RESUMEN
BACKGROUND: Type 2 diabetes is a major risk factor for chronic kidney disease, which substantially increases the risk of cardiovascular disease mortality. This Phase IIb safety study (AleNephro) in patients with stage 3 chronic kidney disease and type 2 diabetes, evaluated the renal effects of aleglitazar, a balanced peroxisome proliferator-activated receptor-α/γ agonist. METHODS: Patients were randomized to 52 weeks' double-blind treatment with aleglitazar 150 µg/day (n=150) or pioglitazone 45 mg/day (n=152), followed by an 8-week off-treatment period. The primary endpoint was non-inferiority for the difference between aleglitazar and pioglitazone in percentage change in estimated glomerular filtration rate from baseline to end of follow-up. Secondary endpoints included change from baseline in estimated glomerular filtration rate and lipid profiles at end of treatment. RESULTS: Mean estimated glomerular filtration rate change from baseline to end of follow-up was -2.7% (95% confidence interval: -7.7, 2.4) with aleglitazar versus -3.4% (95% confidence interval: -8.5, 1.7) with pioglitazone, establishing non-inferiority (0.77%; 95% confidence interval: -4.5, 6.0). Aleglitazar was associated with a 15% decrease in estimated glomerular filtration rate versus 5.4% with pioglitazone at end of treatment, which plateaued to 8 weeks and was not progressive. Superior improvements in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides, with similar effects on glycosylated hemoglobin were observed with aleglitazar versus pioglitazone. No major safety concerns were identified. CONCLUSIONS: The primary endpoint in AleNephro was met, indicating that in stage 3 chronic kidney disease patients with type 2 diabetes, the decrease in estimated glomerular filtration rate after 52 weeks' treatment with aleglitazar followed by 8 weeks off-treatment was reversible and comparable (non-inferior) to pioglitazone. TRIAL REGISTRATION: NCT01043029 January 5, 2010.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Riñón/efectos de los fármacos , Oxazoles/uso terapéutico , PPAR alfa/agonistas , PPAR gamma/agonistas , Insuficiencia Renal Crónica/tratamiento farmacológico , Tiofenos/uso terapéutico , Anciano , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/fisiopatología , Método Doble Ciego , Dislipidemias/sangre , Dislipidemias/complicaciones , Dislipidemias/tratamiento farmacológico , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Oxazoles/farmacología , Pioglitazona , Insuficiencia Renal Crónica/fisiopatología , Equivalencia Terapéutica , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Tiofenos/farmacologíaRESUMEN
BACKGROUND: Aleglitazar is a new, balanced dual peroxisome proliferator-activated receptor (PPAR)α/γ agonist designed to optimize lipid and glycemic benefits and minimize PPAR-related adverse effects. METHODS: SESTA R was a 26-week, randomized, double-blind, multicenter study comparing the effects of a supratherapeutic dosage of aleglitazar (600 µg/day) with pioglitazone (45 mg/day) on change in measured GFR (mGFR) in 174 patients with type 2 diabetes and normal to mildly impaired renal function (estimated GFR [eGFR] 60 to 120 ml/min/1.73 m(2)). RESULTS: In 118 patients with evaluable GFR measurements, baseline mean (± SD) mGFR was 97.6 ± 17.5 ml/min/1.73 m(2) in the aleglitazar group and 101.9±21.6ml/min/1.73m(2) in the pioglitazone group. Mean percent change from baseline mGFR was -16.9% (90% confidence interval -22.0 to -11.5) with aleglitazar and -4.6% (-10.15 to 1.35) with pioglitazone, a mean treatment difference of -13.0% (-19.0 to -6.5). The 17% decrease from baseline in mGFR was consistent with the 19% decrease in eGFR Modification of Diet in Renal Disease (MDRD) observed with aleglitazar, which reached a plateau after 4weeks, with no further progression until treatment discontinuation. Following aleglitazar withdrawal, eGFR values returned to pretreatment levels within the 4-8-week follow-up, which suggests reversible hemodynamic changes in renal function. CONCLUSIONS: Despite the increased incidence of expected, dose-dependent PPAR class side effects (e.g., peripheral edema, weight gain, and congestive heart failure) limiting further development of this supratherapeutic dosage of aleglitazar (600 µg/day), these data, together with the data from the dose-ranging SYNCHRONY study, suggest aleglitazar may be a potential new treatment for cardiovascular risk reduction in post-acute coronary syndrome patients at the therapeutic 150 µg daily dose.