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Lowering and Raising Serum Urate Levels: Off-Label Effects of Commonly Used Medications

      Abstract

      Drug-induced hyperuricemia and gout present an increasingly prevalent problem in clinical practice. Herein, we review the urate-lowering or urate-raising effects of commonly used agents. We performed a PubMed search using the terms gout, urate, and medication, along with the specific agents/classes described herein. Reports were reviewed until 2022, and original studies were considered if they primarily or secondarily reported the effects of 1 or more drugs on serum urate level. Previous reviews were assessed for references to additional studies that described urate-altering effects of medications. Urate-changing drugs are summarized regarding their magnitude of effect, mechanism of action, and clinical significance. Potentially urate-lowering drugs include angiotensin II receptor blockers, calcium channel blockers, high-dose aspirin and salicylates, some nonsalicylate nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, sodium-glucose cotransporter 2 inhibitors, statins, and fenofibrate. Potentially urate-increasing drugs discussed include diuretics, β-blockers, insulin, pyrazinamide, ethambutol, calcineurin inhibitors, low-dose aspirin, testosterone, and lactate. In patients who have or are at risk for hyperuricemia or gout, an increased awareness of drugs that affect serum urate level may allow for prescribing that effectively treats the indicated problem while minimizing adverse effects on hyperuricemia and gout.

      Abbreviations and Acronyms:

      ACE-I (angiotensin-converting enzyme inhibitor), ACR (American College of Rheumatology), AH (asymptomatic hyperuricemia), ARB (angiotensin II receptor blocker), CCB (calcium channel blocker), CKD (chronic kidney disease), GFR (glomerular filtration rate), GLUT9 (glucose transporter 9), HTN (hypertension), IM (intramuscular), MRP4 (multidrug resistance protein 4), NSAID (nonsteroidal anti-inflammatory drug), OAT4 (organic anion transporter 4), RCT (randomized controlled trial), sU (serum urate), SGLT2 (sodium-glucose cotransporter 2), T2DM (type 2 diabetes mellitus), URAT1 (uric acid transporter 1), UA (uric acid)
      Article Highlights
      • Patients with gout may experience elevations or decrements in serum urate (sU) levels due to medications prescribed by physicians. Urate-lowering and urate-increasing capacity is not always a class effect and can be limited to a single drug in the class.
      • We reviewed the literature to identify the magnitude of the urate-lowering or urate-increasing effects of common medications used in primary care and highlight those that can also serve to reduce sU levels.
      • Among lipid-lowering therapies, atorvastatin and fenofibrates have greater sU-lowering effects than most other agents.
      • Among antihypertensives, the angiotensin II receptor blocker losartan most reliably decreases sU levels. Among calcium channel blockers, dihydropyridines have the greatest evidence supporting their ability to lower sU levels. The sU elevation induced by diuretics is dose-dependent. β-Blockers tend to elevate sU levels minimally and less than diuretics.
      • Among the commonly used drugs in the treatment of diabetes, the sodium-glucose cotransporter 2 inhibitors, especially empagliflozin, seem to have a drug class effect of lowering sU levels, whereas insulin may raise sU levels.
      Gout is the most common inflammatory arthritis, and it has significantly increased in worldwide prevalence during the past 50 years.
      • Dalbeth N.
      • Choi H.K.
      • Joosten L.A.B.
      • et al.
      Gout.
      With westernized diets, extended life span, and accumulating renal disease, it is unlikely that gout prevalence will decline any time soon.
      • Mattiuzzi C.
      • Lippi G.
      Recent updates on worldwide gout epidemiology.
      Gout is caused by precipitation and deposition of monosodium urate crystals, inducing both acute inflammatory arthritis (gout flares) and chronic low-level inflammation.
      • Terkeltaub R.
      What makes gouty inflammation so variable?.
      Gout risk correlates with serum urate (sU) level, reflecting total body uric acid (UA) concentration.
      • Campion E.W.
      • Glynn R.J.
      • DeLabry L.O.
      Asymptomatic hyperuricemia: risks and consequences in the normative aging study.
      Hyperuricemia is physiologically defined as an sU level greater than 6.8 mg/dL (to convert to mmol/L, multiply by 0.0595), the saturation concentration for urate at pH 7.4; hyperuricemia in the absence of a history of gout is designated as asymptomatic hyperuricemia (AH).
      • Bursill D.
      • Taylor W.J.
      • Terkeltaub R.
      • et al.
      Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) consensus statement regarding labels and definitions of disease states of gout.
      ,
      • Yip K.
      • Cohen R.E.
      • Pillinger M.H.
      Asymptomatic hyperuricemia: is it really asymptomatic?.
      The absolute annual incidence of gout ranges from 0.5% or less for individuals with sU levels between 7.0 and 8.9 mg/dL, and up to 4.9% for individuals with sU levels of 9 mg/dL or greater.
      • Campion E.W.
      • Glynn R.J.
      • DeLabry L.O.
      Asymptomatic hyperuricemia: risks and consequences in the normative aging study.
      Because 20% of individuals with AH have sU levels greater than 9 mg/dL, a minority of patients with AH are at highest risk for gout.
      • Campion E.W.
      • Glynn R.J.
      • DeLabry L.O.
      Asymptomatic hyperuricemia: risks and consequences in the normative aging study.
      Hyperuricemia affects approximately 38 million adults, or 16.9% of the population in the United States.
      • Chen-Xu M.
      • Yokose C.
      • Rai S.K.
      • Pillinger M.H.
      • Choi H.K.
      Contemporary prevalence of gout and hyperuricemia in the United States and decadal trends: the National Health and Nutrition Examination Survey, 2007-2016.
      Accumulating evidence links hyperuricemia with various metabolic diseases, including chronic kidney disease (CKD), hypertension, coronary artery disease, type 2 diabetes mellitus (T2DM), and fatty liver disease.
      • Yip K.
      • Cohen R.E.
      • Pillinger M.H.
      Asymptomatic hyperuricemia: is it really asymptomatic?.
      Whether elevated sU levels play a causative role in any of these entities remains an area of investigation; the 2020 American College of Rheumatology (ACR) gout treatment guideline conditionally recommends against urate-lowering therapy for AH,
      • FitzGerald J.D.
      • Dalbeth N.
      • Mikuls T.
      • et al.
      2020 American College of Rheumatology guideline for the management of gout.
      whereas the Japanese Society of Gout and Nucleic Acid Metabolism recommends that high sU levels (≥8 mg/dL) in certain patients with AH should be pharmacologically lowered.
      • Yamanaka H.
      Japanese guideline for the management of hyperuricemia and gout: second edition.
      Both societies agree that healthful lifestyle changes are warranted to reduce the risk of gout in patients with AH or to enhance treatment in patients with established gout. In this regard, it is worth noting that multiple drugs unrelated to gout treatment may raise sU levels and promote hyperuricemia. Conversely, other drugs have been shown to incidentally reduce sU levels. Prudent selection of nongout drugs has the potential to provide the patient with optimal management for the indicated conditions while reducing the need for escalation of gout therapy.
      Herein we review the urate-lowering or urate-raising effects of several commonly used agents. We performed a PubMed search using the terms gout, urate, and medication, along with the specific agents/classes described later herein. Reports were reviewed until 2022, and original studies were considered if they primarily or secondarily reported the effects of 1 or more drugs on sU level. Previous reviews were assessed for references to additional studies that described urate-altering effects of medications. In some cases, urate-changing capacity is a class effect; in others, it is limited to a single drug within the class. In patients with hyperuricemia or gout, selection or avoidance of some of these agents may modify the sU concentration, reduce polypharmacy, and increase medication compliance. We exclude medications that are formally indicated for urate-lowering therapy, that is, xanthine oxidase inhibitors, probenecid, lesinurad, and pegloticase.

