Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure. Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients. [The effectiveness of combined insulin and sulfonylurea in treating non-insulin dependent diabetic patients]. Glyburide decreases insulin requirement, increases beta-cell response to mixed meal, and does not affect insulin sensitivity: effects of short- and long-term combined treatment in secondary failure to sulfonylurea. Effects of combination therapy with glyburide and insulin on serum lipid levels in NIDDM patients with secondary sulfonylurea failure. Combined therapy for obese type 2 diabetes: suppertime mixed insulin with daytime sulfonylurea. [Combination therapy with insulin/sulfonylurea in the long-term therapy of type II diabetes following "secondary failure"]. Beginning insulin treatment of obese patients with evening 70/30 insulin plus glimepiride versus insulin alone. Glimepiride Combination Group. [Long-term effect of combination glibenclamide-insulin treatment in the secondary failure of sulfonylurea therapy--results of a one-year double blind study]. Bedtime insulin/daytime glipizide. Effective therapy for sulfonylurea failures in NIDDM. Comparison of different insulin regimens in elderly patients with NIDDM. [The effects of insulin combined with glibenclamide on glucose and lipid metabolism in patients with Type II diabetes mellitus]. Efficacy of bedtime NPH insulin with daytime sulfonylurea for subpopulation of type II diabetic subjects. Insulin versus a combination of insulin and sulfonylurea in the treatment of NIDDM patients with secondary oral failure. Combined therapy with glibenclamide and ultralente insulin in lean patients with NIDDM with secondary failure of sulfonylureas. Follow up at two years. Causes of weight gain during insulin therapy with and without metformin in patients with Type II diabetes mellitus. Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. Sulphonylurea failure in type 2 diabetes: treatment with a basal insulin supplement. [Effectiveness of combined treatment with glibenclamide and insulin in secondary sulfonylurea failure. A controlled multicenter double-blind clinical trial]. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial.
This study assessed the safety profile and efficacy of a new combination therapy (insulin lispro plus sulfonylurea) in patients with type 2 diabetes mellitus experiencing secondary oral agent failure. A total of 423 patients were randomly assigned to 3 treatment groups: preprandial insulin lispro plus sulfonylurea (L + S), bedtime neutral protamine Hagedorn (NPH) insulin plus sulfonylurea (N + S), and preprandial insulin lispro plus bedtime NPH insulin (L + N). Mean decreases in glycosylated hemoglobin from baseline were 1.60%+/-1.27% for patients receiving L + S, 1.21%+/-1.21% for those receiving N + S, and 1.40%+/-1.46% for those receiving L + N (within treatment, P<0.001; for L + S vs. N + S, P = 0.003). Fasting blood glucose level was higher in patients receiving L + S (171+/-46.5 mg/dL) or L + N (166+/-52.5 mg/dL) than in those receiving N + S (144+/-48.2 mg/dL) (P<0.001, for both comparisons). Conversely, postprandial blood glucose level was lower in patients receiving L + S (165+/-41.6 mg/dL) or L + N (165+/-46.3 mg/dL) than in those receiving N + S (213+/-58.3 mg/dL) (P<0.001, for both comparisons). The overall rate of hypoglycemia (episodes per 30 days) was not statistically significant when the L + S, N + S, and L + N therapies were compared (0.99+/-1.74 vs. 0.87+/-2.31 vs. 1.16+/-2.38, respectively). The rate of nocturnal hypoglycemia was lowest in the L + S group (0.00+/-0.00 vs. 0.10+/-0.37 for the N + S group vs. 0.15+/-0.54 for the L + N group; P = 0.004). L + S, which has a safety profile equal to those of N + S and L + N, is an effective treatment for patients with type 2 diabetes who experience oral sulfonylurea agent failure. L + S offers an alternative to these established combination therapies in patients whose type 2 diabetes cannot be controlled with a sulfonylurea alone. Optimal insulin regimens for non-insulin-dependent diabetes mellitus (NIDDM) patients with secondary failure are controversial. We evaluated the efficacy, side effects, and quality of life of patients receiving insulin either alone or in combination with their previous oral hypoglycemic agents (OHAs).
                Fifty-three Chinese patients with NIDDM (mean age 53.9 +/- 12.6 years, duration of diabetes 9.0 +/- 4.9 years, body wt 60.4 +/- 13.3 kg with corresponding body mass index 24.2 +/- 4.3 kg/m2, receiving the maximum dose of sulfonylurea and/or metformin) were confirmed to have OHA failure. Twenty-seven patients were randomized to continue OHAs and were given additional bedtime insulin (combination group); 26 patients were randomized to insulin therapy alone with twice-daily insulin (insulin group). Insulin doses were increased incrementally, aiming at fasting plasma glucose (FPG) < 7.8 mmol/l during a stabilization period of up to 8 weeks. Insulin dosage, body weight, glycemic control, and quality of life were assessed before and at 3 and 6 months after stabilization.
