Actos (Pioglitazone) Renal Protection or Renal Risk: A Clinical Update

Why the kidney question comes up at all

Pioglitazone is a thiazolidinedione and a PPAR-gamma agonist. It lowers glucose by decreasing insulin resistance in the periphery and liver, increasing insulin-dependent glucose disposal and reducing hepatic glucose output, and it is not an insulin secretagogue [1]. Its only approved use is as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, and the label states that conclusive evidence of macrovascular risk reduction, meaning heart attack or stroke, has not been established by clinical studies [1].

The renal interest comes from a separate literature on PPAR-gamma agonists. One review describes reduced urinary albumin and protein excretion with thiazolidinediones and interference with several pathways involved in diabetic nephropathy, with fluid retention as the main adverse effect [5]. Another describes PPAR-gamma agonist renal protection, mainly albuminuria reduction, in diabetic nephropathy, and suggests it may partly reflect lower blood pressure, endothelial protection and vasodilation of the glomerular efferent arterioles [6]. That is a mechanistic story, not a demonstrated clinical renal benefit.

Does the albuminuria effect hold up?

The most direct test was a 44-patient open-label randomized trial in people with overt diabetic nephropathy, comparing pioglitazone with glipizide at similar glucose control [2]. Over 4 months, 24-hour proteinuria rose 6.1% with glipizide (95% CI -11.7% to 23.8%) and fell 7.2% with pioglitazone (95% CI -24.9% to 10.6%); the adjusted 13.2% difference between groups was not statistically significant (P=0.294) [2]. The investigators concluded there was no reduction in proteinuria over 4 months and called for larger, longer studies [2].

The larger test is a retrospective cohort from Taiwan of 742 adults with type 2 diabetes and diabetic kidney disease, defined as an eGFR of 30 to 90 mL/min/1.73 m2 and a urine albumin-to-creatinine ratio of 300 to 5000 mg/g [3]. In that cohort, 111 patients added pioglitazone and 631 received standard care, with a median follow-up of 2 years [3]. Pioglitazone use did not reduce the composite renal endpoint of sustained eGFR below 15, doubling of serum creatinine, or dialysis or transplant (HR 0.97, 95% CI 0.53-1.77), and end-stage renal disease gave an HR of 2.58 (95% CI 0.29-23.04) [3]. The authors also noted a non-significant albuminuria reduction, and baseline HbA1c was higher in the pioglitazone group (8.8% vs 8.1%) [3].

An earlier review had already taken the cautious position, stating that not enough data were available to recommend thiazolidinediones for renal protection [7].

Does kidney function change the dose?

Pioglitazone is metabolized mainly by CYP2C8 and also by CYP3A4 to active metabolites. Its half-life is 3 to 7 hours, its metabolites 16 to 24 hours, and 15% to 30% of a dose is recovered in urine, mostly as metabolites, with the remainder excreted in bile and feces [1]. The Actos label specifies no dose adjustment for renal impairment [1].

The starting dose is 15 mg or 30 mg once daily, taken with or without meals and raised in 15 mg steps to a maximum of 45 mg based on HbA1c; for NYHA class I or II heart failure the starting dose is 15 mg [1]. Women had 20% to 60% higher peak and total exposure than men, with no dose adjustment by sex [1]. Gemfibrozil and other strong CYP2C8 inhibitors raise pioglitazone exposure about 3-fold, and the label caps the dose at 15 mg daily in that situation [1].

The label says to obtain liver tests before starting, and it does not recommend routine liver monitoring afterwards in patients without liver disease [1].

The documented risk: fluid retention and heart failure

Actos carries a boxed warning for congestive heart failure: thiazolidinediones, including Actos, cause or exacerbate heart failure in some patients [1]. The label directs monitoring after initiation and after each dose increase for excessive rapid weight gain, shortness of breath and edema; it states that the drug is not recommended in patients with symptomatic heart failure and that initiation in established NYHA class III or IV heart failure is contraindicated [1]. If heart failure develops, the label says it should be managed according to current standards of care and that discontinuation or dose reduction of Actos must be considered [1].

In PROactive, which followed 5,238 adults with type 2 diabetes and macrovascular disease for a mean of 34.5 months, edema occurred in 26.7% on pioglitazone vs 15.3% on placebo, cardiac failure in 8.1% vs 6.1%, hospitalized heart failure in 5.7% (149/2,605) vs 4.1% (108/2,633), and fatal heart failure in 1.0% vs 0.8% [1]. The main trial report gives hospitalized heart failure as 6% vs 4% and states that fatal heart failure did not differ [8]. PROactive's primary composite endpoint was not significant (HR 0.90, 95% CI 0.80-1.02, P=0.095) [8].