      Urate-Lowering Drugs

      The mechanisms of some sU-lowering drugs are reviewed in Table 1, and supporting studies are described in Table 2.
      Table 1Mechanisms of Some Serum Urate–Altering Drugs
      Drug classDrugsMechanisms
      Urate-lowering drugs
       AntihypertensivesLosartan

      CCBs
      Increases urinary excretion of urate via inhibiting URAT1

      Various
       Anti-inflammatories and immunosuppressivesHigh-dose aspirin

      Leflunomide
      Biphasic effect on urate tubular reabsorption

      Increases urate excretion
       Lipid-lowering agentsStatins

      Fenofibrates
      Unknown

      Increase urate excretion
       Metabolism modulatorsSGLT2 inhibitorsIncrease urate excretion due to glucosuria via GLUT9
       Sex hormonesEstrogenDecreases urate reabsorption
      Urate-increasing drugs
       DiureticsLoop diureticsDecrease secretion via inhibiting MRP4

      Increases uptake via URAT1
       Other antihypertensivesThiazide diuretics

      β-Blockers
      Decrease secretion via inhibiting MRP4

      Increase reabsorption via OAT4

      Unknown
       Antituberculosis agentsPyrazinamide

      Ethambutol
      Increases urate reabsorption via URAT1

      Decreases renal clearance of urate
       Anti-inflammatories and immunosuppressivesLow-dose aspirin

