Repaglinide versus nateglinide monotherapy: a randomized, multicenter study

OBJECTIVE: A randomized, parallel-group, open-label, multicenter 16-week clinical trial compared efficacy and safety of repaglinide monotherapy and nateglinide monotherapy in type 2 diabetic patients previously treated with diet and exercise. RESEARCH DESIGN AND METHODS: Enrolled patients (n = 150) had received treatment with diet and exercise in the previous 3 months with HbA(1c) >7 and < or =12%. Patients were randomized to receive monotherapy with repaglinide (n = 76) (0.5 mg/meal, maximum dose 4 mg/meal) or nateglinide (n = 74) (60 mg/meal, maximum dose 120 mg/meal) for 16 weeks. Primary and secondary efficacy end points were changes in HbA(1c) and fasting plasma glucose (FPG) values from baseline, respectively. Postprandial glucose, insulin, and glucagon were assessed after a liquid test meal (baseline, week 16). Safety was assessed by incidence of adverse events or hypoglycemia. RESULTS: Mean baseline HbA(1c) values were similar in both groups (8.9%). Final HbA(1c) values were lower for repaglinide monotherapy than nateglinide monotherapy (7.3 vs. 7.9%). Mean final reductions of HbA(1c) were significantly greater for repaglinide monotherapy than nateglinide monotherapy (-1.57 vs. -1.04%; P = 0.002). Mean changes in FPG also demonstrated significantly greater efficacy for repaglinide than nateglinide (-57 vs. -18 mg/dl; P < 0.001). HbA(1c) values <7% were achieved by 54% of repaglinide-treated patients versus 42% for nateglinide. Median final doses were 6.0 mg/day for repaglinide and 360 mg/day for nateglinide. There were 7% of subjects treated with repaglinide (five subjects with one episode each) who had minor hypoglycemic episodes (blood glucose <50 mg/dl) versus 0 patients for nateglinide. Mean weight gain at the end of the study was 1.8 kg in the repaglinide group as compared with 0.7 kg for the nateglinide group. CONCLUSIONS: In patients previously treated with diet and exercise, repaglinide and nateglinide had similar postprandial glycemic effects, but repaglinide monotherapy was significantly more effective than nateglinide monotherapy in reducing HbA(1c) and FPG values after 16 weeks of therapy.     

Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes

OBJECTIVE: To evaluate the efficacy and tolerability of nateglinide and metformin alone and in combination in type 2 diabetic patients inadequately controlled by diet, focusing on changes in HbA1c, fasting plasma glucose (FPG), and mealtime glucose excursions. RESEARCH DESIGN AND METHODS: In this randomized double-blind study, patients with an HbA1c level between 6.8 and 11.0% during a 4-week placebo run-in received 24 weeks' treatment with 120 mg nateglinide before meals (n = 179), 500 mg metformin three times a day (n = 178), combination therapy (n = 172), or placebo (n = 172). HbA1c and FPG were evaluated regularly, and plasma glucose levels were determined after Sustacal challenge at weeks 0, 12, and 24. Hypoglycemia and other adverse events were recorded. RESULTS: At study end point, HbA1c was reduced from baseline with nateglinide and metformin but was increased with placebo (-0.5, -0.8, and +0.5%, respectively; P < or = 0.0001). Changes in FPG followed the same pattern (-0.7, -1.6, and +0.4 mmol/l; P < or = 0.0001). Combination therapy was additive (HbA1c -1.4% and FPG -2.4 mmol/l; P < or = 0.01 vs. monotherapy). After Sustacal challenge, there was a greater reduction in mealtime glucose with nateglinide monotherapy compared with metformin monotherapy or placebo (adjusted area under the curve [AUC]0-130 min -2.1, -1.1, and -0.6 mmol x h(-1) x l(-1); p < or = 0.0001). An even greater effect was observed with combination therapy (AUC0-130 min -2.5 mmol x h(-1) x l(-1); P < or = 0.0001 vs. metformin and placebo). All regimens were well tolerated. CONCLUSIONS: Nateglinide and metformin monotherapy each improved overall glycemic control but by different mechanisms. Nateglinide decreased mealtime glucose excursions, whereas metformin primarily affected FPG. In combination, nateglinide and metformin had complementary effects, improving HbA1c, FPG, and postprandial hyperglycemia.     

PRESERVE-beta: two-year efficacy and safety of initial combination therapy with nateglinide or glyburide plus metformin

