Mealtime 50/50 basal + prandial insulin analogue mixture with a basal insulin analogue, both plus metformin, in the achievement of target HbA1c and pre- and postprandial blood glucose levels in patients with type 2 diabetes: a multinational, 24-week, randomized, open-label, parallel-group comparison.

BACKGROUND: In people without diabetes, approximately 50% of daily insulin secretion is basal and the remainder is postprandial. Hence, it would be expected that insulin replacement therapy in a 50/50 ratio with each meal would mimic physiologic insulin secretion better than treatment with once-daily basal insulin in patients with diabetes mellitus. Using lispro mix (LM) 50/50 before meals may be a logical approach to achieving glycemic targets (glycosylated hemoglobin [HbA(lc)] and pre- and postprandial blood glucose [BG] concentrations) in these patients. OBJECTIVE: The aim of this study was to test the hypothesis that treatment with a premixed insulin analogue containing 50/50 basal + prandial insulins administered before each meal would achieve lower overall and mealtime glycemic control than once-daily basal insulin analogue, both plus metformin (Met), in patients with type 2 diabetes mellitus. METHODS: This 24-week, randomized, open-label, parallel-group trial was conducted at 38 sites across Australia, Greece, India, The Netherlands, Poland, Puerto Rico, and the United States. Male and female patients aged 35 to 75 years with type 2 diabetes mellitus and an HbA(1c) level of 6.5% to 11.0%, who were receiving metformin and/or a sulfonylurea with a stable dose of 0 to 2 daily insulin injections over the previous 3 months were eligible. Patients were randomly assigned to receive LM50/50 (50% insulin lispro protamine suspension [ILPS] and 50% lispro) TID plus metformin (to a maximally tolerated daily dosage of 500-1000 mg BID) (LM50/50 + Met) or insulin glargine QD at bedtime plus metformin (500-1000 mg BID) (G + Met) for 24 weeks. With LM50/50 + Met, the insulin dose was titrated to target a fasting BG (FBG) level of <6.7 mmol/L (<120 mg/dL) and a 2-hour post-prandial BG (PPBG) level of <8.0 mmol/L (<144 mg/dL); those who did not reach the FBG target would be switched from presupper LM50/50 to LM75/25 (75% ILPS, 25% lispro). RESULTS: A total of 315 patients were randomized and received treatment (158 women, 157 men; mean age, 57.7 years; mean body mass index, 32.1 kg/m2; LM50/50 + Met, 157 patients; G + Met, 158 patients). At 24 weeks, the mean (SD)HbA(1c) level was significantly lower in the LM50/50 + Met group than in the G + Met group (7.1% [0.9%] vs 7.5% [1.0%]; P<0.001), and the proportion who reached an HbA(1c) target of < or = 7.0% was greater (88 [56.1%] vs 63 [39.9%]; P = 0.005). The G + Met group had a lower mean (SD)FBG value (6.5 [1.6] vs 8.1 [1.8] mmol/L; P<0.001). The LM50/50 + Met group had lower mean preprandial BG levels prelunch (7.4 [1.9] vs 7.9 [2.1] mmol/L; P=0.03) and presupper (8.3 [2.0] vs 8.9 [2.8] mmol/L; P=0.04). The LM50/50 + Met group also had lower mean 2-hour PPBG values postbreakfast (8.7 [2.2] vs 9.2 [2.5] mmol/L; P=0.03), postlunch (8.4 [1.9] vs 9.8 [2.6], mmol/L; p<0.001), and postsupper (8.7 [2.2] vs 10.7 [3.2], mmol/L; P<0.001). The mean (SD) total insulin doses at study end point were 0.7 (0.3) U/kg in the LM50/50 + Met group and 0.6 (0.3) U/kg in the G + Met group (P<0.001). The mean (SD)M-value (an expression of mean glycemia and the effect of glucose swings) was statistically similar between the 2 groups at baseline but significantly lower in the LM50/50 + Met group at end point (17.3 [13.8] vs 25.1 [24.8] mmol/L; P<0.001). During the entire treatment period, mean (SD) overall and nocturnal hypoglycemia rates (episodes per patient for 30 days) were statistically similar between the 2 groups (overall, 0.8 [1.4] vs 0.5 [1.0]; nocturnal, 0.2 [0.7] vs 0.3 [0.6]). At end point, the mean (SD) nocturnal hypoglycemia rates were similar between the 2 groups (0.2 [0.9] vs 0.2 [0.6]), but the overall and non-nocturnal hypoglycemia rates were higher with LM50/50 + Met (overall, 0.7 [1.7] vs 0.3 [0.8]; P=0.02; non-nocturnal, 0.5 [1.2] vs 0.1 [0.4]; P=0.002). CONCLUSION: In these patients with type 2 diabetes, mealtime LM50/50 + Met was associated with lower overall (HbA(1c)) and preprandial BG and PPBG levels (except for FBG), with similar nocturnal hypoglycemia and less glycemic variability, compared with G + Met.

