimepiride or glimepiride plus metformin therapy. The addition of sitagliptin was generally well tolerated, with a modest increase in hypoglycaemia and body weight, consistent with glimepiride therapy and the observed degree of glycaemic improvement.     

Addition of rosiglitazone to glimepirid and metformin combination therapy in type 2 diabetes

The study was planned to determine the efficacy and safety of adding rosiglitazone to a combination of glimepiride and metformin therapy with insufficiently controlled type 2 diabetes. This was an open-label study with a follow-up period of 26 weeks. Thirty patients were taking 3 mg glimepiride two times and 850 mg metformin two times per day. Patients were told to take one rosiglitazone 4 mg tablet before breakfast additionally. The primary efficacy measure was the mean change in HbA1c from baseline to the end of the study. Secondary efficacy parameters included the mean changes from baseline to the end of the study in fasting plasma glucose (FPG) and insulin levels, as well as total cholesterol, HDL-C, LDL-C, triglycerides, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Mean HbA1c levels decreased significantly from 7.54 +/- 0.9% to 6.57 +/- 0.7% (p < 0.001) at 26th week. FPG levels fell from 169.39 +/- 37.8 mg/dl to 135.69 +/- 28.0 mg/dl (p < 0.001), respectively. Insulin levels decreased from 19.60 +/- 9.8 U/L to 14.66 +/- 11.6 U/L (p = 0.026) at 26th week. No one experienced elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels greater than 2.5 times the upper limit of the reference range. This study confirms that the addition of rosiglitazone (4 mg/day) to sulphonylurea and metformin treatment for patients with type 2 diabetes improves glycemic control, is safe, and generally well tolerated.     

Comparison of insulin lispro mixture 25/75 with insulin glargine during a 24-h standardized test-meal period in patients with Type 2 diabetes.

AIM: To compare insulin lispro mixture (25% insulin lispro and 75% NPL; Mix 25/75) twice-daily plus oral glucose-lowering medications (metformin and/or sulphonylurea) with once-daily insulin glargine plus oral agents with respect to postprandial glycaemic control and other glucose and lipid parameters in patients with Type 2 diabetes inadequately controlled with insulin and/or oral glucose-lowering agents. METHODS: This was a randomized, open-label, crossover study. Prestudy oral agents were continued and patients not already on oral agents were treated with metformin. Mix 25/75 and insulin glargine were adjusted over 3 months to attain premeal plasma glucose (PG) < 6.0 mmol/l and were then given during a 24-h in-patient test meal period with frequent PG, serum triglyceride (TG) and free fatty acid (FFA) measurements. RESULTS: Twenty patients (10 F/10 M; mean +/-sd age 54.0 +/- 10.7 years, body mass index 37.0 +/- 8.6 kg/m2, HbA1c 8.4 +/- 1.01%) participated. Mean doses were 23 U before the morning and 37 U before the evening meal for Mix 25/75 and 44 U for insulin glargine. The combined 2-h morning and evening meal postprandial plasma glucose (PPG) was not different between groups (9.2 +/- 2.04 vs. 9.9 +/- 1.66 mmol/l, P = 0.161). Mix 25/75 was associated with a lower mean 2-h PPG for all meals combined (9.0 +/- 1.88 vs. 9.9 +/- 1.80 mmol/l, P < 0.05) and lower mean 24-h PG (6.7 +/- 1.00 vs. 7.5 +/- 1.32 mmol/l, P < 0.01). Eight patients experienced mild hypoglycaemia (PG < 3.5 mmol/l) with Mix 25/75 and 3 with insulin glargine. The endpoint HbA1c was lower with Mix 25/75 (6.9 +/- 0.52% vs. 7.3 +/- 0.81%, P < 0.05). CONCLUSIONS: In a 24-h test-meal setting in 20 patients, Mix 25/75 insulin plus oral glucose-lowering agents was associated with lower mean PPG and 24-h PG, more mild hypoglycaemia and similar TG, FFA and fasting PG concentrations. HbA1c was lower with Mix 75/25 plus oral agents, although it may not have reached steady state due to ongoing dose adjustment.     