OBJECTIVE: To compare long-term efficacy and safety of initial combination therapy with nateglinide/metformin versus glyburide/metformin. RESEARCH DESIGN AND METHODS: We conducted a randomized, multicenter, double-masked, 2-year study of 428 drug-na?ve patients with type 2 diabetes. Patients received 120 mg a.c. nateglinide or 1.25 mg q.d. glyburide plus 500 mg q.d. open-label metformin for the initial 4 weeks. During a subsequent 12-week titration period, glyburide and metformin were increased by 1.25- and 500-mg increments to maximum daily doses of 10 and 2,000 mg, respectively, if biweekly fasting plasma glucose (FPG) > or = 6.7 mmol/l. Nateglinide was not titrated. Blinding was maintained by use of matching placebo for nateglinide and glyburide. An 88-week monitoring period followed, during which HbA1c (A1C), FPG, and postprandial glucose excursions (PPGEs) during an oral glucose tolerance test were measured. RESULTS: In nateglinide/metformin-treated patients, mean A1C was 8.4% at baseline and 6.9% at week 104. In glyburide/metformin-treated patients, mean A1C was 8.3% at baseline and 6.8% at week 104 (P < 0.0001 vs. baseline for both treatments, NS between treatments). The deltaPPGE averaged -96 +/- 19 (P < 0.0001) and -57 +/- 22 mmol.l(-1).min(-1) (P < 0.05) in patients receiving nateglinide/metformin and glyburide/metformin, respectively, whereas deltaFPG was -1.6 +/- 0.2 (P < 0.0001) and -2.4 +/- 0.2 mmol/l (P < 0.0001) in patients receiving nateglinide/metformin and glyburide/metformin, respectively (P < 0.01 between groups). Thus, the two treatments achieved similar efficacy with differential effects on FPG versus PPGE. Hypoglycemia occurred in 8.2 and 17.7% of patients receiving nateglinide/metformin and glyburide/metformin, respectively. CONCLUSIONS: Similar good glycemic control can be maintained for 2 years with either treatment regimen, but nateglinide/metformin may represent a safer approach to initial combination therapy.     

Repaglinide/troglitazone combination therapy: improved glycemic control in type 2 diabetes

OBJECTIVE: This multicenter open-label clinical trial compared the efficacy and safety of repaglinide/troglitazone combination therapy, repaglinide monotherapy, and troglitazone monotherapy in type 2 diabetes that had been inadequately controlled by sulfonylureas, acarbose, or metformin alone. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes (n = 256) who had inadequate glycemic control (HbA1c > or =7.0%) during previous monotherapy were randomly assigned to receive repaglinide (0.5-4.0 mg at meals), troglitazone (200-600 mg once daily), or a combination of repaglinide (1-4 mg at meals) and troglitazone (200-600 mg once daily). After a 4-6 week washout period, the trial assessed 22 weeks of treatment: 3 weeks (weeks 0-2) of forced titration, 11 weeks of fixed-dose treatment (weeks 3-13), and 8 weeks (weeks 14-21) of titration to maximum dose. Changes in HbA1c and fasting plasma glucose (FPG) values were measured. RESULTS: The combination therapy showed a significant reduction in mean HbA1c values (-1.7%) that was greater than with either type of monotherapy Repaglinide monotherapy resulted in a reduction of HbA1c values that was significantly greater than troglitazone (-0.8 vs. -0.4%) (P < 0.05). Combination therapy was more effective in reducing FPG values (-80 mg/dl) than either repaglinide (-43 mg/dl) or troglitazone (-46 mg/dl) monotherapies. Adverse events were similar in all groups. CONCLUSIONS: Combination therapy with repaglinide and troglitazone leads to better glycemic control than monotherapy with either agent alone. Repaglinide monotherapy was more effective in lowering HbA1c levels than troglitazone monotherapy Repaglinide/troglitazone combination therapy was effective and did not show unexpected adverse events.     

Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes.

OBJECTIVE: To compare the effect of repaglinide in combination with metformin with monotherapy of each drug on glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 83 patients with type 2 diabetes who had inadequate glycemic control (HbA1c > 7.1%) when receiving the antidiabetic agent metformin were enrolled in this multicenter, double-blind trial. Subjects were randomized to continue with their prestudy dose of metformin (n = 27), to continue with their prestudy dose of metformin with the addition of repaglinide (n = 27), or to receive repaglinide alone (n = 29). For patients receiving repaglinide, the optimal dose was determined during a 4- to 8-week titration and continued for a 3-month maintenance period. RESULTS: In subjects receiving combined therapy, HbA1c was reduced by 1.4 +/- 0.2%, from 8.3 to 6.9% (P = 0.0016) and fasting plasma glucose by 2.2 mmol/l (P = 0.0003). No significant changes were observed in subjects treated with either repaglinide or metformin monotherapy in HbA1c (0.4 and 0.3% decrease, respectively) or fasting plasma glucose (0.5 mmol/l increase and 0.3 mmol/l decrease respectively). Subjects receiving repaglinide either alone or in combination with metformin, had an increase in fasting levels of insulin between baseline and the end of the trial of 4.04 +/- 1.56 and 4.23 +/- 1.50 mU/l, respectively (P < 0.02). Gastrointestinal adverse events were common in the metformin group. An increase in body weight occurred in the repaglinide and combined therapy groups (2.4 +/- 0.5 and 3.0 +/- 0.5 kg, respectively; P < 0.05). CONCLUSIONS: Combined metformin and repaglinide therapy resulted in superior glycemic control compared with repaglinide or metformin monotherapy in patients with type 2 diabetes whose glycemia had not been well controlled on metformin alone. Repaglinide monotherapy was as effective as metformin monotherapy.     