                Both groups showed similar improvement of glycemic control. For the combination group, FPG decreased from 13.5 +/- 2.7 to 8.9 +/- 3.0 mmol/l at 3 months (P < 0.0001) and to 8.6 +/- 2.5 mmol/l at 6 months (P < 0.0001). For the insulin group, FPG decreased from 13.5 +/- 3.6 to 7.5 +/-3.0 mmol/l at 3 months (P < 0.0001) and to 9.8 +/- 3.5 mmol/l at 6 months (P < 0.0001). No significant differences were observed between the groups. Similarly, both groups had significant improvement of fructosamine and glycosylated hemoglobin (HbA1c). Fructosamine fell from a mean of 458 to 365 mumol/l at 3 months (P < 0.0001) and to 371 mumol/l at 6 months (P < 0.0001) and from 484 to 325 mumol/l at 3 months (P < 0.0001) and to 350 mumol/l at 6 months (P < 0.0001) for the combination and insulin groups, respectively. HbA1c decreased from 10.2 to 8.4% at 3 months (P < 0.0001) and to 8.7% at 6 months (P < 0.0001) in the combination group and from 10.7 to 7.8% at 3 months (P < 0.0001) and to 8.4% at 6 months (P < 0.0001) in the insulin group. Despite similar improvement of glycemia, insulin requirements were very different. At 3 months, the combination group was receiving a mean of 14.4 U/day compared with 57.5 U/day in the insulin group (P < 0.0001). Similar findings were observed at 6 months (15.0 vs 57.2 U/day, P < 0>0001). Both groups gained weight. However, for the combination group, weight gain was 1.6 +/- 1.8 kg at 3 months and 2.1 +/- 2.5% kg at 6 months (both P < 0.0001 vs baseline), whereas for the insulin group, weight gain was 3.5 +/- 4.3 and 5.2 +/- 4.1 kg, respectively (both P < 0.0001 vs baseline). Weight gain was significantly greater in the insulin group (P < 0.05 at 3 months, and P < 0.005 at 6 months). Fasting plasma triglyceride decreased in the insulin group (1.8 +/- 1.0 to 1.4 +/- 0.8 mmol/l at 3 months [P < 0.005] and to 1.4 +/ 0.7 mmol/l at 6 months [P < 0.02] but not in the combination group. No changes were observed in total and high-density lipoprotein cholesterol. No severe hypoglycemic reactions were recorded in either group. Mild reactions occurred with similar frequency in both groups. Well-being and quality of life improved significantly in both groups. The majority of patients (82.7%) wanted to continue insulin beyond 6 months, irrespective of the treatment group.
                In NIDDM patients with secondary OHA failure, therapy with a combination of OHAs and insulin and with insulin alone was equally effective and well tolerated. However, combination therapy was associated with a lower insulin dose and less weight gain. Combination treatment may be considered when OHA failure occurs as a potential intermediate stage before full insulin replacement. The effectiveness of combined therapy with insulin and sulfonylurea in non-insulin dependent diabetes mellitus (NIDDM) patients has, for decades, been a debated issue. In order to probe this question, we studied 33 diabetes mellitus patients aged 40 years and over, having a history of this disease for more than 5 years, treated with one of the sulfonylureas at maximal dosage for three weeks but without effect. These 33 cases were divided into three groups randomly: group A: treated with glurenorm and insulin. B insulin and C glurenorm. The treatment lasted 4 months. During the course of the trial, estimation of the free-insulin, C-peptide, blood glucose etc. was carried out three times i.e. one before the trial and then 2, 4 months after the trial. The data were dealed with U-test and comparison was made before and after the trial and between the three groups. It is shown that combined therapy with sulfonylurea and insulin is effective in NIDDM patients, especially in those with secondary failure of beta-cell function and the combined therapy may be used in NIDDM patients during the transitional period from treatment with sulfonylurea alone to traditional insulin cure. In 20 patients with non-insulin-dependent diabetes mellitus (NIDDM) and secondary failure to sulfonylurea, a