Inhaled insulin as adjunctive therapy in subjects with type 2 diabetes failing oral agents: a controlled proof-of-concept study

AIM: This controlled proof-of-concept study investigated inhaled insulin (INH) as adjunctive therapy to existing oral antidiabetic agents in subjects with type 2 diabetes. METHODS: Twenty-four subjects with type 2 diabetes [19 men and 5 women, 56.1 +/- 6.6 years, body mass index 32.7 +/- 4.2 kg/m(2), glycosylated haemoglobin (HbA1c) 8.4 +/- 0.8% (mean +/- s.d.)] inadequately controlled by metformin and/or sulfonylureas were randomized to receive additional therapy with either INH administered preprandially using a metered-dose inhaler (MDI), or insulin glargine (GLA) injected subcutaneously at bedtime for 4 weeks. Both inhaled and injected insulin doses were titrated to predefined blood glucose (BG) targets. RESULTS: INH and GLA improved metabolic control to a similar extent. Mean daily BG decreased by 2.8 mmol/l in the INH group (p < 0.001) and by 2.4 mmol/l in the GLA group (p < 0.001). Accordingly, fasting BG (-2.7 vs. -3.6 mmol/l for INH vs. GLA), preprandial- and 2-h postprandial BG, HbA1c (-1.23 vs. -1.05%), body weight (-1.9 vs. -2.3 kg) and serum fructosamine were similarly and significantly reduced in both groups (p < 0.05). Triglycerides decreased significantly with INH (-1.15 micromol/l; p < 0.001) but not with GLA [-0.52 micromol/l; not significant (NS)]. Incidence rates of adverse events did not differ significantly, and there were no indications of respiratory tract irritation. CONCLUSIONS: In subjects with type 2 diabetes inadequately controlled by oral agents, preprandial administration of INH delivered by a MDI provided a comparable metabolic control to bedtime GLA and did not show any safety concerns during a 4-week treatment. These results warrant a more extensive investigation of preprandial treatment with INH in longer term studies.     

Low-dose rosiglitazone in patients with insulin-requiring type 2 diabetes

BACKGROUND: The objective was to compare the efficacy and safety of adding low-dose rosiglitazone (2 or 4 mg/d) to insulin therapy vs continued insulin monotherapy in patients with type 2 diabetes mellitus who were unable to achieve glycemic control with insulin therapy alone. METHODS: In this 24-week, double-blind study, 630 individuals with type 2 diabetes mellitus that was inadequately controlled with insulin therapy alone were randomized to treatment with rosiglitazone (2 or 4 mg/d) or placebo in combination with ongoing insulin therapy. The dosage of insulin therapy could be adjusted at the investigator's discretion if required for hypoglycemia or additional glycemic control. RESULTS: The addition of rosiglitazone (2 or 4 mg/d) to insulin therapy significantly decreased mean glycated hemoglobin concentrations compared with placebo plus insulin (-0.3% [P=.02] and -0.4% [P<.001]) and compared with baseline (-0.6% and -0.8% [both P<.001]) after 24 weeks. The addition of 2 or 4 mg/d of rosiglitazone significantly decreased the C-reactive protein level (vs baseline: -22.0% [P<.001] and -34.2% [P<.001]; vs placebo: -22.2% [P=.003] and -32.0% [P<.001]) and fibrinogen (vs baseline: -10.5% and -12.0% [both P<.001]; vs placebo: -7.9% [P=.002] and -7.6% [P=.004]), while 4 mg/d of rosiglitazone significantly reduced matrix metalloproteinase 9 levels (vs baseline: -17.1% [P=.007]; vs placebo: -23.3% [P<.001]). The adverse event profile, including incidence of hypoglycemia and edema, was similar between treatment groups, and most adverse events were mild to moderate in intensity. CONCLUSIONS: The addition of low-dose rosiglitazone to insulin therapy is an effective and well-tolerated treatment option for patients with type 2 diabetes mellitus who continue to have poor glycemic control despite administration of exogenous insulin as monotherapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00054782.