Rapid and short-acting mealtime insulin secretion with nateglinide controls both prandial and mean glycemia

OBJECTIVE: The objective of the study was to assess the efficacy and safety of four fixed doses of nateglinide compared with placebo in the treatment of patients with type 2 diabetes with focus on the prandial state. RESEARCH DESIGN AND METHODS: This randomized double-blind placebo-controlled multicenter study was conducted in 289 patients who received either nateglinide at doses of 30 mg (n = 51), 60 mg (n = 58), 120 mg (n = 63), or 180 mg (n = 57) or placebo (n = 60) before three main meals for 12 weeks. Levels of HbA1c, fasting plasma glucose (FPG), fructosamine, and plasma lipids were measured at predetermined intervals, and the effects of nateglinide on prandial glucose insulin, C-peptide, and triglyceride levels were measured after a liquid standard meal (Sustacal; Mead Johnson, Evansville, IN). Adverse events and hypoglycemic episodes were recorded. RESULTS: After a liquid meal challenge, nateglinide rapidly increased mealtime insulin levels within 30 min of drug intake and reduced mealtime glucose excursions without affecting triglyceride levels. At study end point, reduction of HbA1c levels was statistically significantly greater with nateglinide at doses of 60, 120, and 180 mg than placebo (-0.45, -0.62, and -0.64%, respectively; P<0.05). The mean level of FPG was significantly reduced versus placebo in the nateglinide 120-mg group only (-1.14 mmol/l P<0.01). Overall, nateglinide was well tolerated. CONCLUSIONS: This study demonstrated that nateglinide improves mealtime and mean glycemic control in a dose-dependent manner by restoring early insulin secretion phase. Nateglinide was well tolerated and is suitable for the treatment of patients with type 2 diabetes.     

Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy

OBJECTIVE: This study aimed to assess glycemic response to a mixture of 75% insulin lispro protamine suspension and 25% insulin lispro (Mix 75/25) BID plus metformin versus insulin glargine QD plus metformin in patients with type 2 diabetes mellitus (DM). METHODS: Adults new to insulin therapy were enrolled in a multicenter, randomized, prospective, open-label, crossover study with 16 weeks on each treatment. Variables included glycosylated hemoglobin (HbA(1c)), hypoglycemia rate, fasting blood glucose (FBG), 2-hour postprandial blood glucose (ppBG), and rise in blood glucose after meals. RESULTS: One hundred five patients (mean age, 55 years) were randomized. There was no difference in baseline mean values for either treatment sequence group for body mass index, duration of DM, or HbA(1c). Ninety-five patients completed the study and 67 were included in the efficacy analysis. Mix 75/25 was associated with lower mean (SD) HbA(1c) at end point (7.4% [1.1%] vs 7.8% [1.1%]; P = 0.002). More patients using Mix 75/25 achieved target HbA(1c) < or =7.0% (42% [30/71] vs 18% [13/71]; P < 0.001). With Mix 75/25, the mean (SD) 2-hour ppBG was similar after lunch but lower after breakfast (156.4 [43.6] vs 171.1 [44.9] mg/dL; P = 0.012) and dinner (164.8 [42.5] mg/dL vs 193.8 [51.0] mg/dL; P < 0.001), although FBG was higher (139.3 [36.6] mg/dL vs 123.9 [34.9] mg/dL; P < 0.001). Rise in ppBG was lower with Mix 75/25 after breakfast (16.9 [47.0] mg/dL vs 47.4 [34.8] mg/dL; P < 0.001) and dinner (14.2 [44.1] mg/dL vs 45.9 [41.3] mg/dL; P < 0.001). Gain in mean (SD) body weight was greater with Mix 75/25 than insulin glargine (2.3 [4.0] kg vs 1.6 [4.0] kg; P = 0.006). For all randomized patients, mean (SD) hypoglycemia rates were lower with insulin glargine (0.68 [1.38] vs 0.39 [1.24] episodes/patient per 30 days; P = 0.041), although nocturnal hypoglycemia was similar. CONCLUSION: In this study population, Mix 75/25 plus metformin was associated with lower HbA(1c) than insulin glargine plus metformin, smaller rise in ppBG after breakfast and dinner, and higher proportion of patients achieving HbA(1c) < or =7.0%, with a slight increase in overall (but not nocturnal) hypoglycemia.     

Durability of efficacy and long-term safety profile of glyburide/metformin tablets in patients with type 2 diabetes mellitus: an open-label extension study

BACKGROUND: Intensive glycemic control substantially reduces the microvascular and macrovascular complications of type 2 diabetes mellitus, although less than half of patients with diabetes achieve the target glycosylated hemoglobin (HbA1c) value recommended by the American Diabetes Association. Because monotherapy with an oral agent does not address the multiple pathophysiologic defects of diabetes, use of combination therapy appears to be warranted. A previous 32-week, randomized, double-blind, placebo-controlled trial found that treatment with glyburide/metformin tablets was associated with greater reductions in HbA1c values compared with glyburide monotherapy, metformin monotherapy, and placebo. OBJECTIVES: This study evaluated the durability of efficacy and long-term safety profile of therapy with glyburide/metformin tablets over 52 weeks. METHODS: Patients enrolled in this open-label extension study were drawn from 3 groups: those who completed the 32-week double-blind study, those who were discontinued from the double-blind study, and those who were ineligible for the double-blind study and were enrolled directly in the open-label extension study. Patients with an HbA1c of < 9% received glyburide/metformin 1.25 mg/250 mg tablets BID, and those with an HbA1c of > or = 9% received glyburide/metformin 2.5 mg/500 mg tablets BID. Primary efficacy variables included changes from baseline in HbA1c, fasting plasma glucose (FPG), and body weight at week 52. Safety was assessed based on adverse-event data and the results of physical examinations and laboratory tests. RESULTS: A total of 828 patients were enrolled in the study: 515 who completed the 32-week double-blind study, 138 who were discontinued from the double-blind study, and 175 who were directly enrolled. At week 52, the mean HbA1c value for the entire population had decreased from a baseline value of 8.73% to 7.04% (95% CI, -1.81 to -1.58). Patients who were enrolled directly had the poorest glycemic control at baseline and experienced the greatest reduction in HbA1c (-3.35%; 95% CI, -3.61 to -3.10). A reduction in mean FPG for the total population was observed as early as week 2, from 201 to 141 mg/dL (95% CI, -63.0 to -55.7). Symptoms of hypoglycemia occurred in 19.9% (165/828) of patients, although only one third of these patients had a documented finger-stick blood glucose value of > or = 50 mg/dL. CONCLUSIONS: In this 52-week, open-label extension study, glyburide/metformin tablets were well tolerated and effective in patients with type 2 diabetes. They provided rapid and sustainable reductions in HbA1c values and FPG concentrations.     