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Tasa de Filtración Glomerular/efectos de los fármacos , Oxazoles/efectos adversos , Insuficiencia Renal/inducido químicamente , Tiofenos/efectos adversos , Adolescente , Adulto , Anciano , Diabetes Mellitus Tipo 2/fisiopatología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Oxazoles/administración & dosificación , Pronóstico , Insuficiencia Renal/fisiopatología , Estudios Retrospectivos , Tiofenos/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: Despite previous reports of potential adverse cardiovascular effects of peroxisome proliferator-activated receptor (PPAR) agonists, the promise for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes is of continued interest. The SYNCHRONY study aimed to establish the glucose-lowering and lipid-modifying effects, and safety profile, of the dual PPAR-alpha and PPAR-gamma agonist aleglitazar. METHODS: In this double-blind study, patients with type 2 diabetes (either drug-naive or pre-treated with =two oral agents) were enrolled from 47 sites in seven countries. After a single-blind, 4-5-week placebo run-in period, 332 patients were randomised double-blind (via an interactive voice-response system) to 16 weeks' treatment with aleglitazar at once-daily doses of 50 mug, 150 mug, 300 mug, or 600 mug, or matching placebo (n=55 in each group), or to open-label pioglitazone 45 mg once daily (n=57) as a reference. The primary efficacy endpoint was the change in glycosylated haemoglobin (HbA(1c)) concentration from baseline to the end of treatment. Patients who received at least one dose of study drug and had at least one evaluable post-baseline HbA(1c) measurement were included in the efficacy analysis. This study is registered with ClinicalTrials.gov, number NCT00388518. FINDINGS: The efficacy analysis excluded six patients (n=0 in pioglitazone group; n=1 in each of placebo, 50 mug, 150 mug, and 600 mug aleglitazar groups; and n=2 in 300 mug aleglitazar group). Aleglitazar significantly reduced baseline HbA(1c) versus placebo in a dose-dependent manner, from -0.36% (95% CI 0.00 to -0.70, p=0.048) with 50 mug to -1.35% (-0.99 to -1.70, p<0.0001) with 600 mug. The trend of changes over time suggests that the maximum effect of aleglitazar on HbA(1c) concentration was not yet reached after 16 weeks of treatment. Oedema, haemodilution, and weight gain occurred in a dose-dependent manner. However, at aleglitazar doses less than 300 mug, no patients had congestive heart failure, frequency of oedema was similar to placebo (one case at 50 mug, two at 150 mug, and three with placebo) and less than with pioglitazone (four cases), and bodyweight gain was less than with pioglitazone (0.52 kg at 150 mug vs 1.06 kg). INTERPRETATION: The favourable balance in the safety and efficacy profile of aleglitazar represents encouraging short-term clinical data for this agent and provides good evidence to enter phase III investigation. FUNDING: F Hoffmann-La Roche AG (Switzerland).
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , PPAR alfa/agonistas , PPAR gamma/agonistas , Análisis de Varianza , Enfermedades Cardiovasculares/etiología , Diabetes Mellitus Tipo 2/complicaciones , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Hemoglobina Glucada/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/farmacología , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Oxazoles/farmacología , Oxazoles/uso terapéutico , Pioglitazona , Seguridad , Método Simple Ciego , Tiazolidinedionas/uso terapéutico , Tiofenos/farmacología , Tiofenos/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Pioglitazone and glimepiride improve glycemic control in patients with type 2 diabetes mellitus by different mechanisms. Pioglitazone is a thiazolidinedione that reduces insulin resistance, and glimepiride is a sulfonylurea insulin secretagogue. OBJECTIVE: The goals of this study were to compare changes in measures of glycemic control and insulin sensitivity in Mexican patients with type 2 diabetes who received pioglitazone or glimepiride for 1 year. METHODS: This was a multicenter, 52-week, double-blind, parallel-group trial. Patients were randomized to receive monotherapy with either glimepiride (2 mg QD initially) or pioglitazone (15 mg QD initially). Doses were titrated (maximal doses: pioglitazone 45 mg, glimepiride 8 mg) to achieve glycemic targets (fasting blood glucose < or =7 mmol/L and 1-hour postprandial blood glucose < or =10 mmol/L). Insulin sensitivity (primary end point) was evaluated in terms of the Homeostasis Model Assessment for Insulin Sensitivity (HOMA-S), the Quantitative Insulin Sensitivity Check Index (QUICKI), and fasting serum insulin (FSI) concentrations. Glycemic control was evaluated in terms of glycosylated hemoglobin (HbA(1c)) values and fasting plasma glucose (FPG) concentrations. Patients were encouraged