double-blind randomized study was performed comparing two regimes: insulin plus placebo (IP) and insulin plus glyburide (IG). The protocol included two hospitalization periods (days 1-18 and 78-85) and follow-up at the outpatient clinic for 325 days. The metabolic control was kept as tight as possible. The subjects underwent normoglycemic clamp studies and meal tests with determination of insulin, C-peptide, glucagon, somatostatin, and gastric inhibitory polypeptide in plasma. On IG, they demonstrated marked and long-lasting improvement of metabolic control: HbA1c decreased from 11.1 +/- 0.3% on day 3 to 8.3 +/- 0.4% (P less than .001) on day 78 and 9.1 +/- 0.5% (P less than .001) on day 325. In subjects on IP, the corresponding values were 10.3 +/- 0.5, 8.4 +/- 0.4 (P less than .001), and 8.9 +/- 0.5% (P less than .05). Body weight increased by 6.0 +/- 1.5 kg (P less than .005) on IG and 2.9 +/- 2.1 kg (NS) on IP. The daily insulin requirement decreased on IG from 62.5 +/- 12.9 U/day on day 7 to 33.5 +/- 8.8 U/day on day 83 and 34.6 +/- 8.9 U/day on day 325. On IP the insulin requirement was almost constant: 62.0 +/- 10.7 U/day on day 7, 55.5 +/- 7.7 U/day on day 83, and 54.7 +/- 7.9 U/day on day 325. Insulin sensitivity measured with the hyperinsulinemic clamp (plasma insulin approximately equal to 130 microU/ml) was similar on IP and IG at the initiation of the study and was unchanged on days 18 and 85. A key observation of this study, although the mechanism is unclear, is that isoglycemic-meal-related insulin requirement was diminished by insulin treatment, indicating improvement of meal-related insulin sensitivity. Glyburide increased basal and meal-but not glucagon-stimulated insulin and C-peptide levels, and also augmented the effect of meals on somatostatin release. We conclude that in NIDDM, IG regime promptly and continuously decreased insulin requirement and improved metabolic control. This effect is, at least during the first 3 mo, mainly due to enhanced insulin secretion. IG and IP treatment had no effect on insulin sensitivity during hyperinsulinemic-normoglycemic clamp, whereas meal-related insulin sensitivity was augmented. To compare the long-term effect of combined treatment with insulin and glyburide versus insulin alone on serum lipid levels in non-insulin-dependent diabetic (NIDDM) patients with secondary failure to sulfonylurea therapy.
                The study was a randomized double-blind placebo-controlled parallel trial with a duration of 325 days. The study was conducted at a referral-based endocrinology clinic. Subjects were a sequential sample of 20 patients with NIDDM with failure to respond to glyburide treatment after at least 1 yr of adequate glucose control with this therapy. The patients were randomized to treatment with insulin and glyburide (IG) or insulin and placebo (IP). Insulin was given twice daily to all patients as a mixture of NPH and regular insulins in dosages aiming at optimal glucose control. Glyburide or placebo was taken before breakfast (7 mg) and dinner (3.5 mg).
                Mean HbA1c decreased from 11.1% (range 9.8-12.9%) before insulin to 9.1% (range 6.8-11.4%) on day 325 (P less than 0.001) in IG patients and from 10.3% (range 8.4-13.3%) to 9.0% (range 6.3-11.8%) (P less than 0.05) in IP patients. In both groups, there was an increase in high-density lipoprotein cholesterol of approximately 20% lasting throughout the study (P less than 0.01). During the first 83 days of the study, there was a decrease in serum cholesterol (P less than 0.01) and serum triglycerides (P less than 0.05) in both groups. All changes in lipid variables were comparable in magnitude and duration in both treatment with insulin and glyburide in NIDDM patients with secondary sulfonylurea failure improves lipid metabolism to a similar degree as insulin therapy alone. Combined insulin and sulfonylurea therapy for type 2 diabetes may improve the effectiveness of a single injection of insulin, thereby postponing the need