Meng Tan

Peroxisome proliferator-activated receptors (PPARs) play an important role in regulating both glucose and lipid metabolism. Agonists for both PPAR and PPAR have been used to treat dyslipidemia and hyperglycemia, respectively. In addition to affecting glucose metabolism, PPAR agonists also regulate lipid metabolism. In this review, we will focus on the randomized clinical trials that directly compared the lipid effects of the thiazolidinedione class of PPAR agonists, pioglitazone and rosiglitazone, head-to-head either as monotherapy or in combination with other lipid-altering or glucose-lowering agents

OBJECTIVE—We assessed the effect upon A1C of recruitment to a clinical trial in patients with diabetes who had been screened and interviewed to determine eligibility but whose therapy was otherwise unchanged. RESEARCH DESIGN AND METHODS—Eligible trials were selected from the global program of an insulin manufacturer. Included were studies in which patients were seen on a single screening visit, pharmaceutical therapy was not altered before randomization, and A1C was measured in a central laboratory at both screening and randomization. Three trials involving patients with type 1 diabetes (n = 429) and three trials involving patients with type 2 diabetes (n = 611) were identified for analysis. The main outcome measure was change in A1C. Separate regression equations on the change in A1C were fitted for type 1 and type 2 diabetes and included effects of baseline A1C and the interval between the screening and randomization visits. RESULTS—A1C changed by −0.13% (range +0.09 to −0.26%) in...

OBJECTIVE—Associated with insulin resistance in type 2 diabetes are increased serum triglycerides, decreased HDL cholesterol, and a predominance of large VLDL, small LDL, and small HDL particles. The comparative effects of thiazolidinedione insulin sensitizers on serum lipoprotein particle concentrations and sizes in type 2 diabetes are not known. We studied the effects of pioglitazone (PIO) and rosiglitazone (ROSI) treatments on serum lipoprotein particle concentrations and sizes in type 2 diabetic patients with dyslipidemia. RESEARCH DESIGN AND METHODS—This is a prospective, randomized, double-blind, multicenter, parallel-group study. After a 4-week placebo washout period, patients randomized to PIO (n = 369) were treated with 30 mg q.d. for 12 weeks followed by 45 mg q.d. for another 12 weeks, while patients randomized to ROSI (n = 366) were treated with 4 mg q.d. followed by 4 mg b.i.d. for the same intervals. Lipoprotein subclass particle concentrations and sizes were determine...

OBJECTIVE—The hypothesis that pioglitazone treatment is superior to gliclazide treatment in sustaining glycemic control for up to 2 years in patients with type 2 diabetes was tested. RESEARCH DESIGN AND METHODS—This was a randomized, multicenter, double-blind, double-dummy, parallel-group, 2-year study. Approximately 600 patients from 98 centers participated. Eligible patients had completed a previous 12-month study and consented to continue treatment for a further year. To avoid selection bias, all patients from all centers were included in the primary analysis (a comparison of the time-to-failure distributions of the two groups by using a log-rank test) regardless of whether they continued treatment for a 2nd year. By using repeated-measures ANOVA, time course of least square means of HbA1c and homeostasis model of assessment (HOMA) indexes (HOMA-%S and HOMA-%B) were analyzed. RESULTS—A greater proportion of patients treated with pioglitazone maintained HbA1c <8% over the 2-yea...

OBJECTIVE— PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure. RESEARCH DESIGN AND METHODS— PROactive was an outcome study in 5,238 patients randomized to pioglitazone or placebo. Patients with New York Heart Association Class II–IV heart failure at screening were excluded. A serious adverse event of heart failure was defined as heart failure that required hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity. Heart failure risk was evaluated by multivariate regression. RESULTS— More pioglitazone (5.7%) ...

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...

A basal bolus insulin regimen requires multiple daily insulin injections, which might discourage patient adherence. As a potential solution, a mealtime insulin-delivery system-a 3-day wearable bolus-only patch-was designed to manually administer mealtime insulin discreetly by actuating buttons through clothing, without the need for multiple needle sticks. Extensive functional testing of the patch included dose accuracy (from initial fill of the device to empty), pressure-vacuum leak testing, last-dose lockout and occlusion detection (safety alert features that lock the dosing buttons when no insulin is delivered), assessments of insulin drug stability, toxicological risk (including chemical testing), and system biocompatibility. Dosing accuracy was 2 units ±10% (with U-100 insulin) over a range of environmental conditions, with ≥95% reliability and confidence. The fluid seal performance and the safety alert features performed with ≥95% reliability and ≥95% confidence. The system met...