Improved control of mealtime glucose excursions with coadministration of nateglinide and metformin

OBJECTIVE: Nateglinide, a new short-acting D-phenylalanine derivative for treating type 2 diabetes, reduces mealtime blood glucose excursions by physiologic regulation of insulin secretion. This study evaluated the pharmacokinetic and pharmacodynamic interactions of nateglinide and metformin in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 12 type 2 diabetic subjects with the following baseline characteristics were enrolled: age, 56 +/- 13 years; BMI, 28.7 +/- 4.5 kg/m2; HbA1c, 8.4 +/- 1.3%; and fasting plasma glucose 13 +/- 2.8 mmol/l. All subjects had been previously treated with glyburide and were switched to metformin monotherapy for 3 weeks before study start. Subjects then randomly received, in combination with 500 mg metformin, either 120 mg nateglinide or placebo before meals for 1 day, followed by the alternate treatment 7 days later. After 1 week of washout from both drugs, subjects received 1 day of open-label nateglinide treatment. Plasma concentrations of glucose, insulin, nateglinide, and metformin were assessed frequently during inpatient periods. RESULTS: Postmeal plasma glucose levels were significantly lower in subjects treated with nateglinide plus metformin than in those treated with either drug alone (P < 0.001), especially after lunch and dinner. Coadministration of nateglinide and metformin did not affect the pharmacokinetics of either drug. All treatments were safe and well tolerated. CONCLUSIONS: Combination therapy with nateglinide and metformin was more effective than either treatment alone and did not result in any pharmacokinetic interactions. Coadministration of nateglinide and metformin appears to be an excellent option for treating patients with type 2 diabetes not controlled with monotherapy.     

Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial.

OBJECTIVE: Metformin is the most commonly prescribed oral antidiabetic agent in the U.S. for adults with type 2 diabetes. The incidence of type 2 diabetes in children has increased dramatically over the past 10 years, and yet, metformin has never been formally studied in children with type 2 diabetes. RESEARCH DESIGN AND METHODS: This study evaluated the safety and efficacy of metformin at doses up to 1,000 mg twice daily in 82 subjects aged 10-16 years for up to 16 weeks in a randomized double-blind placebo-controlled trial from September 1998 to November 1999. Subjects with type 2 diabetes were enrolled if they had a fasting plasma glucose (FPG) levels > or =7.0 and < or =13.3 mmol/l (> or =126 and < or =240 mg/dl), HbA(1c) > or =7.0%, stimulated C-peptide > or =0.5 nmol/l (> or =1.5 ng/ml), and a BMI > 50th percentile for age. RESULTS: Metformin significantly improved glycemic control. At the last double-blind visit, the adjusted mean change from baseline in FPG was -2.4 mmol/l (-42.9 mg/dl) for metformin compared with +1.2 mmol/l (+21.4 mg/dl) for placebo (P < 0.001). Mean HbA(1c) values, adjusted for baseline levels, were also significantly lower for metformin compared with placebo (7.5 vs. 8.6%, respectively; P < 0.001). Improvement in FPG was seen in both sexes and in all race subgroups. Metformin did not have a negative impact on body weight or lipid profile. Adverse events were similar to those reported in adults treated with metformin. CONCLUSION: Metformin was shown to be safe and effective for treatment of type 2 diabetes in pediatric patients.     

Achieving glycosylated hemoglobin targets using the combination of repaglinide and metformin in type 2 diabetes: a reanalysis of earlier data in terms of current targets

BACKGROUND: For patients with type 2 diabetes, the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) currently recommend a glycosylated hemoglobin (HbA(1c) ) target of <7%, and the British Medical Association (BMA) Quality and Outcomes Framework recommends an HbA(1c) target of >or=7.5%. OBJECTIVE: This letter presents a reanalysis of data from a previous study of the effect on glycemic control of adding repaglinide to metformin monotherapy in patients with type 2 diabetes to determine the proportion of patients achieving current ADA/EASD and BMA targets. METHODS: PubMed was searched using the terms repaglinide AND metformin AND HbA(1c) to identify published comparisons of monotherapy and combination therapy with these drugs in patients with type 2 diabetes. RESULTS: In the original analysis, which employed an HbA(1c) target of <7.1%, 59%of patients treated with metformin plus repaglinide achieved their glycemic target, compared with approximately 20% of patients treated with metformin or repaglinide alone. On reanalysis of the data according to the current ADA/EASD HbA(1c) target of <7%, 56% of patients receiving metformin and repaglinide achieved that goal,compared with 19%each in the groups treated with metformin or repaglinide monotherapy. On reanalysis of the data according to the BMA Quality and Outcomes Framework HbA(1c) target of >or=7.5%, 89% of patients receiving metformin and repaglinide achieved that goal, compared with 43%and 42% of patients receiving metformin and repaglinide monotherapy, respectively. CONCLUSION: Based on this reanalysis of earlier data in terms of currently recommended HbA(1c) targets, combination therapy with repaglinide and metformin would appear to be a good treatment option for patients with type 2 diabetes.     