Edema is dose-related and most common with insulin: 17.6% at 30 mg plus insulin vs 7.0% with placebo plus insulin over 16 weeks, and 26.1% at 45 mg vs 22.0% at 30 mg in a 24-week insulin add-on trial [1]. With a sulfonylurea, edema was 12.7% at 30 mg vs 2.1% with placebo, and 23.1% at 45 mg vs 10.5% at 30 mg [1]. The label states that weight gain with Actos probably reflects both fluid retention and fat accumulation [1].

Bladder tumors: not a kidney question, but worth stating correctly

The boxed warning covers heart failure only; bladder tumors are a Warnings and Precautions item [1]. The label says Actos may be associated with an increase in the risk of urinary bladder tumors and that there are insufficient data to determine whether pioglitazone is a tumor promoter for these tumors [1]. In PROactive, bladder cancer was diagnosed in 14 of 2,605 (0.54%) on Actos vs 5 of 2,633 (0.19%) on placebo, or 6 (0.23%) vs 2 (0.08%) after excluding exposure under 1 year; across 13 years of trial plus observational follow-up there was no difference (HR 1.00, 95% CI 0.59-1.72) [1]. A US 10-year cohort found no significant increase (HR 1.06, 95% CI 0.89-1.26), while a UK cohort found an association (HR 1.63, 95% CI 1.22-2.19), and the label calls these findings inconsistent and says they preclude conclusive interpretation [1]. The label says not to use Actos in patients with active bladder cancer and to weigh benefit against unknown recurrence risk in those with prior bladder cancer [1].

If the prescription is a combination tablet

Actoplus Met combines pioglitazone with metformin under a separate label, and its renal restrictions apply to that product: it is contraindicated at an eGFR below 30 mL/min, initiation is not recommended at an eGFR of 30 to 45, it should be discontinued if eGFR later falls below 30, and it may need to be stopped at the time of, or before, iodinated contrast imaging [4]. Its boxed warning covers both congestive heart failure and lactic acidosis [4].

How it compares with SGLT2 inhibitors

In CREDENCE, 4,401 adults with type 2 diabetes and albuminuric chronic kidney disease on renin-angiotensin system blockade were randomized to canagliflozin 100 mg or placebo [9]. The trial was stopped early after a planned interim analysis, and canagliflozin reduced the primary composite of end-stage kidney disease, doubling of creatinine, or renal or cardiovascular death by 30% (event rates 43.2 vs 61.2 per 1000 patient-years; HR 0.70, 95% CI 0.59-0.82, P=0.00001) [9].

In an observational cohort of 18,467 people with newly diagnosed diabetes, compared with SGLT2 inhibitors, the other drug classes, including thiazolidinediones, were associated with higher risks of end-stage renal disease (adjusted hazard ratios across classes 3.62 to 19.16) and death [10]. The 2018 ADA-EASD consensus, as summarized in one review, gives preference to an SGLT2 inhibitor when heart failure or renal disease is present, provided eGFR is adequate (above 45 to 60 mL/min/1.73 m2) [11], and another review notes that SGLT2 inhibitors are specifically recommended in albuminuric renal disease [12].

What the label says to watch for

• Fluid: the Actos label advises monitoring after starting treatment and after each dose increase for excessive rapid weight gain, shortness of breath, or edema [1].
• Liver: the label advises prompt liver testing when symptoms such as fatigue, loss of appetite, right upper abdominal discomfort, dark urine, or jaundice occur, and that treatment be interrupted when ALT is more than 3 times the upper limit of the reference range [1].
• Bone: in PROactive, fractures occurred in 5.1% of women on Actos (44/870) vs 2.5% on placebo (23/905), with no increase in men (1.7% vs 2.1%) [1].
• Eyes: macular edema has been reported postmarketing, and the label recommends regular eye exams according to current standards of care [1].
• Hypoglycemia: adding 30 mg to insulin gave hypoglycemia of 15.4% vs 4.8% with placebo; if hypoglycemia occurs, the label directs lowering insulin by 10% to 25%, or lowering the sulfonylurea dose when one is used [1].