Glucocorticoid therapy is effective in reducing harm from many immune system disorders, but can also cause serious side effects.
The metabolic side-effects of glucocorticoid overexposure include truncal obesity, hypertension, hyperglycemia, dyslipidemia, hypercoagulability, fatty liver, osteoporosis, increased infections, and other complications which could also lead to Cushing’s syndrome. This has called for a need to reduce these side effects through pharmaceutical treatment. The study conducted by Pernicova et al. aimed to evaluate the potential of metformin to reverse such effects.
Researchers conducted a randomized, double-blind, placebo-controlled, proof-of-concept, phase 2 trial, involving four hospitals from Barts Health NHS Trusts in the UK, and patients were selected based on 849 cases and laboratory records reviewed from these hospitals. Inclusion criteria included being aged between 18 and 75 years with an inflammatory disease treated with continuous 20 mg/day or longer of prednisolone for four weeks or more, remaining on 10 mg/day or more of prednisolone equivalent for 12 subsequent weeks or longer. Participants also had to have a minimum duration of continuous glucocorticoid exposure for four weeks before enrollment and have a minimum cumulative dose of 560 mg prednisolone equivalent. Exclusion criteria were: the participants had preexisting diabetes, previous therapy with metformin over the previous six months, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of 2∙5 or more upper limit of normal, or serum creatinine of 135 µmol/L or more for men and 110 µmol/L or more for women.
Between July 17, 2012, and Jan 14, 2014, 53 participants were randomly assigned to receive either metformin (n=26) or placebo (n=27) for 12 weeks. The glucocorticoids that the participants were taking were titrated by the treating specialists, independently of the study. The glucocorticoid therapy was established based on patients’ clinical needs, with glucocorticoid dose reduced as soon as the clinical condition would allow. During the one and a half year study, the primary outcome observed was the between-group difference in the visceral-to-subcutaneous fat area ratio over 12 weeks that was accessed by a CT. Secondary outcomes included changes in metabolic, bone, cardiovascular, and inflammatory parameters over 12 weeks.
Adherence was similar between patients taking metformin and placebo (88% [SD 3] vs. 88% ; p=0∙85). The primary outcome, visceral-to-subcutaneous fat area ratio over 12 weeks, did not change between the treatment groups (0∙11 [95% CI –0∙02 to 0∙24]; p=0∙09). The truncal subcutaneous fat area decreased in patients in the metformin group compared with those in the placebo group over 12 weeks (–3835 mm² [95% CI –6781 to –888]; p=0∙01; but not visceral adiposity (2501 mm² [SD 4891] for the metformin group vs. 443 mm²  for the placebo; p=0∙28). There were no significant changes observed in weight and waist circumference. On physical examination, two (10%) of 19 patients in the metformin group and 11 (52%) of 21 in the placebo group were noted to have more pronounced characteristic facial adiposity associated with Cushing’s syndrome (p=0∙007). Glucose and HbA1c decreased in the metformin group, reducing the number of patients with hyperglycemia; in comparison to the baseline variates, four patients in each group had hyperglycemia, whereas at the end of the study none of the patients in the metformin group and seven (33%) of 21 in the placebo group had hyperglycemia (p=0∙009). Metformin prevented worsening of insulin resistance (HOMA2IR) and improved β-cell function, estimated as the HOMA2%B/HOMA2IR disposition index, accounting for a compensatory increase in insulin secretion. Regarding the cardiovascular parameters, metformin was shown to have improved the total cholesterol and LDL cholesterol concentrations in those taking it. It was also observed that liver function tests improved in the metformin group. Changes in the AST-to-ALT ratio (r=–0∙47; p=0∙02) and γ-glutamyl transferase (r=0∙55; p=0∙008) correlated with insulin resistance. With metformin over the study period the metabolic syndrome risk factors showed improvement in waist circumference (r=–0∙57; p=0∙01), HOMA2IR (r=–0∙54; p=0∙02), glucose (r=–0∙62; p=0∙005), triglycerides (r=–0∙63; p=0∙004), LDL (r=–0∙46; p=0∙046), and HDL (r=–0∙49; p=0∙001).
It was concluded that there were no changes for the primary outcome (visceral-to-subcutaneous fat area ratio) between the treatment groups. It was, however, shown that patients treated with metformin had a significant improvement in several prognostic parameters and clinical outcomes. When comparing the metformin group to the placebo group, participants in the metformin group had reduced appetite, truncal and facial subcutaneous fat, insulin resistance, improved β-cell function, glycemia, lipid profile, liver function, fibrinolysis, subclinical atherosclerosis, bone metabolism, infection risk, inflammation, disease activity, and symptom severity, as well as fewer hospital admissions. Results like these might indicate the possibility of a significant improvement in patient care when taking excessive glucocorticoids.
- There were no changes for the primary outcome (visceral-to-subcutaneous fat area ratio) between the metformin and placebo group.
- Patients treated with metformin had a significant improvement in several prognostic parameters and clinical outcomes.
- Using metformin in patients who take an excessive amount of glucocorticoids, this study has shown that there is a high probability that side effects will be reduced.
Pernicova, Ida, et al. “Metformin to Reduce Metabolic Complications and Inflammation in Patients on Systemic Glucocorticoid Therapy: a Randomised, Double-Blind, Placebo-Controlled, Proof-of-Concept, Phase 2 Trial.“ The Lancet Diabetes & Endocrinology, Elsevier, 25 Feb. 2020,www.sciencedirect.com/science/article/pii/S2213858720300218.
Chardae Whitner, 2020 PharmD. Candidate, Lake Erie College of Osteopathic Medicine