Intravenous arginine infusions were performed in two totally pancreatectomized patients and two age/sex-matched normal subjects. Plasma glucagon concentrations did not increase in the pancreatectomized patients, whereas a four- to sixfold rise of the glucagon levels following arginine administration was seen in the control subjects. Measurements of plasma glucagon-like im-munoreactivity revealed no difference between normal and pancreatectomized subjects. The data suggest the absence of a significant number of normally functioning alpha cells in extrapancreatic sites.

Cardiovascular disease is the leading cause of mortality and morbidity among people with diabetes mellitus. Epidemiological studies have shown that individuals with diabetes are at increased risk of premature coronary heart disease and stroke.1,2,3,4 People with non-insulin dependent diabetes mellitus (NIDDM) have age-specific mortality rates which are about double those of the non-diabetic populations5. Most of the excess mortality is attributable to coronary heart disease.6 Poor glycemic control in people with diabetes has been demonstrated to lead to higher rates of cardiovascular events7,8,9.

This study compared the efficacy, safety, device satisfaction, and quality of life (QOL) in people with diabetes using an insulin bolus-patch versus current devices (pen/syringe) to deliver mealtime insulin. Thirty-eight subjects with diabetes (26 with type 1 and 12 with type 2) were randomized to bolus-patch or current injection device (55% pen and 45% syringe) to deliver mealtime insulin in a multicenter, 6-week crossover study. Efficacy was assessed by equivalence in mean daily seven-point blood glucose (MDBG). Safety assessments included severe hypoglycemia episodes, adverse device effects (ADEs), and adverse events (AEs). Device satisfaction was determined by the validated Insulin Delivery System Rating Questionnaire (IDSRQ) and QOL by the validated Diabetes Specific QOL Scale (DSQOLS). Using bolus-patch, MDBG (mean±SE) was equivalent to that using pen/syringe (8.61±0.28 vs. 9.02±0.26 mmol/L; P=0.098). SD of the seven-point blood glucose measurements was lower using bolus-patch...

Despite their comparable glycaemic effects in patients with Type 2 diabetes mellitus (T2DM), pioglitazone and metformin may have different effects on insulin sensitivity because they have different mechanisms of action. We studied the changes in insulin sensitivity, as assessed by the Quantitative Insulin Sensitivity Check Index (QUICKI), in patients with T2DM who used metformin or pioglitazone as monotherapy or in combination therapy with sulphonylurea. Data in this report are from two multicentre, randomized, double-blind, double-dummy studies conducted in Europe (monotherapy) or in Europe and Canada (combination therapy study). Patients were randomized to 52 weeks of treatment consisting of a 12-week forced titration period and a 40-week maintenance period. HbA(1c), fasting plasma glucose (FPG) and fasting serum insulin (FSI) were quantified from a single blood sample at weeks 0, 8, 16, 24, 32, 42 and 52. Insulin sensitivity was assessed with QUICKI, which is calculated from FSI and fasting blood glucose (FBG) concentrations using the formula 1/(log(10) FSI + log(10) FBG). Time course effects of the treatments were compared by repeated measures analysis of covariance. As monotherapy, pioglitazone and metformin increased QUICKI compared with baseline (baseline vs. end point [mean +/- sem]; pioglitazone [0.303 +/- 0.001 vs. 0.321 +/- 0.001; P < 0.001] and metformin [0.304 +/- 0.001 vs. 0.315 +/- 0.001; P < 0.001]). Pioglitazone increased insulin sensitivity more than metformin from week 4 through week 52. There were significant increases in QUICKI from baseline in both combination therapy groups (baseline vs. end point; pioglitazone + sulphonylurea [0.305 +/- 0.001 vs. 0.319 +/- 0.001; P < 0.001] and metformin + sulphonylurea [0.306 +/- 0.001 vs. 0.317 +/- 0.001; P < 0.001]). Overall, pioglitazone + sulphonylurea significantly increased insulin sensitivity more than metformin + sulphonylurea. Pioglitazone differed from metformin in its effects on insulin sensitivity despite both drugs having comparable glycaemic effects.

OBJECTIVE To study the fractional esterification rate of cholesterol on HDL particles (FERHDL) in adults with type 2 diabetes and assess its correlation with serum lipids and other coronary heart disease (CHD) risk factors. RESEARCH DESIGN AND METHODS FERHDL was measured in 90 adult (57 men, 33 women) patients by an isotopic assay method involving several steps, including preparation of VLDL- and LDL-depleted plasma, labeling of the sample with a trace amount of tritiated cholesterol, separation of free and esterified cholesterol fractions by chromatography post incubation, and subsequent counting of radioactivity in the individual fractions. RESULTS Male patients have higher FERHDL values than their female counterparts. When HDL cholesterol was controlled for in a multivariate regression analysis, the sex factor was not significant. There was a significant positive correlation between FERHDL and plasma total cholesterol (r = 0.32), triglycerides (r = 0.82), apolipoprotein B (apo B;...

