Efficacy and safety of prandial premixed therapy using insulin lispro mix 50/50 3 times daily compared with progressive titration of insulin lispro mix 75/25 or biphasic insulin aspart 70/30 twice daily in patients with type 2 diabetes mellitus: a randomized, 16-week, open-label study.

BACKGROUND: Prandial premixed therapy 3 times daily has been proposed recently for type 2 diabetes mellitus (T2DM) patients who fail to achieve glycemic control with commonly used premixed insulin analogs, insulin lispro mix 75/25 (LM75/25) and biphasic insulin aspart 70/30 (BIAsp70/30) BID. OBJECTIVE: The aim of this work was to compare the efficacy and safety of 3-times daily insulin lispro mix 50/50 (TID group) with progressive titration of twice-daily LM75/25 or BIAsp70/30 (BID group) administered along with metformin in T2DM patients. METHODS: This was an open-label, 16-week, multicenter, randomized, parallel trial. End point glycosylated hemoglobin (HbA(1c)) was the primary efficacy measure; HbA(1c) reduction from baseline to end point, percentage of patients reaching target HbA(1c) (<7.0% and ≤6.5%), postprandial blood glucose (BG), and BG excursions after lunch were secondary measures. Safety was evaluated by collecting adverse events. RESULTS: A total of 302 patients with mean (SD) age 57.7 (9.27) years, diabetes duration 11.2 (6.47) years, HbA(1c) 8.5% (1.23), fasting BG 184.0 (53.04) mg/dL, body weight 86.8 (14.79) kg, body mass index 31.7 (4.23) kg/m(2), and daily insulin dose ∼48 IU were randomized. No significant difference was observed in end point HbA(1c) between the 2 groups. Seven-point BG profiles showed lower fasting and postbreakfast BG in the BID group but lower postlunch BG in the TID group. Daily insulin dose change was similar in both groups, with more weight gain in the TID group (P = 0.0009). Overall hypoglycemic rates were similar in both groups, but nocturnal hypoglycemia was more frequent in the BID group (P = 0.0063). CONCLUSIONS: In patients with T2DM who have not achieved adequate glycemic control with LM75/25 and BiAsp70/30 BID plus metformin and who are not candidates for basal bolus therapy, switching either to treatment with LM50/50 TID or to progressive titration of premix insulin analogs BID did not produce sufficient evidence of a difference of overall glycemic control between the 2 treatment groups. Short study duration and less intensive dose adjustments might have contributed to these results.

Improvements in life expectancy in type 1 diabetes patients in the last six decades.

AIMS: To investigate the survival with diabetes in patients treated with insulin from diagnosis. SUBJECTS AND METHODS: We analyzed 845 subjects, 55.9% males, registered at "I. Pavel" Bucharest Diabetes Centre, insulin-treated from diagnosis, aged <40 years and deceased between 1946 and 2005. We divided the subjects in two groups by age at diagnosis: group A <18 years and group B 18-39.99 years. We used 20 years time periods for year of death: 1946-1965, 1966-1985 and 1986-2005. RESULTS: The mean age at diabetes onset was 30.36+/-8.04 years, disease duration at death 20.98+/-11.62 years and age at death 51.34+/-14.37 years. The mean increase in survival with diabetes was 19.3 years for group A and 15.9 years for group B. There was a significant decrease in infections in both groups. The increase in coronary heart diseases and stroke is evident only in group B. CONCLUSIONS: We found no changes in age at onset, which combined with an increase in survival with diabetes lead to a significant increase in age at death over the six decades analyzed.

Mortality trends in noninsulin-treated type 2 diabetes mellitus patients in the 1943-2000 period.

AIMS: To investigate the major aspects of mortality in patients with noninsulin-treated type 2 diabetes mellitus (T2DM), from 1942 till 2000. SUBJECTS AND METHODS: We performed a retrospective study in 9698 noninsulin-treated T2DM patients, 5001 (51.6%) males and 4695 (48.4%) females, registered in Bucharest Diabetes Center and deceased between 1943 and 2000. For each patient the age at diabetes onset, disease duration, age at death, cause of death, sex, height and weight were recorded. RESULTS: The mean age at diabetes onset was 58.3 +/- 9.1 years in 1943-1960 period (no significant differences by sex) and 60.6 +/- 10.3 years in 1981-2000 (59.3 +/- 10.3 years in males and 61.8 +/- 10.1 years in females, p < 0.01 vs. males). The mean disease duration at death was 7.7 +/- 5.2 years in 1943-1960 period (no significant differences by sex) and 11.3 +/- 8.1 years in 1981-2000 (11.9 +/- 8.4 years in males and 10.7 +/- 7.6 years in females, p < 0.01 vs. males). The mean age at death was 66 +/- 9.8 years in 1943-1960 period (no significant differences by sex) and 71.9 +/- 9.7 years in 1981-2000 (71.2 +/- 9.9 years in males and 72.5 +/- 9.5 years in females, p < 0.01 vs. males). In the Cox regression analysis, an increase in mortality was associated with the masculine sex--9.6% (CI 95% 1-19%, p = 0.028) compared with feminine sex; 1 year increase in age at onset--4.8% (CI 95% 4.3-5.3%, p < 0.01); 1 kg/m2 increase in body mass index--2.9% (CI 95% 1.9-3.8%, p < 0.01); 1 mg/dl increase in mean fasting blood glucose--0.1% (CI 95% 0-0.2%, p = 0.025). The major causes of death in noninsulin-treated T2DM patients in the 1981-2000 period were: ischemic heart disease (53.8%), stroke (14.4%), cancer (9%), digestive diseases (6.3%), diabetes (5.3%), end stage renal disease (4.6%), infections (2.7%), diabetes coma (2.2%) and others (1.7%). CONCLUSIONS: There is a statistically significant increase in the proportion of death caused by ischemic heart disease, while infections significantly decreased in importance during the study period. The masculine sex, age at onset, mean fasting blood glucose and body mass index were all significant predictors of mortality in the Cox regression analysis, adjusted for the year of death.

