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.     

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.     

Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes

OBJECTIVE: To assess the 12- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 versus placebo in patients with type 2 diabetes continuing metformin treatment. RESEARCH DESIGN AND METHODS: We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 107 patients with type 2 diabetes with a 40-week extension in those completing the core study and agreeing, together with the investigator, to extend treatment to 1 year. Placebo (n=51) or LAF237 (50 mg once daily, n=56) was added to ongoing metformin treatment (1,500-3,000 mg/day). HbA1c and fasting plasma glucose (FPG) were measured periodically, and standardized meal tests were performed at baseline, week 12, and week 52. RESULTS: In patients randomized to LAF237, baseline HbA1c averaged 7.7 +/- 0.1% and decreased at week 12 (Delta=-0.6 +/- 0.1%), whereas HbA1c did not change from a baseline of 7.9 +/- 0.1% in patients given placebo (between-group difference in DeltaHbA1c=-0.7 +/- 0.1%, P <0.0001). Mean prandial glucose and FPG were significantly reduced in patients receiving LAF237 versus placebo by 2.2 +/- 0.4 mmol/l (P <0.0001) and 1.2 +/- 0.4 mmol/l (P=0.0057), respectively, but plasma insulin levels were not affected. At end point of the extension, the between-group differences in change in mean prandial glucose, insulin, and FPG were -2.4 +/- 0.6 mmol/l (P=0.0001), 40 +/- 16 pmol/l (P=0.0153), and -1.1 +/- 0.5 mmol/l (P=0.0312), respectively. HbA1c did not change from week 12 to week 52 in LAF237-treated patients (n=42) but increased in participants given placebo (n=29). The between-group difference in DeltaHbA1c after 1 year was -1.1 +/- 0.2% (P <0.0001). CONCLUSIONS: Data from this study demonstrate that LAF237 effectively prevents deterioration of glycemic control when added to metformin monotherapy in type 2 diabetes.     

Efficacy and safety of combination therapy: repaglinide plus metformin versus nateglinide plus metformin

OBJECTIVE: An open-label, parallel-group, randomized, multicenter trial was conducted to compare efficacy and safety of repaglinide versus nateglinide, when used in a combination regimen with metformin for treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS: Enrolled patients (n = 192) had HbA(1c) >7% and < or =12% during previous treatment with a sulfonylurea, metformin, or low-dose Glucovance (glyburide < or =2.5 mg, metformin < or =500 mg). After a 4-week metformin run-in therapy period (doses escalated to 1,000 mg b.i.d.), patients were randomized to addition of repaglinide (n = 96) (1 mg/meal, maximum 4 mg/meal) or nateglinide (n = 96) (120 mg/meal, reduced to 60 mg if needed) to the regimen for 16 weeks. Glucose, insulin, and glucagon were assessed after a liquid test meal at baseline and week 16. RESULTS: Final HbA(1c) values were lower for repaglinide/metformin treatment than for nateglinide/metformin (7.1 vs. 7.5%). Repaglinide/metformin therapy showed significantly greater mean reductions of HbA(1c) (-1.28 vs. -0.67%; P < 0.001) and of fasting plasma glucose (FPG) (-39 vs. -21 mg/dl; P = 0.002). Self-monitoring of blood glucose profiles were significantly lower for repaglinide/metformin before breakfast, before lunch, and at 2:00 A.M. Changes in the area under the curve of postprandial glucose, insulin, or glucagon peaks after a test meal were not significantly different for the two treatment groups during this study. Median final doses were 5.0 mg/day for repaglinide and 360 mg/day for nateglinide. Safety assessments were comparable for the two regimens. CONCLUSIONS: The addition of repaglinide to metformin therapy resulted in reductions of HbA(1c) and FPG values that were significantly greater than the reductions observed for addition of nateglinide.     