Objectif Chez des patients diabetiques de type 2 (DT2), la glycemie (GLY), l’insulinemie (INS), la proteine C reactive-us (CRP-us), le facteur de necrose tumorale α (TNFα), l’interleukine6 (IL6) et la nitrotyrosine (NT) augmentent en periode postprandiale (pp) apres un repas mixte hyperlipidique. L’impact de la GLY pp ou de l’INS pp sur l’augmentation des marqueurs inflammatoires (CRP-us, TNFα, IL6) et du stress nitro-oxydant (NT) chez ces patients a ete etudie. Patients et Methodes Apres 24 semaines de traitement, un sous-groupe de patients DT2 participant a une etude prospective, ouverte, en parallele, comparant les effets d’un melange lispro mix 50 (LM50 ; 50 % lispro/50 % lispro protamine suspension) 3/j, n = 25, versus insuline basale glargine au coucher, n = 21, tous deux avec metformine, ont participe a un repas test. La veille du test les patients ont dine et se sont injectes l’insuline assignee. Un petit-dejeuner Mc Donald's® standardise hyperlipidique (MG 39 g, HC 78 g, PROT 24 g) a ete precede de l’injection de LM50 et suivi d’un prelevement a 0, 1, 2, 3, 4, 6, 8 h. L’aire sous la courbe (ASC) de la GLY et l’ASC d’excursion glycemique de 0 a 8 h ont ete calculees. Un modele de regression lineaire multiple a ete applique pour etablir un effet independant potentiel de la GLY pp ou de l’INS pp (variables independantes) sur la CRP-us pp, le TNFα pp, l’IL6 pp et la NT pp (variables dependantes) respectivement, apres ajustement de l’HbA1c, GLY/INS a jeun, âge, sexe et IMC. Resultats L’ASC de la GLY et l’ASC d’excursion glycemique pp ont montre une association significative avec l’ASC pp et l’ASC d’excursion pp de la CRPus, du TNFα, de l’IL6 et de la NT. La force des associations a ete faible pour l’INS pp. Conclusion Chez des patients DT2 apres un repas mixte hyperlipidique, l’augmentation pp de la GLY et non de l’INS entraine une augmentation des marqueurs inflammatoires et du stress nitro-oxydant. Le controle de la GLY pp pourrait etre important pour diminuer l’inflammation pp et le stress nitro-oxydant chez des patients DT2.

To examine the relationship between glycaemic control and hypoglycaemia in patients with type 2 diabetes treated with metformin (Met) and either insulin lispro mixtures, given twice or thrice daily (LM + Met), or insulin glargine, given once daily (G + Met). Data from three randomized clinical trials were pooled to compare effects of LM + Met with G + Met. The LM + Met group achieved lower mean HbA(1c) (mean+/-SE, 7.2+/-0.1 vs. 7.7+/-0.1%, p<0.0001) and all meals combined post-prandial blood glucose (BG) (8.9+/-0.1 vs. 10.2+/-0.1 mmol/L, p<0.0001) compared with the G + Met group, but had higher fasting blood glucose (8.1+/-0.1 vs. 6.8+/-0.1 mmol/L, p<0.0001) and insulin requirement (0.7+/-0.01 vs. 0.6+/-0.01 U/kg, p<0.0001). Over the entire study period, daytime hypoglycaemia was higher for the LM + Met group (10.3 vs. 3.5 episodes/patient/year, p<0.0001) than for the G + Met group; however, nocturnal hypoglycaemia was lower (3.4 vs. 6.6 episodes/patient/year, p=0.003). At endpoint, daytime hypoglycaemia was higher for the LM + Met group (6.2 vs. 1.4 episodes/patient/year, p<0.0001); however, nocturnal hypoglycaemia was similar in both groups (1.9 vs. 3.0 episodes/patient/year). An inverse relationship was observed between all confirmed hypoglycaemia and HbA(1c) at endpoint; for every 1% reduction in HbA(1c), the increase (in slope) was 1.4 episodes/patient/year (p=0.04). Patients with confirmed hypoglycaemia had lower HbA(1c) than patients without hypoglycaemia (7.39 vs. 7.64%, respectively; decrement=0.26%, p=0.026). These studies demonstrated an inverse relationship between HbA(1c) and 24-h and daytime hypoglycaemia. Lispro insulin mixtures provided lower HbA(1c) and post-prandial blood glucose values than glargine, but caused more daytime hypoglycaemia. Frequency of nocturnal hypoglycaemia was similar and severe hypoglycaemia was rare with both insulin regimens.