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1.
Lancet ; 385(9982): 2067-76, 2015 May 23.
Article in English | MEDLINE | ID: mdl-25765696

ABSTRACT

BACKGROUND: The EXAMINE trial showed non-inferiority of the DPP-4 inhibitor alogliptin to placebo on major adverse cardiac event (MACE) rates in patients with type 2 diabetes and recent acute coronary syndromes. Concerns about excessive rates of in-hospital heart failure in another DPP-4 inhibitor trial have been reported. We therefore assessed hospital admission for heart failure in the EXAMINE trial. METHODS: Patients with type 2 diabetes and an acute coronary syndrome event in the previous 15-90 days were randomly assigned alogliptin or placebo plus standard treatment for diabetes and cardiovascular disease prevention. The prespecified exploratory extended MACE endpoint was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularisation due to unstable angina, and hospital admission for heart failure. The post-hoc analyses were of cardiovascular death and hospital admission for heart failure, assessed by history of heart failure and brain natriuretic peptide (BNP) concentration at baseline. We also assessed changes in N-terminal pro-BNP (NT-pro-BNP) from baseline to 6 months. This study is registered with ClinicalTrials.gov, number NCT00968708. FINDINGS: 5380 patients were assigned to alogliptin (n=2701) or placebo (n=2679) and followed up for a median of 533 days (IQR 280-751). The exploratory extended MACE endpoint was seen in 433 (16·0%) patients assigned to alogliptin and in 441 (16·5%) assigned to placebo (hazard ratio [HR] 0·98, 95% CI 0·86-1·12). Hospital admission for heart failure was the first event in 85 (3·1%) patients taking alogliptin compared with 79 (2·9%) taking placebo (HR 1·07, 95% CI 0·79-1·46). Alogliptin had no effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1·00, 95% CI 0·82-1·21) and results did not differ by baseline BNP concentration. NT-pro-BNP concentrations decreased significantly and similarly in the two groups. INTERPRETATION: In patients with type 2 diabetes and recent acute coronary syndromes, alogliptin did not increase the risk of heart failure outcomes. FUNDING: Takeda Development Center Americas.


Subject(s)
Acute Coronary Syndrome/prevention & control , Diabetes Mellitus, Type 2/prevention & control , Diabetic Cardiomyopathies/prevention & control , Heart Failure/chemically induced , Hypoglycemic Agents/adverse effects , Piperidines/adverse effects , Uracil/analogs & derivatives , Aged , Angina, Unstable/etiology , Double-Blind Method , Female , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Myocardial Infarction/chemically induced , Natriuretic Peptide, Brain/metabolism , Peptide Fragments/metabolism , Risk Factors , Stroke/chemically induced , Uracil/adverse effects
2.
N Engl J Med ; 369(14): 1327-35, 2013 Oct 03.
Article in English | MEDLINE | ID: mdl-23992602

ABSTRACT

BACKGROUND: To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. METHODS: We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. CONCLUSIONS: Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.).


Subject(s)
Angina, Unstable/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Hypoglycemic Agents/therapeutic use , Myocardial Infarction/drug therapy , Piperidines/therapeutic use , Uracil/analogs & derivatives , Aged , Angina, Unstable/complications , Cardiovascular Diseases/mortality , Diabetes Mellitus, Type 2/complications , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Double-Blind Method , Female , Glycated Hemoglobin/metabolism , Humans , Hypoglycemic Agents/adverse effects , Male , Middle Aged , Myocardial Infarction/complications , Piperidines/adverse effects , Uracil/adverse effects , Uracil/therapeutic use
3.
J Clin Endocrinol Metab ; 98(12): 4691-701, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24057294