      Calcineurin inhibitors
      Biphasic effect on urate reabsorption

      Decreases urate clearance
       Metabolism modulatorsLactate

      Insulin
      Increases urate reabsorption via URAT1

      Increases urate reabsorption via URAT1 or sodium-dependent anion cotransporter in the proximal tubule
       Sex hormonesTestosteroneIncreases urate reabsorption via URAT1
      CCB = calcium channel blocker; GLUT9 = glucose transporter 9; MRP4 = multidrug resistance protein 4; OAT4 = organic anion transporter 4; SGLT2 = sodium-glucose cotransporter 2; URAT1 = urate transporter 1.
      Table 2Serum Urate–Decreasing Drugs: Supporting Studies
      DrugReference, yearStudy designPatients (No.)DoseDurationSerum urate effect (mg/dL)P value
      LosartanDang et al,
      • Dang A.
      • Zhang Y.
      • Liu G.
      • et al.
      Effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia in chinese population.
      2006
      Multicenter RCT351 with HTN (losartan, n=176; irbesartan, n=175)50 mg/d for 4 wk, then 50 mg or 100 mg/d to wk 88 wk–1.05<.0001 vs baseline
      LosartanMiao et al,
      • Miao Y.
      • Ottenbros S.A.
      • Laverman G.D.
      • et al.
      Effect of a reduction in uric acid on renal outcomes during losartan treatment: a post hoc analysis of the reduction of endpoints in non-insulin-dependent diabetes mellitus with the angiotensin II antagonist losartan trial.
      2011
      Multinational, randomized, double-blind1342 with T2DM and nephropathy (losartan, n=678; placebo, n=664)100 mg6 mo–0.16.031 vs 6 mo of placebo
      AmlodipineBuscemi et al,
      • Buscemi S.
      • Buscemi C.
      • Borzì A.M.
      • et al.
      Metabolic and cardiovascular effects of switching thiazides to amlodipine in hypertensive patients with and without type 2 diabetes (the diuretics and diabetes control study).
      2020
      Parallel-group, single-blind, single-center RCT20 normal glucose tolerant, 20 prediabetic, 20 T2DM2.5-10 mg/d6 wk–1.0<.001 vs 6 wk of hydrochlorothiazide
      AmlodipineChanard et al,
      • Chanard J.
      • Toupance O.
      • Lavaud S.
      • et al.
      Amlodipine reduces cyclosporin-induced hyperuricaemia in hypertensive renal transplant recipients.
      2003
      Randomized, double-blind, parallel group48 renal transplant recipients with HTN taking cyclosporine (amlodipine, n=24)5-10 mg/d60 d–0.8<.001 vs baseline
      NitrendipineWeidmann et al,
      • Weidmann P.
      • Gnädinger M.P.
      • Schohn D.
      • Riesen W.
      • Jahn H.
      Antihypertensive and hypouricaemic effects of nitrendipine in chronic renal failure.
      1989
      Placebo controlled, prospective15 with chronic renal failure and HTN55 mg/d6 wk–1.8<.001 vs placebo
      Verapamil sustained-releaseSchohn et al,
      • Schohn D.C.
      • Jahn H.A.
      • Maareck M.
      Long term effects of sustained release verapamil on the renal and systemic haemodynamic parameters in hypertensive patients with mild to severe chronic renal failure.
      1993
      Placebo controlled, prospective15 with chronic renal failure and HTN240 mg/d4 wk–0.5<.01 vs baseline
      Aspirin (mid dose)Yu and Gutman,
      • Yu T.F.
      • Gutman A.B.
      Study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanisms for excretion of urate in man.
      1959
      Self-controlled, prospective93 g/d4 dNo decline<.05 vs control
      Aspirin (high dose)Yu and Gutman,
      • Yu T.F.
      • Gutman A.B.
      Study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanisms for excretion of urate in man.
      1959
      Self-controlled, prospective155.2 g/d4 d–26% (control range, 5.9-11.7; treatment range, 2.2-10.4)<.05 (vs control)
      LeflunomideEmery et al,
      • Emery P.
      • Breedveld F.C.
      • Lemmel E.M.
      • et al.
      A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis.
      2000
      Multicenter, double-blind999 total active rheumatoid arthritis (n= 501 leflunomide)100 mg/d x 3 d, then 20 mg/d1 y–0.71<.05
      LeflunomideWu et al,
      • Wu J.
      • Duan S.W.
      • Sun X.F.
      • et al.
      Efficacy of leflunomide, telmisartan, and clopidogrel for immunoglobulin a nephropathy: a randomized controlled trial.
      2016
      Multicenter, prospective, double-dummy RCT360 Primary IgA nephropathy patients total (n=100 for leflunomide only)20 mg/d24 wk–0.78<.001
      LeflunomidePerez-Ruiz and Nolla,
      • Perez-Ruiz F.
      • Nolla J.M.
      Influence of leflunomide on renal handling of urate and phosphate in patients with rheumatoid arthritis.
      2003
      Prospective38 total active rheumatoid arthritis100 mg/d x 3 d, then 20 mg/d2 mo–1.47<.05
      SGLT2 inhibitorsZhao et al,
      • Zhao Y.
      • Xu L.
      • Tian D.
      • et al.
      Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: a meta-analysis of randomized controlled trials.
      2018
      Meta-analysis of RCTs34,941 total, 62 trialsNANAMD –0.63 (empagliflozin, MD –0.77)<.05 vs controls
      PravastatinDeedwania et al,
      • Deedwania P.C.
      • Stone P.H.
      • Fayyad R.S.
      • Laskey R.E.
      • Wilson D.J.
      Improvement in renal function and reduction in serum uric acid with intensive statin therapy in older patients: a post hoc analysis of the SAGE trial.
      2015
      RCT858 total (pravastatin, n=425; atorvastatin, n=433)40 mg/d12 mo–0.09 vs –0.52<.0001 (change from baseline, atorvastatin vs pravastatin)
      AtorvastatinDeedwania et al,
      • Deedwania P.C.
      • Stone P.H.
      • Fayyad R.S.
      • Laskey R.E.
      • Wilson D.J.
      Improvement in renal function and reduction in serum uric acid with intensive statin therapy in older patients: a post hoc analysis of the SAGE trial.
      2015
      RCT858 (pravastatin, n=425; atorvastatin, n=433)80 mg/d12 mo–0.52 vs –0.09<.0001 (change from baseline, atorvastatin vs pravastatin)
      AtorvastatinSaku et al,
      • Saku K.
      • Zhang B.
      • Noda K.
      Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial.
      2011
      Prospective, randomized, controlled, parallel, multicenter302 (atorvastatin, n=101; rosuvastatin, n=100; pivtavastatin, n=101)10 mg/d16 wk–0.2<.05 vs baseline
      AtorvastatinDerosa et al,
      • Derosa G.
      • Maffioli P.
      • Reiner Ž.
      • Simental-Mendía L.E.
      • Sahebkar A.
      Impact of statin therapy on plasma uric acid concentrations: a systematic review and meta-analysis.
      2016
      Meta-analysis of RCTs9 trialsNANAMD –0.6<.001
      AtorvastatinTakagi and Umemoto,
      • Takagi H.
      • Umemoto T.
      Atorvastatin therapy reduces serum uric acid levels: a meta-analysis of randomized controlled trials.
      2012
      Meta-analysis of RCTs2774 total, 8 trialsNANAMD –0.57<.00001 vs pooled rosuvastatin, simvastatin, pravastatin, amlodipine
      RosuvastatinSaku et al,
      • Saku K.
      • Zhang B.
      • Noda K.
      Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial.
      2011
      Prospective, randomized, controlled, parallel, multicenter302 (atorvastatin, n=101; rosuvastatin, n=100; pivtavastatin, n=101)2.5 mg/d16 wk–0.18<.05 vs baseline
      SimvastatinDerosa et al,
      • Derosa G.
      • Maffioli P.
      • Reiner Ž.
      • Simental-Mendía L.E.
      • Sahebkar A.
      Impact of statin therapy on plasma uric acid concentrations: a systematic review and meta-analysis.
      2016
      Meta-analysis of RCTs9 trialsNANAMD –0.1.013
      FenofibrateTakagi and Umemoto,
      • Takagi H.
      • Umemoto T.
      Atorvastatin therapy reduces serum uric acid levels: a meta-analysis of randomized controlled trials.
      2012
      Meta-analysis of RCTs2774 total, 8 trialsNANAMD –1.48<.00001 vs atorvastatin
      FenofibrateElisaf et al,
      • Elisaf M.
      • Tsimichodimos V.
      • Bairaktari E.
      • Siamopoulos K.C.
      Effect of micronized fenofibrate and losartan combination on uric acid metabolism in hypertensive patients with hyperuricemia.
      1999
      Prospective64200 mg/dNA–1.9<.001 vs baseline
      EstrogenYahyaoui et al,
      • Yahyaoui R.
      • Esteva I.
      • Haro-Mora J.J.
      • et al.
      Effect of long-term administration of cross-sex hormone therapy on serum and urinary uric acid in transsexual persons.
      2008
      Prospective69 total (n= 47 female-to-male, n=22 male-to-female)Low/medium/high doses1 y–1.2<.01
      EstrogenNicholls et al,
      • Nicholls A.
      • Snaith M.L.
      • Scott J.T.
      Effect of oestrogen therapy on plasma and urinary levels of uric acid.
      1973
      Prospective22 total5-40 mg/d10 mo–0.7<.01
      HTN = hypertension; IM = intramuscular; NA = not applicable; RCT = randomized controlled trial; SGLT2 = sodium-glucose cotransporter 2; T2DM = type 2 diabetes mellitus.

