Pioglitazone Slows Progression of Atherosclerosis in Prediabetes Independent of Changes in Cardiovascular Risk Factors

Abstract

Objective To determine whether changes in standard and novel risk factors during the ACT NOW trial explained the slower rate of CIMT progression with pioglitazone treatment in persons with prediabetes. Methods and Results CIMT was measured in 382 participants at the beginning and up to three additional times during follow-up of the ACT NOW trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76 × 10−3 mm/year, 95% CI, 2.39 × 10−3 – 7.14 × 10−3 mm/year) compared with placebo (9.69 × 10−3 mm/year, 95% CI, 7.24 × 10−3 – 12.15 × 10−3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P < 0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment. Conclusions Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.

Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack

“…A similar effect was not seen in the trial that involved rosiglitazone, 118 but pioglitazone was shown to slow the progression of intima-media thickness in the smaller Actos Now for Prevention of Diabetes (ACT NOW) trial. 121 For patients who have already progressed to DM, preventive care emphasizes good nutrition, treatment of hyperlipidemia and hypertension, smoking cessation, and antiplatelet therapy. 88,122 All patients with DM at risk for vascular disease benefit from statin therapy regardless of pretreatment LDL-C. 123,124 In consideration of RCT data confirming this benefit, the ADA recommends stain therapy for all people with DM with existing CVD, including stroke, 88 and suggests a goal of LDL-C <100 mg/dL (<70 mg/dL optional).…”

Pioglitazone Increases Circulating MicroRNA-24 With Decrease in Coronary Neointimal Hyperplasia in Type 2 Diabetic Patients – Optical Coherence Tomography Analysis –

“…Pioglitazone is known to interact with the PPAR-γ ligand-binding domain, thereby reducing inflammation, LDL-C and insulin resistance in type 2 diabetic patients. 29, 30 In this study, total cholesterol and LDL-C decreased in both groups, with no significant differences in changes vs. baseline between groups because atorvastatin 20 mg or rosuvastatin 10 mg was used in 97.2% of study patients (97.2%, n=35 in the pioglitazone group and 97.2%, n=36 in the control group, P=1.000). The beneficial vascular effects of pioglitazone were independent of its improvement of dyslipidemia and insulin resistance in the present study.…”

The use of statins in people at risk of developing diabetes mellitus: Evidence and guidance for clinical practice

“…More recently, the 18-month Carotid Atherosclerosis: Metformin For Insulin Resistance (CAMERA) trial demonstrated a significant reduction in glycaemia when metformin was added to a statin in non-diabetic subjects with established CVD and large waist circumference (N ¼ 173) but no change in carotid intima-media thickness (CIMT) [76]. Although the Actos Now for Prevention of Diabetes (ACT NOW) trial showed a slower rate of CIMT progression in people with prediabetes treated with pioglitazone versus placebo, this result was independent of changes in glycaemia [77]. Overall, results suggest that the CV risk associated with dysglycaemia is modest and that lifestyle changes together with effective management of dyslipidaemia and blood pressure should be a priority for CV risk reduction in people with, or at risk of developing, T2D.…”