ABSTRACT

CONTEXT: Meta-analyses of clinical studies have suggested an increased incidence of peripheral fractures in postmenopausal women with type 2 diabetes mellitus taking pioglitazone. The mechanism behind this apparent increase is unknown. OBJECTIVE: The objective of the study was to examine the effects of pioglitazone on bone mineral density (BMD) and turnover. DESIGN AND SETTING: Twenty-five sites (in the United States) enrolled participants in this randomized, double-blind, placebo-controlled study. PARTICIPANTS: Postmenopausal women (n = 156) with impaired fasting glucose or impaired glucose tolerance participated in the study. INTERVENTIONS: The intervention consisted of pioglitazone 30 mg/d (n = 78) or placebo (n = 78), increased to 45 mg/d after 1 month, for 12 months of treatment total, followed by 6 months of washout/follow-up. MAIN OUTCOME MEASURES: Percentage changes from baseline to month 12 and from month 12 to month18 in BMD in total proximal femur (primary end point), total body, femoral neck, lumbar spine, and radius were measured. RESULTS: Least squares mean changes from baseline to month 12 in total proximal femur BMD were -0.69% for pioglitazone and -0.14% for placebo (P = .170). No statistically significant between-group differences were observed for any BMD or bone remodeling marker end point. We observed improved glycemic control and insulin sensitivity with pioglitazone treatment. In addition, pioglitazone appeared to increase body fat, which may affect bone density measurements, especially in the lumbar spine. One pioglitazone-treated and three placebo-treated women experienced confirmed fractures. Over 18 months, one pioglitazone-treated (1.3%) and eight placebo-treated women (10.3%) developed overt type 2 diabetes mellitus. The pattern and incidence of adverse events with pioglitazone were consistent with clinical experience with thiazolidinediones. CONCLUSIONS: Maximal-dose pioglitazone had no effects on BMD or bone turnover, while improving glycemic control as expected, in postmenopausal women with impaired fasting glucose or impaired glucose tolerance.


Subject(s)
Bone Remodeling/drug effects , Bone Resorption/chemically induced , Bone and Bones/drug effects , Glucose Intolerance/drug therapy , Hypoglycemic Agents/adverse effects , Prediabetic State/drug therapy , Thiazolidinediones/adverse effects , Adiposity/drug effects , Aged , Biomarkers/blood , Bone Density/drug effects , Double-Blind Method , Female , Follow-Up Studies , Glucose Intolerance/blood , Humans , Hyperglycemia/prevention & control , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Insulin Resistance , Middle Aged , Pioglitazone , Postmenopause , Prediabetic State/blood , Thiazolidinediones/administration & dosage , Thiazolidinediones/therapeutic use
4.
Pharmacotherapy ; 26(10): 1388-95, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16999648

ABSTRACT

STUDY OBJECTIVE: To evaluate the long-term safety and efficacy of glyburide versus pioglitazone in patients with a recent diagnosis of type 2 diabetes mellitus. DESIGN: Prospective, randomized, multicenter, double-blind trial with a 16-week titration period and a 40-week maintenance period. SETTING: Sixty-five investigative sites in the United States and Puerto Rico. PATIENTS: Five hundred two subjects with a recent diagnosis of type 2 diabetes that was unsuccessfully treated with diet and exercise were randomly assigned to study treatment. Of the 251 patients in each treatment group, 128 (51.0%) glyburide-treated patients and 134 (53.4%) pioglitazone-treated patients completed the study. INTERVENTIONS: Dosages of randomly assigned glyburide and pioglitazone were titrated every 4 weeks for 16 weeks in 5-mg/day and 15-mg/day increments, respectively, until a fasting plasma glucose level between 69 and 141 mg/dl was achieved. The optimized regimen was maintained during the subsequent 40-week double-blind phase. MEASUREMENTS AND MAIN RESULTS: At week 56, glyburide and pioglitazone improved glucose control comparably (change in hemoglobin A(1c) -2.02% and -2.07%, respectively, p=0.669). Withdrawal due to lack of efficacy or adverse events occurred more frequently with glyburide (20.8%) than pioglitazone (12.8%, p<0.032). Significantly higher percentages of glyburide- than pioglitazone-treated patients had a hypoglycemic (24.3% vs 4.4%, p=0.0001) or cardiac (8.8% vs 4.4%, p=0.0478) event. Edema (4.8% vs 7.9%, p=0.1443) and weight gain (4.4% vs 4.0%, p=0.8238) did not differ significantly between the glyburide and pioglitazone groups. Only a few patients discontinued study drug because of weight gain (one glyburide, one pioglitazone), edema (one pioglitazone), or a cardiac event (two glyburide). CONCLUSION: With long-term treatment, both glyburide and pioglitazone resulted in comparable glycemic control; however, pioglitazone was associated with less hypoglycemia and fewer withdrawals due to lack of efficacy or adverse events.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glyburide/adverse effects , Hypoglycemic Agents/adverse effects , Thiazolidinediones/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Drug-Related Side Effects and Adverse Reactions , Female , Glyburide/therapeutic use , Humans , Hypoglycemic Agents/therapeutic use , Male , Middle Aged , Pioglitazone , Risk Assessment , Thiazolidinediones/therapeutic use , Time Factors
5.
Diab Vasc Dis Res ; 3(1): 39-44, 2006 May.
Article in English | MEDLINE | ID: mdl-16784180