Importance of early insulin secretion: comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes

OBJECTIVE--This study compared the effects of nateglinide, glyburide, and placebo on postmeal glucose excursions and insulin secretion in previously diet-treated patients with type 2 diabetes. RESEARCH DESIGN AND METHODS--This randomized, double-blind, placebo-controlled multicenter study was conducted in 152 patients who received either nateglinide (120 mg before three meals daily, n = 51), glyburide (5 mg q.d. titrated to 10 mg q.d. after 2 weeks, n = 50), or placebo (n = 51) for 8 weeks. Glucose, insulin, and C-peptide profiles during liquid meal challenges were measured at weeks 0 and 8. At weeks -1 and 7, 19-point daytime glucose and insulin profiles, comprising three solid meals, were measured. RESULTS--During the liquid-meal challenge, nateglinide reduced the incremental glucose area under the curve (AUC) more effectively than glyburide ( = -4.94 vs. -2.71 mmol. h/l, P < 0.05), whereas glyburide reduced fasting plasma glucose more effectively than nateglinide ( = -2.9 vs. -1.0 mmol/l, respectively, P < 0.001). In contrast, C-peptide induced by glyburide was greater than that induced by nateglinide ( = +1.83 vs. +0.95 nmol. h/l, P < 0.01), and only glyburide increased fasting insulin levels. During the solid meal challenges, nateglinide and glyburide elicited similar overall glucose control ( 12-h incremental AUC = -13.2 vs. -15.3 mmol. h/l), but the insulin AUC induced by nateglinide was significantly less than that induced by glyburide ( 12-h AUC = +866 vs. +1,702 pmol. h/l, P = 0.01). CONCLUSIONS--This study demonstrated that nateglinide selectively enhanced early insulin release and provided better mealtime glucose control with less total insulin exposure than glyburide.     

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.     

Control of postprandial hyperglycemia: optimal use of short-acting insulin secretagogues

OBJECTIVE: This study was designed to compare the efficacy of acute premeal administration of glipizide versus nateglinide in controlling postprandial hyperglycemia in subjects with non-insulin-requiring type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 20 subjects (10 female, 10 male) with non-insulin-requiring type 2 diabetes were admitted overnight to the General Clinical Research Center on four occasions. In random order, 10 mg glipizide (30 min premeal), 120 mg nateglinide (15 min premeal), 10 mg glipizide plus nateglinide (30 and 15 min premeal, respectively), or placebo pills (30 and 15 min premeal) were administered in a double-blind fashion before a standardized breakfast. Blood was drawn for analysis of glucose, insulin, and C-peptide at -0.05, 0, 0.5, 1, 2, 3, and 4 h relative to the meal. RESULTS: The subjects were aged 56 +/- 2 years and were moderately obese (BMI 31 +/- 1 kg/m(2)), with a mean HbA(1c) of 7.4 +/- 0.4%. The peak postprandial glucose excursion above baseline was higher with placebo (6.1 +/- 0.5 mmol/l) than glipizide (4.3 +/- 0.6 mmol/l, P = 0.002), nateglinide (4.2 +/- 0.4 mmol/l, P = 0.001), or glipizide plus nateglinide (4.1 +/- 0.5 mmol/l, P = 0.001). The area under the curve for the glucose excursion above baseline was also higher with placebo (14.1 +/- 1.8 mmol/h. l) compared with glipizide (6.9 +/- 2.4 mmol/h. l, P = 0.002), nateglinide (9.7 +/- 2 mmol/h. l, P = 0.004), or glipizide plus nateglinide (5.6 +/- 2.2 mmol/h. l, P < 0.001). Peak and integrated glucose excursions did not differ significantly between glipizide and nateglinide. However, by 4 h postmeal, plasma glucose levels were significantly higher with nateglinide (9 +/- 0.9 mmol/l) compared with the premeal baseline (7.8 +/- 0.6 mmol/l, P = 0.04) and compared with the 4-h postprandial glucose level after administration of glipizide (7.6 +/- 0.6 mmol/l, P = 0.02). Integrated postprandial insulin levels were higher with glipizide (1,556 +/- 349 pmol/h. l) than nateglinide (1,364 +/- 231 pmol/h. l; P = 0.03). Early insulin secretion, as measured by insulin levels at 30 min postmeal, did not differ between glipizide and nateglinide. CONCLUSIONS: Acute premeal administration of nateglinide or glipizide has equal efficacy in controlling postbreakfast hyperglycemia in type 2 diabetes when each drug is administered at the optimum time before the meal. Glipizide causes a more pronounced and sustained postmeal insulin secretory response compared with nateglinide. Glipizide facilitates the return to near-fasting glucose levels at 4 h postmeal, but with the possible risk of increased frequency of postmeal hypoglycemia in drug-naive patients. The clinical decision to use glipizide versus nateglinide should be based on factors other than the control of postprandial hyperglycemia in type 2 diabetes.     