for multiple injections. This concept was tested in 21 obese subjects imperfectly controlled by 20 mg of glyburide daily in a double masked, placebo-controlled, parallel design, 16-week protocol. Premixed 70% NPH/30% Regular insulin was taken before supper, and the dosage was adjusted weekly by an algorithm seeking nearly normal fasting glycemia. Eleven subjects using insulin plus 10 mg glyburide before breakfast had lower mean fasting glucose at 10-16 weeks than 10 subjects using insulin with placebo (mean +/- SEM; 5.9 +/- 0.3 versus 7.5 +/- 0.7 mmol/L; p less than 0.05), and had a greater decrement of glycosylated hemoglobin from baseline values (1.3 +/- 0.1 versus 0.8 +/- 0.2% A1, p less than 0.05). After 16 weeks the combined therapy group used half as much insulin as the insulin-only group (50 +/- 5 versus 101 +/- 13 units/d; p less than 0.01). Fasting serum free insulin values increased 58% from baseline after insulin therapy in the insulin-only group (p less than 0.05) but did not increase with combined therapy. Weight gain was similar in the two groups. These data support this form of combined therapy as one option for treating obese persons with type 2 diabetes no longer responsive to oral therapy alone. In type 2 diabetes with "secondary failure of sulfonylurea therapy" good metabolic control can seldom be achieved by insulin therapy even with high insulin doses. Hyperinsulinemia however is a possible risk factor of cardiovascular disease in type 2 diabetes. Maintaining the effects of sulfonylurea action insulin should be added in as small amounts as possible to avoid hyperinsulinemia and to ameliorate hyperglycemia. 16 type 2 diabetics with "secondary failure" were treated either with insulin alone (group A; n = 8) or with 3.5 mg b.i.d. glibenclamide plus small amounts of intermediate insulin (group B; n = 8) in a randomised order. After the inpatient period outpatient control was performed monthly up to six months, later on four times a year up to two years. Both groups were comparable with regard to age, duration of diabetes, body weight and metabolic control. The daily insulin dose was 14 +/- 2 IU (means +/- SEM) after one month and 19 +/- 2 IU after two years in group B. In contrast 30 +/- 3 IU and 43 +/- 5 IU respectively were needed in group A (p less than 0.001). All patients B were treated with one daily injection, all patients A needed two injections. Resulting in nearly identical metabolic control in group A basal insulin levels exceeded those in group B after two years significantly (28.6 +/- 3.7 vs. 18.6 +/- 1.6 mcU/ml; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) This study tested a simple algorithm for beginning insulin for obese patients with type 2 diabetes after sulfonylurea failure, comparing suppertime 70/30 insulin plus continued glimepiride with insulin alone.
                This was a multicenter ambulatory randomized double-masked parallel comparison. There were 208 subjects with secondary failure to sulfonylureas who took glimepiride titrated to 8 mg b.i.d. for 8 weeks; 145 subjects with fasting plasma glucose (FPG) 180-300 mg/dl (10-16.7 mmol/l) on this treatment were randomized to placebo plus insulin (PI) or glimepiride plus insulin (GI) for 24 weeks. A dosage of 70/30 insulin before supper was titrated, seeking fasting capillary blood glucose (FBG) 120 mg/dl (6.7 mmol/l), equivalent to FPG 140 mg/dl (7.8 mmol/l). Outcome measures included FPG, HbA1c, insulin dosage, weight, serum insulin and lipids, and adverse events.
                FPG and HbA1c were equivalent at baseline: 261 vs. 250 mg/dl (14.5 vs. 13.9 mmol/l), and 9.9 vs. 9.7%. At 24 weeks, the FPG target was achieved in both groups (136 vs. 138 mg/dl, 7.6 vs. 7.6 mmol/l), and HbA1c values were equal (7.7 vs. 7.6%). However, with GI, control improved faster and fewer subjects dropped out (3 vs. 15%, P < 0.01), and less insulin was needed (49 vs. 78 U/d, P < 0.001). The outcomes were alike in other respects. No subject had severe hypoglycemia.