      Antihypertensives

      Angiotensin II Receptor Blockers

      Within the class of angiotensin II receptor blockers (ARBs) there exists significant heterogeneity regarding effect on sU level, which has been attributed to differential effects on uric acid transporter 1 (URAT1),
      • Iwanaga T.
      • Sato M.
      • Maeda T.
      • Ogihara T.
      • Tamai I.
      Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter.
      the primary apical membrane transporter for resorption of UA across the renal tubule lumen.
      • Wright A.F.
      • Rudan I.
      • Hastie N.D.
      • Campbell H.
      A 'complexity' of urate transporters.
      Inhibition of URAT1 promotes increased urinary excretion of UA, a feature exploited for sU lowering by drugs such as probenecid and lesinurad.
      • Miner J.N.
      • Tan P.K.
      • Hyndman D.
      • et al.
      Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney.
      Using URAT1-expressing Xenopus oocytes as a model system, Iwanaga et al
      • Iwanaga T.
      • Sato M.
      • Maeda T.
      • Ogihara T.
      • Tamai I.
      Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter.
      reported that the ARBs losartan, telmisartan, and pratosartan inhibited URAT1-mediated UA uptake, whereas valsartan, candesartan, and olmesartan did not. These effects may not fully or directly translate into human sU lowering, however. One study of hypertensive patients with T2DM found that only losartan lowered sU levels, whereas valsartan, telmisartan, candesartan, and olmesartan had no significant impact.
      • Nishida Y.
      • Takahashi Y.
      • Susa N.
      • et al.
      Comparative effect of angiotensin II type I receptor blockers on serum uric acid in hypertensive patients with type 2 diabetes mellitus: a retrospective observational study.
      A multicenter randomized controlled trial (RCT) involving 351 hypertensive patients with AH compared losartan and irbesartan. The median sU level declined from 7.09 mg/dL to 6.04 mg/dL (a reduction of 1.05 mg/dL; P<.0001) after 8 weeks of losartan therapy compared with a change from 7.04 mg/dL to 6.86 mg/dL (a reduction of 0.18 mg/dL; P<.05) with irbesartan.
      • Dang A.
      • Zhang Y.
      • Liu G.
      • et al.
      Effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia in chinese population.
      In contrast to effects seen with other ARBs, the amount of sU lowering induced by losartan is potentially clinically important and is comparable with that which can be achieved with rigorous dietary modification.
      • Madero M.
      • Rodríguez Castellanos F.E.
      • Jalal D.
      • et al.
      A pilot study on the impact of a low fructose diet and allopurinol on clinic blood pressure among overweight and prehypertensive subjects: a randomized placebo controlled trial.
      A post hoc analysis of the Reduction of Endpoints in Non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial assessed 1342 patients with CKD and T2DM and found a reduction in sU levels by –0.16 mg/dL (a smaller change than most other studies) (95% CI, –0.30 to –0.01; P=.031) in the losartan treatment group compared with the placebo control group. The authors suggested that approximately 20% of losartan’s previously recognized renal protective effects may be due to urate lowering alone and that losartan may be a useful targeted therapy for patients with hyperuricemia and T2DM.
      • Miao Y.
      • Ottenbros S.A.
      • Laverman G.D.
      • et al.
      Effect of a reduction in uric acid on renal outcomes during losartan treatment: a post hoc analysis of the reduction of endpoints in non-insulin-dependent diabetes mellitus with the angiotensin II antagonist losartan trial.
      Although recent studies are mixed as to whether urate lowering is actually renally protective, evidence suggests that some patient subsets, including those with gout, may be more likely to benefit.
      • Goldberg A.
      • Garcia-Arroyo F.
      • Sasai F.
      • et al.
      Mini review: reappraisal of uric acid in chronic kidney disease.
      Overall, when choosing among multiple antihypertensive agents, the selection of losartan, particularly over other agents that can raise sU levels, can significantly affect a patient’s sU level and may have additional benefits. For this reason, the 2020 ACR gout treatment guideline conditionally recommends “choosing losartan preferentially as an antihypertensive agent for patients with gout.”
      • FitzGerald J.D.
      • Dalbeth N.
      • Mikuls T.
      • et al.
      2020 American College of Rheumatology guideline for the management of gout.