The effect of rosiglitazone on urine albumin excretion in patients with type 2 diabetes mellitus and hypertension.

BACKGROUND: Thiazolidinediones are antidiabetic agents that improve insulin sensitivity (IS). Accumulating data indicate that these agents provide beneficial effects beyond glycemic control, such as improvement in vascular function. The aim of this study was to determine the effect of rosiglitazone on urine albumin excretion (UAE) in patients with type 2 diabetes mellitus (DM) and hypertension. METHODS: The study involved 20 subjects with type 2 DM who were already on 15 mg glibenclamide daily but were achieving poor glycemic control and who had either poorly controlled or newly diagnosed hypertension. In these patients, rosiglitazone (4 mg daily) was added to the existing therapeutic regimen for 26 weeks. At baseline and the end of the treatment, subjects gave a 24-h urine collection for direct measurement of albumin and a spot specimen for determination of the albumin-to-creatinine ratio (ACR). Subjects also had a hyperinsulinemic euglycemic clamp and an ambulatory blood pressure (BP) monitoring. RESULTS: At the end of the study, UAE was significantly reduced versus baseline, as measured either directly in the 24-h collection (22.4 +/- 4.6 v 13.8 +/- 3.0 mg/day, P < .05) or with ACR (20.9 +/- 3.8 v 14.0 +/- 2.8 mg/g, P < .05). The percentage changes in UAE (DeltaALB for the 24-h collection and DeltaACR for ACR) correlated with the respective changes in IS (r = -0.64, P < .01 for DeltaALB and r = -0.48, P < .05 for DeltaACR), systolic BP (r = 0.63, P < .01 and r = 0.58, P < .01 respectively), and diastolic BP (r = 0.56, P < .05 and r = 0.50, P < .05 respectively). CONCLUSIONS: In this study, treatment of type 2 diabetic hypertensive patients with rosiglitazone significantly decreased UAE. Lowering of BP and improvement of IS should play roles in this UAE reduction.

Ambulatory blood pressure reduction after rosiglitazone treatment in patients with type 2 diabetes and hypertension correlates with insulin sensitivity increase.

BACKGROUND: Within the metabolic syndrome, insulin resistance and compensatory hyperinsulinemia are associated with blood pressure (BP) elevation through various potential mechanisms. Thiazolidinediones are antihyperglycemic agents that decrease insulin resistance. OBJECTIVE: To determine the effect of the thiazolidinedione rosiglitazone on BP and insulin resistance in patients with type 2 diabetes and hypertension. METHODS: In 20 subjects (nine men and 11 women) with type 2 diabetes but with a poor glycemic control, and with poorly controlled or newly diagnosed hypertension, rosiglitazone 4 mg daily was added-on therapy for 26 weeks. At baseline and at the end of the treatment period patients underwent ambulatory blood pressure monitoring, a hyperinsulinemic euglycemic clamp, and blood tests for glucose, insulin, HbA1c, lipids, and routine laboratory parameters. RESULTS: Insulin sensitivity estimated with the clamp significantly increased (Mbw/I index changed from 33.9 +/- 2.6 to 41.9 +/- 3.2 micromol/min per kg per nmol/l, P < 0.001) and the HOMA-IR index significantly decreased (6.34 +/- 0.39 versus 4.40 +/- 0.33, P < 0.001) during rosiglitazone treatment. Ambulatory BP presented small but significant reductions for the total 24-h period (135.3 +/- 1.8 versus 129.9 +/- 1.7 mmHg, P < 0.001 for systolic BP and 76.0 +/- 1.6 versus 71.9 +/- 1.6 mmHg, P < 0.001 for diastolic BP), daytime and night-time. The changes in systolic and diastolic BP correlated with the change in insulin sensitivity (r = -0.78, P < 0.01 and r = -0.68, P < 0.01, respectively). There were also significant reductions in fasting plasma glucose (9.39 +/- 0.41 versus 7.55 +/- 0.31 mmol/l, P < 0.001), insulin (94.0 +/- 0.41 versus 79.5 +/- 5.6 pmol/l, P < 0.01) and HbA1c (8.15 +/- 0.24 versus 7.24 +/- 0.19%, P < 0.001). CONCLUSIONS: Treatment of type 2 diabetic hypertensive patients with rosiglitazone significantly increased insulin sensitivity and lowered ambulatory BP. These changes were strongly correlated. Thiazolidinediones may thus possess a BP-lowering effect beyond their antihyperglycemic properties.