Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: A randomized, placebo-controlled study

Daniel Einhorn, Marc Rendell, James Rosenzweig, John W. Egan, Annette L. Mathisen, Roberta L. Schneider

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Abstract

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 [HbA 1c] ≥8.0%, fasting C-peptide >1.0 ng/mL) who had been receiving a stable regimen of metformin for ≥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 pio-glitazone + 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 pioglitazone 30 mg + metformin had statistically significant mean decreases in HbA 1c (-0.83%) and fasting plasma glucose (FPG) levels (-37.7 mg/dL) compared with placebo + metformin (P ≤ 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 ≤ 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 HbA 1c 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 ≥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 HbA 1c 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.

Original languageEnglish
Pages (from-to)1395-1409
Number of pages15
JournalClinical Therapeutics
Volume22
Issue number12
DOIs
StatePublished - 2000

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pioglitazone
Metformin
Type 2 Diabetes Mellitus
Placebos
Fasting
Therapeutics
Glucose

All Science Journal Classification (ASJC) codes

  • Pharmacology

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Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus : A randomized, placebo-controlled study. / Einhorn, Daniel; Rendell, Marc; Rosenzweig, James; Egan, John W.; Mathisen, Annette L.; Schneider, Roberta L.

In: Clinical Therapeutics, Vol. 22, No. 12, 2000, p. 1395-1409.

Research output: Contribution to journalArticle

Einhorn, Daniel ; Rendell, Marc ; Rosenzweig, James ; Egan, John W. ; Mathisen, Annette L. ; Schneider, Roberta L. / Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus : A randomized, placebo-controlled study. In: Clinical Therapeutics. 2000 ; Vol. 22, No. 12. pp. 1395-1409.
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title = "Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: A randomized, placebo-controlled study",
abstract = "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 [HbA 1c] ≥8.0{\%}, fasting C-peptide >1.0 ng/mL) who had been receiving a stable regimen of metformin for ≥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 pio-glitazone + 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 pioglitazone 30 mg + metformin had statistically significant mean decreases in HbA 1c (-0.83{\%}) and fasting plasma glucose (FPG) levels (-37.7 mg/dL) compared with placebo + metformin (P ≤ 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 ≤ 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 HbA 1c 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 ≥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 HbA 1c 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.",
author = "Daniel Einhorn and Marc Rendell and James Rosenzweig and Egan, {John W.} and Mathisen, {Annette L.} and Schneider, {Roberta L.}",
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T1 - Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus

T2 - A randomized, placebo-controlled study

AU - Einhorn, Daniel

AU - Rendell, Marc

AU - Rosenzweig, James

AU - Egan, John W.

AU - Mathisen, Annette L.

AU - Schneider, Roberta L.

PY - 2000

Y1 - 2000

N2 - 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 [HbA 1c] ≥8.0%, fasting C-peptide >1.0 ng/mL) who had been receiving a stable regimen of metformin for ≥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 pio-glitazone + 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 pioglitazone 30 mg + metformin had statistically significant mean decreases in HbA 1c (-0.83%) and fasting plasma glucose (FPG) levels (-37.7 mg/dL) compared with placebo + metformin (P ≤ 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 ≤ 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 HbA 1c 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 ≥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 HbA 1c 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.

AB - 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 [HbA 1c] ≥8.0%, fasting C-peptide >1.0 ng/mL) who had been receiving a stable regimen of metformin for ≥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 pio-glitazone + 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 pioglitazone 30 mg + metformin had statistically significant mean decreases in HbA 1c (-0.83%) and fasting plasma glucose (FPG) levels (-37.7 mg/dL) compared with placebo + metformin (P ≤ 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 ≤ 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 HbA 1c 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 ≥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 HbA 1c 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.

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