The effect of empagliflozin and fenofibrate therapies, alone and in combination, on the serum urate concentration in hyperuricaemic type 2 diabetes

People with type 2 diabetes are more likely to have raised serum urate concentrations1 and a greater risk of associated complications2 than people without diabetes. Medications used in diabetes management that also lower serum urate could help manage hyperuricaemia, including sodium-glucose co-transporter-2 inhibitors (SGLT2is) and fibrates. Average serum urate reductions in clinical trials/volunteer studies with fenofibrate and SGLT2is are 0.06-0.083 and 0.04-0.05 mmol/L,4 respectively. Fibrates act through the tubular urate transporter urate transporter 1,5 while SGLT2is increase uricosuria by suppression of glucose transporter 9b activity.6 Given these independent mechanisms, an additive reduction is plausible, but has not been evaluated. Our aim was to examine serum urate responses in hyperuricaemic people with type 2 diabetes treated with an SGLT2i and/or fibrate. The hypotheses to be tested were that empagliflozin, fenofibrate and combination therapy will reduce the serum urate by ≥ 0.04, ≥ 0.06 and ≥ 0.10 mmol/L, respectively. This single-group, open-label, randomized, crossover pilot study (Australian New Zealand Clinical Trials Registry ACTRN12621000829819) was approved by the University of Western Australia Human Research Ethics Committee (2021/ET000063) and was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent. Participants attended for eligibility screening (Table S1) and six further visits over 5 weeks. All participants received empagliflozin 25 mg (Jardiance; Boehringer Ingelheim Pty Ltd, North Ryde, NSW, Australia), fenofibrate 145 mg (Lipidil; Viatris Pty Ltd, Millers Point, NSW, Australia) and empagliflozin-fenofibrate once daily for 1 week, with treatment order randomized and each treatment period separated by a 1-week washout. At the beginning and end of each treatment week, blood was taken for biochemical tests and allocated treatment was given with a standard breakfast. A further blood sample was drawn at 6 hours postdose at maximal drug concentrations.5, 7 Another 6 days of daily treatment was provided to be taken at home. Participants recorded their blood glucose concentrations at least each morning and documented any side effects. They were asked to keep well hydrated and maintain their usual diet/alcohol intake. The primary outcome was the change in fasting serum urate after 1 week of allocated therapy. Secondary outcomes were the change in serum urate at 6 hours postdose, the proportion achieving serum urate of less than 0.36 mmol/L (the target for urate-lowering therapy8) and the change in the estimated glomerular filtration rate (eGFR) after 1 week of therapy. Analysis was by analysis of variance, linear/logistic regression or Fisher–Freeman–Halton exact test. Eight participants (Table 1) completed all study procedures, except for one individual who declined 6-hour sampling. The allocated treatments were well tolerated and there was full adherence. Two male participants developed genital mycotic infections on empagliflozin that responded to topical antifungal treatment and did not require cessation of therapy. The mean fasting serum urate concentrations on day 1 and day 8 are shown in Table 2. After adjustment for pretreatment serum urate concentration and randomization order, there was a significant trend in the change in serum urate from day 1 to day 8 by treatment group (analysis of variance, P = .003), but no statistically significant difference between the two monotherapies (P = .339). The reduction with the combination was significantly greater than that for empagliflozin alone (P = .035), but not for fenofibrate (P = .215). The mean changes in serum urate from 0 to 6 hours after the first dose (Table 2) were small and did not differ by allocated treatment (P = .101 after full adjustment). Most participants achieved a serum urate of less than 0.36 mmol/L and there were no statistically significant between-group differences (Table 2). The changes in eGFR from day 1 to day 8 by allocated treatment are shown in Table 2. There were small non-significant changes in the two monotherapy groups, but a much larger reduction with combination therapy (P = .015 and P = .039 vs. treatment with empagliflozin and fenofibrate, respectively, after full adjustment). The present data confirm that empagliflozin and fenofibrate monotherapies lower fasting serum urate concentrations in type 2 diabetes, but also suggest that their effects are additive when given in combination. The mean reduction (0.14 mmol/L) with recommended maximum daily doses of combination therapy (i.e. empagliflozin 25 mg plus fenofibrate 145 mg) was associated with three-quarters of the participants achieving a serum urate of less than 0.36 mmol/L, after all of them had started above this level. There was evidence that the combination was synergistic in its effect on eGFR. Although neither drug is nephrotoxic,6, 9 and neither had a statistically significant effect on eGFR when given alone in our study, the significant mean eGFR reduction of 10.2 mL/min/1.73m2 with combination therapy may have clinical implications. The mean 0.07 mmol/L serum urate reduction after 1 week of fenofibrate in our participants was close to the 0.06 mmol/L mean decrease after 6 weeks of treatment in a large clinical trial in type 2 diabetes10 and the 0.08 mmol/L reduction in a metanalysis.3 Similarly, the reduction in serum urate with SGLT2i therapy in clinical trials of 0.04-0.05 mmol/L4 was close to the mean 0.06 mmol/L in the present study. Monotherapy with SGLT2is, a class with an established place in diabetes management, and fenofibrate, which could be used when there is hypertriglyceridaemia and/or retinopathy,11 would thus have the added benefit of lowering serum urate. The pharmacodynamic effects of allopurinol are complex, but the dose required to achieve a serum urate of less than 0.36 mmol/L from the mean baseline level in our participants (0.43 mmol/L) is 125 mg daily.8 Use of an SGLT2i or fenofibrate could help in reaching this target, but the combination, although probably more effective than either drug alone, would need careful consideration given the potential eGFR effects. Although the changes in eGFR with both empagliflozin and fenofibrate, and with the combination in the present study based on serum creatinine concentrations after washout, are reversible upon cessation of therapy,6, 9 the reduction in eGFR with the combination was much greater than either agent alone. This is consistent with a synergistic effect. It has been suggested that fenofibrate treatment should be withheld if the serum creatinine increases by 30% or more,12 as occurred in three of our participants (38%) on combination therapy. Indeed, a significant increase in serum creatinine may have implications for dose regimens of other medications, including metformin, used in the management of type 2 diabetes that are affected by renal function. The present study suggests that, if combination SGLT2i-fenofibrate therapy were used, at least initial close monitoring of renal function should be implemented. The present study had limitations. The sample size was small, but a crossover design was utilized. In addition, the monotherapy changes in serum urate were consistent with those in larger studies. Our participants had a mean age of older than 70 years, but this age group is at the greatest risk of gout in the general population.13 The strengths of the study include near complete data collection and a randomized design with statistical adjustment for allocation order, given the possibility that the 1-week washout period may have been insufficient to allow restoration of normal urate metabolism post-treatment. In conclusion, our data suggest that combining an SGLT2i and fenofibrate produces additive serum urate-lowering effects in type 2 diabetes. This could allow rationalization of treatment for gout, simplifying the usual polypharmacy employed in diabetes management. Biochemical monitoring after initiation of combination therapy should include renal function given the observed eGFR changes. Our 6-hour data suggest that a non-fasting sample could be used in this context. TMED and HK designed the study. SM and CC collected the data. WAD performed all statistical analyses. TMED produced the initial version of the manuscript, which was reviewed/edited by HK, WAD, SM and CC. We thank the participants for their involvement and PathWest Laboratory Medicine for performing all laboratory tests. This study was funded by a grant from Arthritis Australia. TMED is supported by a Medical Research Future Fund Practitioner Fellowship. The authors have no conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15295. The research data are available on reasonable request. Table S1. Eligibility criteria. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.