      Angiotensin-Converting Enzyme Inhibitors

      Similar to ARBs, angiotensin-converting enzyme Inhibitors (ACE-Is) are antihypertensives with renoprotective properties. Also, ACE-Is provide afterload reduction in congestive heart failure. However, the class effect of ACE-Is on sU levels is unclear.
      A uricosuric property of enalapril and captopril has been ascribed to effects on the proximal convoluted tubule, with resultant increases in renal fractional excretion of UA in healthy volunteers.
      • Lant A.F.
      • McNabb R.W.
      • Noormohamed F.H.
      Kinetic and metabolic aspects of enalapril action.
      ,
      • Leary W.P.
      • Reyes A.J.
      • van der Byl K.V.
      • Acosta-Barrios T.N.
      Effects of captopril, hydrochlorothiazide, and their combination on timed urinary excretions of water and solutes.
      However, larger studies have revealed nonsignificant results. One multicenter study looking at a subgroup of 69 hypertensive patients treated with captopril revealed a nonsignificant decline in sU level from 5.55 mg/dL to 5.38 mg/dL.
      • Weinberger M.H.
      Blood pressure and metabolic responses to hydrochlorothiazide, captopril, and the combination in black and white mild-to-moderate hypertensive patients.
      Conversely, the Captopril Research Group of Japan performed a multicenter double-blind RCT in which 133 patients received captopril and found a nonsignificant increase in mean ± SD sU levels from 5.8±1.7 mg/dL to 6.0±1.5 mg/dL.
      Captopril Research Group of Japan
      Clinical effects of low-dose captopril plus a thiazide diuretic on mild to moderate essential hypertension: a multicenter double-blind comparison with propranolol.
      Meanwhile, perindopril seemed to promote UA excretion in a dose-dependent manner, but the effects of even maximal doses were not found to be statistically significant.
      • Reyes A.J.
      • Leary W.P.
      • Van Der Byl K.
      • Santoni J.P.
      Effects of the angiotensin-I converting enzyme inhibitor perindopril on timed urinary excretion of water and solutes in healthy subjects.
      Schmidt et al
      • Schmidt A.
      • Gruber U.
      • Böhmig G.
      • Köller E.
      • Mayer G.
      The effect of ACE inhibitor and angiotensin II receptor antagonist therapy on serum uric acid levels and potassium homeostasis in hypertensive renal transplant recipients treated with CSA.
      performed a prospective randomized 2-way crossover trial comparing enalapril and losartan in 13 hypertensive patients with renal transplants and found that losartan lowered the mean ± SD sU level (from 7.8±2.4 mg/dL to 7.3±1.8 mg/dL; P=.6) and enalapril raised it (from 7.8±1.9 mg/dL to 8.2±1.8 mg/dL; P=.5), although the results were not significant due to the small sample size. Tikkanen et al
      • Tikkanen I.
      • Omvik P.
      • Jensen H.A.
      Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril in patients with essential hypertension.
      performed a multicenter double-dummy, double-blind RCT also comparing losartan and enalapril in patients with essential hypertension over 12 weeks, finding that losartan significantly reduced UA levels (from 5.6 mg/dL to 5.41 mg/dL; P<.01) and enalapril non–statistically significantly increased it from 5.83 mg/dL to 5.95 mg/dL. Taken together, the evidence does not currently support a clinically meaningful urate-modulating effect by ACE-Is.

      Calcium Channel Blockers

      Several clinical studies indicate that different subclasses of calcium channel blockers (CCBs) may have urate-lowering effects. The most frequently studied CCBs are the dihydropyridines. In one study, amlodipine decreased sU levels by 1.1 mg/dL (from a mean ± SD of 6.1±1.1 mg/dL to 5.0±1.4 mg/dL) after 6 weeks of treatment,
      • Buscemi S.
      • Buscemi C.
      • Borzì A.M.
      • et al.
      Metabolic and cardiovascular effects of switching thiazides to amlodipine in hypertensive patients with and without type 2 diabetes (the diuretics and diabetes control study).
      and in another study, from 8.1 mg/dL to 7.3 mg/dL after 9 weeks (60 days) of treatment (P<.001).
      • Chanard J.
      • Toupance O.
      • Lavaud S.
      • et al.
      Amlodipine reduces cyclosporin-induced hyperuricaemia in hypertensive renal transplant recipients.
      Nitrendipine treatment for 6 weeks decreased sU levels from 7.6 to 5.8 mg/dL (vs placebo; P<.001).
      • Weidmann P.
      • Gnädinger M.P.
      • Schohn D.
      • Riesen W.
      • Jahn H.
      Antihypertensive and hypouricaemic effects of nitrendipine in chronic renal failure.
      These degrees of urate lowering are similar to that of losartan and represent a potentially clinically significant effect. The mechanism of urate lowering by dihydropyridines is likely through inhibition of renal tubular UA resorption. A preclinical study compared the effect of dihydropyridines on the renal tubule UA-resorbing transporter URAT1 and on xanthine oxidase, the rate-limiting enzyme for urate production, and found that nifedipine, nilvadipine, and nitrendipine strongly inhibited URAT1-mediated UA reuptake but did not inhibit xanthine oxidase–mediated urate production.
      • Go T.
      • Takayuki H.
      • Nobuyuki O.
      • et al.
      Molecular mechanism of the urate-lowering effects of calcium channel blockers.
      The uricosuric effects of CCBs may additionally relate to their capacity to increase renal blood flow and glomerular filtration rate (GFR) by dilating renal afferent arterioles.
      • Hayashi K.
      • Ozawa Y.
      • Fujiwara K.
      • et al.
      Role of actions of calcium antagonists on efferent arterioles: with special references to glomerular hypertension.
      • Konno Y.
      • Kimura K.
      Vasodilatory effect of cilnidipine, an L-type and N-type calcium channel blocker, on rat kidney glomerular arterioles.
      • Rubio-Guerra A.F.
      • Garro-Almendaro A.K.
      • Elizalde-Barrera C.I.
      • Suarez-Cuenca J.A.
      • Duran-Salgado M.B.
      Effect of losartan combined with amlodipine or with a thiazide on uric acid levels in hypertensive patients.
      For example, amlodipine was reported to increase fluid output from proximal tubules, demonstrated by decreased fractional proximal reabsorption of sodium.
      • Chanard J.
      • Toupance O.
      • Lavaud S.
      • et al.
      Amlodipine reduces cyclosporin-induced hyperuricaemia in hypertensive renal transplant recipients.
      The effects of nondihydropyridine CCBs on sU levels are less well studied. Treatment with verapamil for 4 weeks decreased the mean sU level by 0.5 mg/dL, from a mean ± SD of 7.1±0.9 mg/dL to 6.6±0.5 mg/dL in a study of 15 patients with hypertension and CKD (P<.01).
      • Schohn D.C.
      • Jahn H.A.
      • Maareck M.
      Long term effects of sustained release verapamil on the renal and systemic haemodynamic parameters in hypertensive patients with mild to severe chronic renal failure.
      A preclinical study in rats found that nicardipine-induced uricosuria was accompanied by increased GFR and renal blood flow, whereas diltiazem (nondihydropyridine) induced uricosuria without increasing GFR.
      • Sugino H.
      • Shimada H.
      A comparison of the uricosuric effects in rats of diltiazem and derivatives of dihydropyridine (nicardipine and nifedipine).
      Diltiazem increased excreted UA without an increase in urine volume, as evidenced by a significantly increased UA-to-inulin clearance ratio. These findings suggest that dihydropyridines and nondihydropyridines both have uricosuric effects but potentially through different mechanisms, perhaps due to pharmacophore differences between the classes. More studies need to be performed on the effect of nondihydropyridines on URAT1.
      Finally, studies have found that cilnidipine, a novel non–Food and Drug Administration–approved CCB that blocks both L- and N-type calcium channels, also has uricosuric effects.
      • Uchida S.
      • Takahashi M.
      • Sugawara M.
      • et al.
      Effects of the N/L-type calcium channel blocker cilnidipine on nephropathy and uric acid metabolism in hypertensive patients with chronic kidney disease (j-circle study).
      • Das A.
      • Kumar P.
      • Kumari A.
      • et al.
      Effects of cilnidipine on heart rate and uric acid metabolism in patients with essential hypertension.
      • Masaki M.
      • Mano T.
      • Eguchi A.
      • et al.
      Long-term effects of L- and N-type calcium channel blocker on uric acid levels and left atrial volume in hypertensive patients.
      In one human study, cilnidipine induced significant reduction in blood pressure and sU level from a mean ± SD at baseline of 5.6±0.3 mg/dL to 5.1±0.2 mg/dL (P<.01).
      • Hamada T.
      • Yamada K.
      • Mizuta E.
      • et al.
      Effects of cilnidipine on serum uric acid level and urinary nitrogen monoxide excretion in patients with hypertension.
      Perhaps consistent with a urate-lowering effect, studies also indicate that CCBs may decrease the risk of gout.
      • Bruderer S.
      • Bodmer M.
      • Jick S.S.
      • Meier C.R.
      Use of diuretics and risk of incident gout: a population-based case-control study.
      ,
      • Choi H.K.
      • Soriano L.C.
      • Zhang Y.
      • Rodríguez L.A.
      Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study.
      Compared with no use of CCBs, CCB use was found to be associated with a 0.87 (95% CI, 0.82 to 0.93) relative risk for incident gout in patients with hypertension after adjusting for age, sex, and use of other antihypertensive drugs.
      • Choi H.K.
      • Soriano L.C.
      • Zhang Y.
      • Rodríguez L.A.
      Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study.
      The multivariate relative risks (95% CIs) for individual CCBs were 0.79 (0.73 to 0.86) for amlodipine, 0.86 (0.75 to 0.99) for diltiazem, and 0.87 (0.78 to 0.97) for nifedipine.