Efficacy and Safety of Switching From the DPP-4 Inhibitor Sitagliptin to the Human GLP-1 Analog Liraglutide After 52 Weeks in Metformin-Treated Patients With Type 2 Diabetes: A randomized, open-label trial

OBJECTIVE To assess the efficacy and safety of switching from sitagliptin to liraglutide in metformin-treated adults with type 2 diabetes. RESEARCH DESIGN AND METHODS In an open-label trial, participants randomized to receive either liraglutide (1.2 or 1.8 mg/day) or sitagliptin (100 mg/day), each added to metformin, continued treatment for 52 weeks. In a 26-week extension, sitagliptin-treated participants were randomly allocated to receive instead liraglutide at either 1.2 or 1.8 mg/day, while participants originally randomized to receive liraglutide continued unchanged. RESULTS Although 52 weeks of sitagliptin changed glycosylated hemoglobin (HbA(1c)) by -0.9% from baseline, additional decreases occurred after switching to liraglutide (1.2 mg/day, -0.2%, P = 0.006; 1.8 mg/day, -0.5%, P = 0.0001). Conversion to liraglutide was associated with reductions in fasting plasma glucose (FPG) (1.2 mg/day, -0.8 mmol/L, P = 0.0004; 1.8 mg/day, -1.4 mmol/L, P < 0.0001) and body weight (1.2 mg/day, -1.6 kg; 1.8 mg/day, -2.5 kg; both P < 0.0001) and with an increased proportion of patients reaching HbA(1c) <7% (from ～30% to ～50%). Overall treatment satisfaction, assessed by the Diabetes Treatment Satisfaction Questionnaire, improved after switching to liraglutide (pooled 1.2 and 1.8 mg/day, 1.3; P = 0.0189). After switching, mostly transient nausea occurred in 21% of participants, and minor hypoglycemia remained low (3-4% of participants). Continuing liraglutide treatment at 1.2 mg/day and 1.8 mg/day for 78 weeks reduced HbA(1c) (baseline 8.3 and 8.4%, respectively) by -0.9 and -1.3%, respectively; FPG by -1.3 and -1.7 mmol/L, respectively; and weight by -2.6 and -3.1 kg, respectively, with 9-10% of participants reporting minor hypoglycemia. CONCLUSIONS Glycemic control, weight, and treatment satisfaction improved after switching from sitagliptin to liraglutide, albeit with a transient increase in gastrointestinal reactions.     

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%.     