The effect of magnesium deficit on serum immunoglobulin concentrations in type 1 diabetes mellitus.

The aim of this study was to evaluate the correlation between changes in the concentration of serum magnesium and serum immunoglobulin concentrations in type 1 diabetes mellitus. In this study were included 110 patients with type 1 diabetes mellitus (64 men and 46 women) with ages ranging from 19 to 54 years (mean age 41.6+/-6.8 years). The mean duration of the disease was 8.7+/-7.5 years. Thirty-six healthy subjects served as a control group. The serum magnesium concentrations were evaluated by VITROS 750 XRC, Johnson & Johnson kit, (Ortho Clinical Diagnostics). Total serum IgA, IgG and IgM were determined by laser nephelometry (MININEPH The Binding Site kit). Values are means (x) + standard deviations (SD). Serum magnesium concentrations confirmed the magnesium deficit in patients with type 1 diabetes mellitus (1.8+/-0.11 mg/dL, range 1.73-2.47 mg/dL vs 2.2+/-0.2 mg/dL, range 1.6-2.4 mg/dL). In patients with type 1 diabetes mellitus, IgA levels are mildly elevated (4.03+/-0.51 g/L vs 3.43+/-0.48 g/L; p<0.05), while IgG levels are decreased (7.38+/-0.76 g/L vs 9.92+/-1.32 g/L; p<0.001) and IgM levels are almost constantly normal (1.18+/-0.16 g/L vs 1.22+/-0.15 g/L; p>0.05). Therefore, magnesium deficit has profound immunosuppressive capabilities in patients with type 1 diabetes mellitus by significantly reducing the number of IgG synthesizing cells and serum IgG concentrations.

Humalog Mix 25 in patients with type 2 diabetes which do not achieve acceptable glycemic control with oral agents: results from a phase III, randomized, parallel study.

BACKGROUND: Humalog Mix 25 (Mix 25) is a premixed insulin mixture of 25% lispro and 75% neutral protamine lispro. Insulin lispro is an analog of human insulin. It is created when the amino acids at positions 28 and 29 of the B-chain of insulin are reversed. The natural sequence in human insulin at this position is proline at B28 and lysine at B29. The pharmacokinetic and pharmacodynamic profiles of insulin lispro indicate that it is more rapid acting, and therefore more physiological mealtime insulin than regular human insulin. OBJECTIVE: Primary objective of this study was to compare twice daily treatment with insulin lispro low mixture (Mix 25) to oral treatment with glibenclamide in patients with type 2 diabetes, with respect to the mean 2-hour postprandial blood glucose excursions after breakfast and dinner. SECONDARY OBJECTIVES: to compare the two treatments with regard to the following: hemoglobin A1c, fasting blood glucose, pre-dinner blood glucose, frequency of hypoglycemia, body weight, treatment satisfaction (by questionnaire). METHODS: The study described is a randomized, open-label, parallel group comparison of two treatment regimens in patients with type 2 diabetes. The study included two periods. The lead-in period lasted 10 +/- 7 days, all patients were taking glibenclamide. The treatment period lasted 16 weeks. Patients were randomized to receive either glibenclamide 15 mg daily or switch to Mix 25 before breakfast and dinner. Study design is illustrated in Fig. 1. Glycemic control was assessed by glycosylated hemoglobin (HbA1c) measurements, 4-point self monitoring blood glucose profiles, and patient reported hypoglycemia. One treatment satisfaction questionnaire (Appendix 1) was completed by each participant. RESULTS: 175 patients were included from the two participating countries (Romania--100 patients and Russia--75 patients). 85 were randomized to receive Mix 25 and 90 to glibenclamide arm. 172 patients were included in the efficacy analysis. Baseline patient characteristics did not show any differences between treatment groups for any of the demographic (age, gender, height, body weight, body mass index) or efficacy parameters (HbA1c or self monitored BG values). 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 glibenclamide group and 9.85 +/- 1.2% and 12.2 +/- 2.9 mmol/L, respectively, in the Mix 25 group. At the end point, all efficacy parameters were better improved in Mix 25 group (HbA1c, fasting blood glucose, 2-hour postprandial blood glucose). Mean HbA1c was significantly lower in the Mix 25 group than in the GB group (Mix 25, 8.5% +/- 1.3%; GB, 9.4 +/- 1.8%; P = 0.001). For all self-monitored blood glucose values (Fig. 2) a larger decrease from baseline was observed in the Mix 25 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). Percentage of patients experiencing at least 1 episode of hypoglycemia was--as predicted--higher in the Mix 25 group (44.7% versus 10.3%; P = 0.01). Patients expressed more satisfaction with Mix 25 than with GB, as measured by the weighted combined score on a treatment satisfaction questionnaire (2.0 +/- 1.3 vs 0.7 +/- 1.3). CONCLUSIONS: When glycemic control can no longer be achieved by oral antidiabetic agents, treatment with insulin should be considered as the next therapeutic option. Mix 25 provided good overall glycemic control, as well as patient treatment satisfaction.