The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes

OBJECTIVE--To investigate the efficacy and safety of miglitol in combination with metformin in improving glycemic control in outpatients in whom type 2 diabetes is insufficiently controlled by diet alone. RESEARCH DESIGN AND METHODS--In this multicenter, double-blind, placebo-controlled study, 324 patients with type 2 diabetes were randomized, after an 8-week placebo run-in period, to treatment with either placebo, miglitol alone, metformin alone, or miglitol plus metformin for 36 weeks. The miglitol was titrated to 100 mg three times a day and metformin was administered at 500 mg three times a day. The primary efficacy criterion was change in HbA(1c) from baseline to the end of treatment. Secondary parameters included changes in fasting and postprandial plasma glucose and insulin levels, serum triglyceride levels, and responder rate. RESULTS--A total of 318 patients were valid for intent-to-treat analysis. A reduction in mean placebo-subtracted HbA(1c) of -1.78% was observed with miglitol plus metformin combination therapy, which was significantly different from treatment with metformin alone (-1.25; P = 0.002). Miglitol plus metformin also resulted in better metabolic control than metformin alone for fasting plasma glucose (-44.8 vs. -20.4 mg/dl; P = 0.0025), 2-h postprandial glucose area under the curve (-59.0 vs. -18.0 mg/dl; P = 0.0001), and responder rate (70.6 vs. 45.52%; P = 0.0014). All therapies were well tolerated. CONCLUSIONS--In type 2 diabetic patients, miglitol in combination with metformin gives greater glycemic improvement than metformin monotherapy.     

Repaglinide versus metformin in combination with bedtime NPH insulin in patients with type 2 diabetes established on insulin/metformin combination therapy

OBJECTIVE: To compare the effect on glycemic control and weight gain of repaglinide versus metformin combined with bedtime NPH insulin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 80 subjects treated with 850 or 1,000 mg t.i.d. metformin combined with bedtime NPH insulin were randomized to 13 weeks of open-label treatment with 4 mg t.i.d. repaglinide (n = 39) or metformin (dose unchanged) (n = 41). Insulin dose was titrated at the clinician's discretion, aiming for a fasting blood glucose (FBG) < or =6.0 mmol/l. RESULTS: Baseline age, diabetes duration, insulin requirement, weight, BMI, FBG, and HbA(1c) (Diabetes Control and Complications Trial-aligned assay, normal range 4.6-6.2%) were similar. Glycemic control improved (nonsignificantly) with insulin/metformin by (mean) 0.4%, from 8.4 to 8.1% (P = 0.09) but deteriorated with insulin/repaglinide by (mean) 0.4%, from 8.1 to 8.6% (P = 0.03; P = 0.005 between groups). Weight gain was less with insulin/metformin: 0.9 +/- 0.4 kg (means +/- SE) (P = 0.01) versus 2.7 +/- 0.4 kg (P < 0.0001) (P = 0.002 between groups). The Diabetes Treatment Satisfaction Questionnaire score (potential range 0 [minimum] to 36 [maximum]) increased from 32.4 +/- 0.8 to 34.1 +/- 0.5 (P = 0.01) with insulin/metformin but decreased from 32.5 +/- 0.9 to 29.1 +/- 1.3 (P < 0.002) with insulin/repaglinide. CONCLUSIONS: Combined with bedtime NPH insulin, metformin provides superior glycemic control to repaglinide with less weight gain and improved diabetes treatment satisfaction.     

One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes

OBJECTIVE: The goal was to assess the 1-year efficacy and safety of the addition of pioglitazone or metformin to existing sulfonylurea (SU) therapy in patients with inadequately controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: In this multicenter, double-blind study, patients were randomized to receive either pioglitazone 15 mg (n = 319) or metformin 850 mg (n = 320) and up to 45 mg/day and 2,550 mg/day, respectively. The primary efficacy endpoint was HbA(1c) at week 52. Fasting plasma glucose, insulin, and lipid profiles were also measured. RESULTS: HbA(1c) was reduced by 1.20% in the SU plus pioglitazone group and 1.36% in the SU plus metformin group, and fasting plasma glucose was reduced by 2.2 and 2.3 mmol/l in the respective groups. Fasting insulin levels were also reduced (pioglitazone arm -1.3 micro IU/ml; metformin arm -0.8 micro IU/ml). There were no significant between-treatment differences in these three parameters. Pioglitazone addition to SU significantly reduced triglycerides (-16 vs. -9%; P = 0.008) and increased HDL cholesterol (14 vs. 8%; P < 0.001) compared with metformin addition. LDL cholesterol was increased 2% by the addition of pioglitazone and decreased 5% by the addition of metformin to SU (P < 0.001). Urinary albumin-to-creatinine ratio was reduced by 15% in the SU plus pioglitazone group and increased 2% in the SU plus metformin group (P = 0.017). Both combinations were well tolerated with no evidence of hepatic or cardiac toxicity in either group. CONCLUSIONS: Clinically equivalent improvements in glycemic control were observed for both combinations. Compared with metformin plus SU, addition of pioglitazone to SU resulted in a reduction of the urinary albumin-to-creatinine ratio, a small but significant rise in LDL cholesterol, and significantly greater improvements in triglyceride levels and HDL cholesterol levels. Metformin plus SU was associated with a significant reduction in LDL cholesterol. SU plus pioglitazone is an effective and well-tolerated combination regimen that may provide additional beneficial effects for patients with type 2 diabetes.     

Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients

OBJECTIVE: To evaluate the efficacy and safety of add-on insulin glargine versus rosiglitazone in insulin-na?ve patients with type 2 diabetes inadequately controlled on dual oral therapy with sulfonylurea plus metformin. RESEARCH DESIGN AND METHODS: In this 24-week multicenter, randomized, open-label, parallel trial, 217 patients (HbA(1c) [A1C] 7.5-11%, BMI >25 kg/m(2)) on > or =50% of maximal-dose sulfonylurea and metformin received add-on insulin glargine 10 units/day or rosiglitazone 4 mg/day. Insulin glargine was forced-titrated to target fasting plasma glucose (FPG) < or =5.5-6.7 mmol/l (< or =100-120 mg/dl), and rosiglitazone was increased to 8 mg/day any time after 6 weeks if FPG was >5.5 mmol/l. RESULTS: A1C improvements from baseline were similar in both groups (-1.7 vs. -1.5% for insulin glargine vs. rosiglitazone, respectively); however, when baseline A1C was >9.5%, the reduction of A1C with insulin glargine was greater than with rosiglitazone (P < 0.05). Insulin glargine yielded better FPG values than rosiglitazone (-3.6 +/- 0.23 vs. -2.6 +/- 0.22 mmol/l; P = 0.001). Insulin glargine final dose per day was 38 +/- 26 IU vs. 7.1 +/- 2 mg for rosiglitazone. Confirmed hypoglycemic events at plasma glucose <3.9 mmol/l (<70 mg/dl) were slightly greater for the insulin glargine group (n = 57) than for the rosiglitazone group (n = 47) (P = 0.0528). The calculated average rate per patient-year of a confirmed hypoglycemic event (<70 mg/dl), after adjusting for BMI, was 7.7 (95% CI 5.4-10.8) and 3.4 (2.3-5.0) for the insulin glargine and rosiglitazone groups, respectively (P = 0.0073). More patients in the insulin glargine group had confirmed nocturnal hypoglycemia of <3.9 mmol/l (P = 0.02) and <2.8 mmol/l (P < 0.05) than in the rosiglitazone group. Effects on total cholesterol, LDL cholesterol, and triglyceride levels from baseline to end point with insulin glargine (-4.4, -1.4, and -19.0%, respectively) contrasted with those of rosiglitazone (+10.1, +13.1, and +4.6%, respectively; P < 0.002). HDL cholesterol was unchanged with insulin glargine but increased with rosiglitazone by 4.4% (P < 0.05). Insulin glargine had less weight gain than rosiglitazone (1.6 +/- 0.4 vs. 3.0 +/- 0.4 kg; P = 0.02), fewer adverse events (7 vs. 29%; P = 0.0001), and no peripheral edema (0 vs. 12.5%). Insulin glargine saved $235/patient over 24 weeks compared with rosiglitazone. CONCLUSIONS: Low-dose insulin glargine combined with a sulfonylurea and metformin resulted in similar A1C improvements except for greater reductions in A1C when baseline was > or =9.5% compared with add-on maximum-dose rosiglitazone. Further, insulin glargine was associated with more hypoglycemia but less weight gain, no edema, and salutary lipid changes at a lower cost of therapy.     

Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial

Background: Combining metformin (XR) with dapagliflozin to initiate pharmacotherapy in patients with type 2 diabetes (T2D) and high baseline HbA1c may be advantageous. We conducted two randomised, double‐blind, three‐arm 24‐week trials in treatment‐naïve patients to compare dapagliflozin plus metformin, dapagliflozin alone and metformin alone. Methods: Eligible patients had baseline HbA1c 7.5–12%. Each trial had three arms: dapagliflozin plus metformin, dapagliflozin monotherapy and metformin monotherapy. Dapagliflozin in combination and as monotherapy was dosed at 5 mg (Study 1) and 10 mg (Study 2). Metformin in combination and as monotherapy was titrated to 2000 mg. The primary endpoint was HbA1c change from baseline; secondary endpoints included change in fasting plasma glucose (FPG) and weight. Results: In both trials, combination therapy led to significantly greater reductions in HbA1c compared with either monotherapy: ?2.05 for dapagliflozin + metformin, ?1.19 for dapagliflozin, and ?1.35 for metformin (p < 0.0001) (Study 1); ?1.98 for dapagliflozin + metformin, ?1.45 for dapagliflozin and ?1.44 for metformin (p < 0.0001) (Study 2). Combination therapy was statistically superior to monotherapy in reduction of FPG (p < 0.0001 for both studies); combination therapy was more effective than metformin for weight reduction (p < 0.0001). Dapagliflozin 10 mg was non‐inferior to metformin in reducing HbA1c (Study 2). Events suggestive of genital infection were reported in 6.7%, 6.9% and 2.0% (Study 1) and 8.5%, 12.8% and 2.4% (Study 2) of patients in combination, dapagliflozin and metformin groups; events suggestive of urinary tract infection were reported in 7.7%, 7.9% and 7.5% (Study 1) and 7.6%, 11.0% and 4.3% (Study 2) of patients in the respective groups. No major hypoglycaemia was reported. Conclusion: In treatment‐naïve patients with T2D, dapagliflozin plus metformin was generally well tolerated and effective in reducing HbA1c, FPG and weight. Dapagliflozin‐induced glucosuria led to an increase in events suggestive of urinary tract and genital infections.     

Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group

BACKGROUND: Their complimentary mechanisms of action suggest that a combination of pioglitazone hydrochloride and metformin may have clinically beneficial effects in the treatment of patients with type 2 diabetes. OBJECTIVE: This study was undertaken to assess the efficacy and tolerability of pioglitazone in combination with metformin in patients with type 2 diabetes mellitus. METHODS: This was a 16-week, double-blind study with the option of enrollment in a separate open-ended, open-label study. It included patients with poorly controlled diabetes mellitus (glycated hemoglobin [HbA1c] > or =8.0%, fasting C-peptide >1.0 ng/mL) who had been receiving a stable regimen of metformin for > or =30 days. Patients with diabetic retinopathy, nephropathy, or neuropathy; impaired liver or kidney function; or unstable cardiovascular or cerebrovascular conditions were excluded. Patients were randomized to receive once-daily pioglitazone 30 mg + metformin or placebo + metformin. Patients in the open-label extension received pioglitazone 30 mg (with optional titration to 45 mg) + metformin. RESULTS: Three hundred twenty-eight patients were randomized to treatment (168 pioglitazone + metformin, 160 placebo + metformin), and 249 completed the study. Of these, 154 elected to enter the open-label extension study. Patients' mean age was 56 years; most (84%) were white and slightly more than half (57%) were male. Patients receiving piogli- tazone 30 mg + metformin had statistically significant mean decreases in HbA1c (-0.83%) and fasting plasma glucose (FPG) levels (-37.7 mg/dL) compared with placebo + metformin (P < or = 0.05). Decreases in FPG levels occurred as early as the fourth week of therapy, the first time point at which FPG was measured. The pioglitazone + metformin group had significant mean percentage changes in levels of triglycerides (-18.2%) and high-density lipoprotein cholesterol (+8.7%) compared with placebo + metformin (P < or = 0.05). Mean percentage increases were noted in low-density lipoprotein cholesterol levels (7.7%, pioglitazone + metformin; 11.9%, placebo + metformin) and total cholesterol (4.1%, pioglitazone + metformin; 1.1%, placebo + metformin), with no significant differences between groups. In the extension study, patients treated with open-label pioglitazone + metformin for 72 weeks had mean changes from baseline of -1.36% in HbA1c and -63.0 mg/dL in FPG. The incidence of adverse events was similar in both groups. Throughout the study, no patient in either treatment group had an alanine aminotransferase (ALT) value > or =3 times the upper limit of normal, a commonly used marker of potential liver damage. Thus, no evidence of drug-induced hepatotoxicity or drug-induced elevations in serum ALT was observed. CONCLUSIONS: In this study in patients with type 2 diabetes mellitus, pioglitazone + metformin significantly improved HbA1c and FPG levels, with positive effects on serum lipid levels and no evidence of drug-induced hepatotoxicity. These effects were maintained for >1.5 years, including the open-label extension.     

Multicenter,randomized, double-masked,parallel-group assessment of simultaneous glipizide/metformin as second-line pharmacologic treatment for patients with type 2 diabetes mellitus that is inadequately controlled by a sulfonylurea