to maintain their individual diet and exercise regimens throughout the study. RESULTS: Two hundred forty-four patients (125 women, 119 men; all but 1 Hispanic) were randomized to receive pioglitazone (n = 121) or glimepiride (n = 123). In the intent-to-treat sample, pioglitazone and glimepirede produced comparable reductions in HbA(1c) from baseline to the end of the study (-0.78% and -0.68%, respectively). The pioglitazone group had significantly higher HbA(1c) values compared with the glimepiride group after 12 weeks of therapy (8.66% vs 7.80%; P = 0.007) but had significantly lower values after 52 weeks (7.46% vs 7.77%; P = 0.027). Pioglitazone significantly reduced FPG compared with glimepiride (-0.6 vs 0.6 mmol/L; P = 0.01). Pioglitazone therapy was associated with significant increases in insulin sensitivity (reduced insulin resistance), whereas glimepiride had no effect. HOMA-S values changed 18.0% for pioglitazone and -7.9% for glimepiride (P < 0.001), QUICKI values changed a respective 0.013 and -0.007 (P < 0.001), and FSI values were -21.1 and 15.1 pmol/L (P< 0.001). Both drugs were well tolerated, with pioglitazone associated with more peripheral edema (number of treatment-emergent cases: 35/121[28.9%] vs 17/123 [13.8%]; P = 0.005) and fewer hypoglycemic episodes (19 [15.7%] vs 38 [30.9%]; P = 0.024). The incidence of weight gain was not significantly different between treatment groups. CONCLUSIONS: These data suggest that long-term treatment with pioglitazone enhances insulin sensitivity relative to glimepiride in Mexican patients with type 2 diabetes and that pioglitazone may have a more sustained antihyperglycemic effect.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Compuestos de Sulfonilurea/uso terapéutico , Tiazolidinedionas/uso terapéutico , Glucemia/metabolismo , Método Doble Ciego , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/farmacología , Insulina/sangre , Lípidos/sangre , Masculino , México , Persona de Mediana Edad , Pioglitazona , Compuestos de Sulfonilurea/farmacología , Tiazolidinedionas/farmacologíaRESUMEN
OBJECTIVE: The goal of this study was to compare the effects of 2 doses of pioglitazone hydrochloride (a thiazolidinedione insulin sensitizer) with placebo on glycated hemoglobin (HbA(1c)), insulin sensitivity, and lipid profiles in patients with type 2 diabetes mellitus who had suboptimal glycemic control and mild dyslipidemia. METHODS: Patients with type 2 diabetes mellitus (HbA(1c) >/=6.5% and =9.8%) who had not previously received insulin or oral antihyperglycemic medications (OAMs) were randomized to treatment with placebo, pioglitazone 30 mg QD, or pioglitazone 45 mg QD in double-blind fashion for 16 weeks at 41 centers in Canada and Spain. RESULTS: A total of 297 patients were randomized (99 in each group). Overall, 286 (96.3%) were white. Mean (SD) age was 58.4 (10.9) years (range, 24-85 years), mean (SD) body mass index was 31.4 (4.8) kg/m(2), mean (SD) duration of type 2 diabetes mellitus was 20.0 (37.4) months, and 30.6% of patients were receiving medication for dyslipidemia. Treatment with pioglitazone 30 or 45 mg QD for 16 weeks reduced mean HbA(1c) by 0.8% and 0.9% from baseline, respectively (both P < 0.001 vs baseline and placebo). A reduction in HbA(1c) of 0.2% was observed in the placebo group (P = 0.025). In patients with medium (>/=7% to <8%) or high (>/=8% to =9.8%) baseline HbA(1c), both doses of pioglitazone significantly reduced HbA(1c) (both P < 0.001 vs placebo). Pioglitazone 30 and 45 mg significantly reduced fasting serum insulin versus placebo (P = 0.008 and P = 0.006, respectively) and increased insulin sensitivity by Homeostasis Model Assessment versus placebo (P = 0.039 and P = 0.001, respectively). Relative to placebo, pioglitazone 30 and 45 mg significantly increased high-density lipoprotein cholesterol (HDL-C [P = 0.028 and P < 0.001, respectively]) and lowered the atherogenic index of plasma (P = 0.018 and P < 0.001, respectively). Pioglitazone 45 mg also significantly reduced serum triglycerides, apolipoprotein B, and total cholesterol:HDL-C ratio versus placebo (P = 0.007, P = 0.015, and P = 0.005, respectively). Pioglitazone 30 and 45 mg were associated with a significant reduction in serum alanine aminotransferase relative to placebo (P = 0.036 and P = 0.005, respectively). Pioglitazone appeared to be safe and was well tolerated. CONCLUSIONS: In the present study, pioglitazone 30 and 45 mg produced significant improvements in HbA(1c), insulin sensitivity, and lipid profile in OAM-naive patients with type 2 diabetes mellitus with suboptimal glycemic control and mild dyslipidemia.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperlipidemias/complicaciones , Hipoglucemiantes/uso terapéutico , Tiazoles/uso terapéutico , Tiazolidinedionas , Adulto , Anciano , Anciano de 80 o más Años , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hiperlipidemias/sangre , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Insulina/sangre , Lípidos/sangre , Masculino , Persona de Mediana Edad , Pioglitazona , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Resultado del TratamientoRESUMEN