                Injection of 70/30 insulin before supper safely restored glycemic control of type 2 diabetes not controlled by glimepiride alone. Control was restored more rapidly and with less injected insulin when glimepiride was continued. The long-term efficacy of combined insulin-glibenclamide treatment was investigated in 79 secondary drug failure patients by means of a double-blind, randomized placebo-controlled study. During a one-year follow-up period the patients on insulin plus glibenclamide required significantly lower exogenous insulin doses. Coincidentally, C-peptide concentrations were significantly raised in the verum versus the placebo group. Additionally, the administration of glibenclamide resulted in a decreased level of hyperglycaemia during the first six months of the observation period. Glibenclamide withdrawal after six and again after twelve months of the combined therapy provoked a deterioration of glycaemic control, as well as a lowering of the C-peptide concentrations. The findings demonstrate a prolonged beneficial effect of the combined treatment, in contrast to the solely short-term effects predicted by numerous studies. The metabolic improvement must be ascribed in part to the beta-cytotropic effect of glibenclamide. Extrapancreatic pathways via receptor/postreceptor mechanisms cannot be excluded. Bedtime insulin (BI)/daytime sulfonylurea (DSU) therapy was studied double-blind in 30 non-insulin-dependent diabetes mellitus subjects in whom sulfonylurea (SU) therapy had failed. Subjects were switched to glipizide for 2 months (phase I) to confirm failure (fasting plasma glucose [FPG] 12.0 +/- 0.4 mmol/l) and then randomly assigned into three groups: BI-DSU; BI-no DSU; and DSU-no BI. During phase II (3 months), the BI dose was fixed (20 U/1.73 m2, low-dose). In phase III (3 months), BI was titrated up (high-dose) to achieve good control or until hypoglycemic symptoms prevented further dose increases. In phase IV (6 months), 25 of the 30 original subjects received open-labeled, high-dose BI-DSU. Low-dose BI-DSU markedly reduced FPG (13.6 +/- 0.8 to 8.0 +/- 0.6 mmol/l, P < 0.001), mean 24-h glucose (P < 0.001), HbA1c (8.9 +/- 0.7 to 7.6 +/- 0.3%, P = 0.07), and basal hepatic glucose production (HGP) (P < 0.005). A positive correlation (r = 0.69, P < 0.05) between the declines in FPG and HGP was observed. Neither low-dose BI alone nor DSU alone reduced FPG, mean 24-h glucose, HbA1c, or basal HGP. High-dose (40 +/- 5 U/day) BI plus DSU further reduced the FPG (6.3 +/- 0.6 mmol/l), HbA1c (7.1 +/- 0.3%), mean 24-h plasma glucose, and basal HGP (all P < 0.05 vs. phase II).(ABSTRACT TRUNCATED AT 250 WORDS) To compare the metabolic effects of three different frequently used regimens of insulin administration on blood glucose control and serum lipids, and the costs associated with this treatment, in subjects with NIDDM, who were poorly controlled with oral antihyperglycemic agents.
                We studied 95 elderly patients with NIDDM (age 68 +/- 9 years, BMI 26.0 +/- 4.6 kg/m2, and median time since diagnosis of diabetes 9 years [range 1-37]; 37 men, 58 women), who were poorly controlled, despite diet and maximal doses of oral antihyperglycemic agents. Three insulin administration regimens were compared during a 6-month period: patients were randomized for treatment with a two-injection scheme (regimen A) or a combination of glibenclamide with one injection of NPH insulin, administered either at bedtime (regimen B) or before breakfast (regimen C), and insulin treatment was mainly instituted in an outpatient setting.
                After 6 months of insulin treatment, fasting blood glucose of the total patient population had decreased from an average of 14.1 +/- 2.2 to 8.3 +/- 2.0 mmol/L (P < 0.001), and HbA1c fell from 11.0 +/- 1.3 to 8.3 +/- 1.2% (P < 0.001); 34 patients reached HbA1c levels below 8.0%, 25 of them even below 7.5%. With two insulin injections daily, HbA1c decreased from 11.2 +/- 1.3 to 8.2 +/- 1.2%, while during combined treatment, HbA1c fell from 10.5 +/- 1.2 to 8.1 +/- 1.1% (regimen B) and from 11.1 +/- 1.3 to 8.5 +/- 1.1% (regimen C). Comparable improvement of the other measures of glycemic control, lipids and lipoproteins, was observed in the different treatment regimens. Body weight increase was moderate (mean +/- 4.0 kg) and similar in all patient groups. One-third of patients starting with one insulin injection daily needed a second injection to control glycemia. One episode of severe hypoglycemia was observed. Combined insulin-sulfonylurea treatment was almost 20% more expensive than twice-daily administration of insulin alone.
