Pioglitazone: inexpensive; very effective at reducing HbA<sub>1c</sub>; no evidence of bladder cancer risk; plenty of evidence of cardiovascular benefit

Ryder, Robert E.; DeFronzo, Ralph A.

doi:10.1111/dme.14053

Cited by 6 publications

(6 citation statements)

References 11 publications

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“…The use of pioglitazone has been questioned due to a purported higher risk for bladder cancer in older men with diabetes. A 10-year prospective study performed by the FDA to evaluate this connection concluded that it was non-existing [ 55 ]; accordingly, this association is considered to have been a “red herring” [ 56 ]. In adolescents with PCOS, low-dose pioglitazone (7.5 mg/day) has an excellent safety profile [ 43 , 44 ]; pioglitazone appears to be well tolerated by children since no side effects were identified in children (with autism) receiving a 10-fold higher dose [ 57 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol

Bassols

Zegher

Díaz

et al. 2023

Trials

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Background A “mismatch” sequence of less prenatal weight gain and more postnatal weight gain may lead to ectopic lipid accumulation, and trigger the development of early adrenarche/pubarche and the activation of the gonadotropic axis resulting in early puberty and ending up in full-blown adolescent polycystic ovary syndrome (PCOS). In the present study, we assess whether a low-dose combination of generics that collectively reduce ectopic fat through different pathways can slow down the accelerated maturation in “mismatch” girls with early puberty. Methods Randomized, placebo-controlled, multicenter, phase 2a, study in 64 girls [age, 8.0–9.3 years; birthweight (BW) for gestational age in lower tertile (−1.96< Z-score <−0.44), body mass index (BMI) in upper tertile (+0.44< Z-score < +1.96) and early progressive puberty (Tanner B2 at 7.7–9.0 years)]. Pharmacological intervention will be with a half-dose version of SPIOMET (mini-spiomet), a combination that reverts the PCOS phenotype in “mismatch” adolescents; mini-spiomet will contain spironolactone (25 mg/day, to raise brown adipose tissue activity), pioglitazone (3.75 mg/day, to raise adiponectin and insulin sensitivity), and metformin (425 mg/day, to raise AMPK activity and GDF15). Recruitment: 1 year; double-blind treatment: 1 year; open follow-up: 1 year; analyses and reporting: 1 year. Interventions: randomization (1:1) for placebo vs mini-spiomet. Primary outcome: annualized bone age advancement (0–1 year) by BoneXpert; secondary outcomes: insulin, IGF-I, high-molecular-weight adiponectin (HMW-adip), sex hormone binding globulin (SHBG), ultra-sensitive C-reactive protein (usCRP), androgens, luteinizing hormone (LH), follicle-stimulating hormone (FSH), oestradiol, growth-and-differentiation factor 15 (GDF15), C-X-C motif chemokine ligand-14 (CXCL14), safety parameters, and quantification of hepato-visceral fat. Discussion The present study, if successful, may provide a first proof of the concept that the rapid maturation of girls with an upward mismatch between pre- and post-natal weight gain can be slowed down with a fixed low-dose combination of old and safe generics jointly targeting a reduction of ectopic fat without necessarily lowering body weight. Trial registration EudraCT 2021-006766-21. Registered on May 30, 2022.

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Section: Introductionmentioning

confidence: 99%

Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol

Bassols

Zegher

Díaz

et al. 2023

Trials

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“…Pioglitazone caused weight gain as a common adverse effect in these studies 100–103 and may be associated with increased risk of bone fracture 105 . There has also been concern about bladder cancer, but this remained controversial 106–111 . Vitamin E at a dose of 800 IU/day demonstrated improvement in serum aminotransferases 100,112,113 .…”

Section: Resultsmentioning

confidence: 99%

“…105 There has also been concern about bladder cancer, but this remained controversial. [106][107][108][109][110][111] Vitamin E at a dose of 800 IU/day demonstrated improvement in serum aminotransferases. 100,112,113 Although vitamin E has not been consistently shown to result in overall improvement in the NAFLD activity score, 113 it has been consistently shown to improve liver steatosis.…”