      Anti-inflammatories and Immunosuppressives

      High-Dose Aspirin and Salicylates

      Aspirin has been shown to have a biphasic effect on sU lowering, wherein low doses (≤2 g/d) raise the sU level
      • Yu T.F.
      • Gutman A.B.
      Study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanisms for excretion of urate in man.
      ,
      • Segal R.
      • Lubart E.
      • Leibovitz A.
      • et al.
      Early and late effects of low-dose aspirin on renal function in elderly patients.
      but high doses (>3 g/d) decrease it.
      • Yu T.F.
      • Gutman A.B.
      Study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanisms for excretion of urate in man.
      These effects may be explained by 2 modes of salicylate interaction with URAT1: at low doses salicylate acts as an exchange substrate to facilitate UA reabsorption, but at high doses it inhibits tubular reabsorption.
      • Ohtsu N.
      • Anzai N.
      • Fukutomi T.
      • et al.
      Human renal urate transpoter urat1 mediates the transport of salicylate. Article in Japanese.
      In a study by Yu and Gutman et al,
      • Yu T.F.
      • Gutman A.B.
      Study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanisms for excretion of urate in man.
      1 g of aspirin daily resulted in a mean increase in sU level of 6%. In contrast, 3 g daily led to no decline in sU level and 5 g daily led to a mean decrease of 26%. Because such high doses of salicylates are no longer routinely used in clinical practice, their urate-lowering effects currently have little clinical implication.

      Nonsalicylate Nonsteroidal Anti-inflammatory Drugs

      Nonsalicylate nonsteroidal anti-inflammatory drugs (NSAIDs) are standard anti-inflammatory therapy for acute gout flares and for flare prophylaxis during the administration of urate-lowering therapy, but it remains unclear whether they have uricosuric or UA-retaining effects themselves. Some investigators have reported decreases in sU levels in patients with gout treated with NSAIDs.
      • Murphy J.E.
      Piroxicam in the treatment of acute gout: a multicentre open study in general practice.
      • Tiitinen S.
      • Nissilä M.
      • Ruutsalo H.M.
      • Isomäki H.
      Effect of nonsteroidal anti-inflammatory drugs on the renal excretion of uric acid.
      • Shin H.J.
      • Takeda M.
      • Enomoto A.
      • et al.
      Interactions of urate transporter URAT1 in human kidney with uricosuric drugs.
      One study of 29 patients found that piroxicam (40 mg/d for 5 days) relieved acute gout flare with a concomitant decreased sU level (P<.05). However, sU level often falls during a gout flare, even without uricosuric treatment, so the causal role of piroxicam remained uncertain.
      • Murphy J.E.
      Piroxicam in the treatment of acute gout: a multicentre open study in general practice.
      In contrast, Tiitinen et al
      • Tiitinen S.
      • Nissilä M.
      • Ruutsalo H.M.
      • Isomäki H.
      Effect of nonsteroidal anti-inflammatory drugs on the renal excretion of uric acid.
      reported that piroxicam resulted in decreased UA excretion in 8 of 11 patients (P<.05) seen 2 to 3 hours after ingestion of the drug, suggesting that piroxicam increases the sU level. Among other NSAIDs in that study, only indomethacin significantly increased UA excretion. In 2011, a study using canine kidney cells expressing URAT1 found that multiple NSAIDs (indomethacin, phenylbutazone, and salicylate) dose-dependently inhibited UA cellular reuptake, suggesting a uricosuric class effect of NSAIDs that might promote sU lowering,
      • Shin H.J.
      • Takeda M.
      • Enomoto A.
      • et al.
      Interactions of urate transporter URAT1 in human kidney with uricosuric drugs.
      potentially through the ability of planar anionic NSAIDs, when protonated, to intercalate into lipid bilayers.
      • Abramson S.B.
      • Weissmann G.
      The mechanisms of action of nonsteroidal antiinflammatory drugs.
      On the other hand, NSAIDs decrease the GFR via prostaglandin inhibition at renal afferent and efferent arterioles, potentially reducing urate filtration and promoting sU elevation. Overall, more research needs to be conducted on the effects of NSAIDs on sU level.