                Insulin treatment can safely be instituted in elderly patients with NIDDM. However, it is difficult to obtain optimal glycemic control. Insulin has moderate beneficial effects on serum lipoproteins. Although on the basis of glycemic control and weight gain, no preference for any treatment regimen can be discerned, twice-daily insulin administration is the most simple and cost-effective regimen. We compared the effects of twice-daily insulin injections (n = 22) with combined insulin-glibenclamide therapy (n = 25) on glucose and lipid metabolism in 47 type II diabetic patients (age 69 (SD 9) years, BMI 25.5 (4.8) kg/m2, diabetes duration 9 (range 1-34) years) with secondary failure to sulphonylurea. After 6 months, weight gain averaged 4.2 kg (p less than 0.05), fasting blood glucose had decreased from 14.6 to 8.5 mmol/l (p less than 0.001), HbA1c from 10.9% to 8.1% (p less than 0.001). Twenty-one patients reached HbA1c levels less than 8.0%. Patients on insulin alone injected more insulin (42 vs 26 U daily, p less than 0.01). The decrease of fasting blood glucose and HbA1c was comparable in both groups (p less than 0.001). HDL-cholesterol increased (insulin: 1.10 to 1.24 mmol/l, combined therapy: 1.03 to 1.14 mmol/l, both p less than 0.01), while plasma triglycerides and NEFA decreased (p less than 0.01). Only in patients on insulin alone did total cholesterol decrease from 7.1 to 6.3 mmol/l (p less than 0.001), and LDL-cholesterol from 4.7 to 4.1 mmol/l (p less than 0.05). Apolipoproteins AI, AII and B did not show significant changes. Almost all patients reported improved wellbeing; no severe hypoglycaemias were observed. Although insulin and sulfonylureas often have additive clinical effects when used in combination for type II (non-insulin-dependent) diabetes, these results are variable and a clinical role for this approach is not yet established. This study tests the efficacy of a specific combined regimen for a subpopulation of patients with a randomized double-masked placebo-controlled crossover design and under conditions similar to those of clinical practice. Twenty subjects with limited duration (less than 15 yr) type II diabetes who were moderately obese (less than 160% ideal wt) and proved imperfectly controlled on 10 mg glyburide twice daily completed two 4-mo crossover protocols, comparing a single injection of NPH insulin in the evening plus 10 mg glyburide in the morning with insulin plus placebo. Insulin dose was adjusted by experienced endocrinologists seeking the best glycemic control consistent with safety. All subjects had glycosylated hemoglobin values less than or equal to 150% of the control mean on combined therapy, and combined therapy was superior to insulin alone (fasting plasma glucose 8.0 +/- 0.3 vs. 11.1 +/- 0.6 mM, P less than .01; glycosylated hemoglobin 9.8 +/- 0.1 vs. 10.6 +/- 0.2%, P less than .01). Despite greater weight gain on combined therapy, blood pressure and plasma lipid concentrations were the same on the two regimens. These results suggest this simple regimen offers another option, besides multiple injections of insulin, for patients of this kind who are unsuccessful with a sulfonylurea or a single injection of insulin alone. Comparison of the effectiveness of combined therapy vs. an insulin regimen in NIDDM patients with secondary failure of oral hypoglycemic agents. RESEARCH DESIGN, PATIENTS AND METHODS: 27 NIDDM patients were randomly allocated to Group A (n = 14, insulin) and Group B (n = 13, insulin and sulfonylurea) with crossover after 3 months. After the next 3 months a decision was made about the further treatment according to the metabolic control. The patients were then treated for another year with the more successful regimen. Metabolic control, residual beta-cell secretory capacity, degree of peripheral insulin resistance (clamp) and insulin dose were followed during the whole study.
                (median, interquartile range, in brackets; *, statistically significant difference at P < 0.05): the combined therapy was better than insulin alone in 2/3 of patients. Glycemic control was better (HbA1c at 3 months: Group A = 7.9(1.1)% vs. Group B = 7.0(0.5)%*; HbA1c at 6 months: Group A = 7.4(1.5)% vs. Group B = 8.1(1.5)%. Insulin dose was lower during the combined therapy in the first 3 months: Group A = 0.62(0.18) U/kg body weight vs. Group B = 0.39(0.16) U/kg body weight*. Combined treatment was associated with increased C-peptide excretion both fasting and postprandially. No significant differences in peripheral insulin resistance were noted between the two groups. The combined treatment remained successful even after one year. The two groups of patients with different effective treatment did not differ significantly in any of the observed parameters.
                the combined therapy was more effective than insulin alone. Its favourable effect persisted after treatment for a year. It seems better to start the treatment of the oral failure with combined therapy compared with insulin first and later followed by combined therapy. On the basis of the observed parameters it is impossible to determine in advance which kind of treatment is more suitable for the individual patient. Nine lean diabetic patients with secondary failure of oral hypoglycemic agents and with a poor residual insulin release under treatment with glibenclamide (15 mg/day) entered a cross-over study, in which ultralente insulin was administered alone or in combination with glibenclamide (15 mg/day). Combined therapy was accompanied by increased serum free-insulin levels and was more effective than glibenclamide alone on daily blood glucose profile, on glycosylated haemoglobin (HbA1C) and on Beta-OH butyrate; in 6 patients a near normalization of blood glucose control (daily blood glucose levels less than 180 mg/dl) occurred. C peptide release, evaluated as daily profile and as response to i.v. glucagon, did not significantly change. When patients received insulin alone, daily blood glucose profile and HbA1C worsened, and serum free-insulin levels and C peptide release decreased, while Beta-OH butyrate levels remained low. These data indicate that combined therapy is effective since it maintains insulin release and enhances free insulin levels in insulinopenic patients. Four responders continued combined therapy for 2 years: the treatment was still effective and was accompanied by an increased C peptide release, probably due to persistent euglycemia. To determine causes of weight gain during insulin therapy with and without metformin in Type II (non-insulin-dependent) diabetes mellitus.