Efficacy of benfluorex in combination with sulfonylurea in type 2 diabetic patients: an 18-week, randomized, double-blind study

OBJECTIVE: The aim of this study was to demonstrate the superiority of benfluorex over placebo as an add-on therapy in type 2 diabetic patients in whom diabetes is insufficiently controlled by sulfonylurea monotherapy and who have a limitation for the use of metformin. RESEARCH DESIGN AND METHODS: Type 2 diabetic patients with HbA(1c) (A1C) (7-10%) who were receiving the maximum tolerated sulfonylurea dose and had a contraindication to or poor tolerance of metformin were randomly assigned (double blind) to receive benfluorex 450 mg/day (n = 165) or placebo (n = 160) for 18 weeks. The main efficacy criterion was A1C, analyzed as the change from baseline to the end of treatment using ANCOVA with baseline and country as covariates. Secondary criteria were fasting plasma glucose (FPG), insulin resistance, and plasma lipid level. RESULTS: Both groups were similar at baseline in the intention-to-treat population. A1C significantly decreased with benfluorex from 8.34 +/- 0.83 to 7.52 +/- 1.04% (P < 0.001) and tended to increase with placebo from 8.33 +/- 0.87 to 8.52 +/- 1.36% (NS), resulting in a mean adjusted difference between groups of -1.01% (95% CI -1.26 to -0.76; P < 0.001). The target A1C (< or =7%) was achieved in 34% of patients receiving benfluorex versus 12% of patients receiving placebo. Significant between-group differences in favor of benfluorex were observed for mean FPG (-1.65 mmol/l) (P < 0.001) and for homeostasis model assessment of insulin resistance. Overall tolerance was similar in both groups. Serious adverse events were more frequent in the benfluorex group, without evidence of causality relationship. CONCLUSIONS: Benfluorex as an add-on therapy was superior to placebo in lowering A1C with a between-group difference of 1% in type 2 diabetic patients whose disease was insufficiently controlled with sulfonylurea alone and in whom metformin was contraindicated or not tolerated.     

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.     

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.     

Improving metabolic control leads to better working memory in adults with type 2 diabetes

OBJECTIVE: The goals of this study were to determine whether improvements in metabolic control can ameliorate the cognitive dysfunction associated with type 2 diabetes and evaluate the possibility that such improvements are mediated by changes in circulating insulin or insulin resistance. RESEARCH DESIGN AND METHODS: This randomized double-blind trial enrolled 145 subjects at 18 centers in the U.S. Older adults with type 2 diabetes receiving metformin monotherapy received add-on therapy with either rosiglitazone, a thiazolidinedione insulin sensitizer, or glyburide. Cognitive function was assessed at baseline and week 24 using the Digit Symbol Substitution Test, the Rey Auditory Verbal Learning Test, and the Cambridge Neuropsychological Test Automated Battery. RESULTS: Pretreatment fasting plasma glucose (FPG) in both groups was similar, and after 24 weeks both treatment groups showed similar significant reductions in FPG (2.1-2.3 mmol/l). Working memory improved with both rosiglitazone (P < 0.001) and glyburide (P = 0.017). Improvement (25-31% reduction in errors) was most evident on the Paired Associates Learning Test and was significantly correlated (r = 0.30) with improved glycemic control as measured by FPG. CONCLUSIONS: Similar and statistically significant cognitive improvement was observed with both rosiglitazone and glyburide therapy, and the magnitude of this effect was correlated with the degree to which FPG improved. These results suggest that a cognitive benefit is achievable with pharmacological interventions targeting glycemic control.     

Effects of metformin and rosiglitazone monotherapy on insulin-mediated hepatic glucose uptake and their relation to visceral fat in type 2 diabetes