Section: Lifestyle Intervention Is the Cornerstone Of Management Of M...mentioning

confidence: 98%

Malaysian Society of Gastroenterology and Hepatology consensus statement on metabolic dysfunction‐associated fatty liver disease

Chan

Tan

Chan

et al. 2022

J of Gastro and Hepatol

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The Malaysian Society of Gastroenterology and Hepatology saw the need for a consensus statement on metabolic dysfunction‐associated fatty liver disease (MAFLD). The consensus panel consisted of experts in the field of gastroenterology/hepatology, endocrinology, bariatric surgery, family medicine, and public health. A modified Delphi process was used to prepare the consensus statements. The panel recognized the high and increasing prevalence of the disease and the consequent anticipated increase in liver‐related complications and mortality. Cardiovascular disease is the leading cause of mortality in MAFLD patients; therefore, cardiovascular disease risk assessment and management is important. A simple and clear liver assessment and referral pathway was agreed upon, so that patients with more severe MAFLD can be linked to gastroenterology/hepatology care, while patients with less severe MAFLD can remain in primary care or endocrinology, where they are best managed. Lifestyle intervention is the cornerstone in the management of MAFLD. The panel provided a consensus on the use of statin, angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker, sodium–glucose cotransporter‐2 inhibitor, glucagon‐like peptide‐1 agonist, pioglitazone, vitamin E, and metformin, as well as recommendations on bariatric surgery, screening for gastroesophageal varices and hepatocellular carcinoma, and liver transplantation in MAFLD patients. Increasing the awareness and knowledge of the various stakeholders on MAFLD and incorporating MAFLD into existing noncommunicable disease‐related programs and activities are important steps to tackle the disease. These consensus statements will serve as a guide on MAFLD for clinicians and other stakeholders.

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“…insulin infusion. In their Letter to the Editor [1], the authors asserted that biased and inconsistent studies were included in a metaanalysis by Ripamonti et al [2] Let us clarify that in the cited paper [2] we showed heterogeneity measures, but no pooled estimate has been calculated for any effect measure, exactly for the reason that included studies were, for different reasons, biased or poorly conducted. IIn the light of this premise, our systematic review showed how no conclusion on the association between pioglitazone and bladder cancer can be posited, as most studies in this area are affected by different sources of bias, most notably time-related biases.…”

mentioning

confidence: 93%

“…IIn the light of this premise, our systematic review showed how no conclusion on the association between pioglitazone and bladder cancer can be posited, as most studies in this area are affected by different sources of bias, most notably time-related biases. This specific point seems to be ignored by the authors of the Letter to the Editor [1], who stated that it is not 'appropriate, as suggested by Ripamonti et al, to devote further resources to yet more research into a connection between pioglitazone and bladder cancer'. To justify their assertion, they referred to the results of the Insulin Resistance Intervention after Stroke (IRIS) study [3] and they also invoked more randomized controlled trials on the potential protective effect of pioglitazone on cardiovascular events.…”

mentioning

confidence: 99%

Pioglitazone and bladder cancer: improving research methods

et al. 2020

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Pioglitazone: inexpensive; very effective at reducing HbA_1c; no evidence of bladder cancer risk; plenty of evidence of cardiovascular benefit

Cited by 6 publications

References 11 publications

Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol

Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol

Malaysian Society of Gastroenterology and Hepatology consensus statement on metabolic dysfunction‐associated fatty liver disease

Pioglitazone and bladder cancer: improving research methods

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Pioglitazone: inexpensive; very effective at reducing HbA1c; no evidence of bladder cancer risk; plenty of evidence of cardiovascular benefit

Cited by 6 publications

References 11 publications

Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol

Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol

Malaysian Society of Gastroenterology and Hepatology consensus statement on metabolic dysfunction‐associated fatty liver disease

Pioglitazone and bladder cancer: improving research methods

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Pioglitazone: inexpensive; very effective at reducing HbA_1c; no evidence of bladder cancer risk; plenty of evidence of cardiovascular benefit