      Leflunomide

      Leflunomide is a disease-modifying therapy used to treat rheumatoid arthritis and other autoimmune conditions. After 1 year of treatment with leflunomide, the level of sU decreased significantly by 0.71 mg/dL in a cohort of patients with rheumatoid arthritis. No further changes were noted at year 2 of treatment.
      • Emery P.
      • Breedveld F.C.
      • Lemmel E.M.
      • et al.
      A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis.
      The effects of leflunomide on sU levels in that study are consistent with those of other studies in patients with IgA nephropathy
      • Wu J.
      • Duan S.W.
      • Sun X.F.
      • et al.
      Efficacy of leflunomide, telmisartan, and clopidogrel for immunoglobulin a nephropathy: a randomized controlled trial.
      and rheumatoid arthritis,
      • Perez-Ruiz F.
      • Nolla J.M.
      Influence of leflunomide on renal handling of urate and phosphate in patients with rheumatoid arthritis.
      where sU levels decreased by 0.78 mg/dL and 1.47 mg/dL, respectively. Because creatinine level was not significantly changed in patients with rheumatoid arthritis in the previously mentioned studies, the decreased sU level is more likely to be due to increased renal UA excretion than to changes in estimated GFR.

      Metabolism Modulators: Sodium-Glucose Cotransporter 2 Inhibitors

      Among the commonly used drugs in the treatment of DM, the sodium-glucose cotransporter 2 (SGLT2) inhibitors seem to have a drug class effect of hypouricemia. In a meta-analysis of 62 RCTs involving 34,941 patients with T2DM, SGLT2 inhibitors were found to have significant sU-lowering effects compared with controls, ranging from –0.29 to –0.77 mg/dL, with a total weighted mean of –0.63 mg/dL.
      • Zhao Y.
      • Xu L.
      • Tian D.
      • et al.
      Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: a meta-analysis of randomized controlled trials.
      The SGLT2 inhibitors included empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin. Treatment with empagliflozin resulted in superior reduction in sU level of 0.77 mg/dL. The underlying mechanism for the sU-lowering effect of SGLT2 inhibitors is likely glucosuria increasing urinary UA excretion. Chino et al
      • Chino Y.
      • Samukawa Y.
      • Sakai S.
      • et al.
      SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria.
      found that an increase in urinary excretion of UA correlates with an increase in glucose excretion. No direct interaction between SGLT2 inhibitors and major UA transporters was found. The efflux of UA in a Xenopus oocyte model expressing glucose transporter–like protein-9 isoform 2 was trans-stimulated by glucose, and the uptake of UA by oocytes was cis-inhibited by glucose. Thus, it is likely that UA urinary excretion is increased by SGLT2-induced glycosuria. In patients with T1DM, after induction of glycosuria with SGLT2 inhibition while maintaining euglycemia, sU level decreased (P<.0001) and urinary excretion of UA increased (P<.0001), suggesting again that glycosuria, not hyperglycemia, increases uricosuria in patients with diabetes.
      • Lytvyn Y.
      • Škrtić M.
      • Yang G.K.
      • et al.
      Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus.
      Although the effect is modest, it may be worth considering when selecting treatments for diabetes in patients with gout.

