Spironolactone for Acne: Evidence Base Graded by GRADE

What GRADE rating does spironolactone have for acne?

The formal GRADE assessment of oral spironolactone for acne is a 2017 hybrid systematic review by Layton and colleagues in the American Journal of Clinical Dermatology [1]. It retrieved 10 randomised controlled trials and 21 case series. Every trial was judged to be at high risk of bias, and the quality of evidence was rated low or very low for all outcomes [1].

GRADE rates the certainty of an effect estimate, not the size of the effect. A low rating is not a finding that spironolactone fails; it reflects the quality of the trials behind the estimate.

What those trials showed: apart from a single crossover trial in which 200 mg daily was statistically superior to placebo for inflamed lesions, the remaining trial data were unhelpful for establishing how effective lower doses are compared with placebo or an active comparator [1]. Menstrual side effects were significantly more common at 200 mg and were significantly reduced when a combined oral contraceptive was used alongside [1]. Pooled potassium results supported the conclusion that routine potassium monitoring is not required in this population [1].

What did the SAFA trial add?

SAFA, reported by Santer and colleagues in Health Technology Assessment in 2024, is a pragmatic, parallel-group, double-blind, randomised superiority trial run across UK primary care, secondary care and community settings [2]. Participants were women aged 18 or older with facial acne persisting at least 6 months that was judged potentially to warrant oral antibiotics, and they continued their usual topical treatment [2].

Of 1,267 women assessed, 410 were randomised 1:1 using an independent web-based procedure, 201 to spironolactone and 209 to placebo, and 342 were included in the primary analysis (176 and 166) [2]. The dose was 50 mg daily until week 6, then 100 mg daily until week 24 [2].

At 12 weeks, the primary endpoint, the Acne-Specific Quality of Life symptom subscale favoured spironolactone by an adjusted mean difference of 1.27 (95% CI 0.07 to 2.46), widening to 3.77 (95% CI 2.50 to 5.03) at 24 weeks [2]. Investigator's Global Assessment success at week 12 was 18.5% with spironolactone versus 5.6% with placebo (adjusted OR 5.18, 95% CI 2.18 to 12.28) [2]. By week 24, 81.9% of participants on spironolactone rated themselves improved versus 63.3% on placebo [2].

Headache was reported by 20.4% on spironolactone versus 12.0% on placebo. There were no serious adverse reactions, and other adverse reactions were similar between the two arms [2].

Does one good trial move the GRADE rating?

The Layton review was published in 2017, before the SAFA results existed, so its low-to-very-low rating does not cover the newer trial [1][2].

SAFA was double-blind, randomised 1:1 by an independent web-based procedure, and had treated and control groups of similar size (201 and 209) [2]. It is still one trial that ran for 24 weeks, and 342 of the 410 randomised women were in the primary analysis [2].

Which doses have been tested?

Three dose levels have direct trial support:

• 200 mg daily. One crossover trial showed statistical superiority over placebo for inflamed lesions, with more menstrual side effects at this dose [1].
• 100 mg daily. The maintenance dose in SAFA, reached after 6 weeks at 50 mg [2].
• 50 mg daily. The SAFA starting dose. SAFA tested 50 mg then 100 mg as a package, so its results do not separate the two [2].

The Aldactone label doses are for labeled indications, not acne: heart failure starts at 25 mg once daily, hypertension at 25 to 100 mg daily, edema at 100 mg daily (range 25 to 200 mg), and primary hyperaldosteronism at 100 to 400 mg daily before surgery [3]. The label says the drug can be taken with or without food but should be taken consistently with respect to food, and notes that food raised bioavailability by about 95% [3].

Uncontrolled series describe longer routine use. In a single-centre series of 403 adult women, 75.5% of those with facial data, 84.0% with chest data and 80.2% with back data had reduction or clearance at first follow-up; mean drug survival was 470.7 days, and menstrual side effects were less common among women using combined oral contraception (OR 0.23, 95% CI 0.11 to 0.50) [4]. An earlier series of 110 women reported average improvement of 73.1% on the face, 75.9% on the chest and 77.6% on the back, with 6 of the 110 stopping because side effects were bothersome [5]. Neither series had a control group.

What does the Aldactone label say about safety?

The current Aldactone label has no boxed warning [3]. Some older-format generic and repackager labels still carry the old boxed warning stating that spironolactone was a tumorigen in chronic rat toxicity studies [6].

Hyperkalemia is a labeled warning. The label says to monitor serum potassium within 1 week of starting or titrating the drug and regularly thereafter, with more frequent checks in renal impairment or when other potassium-raising drugs are used [3]. Risk rises with impaired renal function, potassium supplements, potassium-containing salt substitutes, ACE inhibitors and angiotensin receptor blockers [3]. Hyperkalemia, Addison's disease and concomitant eplerenone are contraindications [3].

Acne-specific potassium data come from a retrospective study of 974 healthy young women, which found 13 abnormal potassium values in 1,802 measurements (0.72%), against a 0.76% baseline rate in 1,165 comparison women; 6 of the 13 repeated normal, and the authors concluded routine monitoring has low usefulness in this group, which excluded women with cardiovascular disease, renal failure, and drugs affecting the renin-angiotensin-aldosterone system [7].

Gynecomastia is the label's most common adverse reaction. In RALES, men with heart failure on a mean dose of 26 mg daily, about 9% developed it; risk increases with dose, onset varies from 1 to 2 months to over a year, and it is usually reversible [3]. The label also lists irregular menses or amenorrhea, postmenopausal bleeding, and breast and nipple pain among reported reproductive reactions, without giving rates [3]. Hypotension and worsening renal function are listed risks, particularly with salt depletion, ACE inhibitors or ARBs, and nephrotoxic drugs such as NSAIDs, aminoglycosides and cisplatin [3].

On pregnancy, the label says to avoid spironolactone in pregnant women or to advise them of the potential risk to a male fetus, based on anti-androgenic properties and rat data showing feminization of male fetuses; limited human case reports did not demonstrate an association with major malformations [3].

What the evidence still does not settle

The 2017 review found the trial data for doses below 200 mg unhelpful for establishing efficacy [1], and the SAFA trial followed women for 24 weeks on one dosing schedule [2]. Longer-term and dose-comparison evidence comes mainly from uncontrolled series [4][5].