                Twenty-six patients with Type II diabetes (body mass index 28+/-1 kg/m2) were treated with insulin alone (n = 13) or insulin and with metformin (n = 13). Components of energy balance (basal metabolic rate, energy intake, glucosuria) were measured at 0 and 12 months.
                Glycaemic control improved similarly in patients using (HbA1c 10.5+/-0.3 vs 7.6+/-0.2%, p<0.001) and not using (10.2+/-0.3 vs 7.8+/-0.3%, p < 0.001) metformin. The metformin group required 47 % less insulin than the group not using metformin (p < 0.001). Body weight increased by 3.8+/-0.8 and 7.5+/-1.6 kg (p < 0.05), respectively. Basal metabolic rate and glucosuria were similar at 0 and 12 months in both groups but the metformin group decreased energy intake by 1.12+/-0.46 MJ/day, whereas it remained unchanged in the other group (0.15+/-0.42 MJ/day). Changes in body weight and glycaemia were statistically significant independent determinants of basal metabolic rate. Their change in opposite directions explained why basal metabolic rate remained unchanged.
                Improved glycaemia promotes weight gain by decreasing both basal metabolic rate and glucosuria. Use of metformin decreases weight gain by reducing energy intake and is therefore a useful adjunct to insulin therapy in patients with Type II diabetes. Insulin is widely used to improve metabolic control in patients with non-insulin-dependent diabetes mellitus (NIDDM), but there is no consensus about the optimal regimen of insulin treatment.
                We treated 153 patients with NIDDM for three months with five regimens: (1) oral hypoglycemic drug therapy plus NPH insulin given at 7 a.m. (the morning-NPH group), (2) oral hypoglycemic drug therapy plus NPH insulin given at 9 p.m. (the evening-NPH group), (3) NPH and regular insulin (ratio, 70 units to 30 units) given before breakfast and dinner (the two-insulin-injection group), (4) NPH insulin at 9 p.m. and regular insulin before meals (the multiple-insulin-injection group), and (5) continued oral hypoglycemic drug therapy (the control group).
                The mean (+/- SE) value for glycosylated hemoglobin decreased similarly in all four insulin-treatment groups (1.7 +/- 0.3, 1.9 +/- 0.2, 1.8 +/- 0.3, and 1.6 +/- 0.3 percent, respectively). The decrease was significantly greater in these four groups than in the control group (0.5 +/- 0.2 percent; P < 0.001 vs. all insulin-treated groups). Weight gain was significantly less (1.2 +/- 0.5 kg) in the evening-NPH group than in the other insulin-treatment groups (2.2 +/- 0.5 kg in the morning-NPH group, 1.8 +/- 0.5 kg in the two-insulin-injection group, and 2.9 +/- 0.5 kg in the multiple-injection group; P < 0.05). In addition, the increment in the mean diurnal serum free insulin concentration was 50 to 65 percent smaller in the evening-NPH group than in the other insulin-treatment groups. Subjective well-being improved significantly more in the insulin-treatment groups than in the control group (P < 0.001).
