Efficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance

Abstract

Aims: Pioglitazone is a potent insulin-sensitizing drug with anti-atherosclerotic properties, but adverse effects have limited its use. We assessed the benefits and risks of lower versus higher doses of pioglitazone taken by participants in the Insulin Resistance Intervention in Stroke Trial. Materials and Methods: Efficacy [myocardial infarction (MI) or recurrent stroke]new-onset diabetes) and adverse outcomes (oedema, weight gain, heart failure and bone fracture) were examined for subjects assigned to pioglitazone or placebo within strata defined by mode dose of study drug taken (i.e. the dose taken on most days in the study).Results: Among the 1938 patients randomized to pioglitazone, the mode dose was <15 mg/day in 546 participants, 15 mg/day in 128, 30 mg/day in 89, and 45 mg/day in 1175. There was no significant effect on stroke/MI or new-onset diabetes with <15 mg/day. For 15 mg/30 mg/day pooled, the adjusted hazard ratios (95% CI) for stroke/MI were 0.48 (0.30, 0.76; p = .002) and 0.74 (0.69, 0.94) for 45 mg/day. For new-onset diabetes, the adjusted hazard ratios were 0.34 (0.15, 0.81; p = .001) and 0.31 (0.59, 0.94; p = .001) respectively.For oedema, weight gain and heart failure, the risk estimates for pioglitazone were lower for subjects taking <45 mg daily. For fractures, the increased risk with pioglitazone was similar across all dose strata.Conclusions: Lower doses of pioglitazone appear to confer much of the benefit with less adverse effects than the full dose. Further study is needed to confirm these findings so that clinicians may optimize dosing of this secondary prevention strategy in patients with stroke.

3. Prevention or Delay of Diabetes and Associated Comorbidities: Standards of Care in Diabetes—2023

“…At 4.8 years, the risk of stroke or myocardial infarction, as well as the risk of diabetes, was lower within the pioglitazone group than with placebo, though risks of weight gain, edema, and fracture were higher in the pioglitazone treatment group (107-109). Lower doses may mitigate the adverse effects, though further study is needed to confirm the benefit at lower doses (110). (112).…”

The Pre-Stroke Induction and Normalization of Insulin Resistance Respectively Worsens and Improves Functional Recovery

“…Therefore, a positive outcome from these studies will have novel clinical implications, which could benefit an enormous group of people. The PPARγ agonist Pioglitazone was recently associated with lower risk of recurrent stroke in patients with IR, prediabetes and T2D with a history of stroke or transient ischemic attack ([ 51 ]) (reviewed in [ 14 , 52 ]). Moreover, a preclinical study using pre-stroke Pioglitazone administration to db/db mice ameliorated neurological outcomes 24 h after tMCAO ([ 53 ]).…”

Nonalcoholic fatty liver disease and osteoporosis: A potential association with therapeutic implications

“…However, pioglitazone has been associated with a small increase in the risk of osteoporotic fractures, 83 although a recent meta‐analysis failed to verify it 84 . Any effect of pioglitazone on fracture risk may not be higher with higher doses, a conclusion indirectly derived from studies with populations other than NAFLD 85 . Thus, pioglitazone should be prescribed with caution in NASH patients with concomitant osteoporosis or even avoided in those who are at high risk of fracture 82 .…”

“…84 Any effect of pioglitazone on fracture risk may not be higher with higher doses, a conclusion indirectly derived from studies with populations other than NAFLD. 85 Thus, pioglitazone should be prescribed with caution in NASH patients with concomitant osteoporosis or even avoided in those who are at high risk of fracture. 82 Newer selective PPAR modulators (eg, INT131) are expected to exert a similar effect on NAFLD, without the adverse effects of pioglitazone, including the unfavourable effect on bone metabolism.…”