OBJECTIVE: Impaired insulin-mediated hepatic glucose uptake (HGU) has been implicated in the hyperglycemia of type 2 diabetes. We examined the effects of metformin (2 g/day) and rosiglitazone (8 mg/day) monotherapy on HGU and its relation to subcutaneous fat, visceral fat (VF), and whole-body insulin-mediated glucose metabolism in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Glucose uptake was measured before and after 26 weeks of treatment using positron emission tomography with [(18)F]2-fluoro-2-deoxyglucose during euglycemic hyperinsulinemia; fat depots were quantified by magnetic resonance imaging. RESULTS: Fasting plasma glucose levels were significantly decreased after either rosiglitazone (-0.9 +/- 0.5 mmol/l) or metformin treatment (-1.1 +/- 0.5 mmol/l) in comparison with placebo; only metformin was associated with weight loss (P < 0.02 vs. placebo). When controlling for the latter, the placebo-subtracted change in whole-body glucose uptake averaged -1 +/- 4 micromol x min(-1) x kg(-1) in metformin-treated patients (NS) and +9 +/- 3 micromol x min(-1) x kg(-1) in rosiglitazone-treated patients (P = 0.01). Both rosiglitazone and metformin treatment were associated with an increase in HGU; versus placebo, the change reached statistical significance when controlling for sex (placebo-subtracted values = +0.008 +/- 0.004 micromol x min(-1) x kg(-1) x pmol/l(-1), P < 0.03, for metformin; and +0.007 +/- 0.004, P < 0.07, for rosiglitazone). After treatment with either drug, insulin-mediated VF glucose uptake (VFGU) was higher than with placebo. In the whole dataset, changes in HGU were negatively related to changes in HbA(1c) (r = 0.43, P = 0.01) and positively associated with changes in VFGU (r = 0.48, P < 0.01). CONCLUSIONS: We conclude that both metformin and rosiglitazone monotherapy increase HGU in type 2 diabetes; direct drug actions, better glycemic control, and enhanced VF insulin sensitivity are likely determinants of this phenomenon.     

Comparison of glargine insulin versus rosiglitazone addition in poorly controlled type 2 diabetic patients on metformin plus sulfonylurea

OBJECTIVE: We sought to examine the mechanisms by which the addition of glargine insulin or rosiglitazone improves glycemic control in type 2 diabetic subjects poorly controlled on maximally effective doses of metformin plus sulfonylurea. RESEARCH DESIGN AND METHODS: Subjects (aged 47 +/- 11 years, BMI 31 +/- 5 kg/m(2), HbA(1c) [A1C] 9.4 +/- 1.3%) received bedtime glargine insulin (titrated based on the fasting plasma glucose [FPG], n = 10) or rosiglitazone (4 mg twice daily, n = 10). At baseline and after 4 months, A1C was measured and an oral glucose tolerance test and a 3-h euglycemic insulin (80 mU/m(2) per min) clamp with [3-(3)H]glucose were performed. RESULTS: A1C and FPG decreased similarly in the glargine insulin (9.1 +/- 0.4 to 7.6 +/- 0.3% and 212 +/- 14 to 139 +/- 5 mg/dl, respectively, both P < 0.0001) and rosiglitazone (9.4 +/- 0.3 to 7.6 +/- 0.4% and 223 +/- 14 to 160 +/- 19 mg/dl, respectively, both P < 0.005) groups. After 4 months, endogenous glucose production (EGP) declined similarly with glargine insulin (2.27 +/- 0.10 to 1.73 +/- 0.12 mg . kg(-1) . min(-1), P < 0.0001) and rosiglitazone (2.21 +/- 0.12 to 1.88 +/- 0.12 mg . kg(-1) . min(-1), P = 0.01). The hepatic insulin resistance index declined in the rosiglitazone group (32 +/- 3 to 21 +/- 1 mg . kg(-1) . min(-1) x microU/ml, P = 0.03 vs. baseline and P < 0.05 vs. glargine insulin) and did not change in the glargine group (22 +/- 5 to 20 +/- 3 mg . kg(-1) . min(-1) x microU/ml, P = NS). At 4 months, glargine insulin (3.6 +/- 0.5 to 4.2 +/- 0.4 mg . kg(-1) . min(-1), P < 0.01) and rosiglitazone (2.7 +/- 0.3 to 3.8 +/- 0.3 mg . kg(-1) . min(-1), P < 0.0005) increased R(d), but the increment was greater in the rosiglitazone group (P < 0.05). Diastolic blood pressure was reduced only by rosiglitazone (P < 0.01). CONCLUSIONS: Triple therapy with glargine insulin or rosiglitazone similarly reduced A1C, primarily by suppressing basal EGP (hepatic). Glargine insulin reduced basal EGP by increasing plasma insulin levels, while rosiglitazone decreased basal hepatic glucose production by improving hepatic insulin sensitivity.     