                In patients with NIDDM who are receiving oral hypoglycemic drug therapy, the addition of NPH insulin in the evening improves glycemic control in a manner similar to combination therapy with NPH insulin in the morning, a two-insulin-injection regimen, or a multiple-insulin-injection regimen, but induces less weight gain and hyperinsulinemia. The data thus suggest that patients with NIDDM do not benefit from multiple insulin injections and that nocturnal insulin administration appears preferable to daytime administration. Many diabetic patients continue to have hyperglycaemia on maximal sulphonylurea therapy. Five different therapeutic options, with the prime aim of achieving normal fasting plasma glucose concentrations, have been compared in 15 asymptomatic, sulphonylurea-treated type 2 diabetic patients in a randomized crossover study of 8-week periods. In 24 h metabolic profiles the overnight mean (+/- 1SD) basal plasma glucose level on sulphonylurea therapy was 8.9 +/- 4.2 mmol/l. This was slightly improved with added metformin therapy (7.3 +/- 4.3 mmol/l, p = 0.013), but reduced to normal by added ultralente insulin (5.2 +/- 3.2 mmol/l, p less than 0.001), ultralente insulin alone (5.1 +/- 1.6 mmol/l, p = 0.005) or by ultralente and soluble insulin (4.7 +/- 1.4 mmol/l, p = 0.003). The mean glycosylated haemoglobin concentration was reduced significantly only by the treatments which included insulin. None of the patients had severe or incapacitating hypoglycaemia and only when on additional soluble insulin did patients show a significant gain in weight. Combining sulphonylurea therapy with ultralente insulin did not significantly improve overall glucose control over treatment with ultralente alone, although the insulin dose required to restore fasting normoglycaemia was significantly lower (median (interquartile range), 25 (12-41) versus 40 (27-80) U/day, p = 0.001). In type 2 diabetic patients who continue to have fasting hyperglycaemia on maximal sulphonylurea therapy, fasting normoglycaemia can be achieved easily, without minimal changes in diet or lifestyle, by means of a basal insulin supplement. The effectiveness of combined insulin and glibenclamide was compared with that of insulin alone in a multicenter double-blind trial of secondary sulphonylurea failures. Protocols of 176 patients at 26 centers were available, but only 68 could ultimately be included in the analysis. Combined insulin and glibenclamide (Euglucon N) had been taken by 37 patients, combined insulin and placebo by 31. The final criterion, postprandial one-hour blood sugar level of less than or equal to 220 mg/100 ml after 24 weeks, was attained by nearly 75% of patients in both groups. Fasting blood sugar and postprandial one-hour blood sugar as well as HbA1 did not differ during the entire test period of 24 weeks. Mean daily insulin dose was 20 IU in the insulin/glibenclamide group, 35 IU in the insulin/placebo group. This increased the number of second evening insulin injections by 50% in the insulin/placebo group compared with the insulin/glibenclamide group. The frequency of mild hypoglycemia was similar in the two groups. The results indicate that combined insulin/glibenclamide, given over a period of six months to patients with secondary sulphonylurea failure, provided metabolic results as good as those with insulin alone. The required insulin dosage was thus reduced by more than a third. Compared with other insulin regimens, combination therapy with oral hypoglycemic agents and bedtime insulin produces similar improvement in glycemic control but induces less weight gain.
                To determine whether bedtime insulin regimens differ with respect to their effects on weight gain in patients with type 2 diabetes.
                Randomized, controlled trial.
                Four outpatient clinics at central hospitals.
                96 patients (mean age, 58 +/- 1 years; mean body mass index, 29 +/- 1 kg/m2) whose type 2 diabetes was poorly controlled with sulfonylurea therapy (mean glycosylated hemoglobin value, 9.9% +/- 0.2%; mean fasting plasma glucose level, 11.9 +/- 0.3 mmol/L [214 +/- 5 mg/dL]).
                Random assignment to 1 year of treatment with bedtime intermediate-acting insulin plus glyburide (10.5 mg) and placebo, metformin (2 g) and placebo, glyburide and metformin, or a second injection of intermediate-acting insulin in the morning. Patients were taught to adjust the bedtime insulin dose on the basis of fasting glucose measurements.
                Body weight, biochemical and symptomatic hypoglycemias, and indices of glycemic control.
                At 1 year, body weight remained unchanged in patients receiving bedtime insulin plus metformin (mean change, 0.9 +/- 1.2 kg; P < 0.001 compared with all other groups) but increased by 3.9 +/- 0.7 kg, 3.6 +/- 1.2 kg, and 4.6 +/- 1.0 kg in patients receiving bedtime insulin plus glyburide, those receiving bedtime insulin plus both oral drugs, and those receiving bedtime and morning insulin, respectively. The greatest decrease in the glycosylated hemoglobin value was observed in the bedtime insulin and metformin group (from 9.7% +/- 0.4% to 7.2% +/- 0.2% [difference, -2.5 +/- 0.4 percentage points] at 1 year; P < 0.001 compared with 0 months and P < 0.05 compared with other groups). This group also had significantly fewer symptomatic and biochemical cases of hypoglycemia (P < 0.05) than the other groups.
                Combination therapy with bedtime insulin plus metformin prevents weight gain. This regimen also seems superior to other bedtime insulin regimens with respect to improvement in glycemic control and frequency of hypoglycemia.
Bedtime NPH insulin combined with oral hypoglycaemic agents provides comparable glycaemic control to insulin monotherapy and is associated with less weight gain if metformin is used.