Pioglitazone, a thiazolidinedione, improves glycemic control primarily by increasing peripheral insulin sensitivity in patients with type 2 diabetes, whereas metformin, a biguanide, exerts its effect primarily by decreasing hepatic glucose output. In the first head-to-head, double-blind clinical trial comparing these two oral antihyperglycemic medications (OAMs), we studied the effect of 32-wk monotherapy on glycemic control and insulin sensitivity in 205 patients with recently diagnosed type 2 diabetes who were naive to OAM therapy. Subjects were randomized to either 30 mg pioglitazone or 850 mg metformin daily with titrations upward to 45 mg (77% of pioglitazone patients) and 2550 mg (73% of metformin patients), as indicated, to achieve fasting plasma glucose levels of less than 7.0 mmol/liter (126 mg/dl). Pioglitazone was comparable to metformin in improving glycemic control as measured by hemoglobin A1C and fasting plasma glucose. At endpoint, pioglitazone was significantly more effective than metformin in improving indicators of insulin sensitivity, as determined by reduction of fasting serum insulin (P = 0.003) and by analysis of homeostasis model assessment for insulin sensitivity (HOMA-S; P = 0.002). Both OAM therapies were well tolerated. Therefore, pioglitazone and metformin are equally efficacious in regard to glycemic control, but they exert significantly different effects on insulin sensitivity due to differing mechanisms of action. The more pronounced improvement in indicators of insulin sensitivity by pioglitazone, as compared with metformin monotherapy in patients recently diagnosed with type 2 diabetes who are OAM-naive, may be of interest for further clinical evaluation.
Asunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Metformina/uso terapéutico , Tiazoles/uso terapéutico , Tiazolidinedionas , Adulto , Apolipoproteínas B/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Método Doble Ciego , Ayuno , Femenino , Hemoglobina Glucada/análisis , Homeostasis , Humanos , Insulina/sangre , Masculino , Metformina/efectos adversos , Persona de Mediana Edad , Pioglitazona , Tiazoles/efectos adversos , Triglicéridos/sangreRESUMEN
BACKGROUND: Humalog Mix75/25 (Mix75/25) is a novel premixed insulin containing 75% neutral protamine lispro (an intermediate-acting insulin) and 25% insulin lispro. OBJECTIVE: The purpose of this study was to compare glycemic control and hypoglycemia rates with Mix75/25 versus glyburide, and with preprandial versus postprandial Mix75/25, in patients aged 60 to 80 years with type 2 diabetes mellitus and persistent hyperglycemia on sulfonylurea therapy. METHODS: In this open-label, 16-week, parallel-group study, patients were randomized to 1 of 2 treatments: glyburide 15 mg/d (or up to the maximum daily dose) or Mix75/25. The Mix75/25 group was randomly subdivided into preprandial (immediately before breakfast and dinner) and postprandial (within 15 minutes after the start of breakfast and dinner) injection subgroups. The primary outcomes were glycemic control and rate of hypoglycemia. RESULTS: A total of 143 patients were randomized; 127 completed the study. The change in glycosylated hemoglobin (HbA(1c)) from baseline to end point was significantly greater with Mix75/25 than with glyburide (mean +/- SEM, -1.14% +/- 0.18% vs -0.36% +/- 0.15%, P = 0.001). HbA(1c) changes with preprandial and postprandial Mix75/25 were not significantly different (-1.20% +/- 0.26% vs -1.08% +/- 0.26%, P = 0.748). Fasting blood glucose (BG), 2-hour postprandial BG, and mean daily BG reductions were greater with Mix75/25 than with glyburide (P < 0.001); preprandial and postprandial Mix75/25 administration did not differ significantly with respect to any of these BG variables. The hypoglycemia rate increased with Mix75/25 by 0.17 +/- 0.02 episodes per patient per 30 days, but there was no change with glyburide (P = 0.077). Body weight increased by 1.02 +/- 0.35 kg with Mix75/25 and decreased by 0.85 +/- 0.18 kg with glyburide (P < 0.001). CONCLUSIONS: Compared with glyburide, Mix75/25 significantly improved glycemic control in older patients with type 2 diabetes mellitus, could be administered after meals without compromising glycemic control, and was well tolerated.