BACKGROUND: Many patients with type 2 diabetes mellitus (DM) with inadequate long-term blood glucose control with sulfonylurea or metformin monotherapy require additional treatment. The synergistic effects of combining glipizide with metformin on glucose control may be realized by treating the primary effects of type 2 DM, impaired insulin secretion, and insulin resistance. OBJECTIVE: This study assessed therapy with glipizide/metformin combination tablets in patients with type 2 DM that is uncontrolled by at least half the maximum labeled daily dose of a sulfonylurea. METHODS: In this multicenter, double-masked, parallel-group, active-controlled study, patients were randomized to receive glipizide 30-mg, metformin 500-mg, or glipizide/metformin 5/500 mg tablets for 18 weeks (metformin and glipizide/metformin doses were titrated to achieve blood glucose control). Maximum total daily doses were glipizide 30 mg, metformin 2000 mg, and glipizide/ metformin 20/2000 mg. RESULTS: A total of 247 patients were included in the study. The mean (SD) age was 56.2 (10.1) years; 61.5% of patients were male; 70.0% were white, 15.8% were Hispanic/Latino, 13.0% were black, and 1.2% were Asian/Pacific Islanders. Patients were, on average, obese (mean [SD] body mass index, 31.3 [4.7] kg/m2), had moderate to severe hyperglycemia (mean [SD] glycated hemoglobin [HbA1c], 8.7% [1.1]), and had a mean (SD) DM duration of 6.5 (4.9) years. Glipizide/ metformin tablets controlled the HbA1c level more effectively than did either glipizide or metformin monotherapies (mean treatment differences, in favor of glipizide/ metformin, of -1.06% and -0.98%, respectively, P < 0.001). At study end, an HbA1c level < 7.0% was achieved in approximately 4-fold more patients who were treated with glipizide/metformin (36.3%) compared with glipizide (8.9%) or metformin (9.9%) monotherapies. Glipizide/metformin tablets also reduced the fasting plasma glucose (FPG) level and the 3-hour postprandial glucose area under the concentration-time curve more effectively than did either monotherapy, without increasing the fasting insulin level. The greater blood glucose control with glipizide/ metformin tablets was achieved at a mean daily dose of glipizide/metformin 17.5/1747 mg, compared with mean doses of glipizide 30.0 mg or metformin 1927 mg. Treatments were well tolerated, with a low incidence of symptoms of hypoglycemia evidenced by a fingerstick blood glucose measurement < or = 50 mg/dL in the combination group (12.6%); 1 patient discontinued the study treatment for this reason. No patient required medical assistance for hypoglycemia. CONCLUSIONS: Glipizide/metformin tablets were more effective than either glipizide or metformin monotherapy in controlling HbA1c and in reducing FPG compared with baseline in patients with blood glucose that was uncontrolled with previous sulfonylurea treatment. In addition, patients receiving glipizide/ metformin were more likely to achieve an HbA1c level < 7.0%. These results were consistent with the synergistic effects on insulin resistance and beta cell dysfunction. Glipizide/metformin was well tolerated, with a low incidence of hypoglycemia.     

Addition of nateglinide to rosiglitazone monotherapy suppresses mealtime hyperglycemia and improves overall glycemic control

OBJECTIVE: To determine the effects of nateglinide added to rosiglitazone monotherapy on glycemic control and on postprandial glucose and insulin levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This 24-week, multicenter, double-blind, randomized study compared the efficacy of nateglinide (120 mg a.c.) and placebo added to rosiglitazone monotherapy (8 mg q.d.) in 402 patients with type 2 diabetes with HbA(1c) between 7 and 11% (inclusive). Efficacy parameters tested included HbA(1c) and plasma glucose and insulin levels in the fasting state and after a standardized meal challenge. Safety data were also collected. RESULTS: In placebo-treated patients, HbA(1c) did not change (Delta = 0.0 +/- 0.1%). In patients randomized to nateglinide, HbA(1c) decreased from 8.3 to 7.5% (Delta = -0.8 +/- 0.1%, P < 0.0001 vs. placebo). Target HbA(1c) (<7.0%) was achieved by 38% of patients treated with combination therapy and by 9% of patients remaining on rosiglitazone monotherapy. In nateglinide-treated patients, fasting plasma glucose levels decreased by 0.7 mmol/l, 2-h postprandial glucose levels decreased by 2.7 mmol/l, and 30-min insulin levels increased by 165 pmol/l compared with no changes from baseline of these parameters with placebo added to rosiglitazone (P < 0.001). CONCLUSIONS: By selectively augmenting early insulin release and decreasing prandial glucose excursions, nateglinide produced a clinically meaningful improvement in overall glycemic exposure in patients with type 2 diabetes inadequately controlled with rosiglitazone. Therefore, nateglinide substantially improves the likelihood of achieving a therapeutic target of HbA(1c) <7.0%.     

Glycemic control in patients with type 2 diabetes mellitus switched from twice-daily immediate-release metformin to a once-daily extended-release formulation

BACKGROUND: The extended-release formulation of metformin (MXR) prolongs drug absorption in the upper gastrointestinal tract and permits once-daily dosing in patients with type 2 diabetes mellitus. This newer formulation may enhance patient compliance with oral therapy and improve long-term control of diabetes compared with the conventional immediate-release formulation of metformin (MIR). OBJECTIVE: The goal of this study was to determine the effects on glycemic control of a switch to MXR therapy in patients with type 2 diabetes currently treated with MIR. METHODS: This was a multicenter, randomized, double-blind, parallel-group study in patients with established type 2 diabetes. Eligible patients were to have a glycated hemoglobin (HbA1c) value < or = 8.5% and mean fasting plasma glucose (FPG) concentrations < or = 200 mg/dL while receiving MIR 500 mg BID for at least 8 weeks. After a 2-week, single-blind lead-in period, patients were randomly assigned to receive MXR 1000 or 1500 mg QD for 24 weeks or to continue MIR 500 mg BID for 24 weeks. The primary efficacy variable was change in HbA1c from baseline to week 12. Other variables included change in FPG levels; change in HbA1c; distribution of HbA1c values; mean daily blood glucose concentrations (self-monitored); levels of fructosamine, serum insulin, and lipids; and body weight. RESULTS: Two hundred seventeen patients were randomized to treatment. The mean change from baseline in HbA1c values at weeks 12 and 24 were small and similar in the 3 treatment groups. At week 12, the mean change from baseline in HbA1c was 0.15% for MIR, 0.23% for MXR 1000 mg, and 0.04% for MXR 1500 mg. The corresponding mean changes at week 24 were 0.06%, 0.25%, and 0.14%. CONCLUSIONS: In this study, patients with type 2 diabetes who had been receiving twice-daily MIR achieved comparable glycemic control when therapy was switched to once-daily MXR at the same or a greater total daily dose.