ABSTRACT

The aim of this study was to evaluate changes in lipid profiles in patients with type 2 diabetes after treatment conversion from rosiglitazone to pioglitazone while maintaining stable statin and other lipid-altering therapies. A total of 305 patients were enrolled in this open-label study. Patients had been taking stable dosages of rosiglitazone and statins for > 90 days. At baseline, patients discontinued rosiglitazone and started pioglitazone 30 mg/day, but continued statins and other lipid-altering therapies. The primary end point was change from baseline in fasting triglyceride levels. At 17 weeks after treatment conversion, patients had significant reductions in triglycerides (-15.2%), total cholesterol (-9.0%), and low-density lipoprotein (LDL) particle concentration (-189 nmol/L), and increases in LDL cholesterol (+2.2%), high-density lipoprotein (HDL) cholesterol (+1.8%), and LDL particle diameter (+0.23 nm). In conclusion, after treatment conversion from rosiglitazone to pioglitazone while maintaining stable statin therapy, patients with type 2 diabetes had marked improvements in lipid profiles along with stable glycaemic control.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dyslipidemias/drug therapy , Hypoglycemic Agents/pharmacology , Lipid Metabolism/drug effects , Thiazolidinediones/pharmacology , Adolescent , Adult , Aged , Apolipoproteins/blood , Blood Glucose/drug effects , Blood Pressure/drug effects , C-Reactive Protein/metabolism , Cholesterol/blood , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypoglycemic Agents/therapeutic use , Lipids/blood , Middle Aged , Pioglitazone , Rosiglitazone , Thiazolidinediones/therapeutic use , Triglycerides/blood
6.
Diabetes Care ; 28(7): 1547-54, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15983299

ABSTRACT

OBJECTIVE: Published reports suggest that pioglitazone and rosiglitazone have different effects on lipids in patients with type 2 diabetes. However, these previous studies were either retrospective chart reviews or clinical trials not rigorously controlled for concomitant glucose- and lipid-lowering therapies. This study examines the lipid and glycemic effects of pioglitazone and rosiglitazone. RESEARCH DESIGN AND METHODS: We enrolled subjects with a diagnosis of type 2 diabetes (treated with diet alone or oral monotherapy) and dyslipidemia (not treated with any lipid-lowering agents). After a 4-week placebo washout period, subjects randomly assigned to the pioglitazone arm (n = 400) were treated with 30 mg once daily for 12 weeks followed by 45 mg once daily for an additional 12 weeks, whereas subjects randomly assigned to rosiglitazone (n = 402) were treated with 4 mg once daily followed by 4 mg twice daily for the same intervals. RESULTS: Triglyceride levels were reduced by 51.9 +/- 7.8 mg/dl with pioglitazone, but were increased by 13.1 +/- 7.8 mg/dl with rosiglitazone (P < 0.001 between treatments). Additionally, the increase in HDL cholesterol was greater (5.2 +/- 0.5 vs. 2.4 +/- 0.5 mg/dl; P < 0.001) and the increase in LDL cholesterol was less (12.3 +/- 1.6 vs. 21.3 +/- 1.6 mg/dl; P < 0.001) for pioglitazone compared with rosiglitazone, respectively. LDL particle concentration was reduced with pioglitazone and increased with rosiglitazone (P < 0.001). LDL particle size increased more with pioglitazone (P = 0.005). CONCLUSIONS: Pioglitazone and rosiglitazone have significantly different effects on plasma lipids independent of glycemic control or concomitant lipid-lowering or other antihyperglycemic therapy. Pioglitazone compared with rosiglitazone is associated with significant improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Hyperlipidemias/blood , Lipids/blood , Thiazolidinediones/therapeutic use , Aged , Apolipoproteins B/blood , Blood Glucose/drug effects , C-Peptide/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Diabetes Mellitus, Type 2/complications , Female , Humans , Hypoglycemic Agents/therapeutic use , Male , Middle Aged , Pioglitazone , Placebos , Rosiglitazone , Triglycerides/blood
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