Efficacy and safety of pioglitazone in type 2 diabetes: a randomised, placebo-controlled study in patients receiving stable insulin therapy.

The glycaemic and lipid effects of treatment with pioglitazone in combination with a stable insulin regimen were evaluated in patients with type 2 diabetes. Patients (n=566) receiving stable insulin regimens for > or = 30 days yet who had HbA1c > or = 8.0% and C-peptide > 0.7 microg/l were randomised to receive once-daily 15 mg pioglitazone, 30 mg pioglitazone, or placebo in a 16-week multicentre, double-blind, placebo-controlled trial. Per study protocol, the insulin dose was to remain unchanged, but could be decreased in response to hypoglycaemia. At the end of double-blind treatment, patients receiving pioglitazone (15 mg or 30 mg) showed statistically significant mean decreases relative to baseline HbA1c (-1.0 and -1.3, respectively; p<0.0001) and fasting plasma glucose (FPG) (-34.5 mg/dl [-1.92 mmol/l] and -48.0 mg/dl [-2.67 mmol/l], respectively; p<0.0001); these differences compared with placebo were also significant (p<0.0001). Pioglitazone (15 or 30 mg) yielded significant increases in HDL-C levels (mean increases ranging from +7.1% to + 9.3%) compared with baseline or placebo (p<0.01). The 30 mg dose also significantly reduced mean triglyceride levels (-23.7%) compared with placebo (p=0.0218). No consistent changes in TC or LDL-C levels were observed. The incidence of adverse events was similar in all treatment groups, although the incidences of weight increase, hypoglycaemia and oedema were higher among patients receiving insulin plus pioglitazone. There was no evidence of hepatotoxicity or drug-induced elevations of serum ALT > or = 3 x ULN. Pioglitazone, when added to stable insulin regimens, significantly improved HbA1c and FPG in type 2 diabetes. Pioglitazone treatment also provided significant benefit with respect to plasma HDL-C and triglyceride levels. Whether these lipid changes have an impact on overall diabetic complications remains to be determined.

The genesis and consequences of postprandial hyperglycemia.

Blood glucose levels after meals may be a misunderstood or overlooked aspect of management of type 2 diabetes. Emerging data suggest that postprandial glucose (PPG) excursions-meaning excessive increases in plasma glucose levels after meals-may be even more representative of overall glucose control than fasting glucose concentrations. In fact, evidence is accumulating that supports a close relationship between PPG levels and diabetes-related morbidity and mortality. Thus, interventions directed at postprandial glucose control could prove to be an effective and physiologic means of improving overall glucose homeostasis and reducing the incidence and progression of diabetic complications.

Panel discussion on achieving glycemic control.

This discussion contains excerpts from the satellite symposium, "Achieving Better Glycemic Control Through Management of Mealtime Glucose," presented at the American Association of Clinical Endocrinologists Tenth Annual Meeting and Clinical Congress in San Antonio, Texas, May 2, 2001.

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

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

Performance evaluation of the MiniMed continuous glucose monitoring system during patient home use.

BACKGROUND: The recent availability of a continuous glucose monitor offers the opportunity to match the demands of intensive diabetes management with a period of equally intensive blood glucose monitoring. The present study evaluates the performance of the MiniMed continuous glucose monitoring system (CGMS) in patients with diabetes during home use. METHODS: Performance data and demographic information were obtained from 135 patients who were (mean +/- SD) 40.5+/-14.5 years old, had an average duration of diabetes of 18.0+/-9.8 years, 50% were female, 90% were Caucasian, and 87% of whom had been diagnosed with type 1 diabetes. Patients were selected by their physician, trained on the use of the CGMS and wore the device at home for 3 days or more. The performance of the CGMS was evaluated against blood glucose measurements obtained using each patient's home blood glucose meter. Evaluation statistics included correlation, linear regression, mean difference and percent absolute difference scores, and Clarke error grid analysis. RESULTS: The CGMS values were compared to 2477 SMBG tests (r = 0.91, slope = 0.93, intercept = 14.5 mg/dL, mean absolute difference = 18.0%+/-19.8%). Clarke error grid analysis showed 96.2% of the data pairs falling within the clinically acceptable regions (zones A and B). CONCLUSIONS: These results demonstrate the agreement of the CGMS to blood glucose meter values, under conditions of home use, in patients selected by their physicians as candidates for continuous monitoring. The detailed glucose information provided by the CGMS should make successful management of diabetes more easily achieved.

A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes.