Glycemic control with Humalog Mix25 in type 2 diabetes inadequately controlled with glyburide.

BACKGROUND: Humalog Mix25 (Mix25) is a premixed insulin mixture of 25% insulin lispro and 75% neutral protamine lispro. OBJECTIVE: The aim of this study was to quantitate the improvement in glycemic control achieved with Mix25 versus the maximum dose of glyburide (GB) in patients with type 2 diabetes inadequately controlled with GB. METHODS: In this randomized, parallel, open-label comparative study, patients with type 2 diabetes received either Mix25 before the morning and evening meals for 4 months or GB 15 mg daily for 4 months. Glycemic control was assessed by glycosylated hemoglobin (HbA1c) measurements, 4-point self-monitored blood glucose profiles, and patient-reported hypoglycemia. Patients also completed a treatment satisfaction questionnaire at the end of the study. RESULTS: All 172 patients were white; 85 were randomized to receive Mix25. The mean age was 59.5 +/- 8.2 years, and 35.5% (61/172) were men. The mean body mass index was 27.2 kg/m2. The mean duration of type 2 diabetes was 10.2 +/- 6.6 years, and the mean duration of sulfonylurea treatment was 5.8 +/- 5.9 years. The mean HbA1c and fasting blood glucose levels were 10.07% +/- 1.4% and 11.6 +/- 2.8 mmol/L, respectively, in the glyburide group and 9.85% +/- 1.2% and 12.2 +/- 2.9 mmol/L, respectively, in the Mix25 group. There were no statistically significant differences between the treatment groups at baseline for any of the demographic or efficacy variables. At end point, mean HbA1c was significantly lower in the Mix25 group than in the GB group (Mix25, 8.5% +/- 1.3%; GB, 9.4% +/- 1.8%; P = 0.001). A larger decrease from baseline in HbA1c and in all self-monitored blood glucose values was observed in the Mix25 group: -1.4% versus -0.7% for HbA1c, P = 0.004; -2.8 mmol/L versus -1.1 mmol/L for fasting blood glucose, P < 0.01; -5.1 mmol/L versus -1.7 mmol/L for the morning 2-hour postprandial blood glucose, P < 0.001; -2.2 mmol/L versus -0.8 mmol/L for the evening preprandial blood glucose, P < 0.05; and -4.4 mmol/L versus -1.5 mmol/L for the evening 2-hour postprandial blood glucose, P < 0.001. Patients expressed more satisfaction with Mix25 than with GB, as measured by the weighted combined score on a treatment satisfaction questionnaire (2.0 +/- 1.3 vs 0.7 +/- 1.3). The mean hypoglycemia rate (events per patient per 30 days) was significantly higher in the Mix25 group at end point (Mix25, 0.30 +/- 0.53; GB, 0.05 +/- 0.20; P < 0.001). CONCLUSIONS: Compared with maximum-dose GB, twice-daily injections of Mix25 resulted in improved glycemic control and treatment satisfaction, and were associated with a predictably higher rate of hypoglycemia in this group of patients with type 2 diabetes who were inadequately controlled with maximum-dose GB. Although the inclusion of patients who were inadequately controlled with GB was intended to allow a comparison of the 2 treatments with respect to efficacy and tolerability in a real-life setting, a double-blind comparison in treatment-naive individuals may have resulted in a different outcome.     

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.     

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.     

Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year

OBJECTIVE: To examine the effects of dipeptidyl peptidase-IV (DPP-4) inhibition on meal-related beta-cell function and insulin sensitivity over 52 weeks in type 2 diabetes. RESEARCH DESIGN AND METHODS: In a 12-week core study, placebo (n = 51) or vildagliptin (n = 56; 50 mg OD) was added to metformin treatment (1.5-3.0 mg/day). A 40-week extension followed in 71 patients. Meal tests were performed at 0, 12, 24, and 52 weeks; glucose, insulin, and C-peptide were evaluated. RESULTS: In subjects completing 52 weeks with participation in all meal tests (n = 57), HbA(1c) (A1C) decreased in the vildagliptin/metformin group (VM group, n = 31) but increased in the placebo/metformin group (PM group, n = 26; between-group difference -1.0 +/- 0.2%; P < 0.001; baseline of all subjects combined 7.7 +/- 0.1%). Also, fasting glucose decreased in the VM group but increased in the PM group (difference -0.9 +/- 0.3 mmol/l, P = 0.016; baseline 9.8 +/- 0.3 mmol/l). Insulin secretion (postmeal suprabasal area under the 0- to 30-min C-peptide curve divided by the 30-min increase in glucose) was increased in the VM group but was reduced in the PM group (difference +0.011 +/- 0.03 pmol/l 30 min/mmol/l, P = 0.018; baseline 0.036 +/- 0.02). Insulin sensitivity during meal ingestion (oral glucose insulin sensitivity) increased in the VM group but was not altered in the PM group (difference +27 +/- 4 ml x min(-1) x m(-2), P = 0.036; baseline 246 +/- 6). Insulin secretion related to insulin sensitivity (adaptation index) increased in the VM group but decreased in the PM group (difference +3.2 +/- 1.0, P = 0.040; baseline 9.1 +/- 0.5). The change in adaptation index correlated to the change in A1C (r = -0.39, P = 0.004). CONCLUSIONS: This study presents evidence that DPP-4 inhibition by vildagliptin when added to metformin in type 2 diabetes over 52 weeks improves beta-cell function along with improved postmeal insulin sensitivity.     

A randomized trial of sibutramine in the management of obese type 2 diabetic patients treated with metformin

OBJECTIVE: To evaluate the effects of sibutramine (15 and 20 mg/day) on weight, metabolic control, and blood pressure in metformin-treated obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: A 12-month randomized prospective placebo-controlled double-blind study was performed. It included 21 primary and secondary care centers in England, Canada, France, and Belgium. A total of 195 subjects (44% male) with type 2 diabetes and a BMI >27 kg/m(2) were studied. Changes were assessed in weight, blood pressure and resting heart rate, HbA(1c), fasting glucose, and lipids. RESULTS: Sibutramine induced significant weight loss (P < 0.001) with both 15 mg/day (5.5 +/- 0.6 kg at 12 months) and 20 mg/day (8.0 +/- 0.9 kg), whereas placebo did not (0.2 +/- 0.5 kg). Weight loss > or = 10% was achieved by 14 and 27% of subjects receiving 15 and 20 mg, respectively, but by none given placebo. Glycemic control improved in parallel with weight loss, and subjects who lost > or = 10% weight showed significant decreases in both HbA(1c) (1.2 +/- 0.4%, P < 0.0001) and fasting plasma glucose (1.8 mmol/l, P < 0.001). HDL cholesterol increased slightly with the higher dose, whereas plasma triglycerides fell with both doses, especially in subjects with weight loss of > or = 10% (a 29% decrease, P < 0.01). Treatment was generally well tolerated. Sibutramine treatment raised sitting diastolic blood pressure by > or = 5 mmHg in a higher proportion of patients than did placebo (43% with 15 mg/day vs. 25% with placebo, P < 0.05), but this effect was less evident in subjects who had a weight loss of > or = 10% weight. Pulse rate increased significantly more with sibutramine, being > or = 10 bpm higher in 42% of treated patients versus 17% with placebo (P < 0.01). CONCLUSIONS: Sibutramine can be an effective adjunct to metformin treatment in selected obese type 2 diabetic subjects and improves metabolic control in individuals who lose weight.