OBJECTIVE: The objective of the study was to assess the efficacy and safety of repaglinide compared with placebo in the treatment of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a phase II multicenter, double-blind, placebo-controlled, randomized, dose-adjustment and maintenance trial. After screening and a 2-week washout period, 99 patients were randomized to receive either repaglinide (n = 66) or placebo (n = 33). Patients underwent 6 weeks of dose adjustment followed by 12 weeks of dose maintenance. Fasting and stimulated glycosylated hemoglobin (HbA1c), plasma glucose, insulin, and C-peptide were measured at predetermined intervals. Adverse events and hypoglycemic episodes were recorded. RESULTS: From baseline to last visit, mean HbA1c decreased from 8.5 to 7.8% in patients treated with repaglinide and increased from 8.1 to 9.3% in patients receiving placebo, with a statistically significant difference of - 1.7% (P < 0.0001) between treatment groups at the last visit. Mean fasting plasma glucose and postprandial glucose increased in patients receiving placebo and decreased in patients treated with repaglinide, with statistically significant (P < 0.01) differences between groups at the last visit. Concentrations of fasting and postprandial insulin and C-peptide were lower at the last visit compared with baseline for patients treated with placebo and higher for patients treated with repaglinide, and the differences between groups were statistically significant (P < 0.05). Overall, repaglinide was well tolerated. CONCLUSIONS: This study demonstrated that repaglinide was safe and efficacious in lowering blood glucose concentrations. In addition to overall improvement in glycemic control noted with repaglinide in both sulfonylurea-treated patients and oral hypoglycemic agent-naive patients, repaglinide had a potent glucose-lowering effect in the postprandial period.

Effect of premixed nph and regular insulin on glucose control and health-related quality of life in patients with type 2 diabetes mellitus.

OBJECTIVE: To compare the effect of the addition of regular insulin as a premixed 70/30 insulin to the treatment regimen of patients with type 2 diabetes who had used NPH insulin alone relative to overall glycemic control (postprandial blood glucose), patient satisfaction, and health-related quality of life. METHODS: We studied 90 patients with type 2 diabetes in a 10-week, randomized, double-blind, crossover trial involving 9 clinical investigators. Patients previously treated with NPH insulin alone were transferred to 30% regular insulin added to 70% NPH as a premixed insulin (70/30) administered twice daily. Patients in one sequence group received NPH insulin twice daily for 4 weeks followed by 70/30 insulin for 4 weeks; in the second sequence group, the order was reversed. RESULTS: The magnitude of the 1.5- and 2-hour postprandial glucose excursion was reduced with 70/30 insulin in comparison with NPH insulin, and patients treated with 70/30 insulin experienced fewer hypoglycemic events than with NPH insulin. With regard to health-related quality of life, patients treated with 70/30 insulin rated their physical functioning as better; rated their ability to be spontaneous, follow the meal plan, and interact socially to be less difficult; and had less fear of hypoglycemia and perceived their diabetes to be better controlled than when treated with NPH insulin alone. CONCLUSION: In patients with type 2 diabetes mellitus, premixed 70/30 insulin improved postprandial glycemic control and health-related quality of life without increasing the frequency of hypoglycemic events and without any additional cost.

Effects of an anti-CD5 immunoconjugate (CD5-plus) in recent onset type I diabetes mellitus: a preliminary investigation. The CD5 Diabetes Project Team.

Type-I (insulin-dependent) diabetes mellitus is an immunologically mediated disease that results in destruction of the insulin secreting beta cells of the pancreas. T cells have been implicated in the pathogenesis of this disease. One novel form of anti-T-cell therapy is the immunoconjugate CD5-Plus. This agent is composed of the murine IgG1 monoclonal antibody H65, which is directed toward the CD5+ antigen; and ricin A chain, a ribosomal inhibitor protein. We performed a pilot study to evaluate the safety of the immunoconjugate in subjects with type-I diabetes mellitus. We conducted a dose-escalation study using CD5-Plus given as an intravenous infusion for 5 consecutive days. Fifteen subjects (12 men and 3 women) with a mean age of 26 years, a mean duration of diabetes of 4.8 months, and a minimum stimulated C peptide of 0.3 pmol/mL were entered. Six subjects each were treated at the 0.1 and 0.2 mg/kg/day dosage levels, and three subjects were treated at the 0.33 mg/kg/day dose. Glycemic control was determined monthly by recording the glycohemoglobin, total daily insulin requirements, and fasting blood glucoses. Beta-cell function was measured by determining the C-peptide response to a mixed formula meal (Sustacal) at baseline and at 1,3,6,9, and 12 months after treatment. The area under the curve (AUC) of the C-peptide response was calculated and, to reduce variability, related to that of the same subject at baseline. An analysis of subjects who retained at least 80% of their baseline beta-cell function as measured by the AUC was performed.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypotensive effect of fasting: possible involvement of the sympathetic nervous system and endogenous opiates.

Fasting lowers blood pressure to a greater extent in spontaneously hypertensive rats than in normotensive rats. While fasting reduced cardiac sympathetic activity to an equivalent extent in both groups of animals, only in the hypertensive rats did fasting elicit an opiate-mediated vasodepressor response that was independent of sympathetic withdrawal. Both sympathetic nervous system suppression and endogenous opiate activation, therefore, may contribute to the hypotensive effect of fasting in the spontaneously hypertensive rat.

Good outcome in a catatonic patient with enlarged ventricles.

In the differential diagnosis of the catatonic syndrome, the demonstration of an intracranial anomaly is often taken as evidence of irreversibility. We present the case of a 27-year-old white female with catatonia who was found to have enlarged ventricles on automatic computerized tomographic axial scan. She had a complete resolution of the catatonia and psychotic symptoms without any change in the size of the ventricles. This resolution occurred when the patient was treated for her ulcerative colitis with colectomy and the steroids she received for the colitis were gradually withdrawn. The discovery of a structural anomaly of the brain per se should not discourage the clinician from identifying and treating all other factors that might contribute to the catatonic syndrome.