      Lipid-Lowering Drugs: Statins and Fenofibrates

      Atorvastatin has been reported to decrease sU level and increase GFR in a retrospective study of patients with CKD stage 3, in contrast to rosuvastatin, which had no effect.
      • Cappuccio F.P.
      • Strazzullo P.
      • Farinaro E.
      • Trevisan M.
      Uric acid metabolism and tubular sodium handling: results from a population-based study.
      In an RCT of 893 individuals followed for 12 months comparing pravastatin 40 mg/d with atorvastatin 80 mg/d, modest sU reductions occurred in both treatment arms, but a greater decline was observed with atorvastatin than with pravastatin (–0.52 mg/dL vs –0.09 mg/dL; P<.0001).
      • Deedwania P.C.
      • Stone P.H.
      • Fayyad R.S.
      • Laskey R.E.
      • Wilson D.J.
      Improvement in renal function and reduction in serum uric acid with intensive statin therapy in older patients: a post hoc analysis of the SAGE trial.
      In another study, sU levels decreased after atorvastatin or rosuvastatin treatment but increased after pitavastatin use.
      • Ogata N.
      • Fujimori S.
      • Oka Y.
      • Kaneko K.
      Effects of three strong statins (atorvastatin, pitavastatin, and rosuvastatin) on serum uric acid levels in dyslipidemic patients.
      In the ATOROS (ATOrvastatin and ROSuvastatin) study,
      • Milionis H.J.
      • Rizos E.
      • Kostapanos M.
      • et al.
      Treating to target patients with primary hyperlipidaemia: comparison of the effects of atorvastatin and rosuvastatin (the ATOROS study).
      only atorvastatin was found to lower sU levels. Finally, in the PATROL (Pitavastatin, Atorvastatin, Rosuvastatin for Safety and Efficacy) trial,
      • Saku K.
      • Zhang B.
      • Noda K.
      Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial.
      the mean ± SD sU level was decreased in the atorvastatin and rosuvastatin groups (from 5.19±1.23 mg/dL to 4.99±1.12 mg/dL and from 5.42±1.48 mg/dL to 5.24±1.54 mg/dL, respectively; P<.05) but not in the pitavastatin group. A systematic review and meta-analysis by Derosa et al
      • Derosa G.
      • Maffioli P.
      • Reiner Ž.
      • Simental-Mendía L.E.
      • Sahebkar A.
      Impact of statin therapy on plasma uric acid concentrations: a systematic review and meta-analysis.
      incorporated 9 RCTs and found significant reductions in sU levels with use of atorvastatin (MD (mean difference) –39.62 μmol/L; 95% CI, –60.78 to –18.46 μmol/L; P<.001) and simvastatin (MD –5.95 μmol/L; 95% CI, –10.62 to –1.28 μmol/L; P=.013) but not with use of pravastatin, rosuvastatin, or lovastatin. Thus, across multiple studies, a consistent signal for limited urate lowering is seen with atorvastatin, with mixed data on a possible benefit of rosuvastatin and simvastatin and no beneficial effect with other statins.
      • Takagi H.
      • Umemoto T.
      Atorvastatin therapy reduces serum uric acid levels: a meta-analysis of randomized controlled trials.
      On the other hand, colchicine is used by many patients with gout, and because of interactions at the CYP3A4 hepatic enzyme, atorvastatin but not some other statins must be used with caution when administered with colchicine.
      • Tufan A.
      • Dede D.S.
      • Cavus S.
      • et al.
      Rhabdomyolysis in a patient treated with colchicine and atorvastatin.
      Fenofibrate has also been reported to significantly decrease sU levels. In one study, fenofibrate (200 mg daily administered to 64 dyslipidemic patients) significantly reduced sU levels by 1.9 mg/dL (from 6.8 mg/dL to 4.9 mg/dL; P<.001) via increased renal fractional excretion of UA (from 8%±3% to 13%±4%; P<.01).
      • Elisaf M.
      • Tsimichodimos V.
      • Bairaktari E.
      • Siamopoulos K.C.
      Effect of micronized fenofibrate and losartan combination on uric acid metabolism in hypertensive patients with hyperuricemia.
      The fenofibrate-induced decrease in sU levels was independent of changes in serum triglyceride levels or other lipid parameters, confirming the direct hypouricemic action of the drug. A meta-analysis
      • Takagi H.
      • Umemoto T.
      Atorvastatin therapy reduces serum uric acid levels: a meta-analysis of randomized controlled trials.
      of 8 prospective clinical trials including 2774 patients compared atorvastatin with fenofibrates and other drugs, including rosuvastatin, simvastatin, pitavastatin, and amlodipine. Pooled analysis found significantly lower final sU levels by 0.57 mg/dL in the atorvastatin group compared with other nonfenofibrate agents (MD –0.57 mg/dL; 95% CI, –0.81 to –0.34 mg/dL; P<.00001). On the other hand, compared with fenofibrate use, atorvastatin therapy was associated with significantly higher final sU levels (ie, less sU lowering) (MD 1.48 mg/dL; 95% CI, 0.88 to 2.08 mg/dL; P<.00001).
      In summary, atorvastatin has consistently been found to result in modestly decreased sU concentrations and greater sU-decreasing effects than most statins, although some other statins may have weak sU-lowering effects. Fenofibrates also decrease sU levels, probably more so than atorvastatin, although further study is needed. Moreover, statins are generally preferred to fenofibrates for lipid lowering, and the ACR, therefore, conditionally recommends against choosing fenofibrate over other lipid-lowering agents for patients with gout.
      • FitzGerald J.D.
      • Dalbeth N.
      • Mikuls T.
      • et al.
      2020 American College of Rheumatology guideline for the management of gout.

      Sex Hormones: Estrogen

      Estrogen has been associated with reduced levels of sU.
      • Yahyaoui R.
      • Esteva I.
      • Haro-Mora J.J.
      • et al.
      Effect of long-term administration of cross-sex hormone therapy on serum and urinary uric acid in transsexual persons.
      ,
      • Nicholls A.
      • Snaith M.L.
      • Scott J.T.
      Effect of oestrogen therapy on plasma and urinary levels of uric acid.
      In a prospective study of 69 healthy transsexual persons, after 1 year of hormone therapy, sU levels increased in female-to-male transitions (from 3.91 mg/dL to 5.07 mg/dL, testosterone therapy) and decreased in male-to-female transitions (from 4.87 mg/dL to 3.67 mg/dL, estrogen therapy).
      • Yahyaoui R.
      • Esteva I.
      • Haro-Mora J.J.
      • et al.
      Effect of long-term administration of cross-sex hormone therapy on serum and urinary uric acid in transsexual persons.
      Levels of sU were lower (P=.03) and fractional excretion of UA was higher (P=.04) in those who had received higher doses of estrogen (P=.03). Studies have also found that tubular urate level after secretory reabsorption was significantly lower and resulted in higher urinary urate excretion and lower sU levels in women of fertility age than in men (P<.01).
      • Antón F.M.
      • García Puig J.
      • Ramos T.
      • González P.
      • Ordás J.
      Sex differences in uric acid metabolism in adults: evidence for a lack of influence of estradiol-17 beta (e2) on the renal handling of urate.

      Urate-Increasing Drugs

      In contrast to drugs that incidentally lower sU levels, several drugs incidentally raise sU levels as an adverse effect (Tables 1 and 3). In patients with gout or hyperuricemia, substituting equally efficacious alternatives for some of these agents may facilitate sU management.
      Table 3Serum Urate–Increasing Drugs: Supporting Studies
      DrugReference, yearStudy designPatients (No.)DoseDurationSerum urate effect (mg/dL)P value
      BendroflumethiazideCarlsen et al,
      • Carlsen J.E.
      • Køber L.
      • Torp-Pedersen C.
      • Johansen P.
      Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects.
      1990
      Double-blind, parallel group2571.25, 2.5, 5.0, or 10.0 mg/d10 wk+0.3-1.1<.01 vs baseline
      HydrochlorothiazideBuscemi et al,
      • Buscemi S.
      • Buscemi C.
      • Borzì A.M.
      • et al.
      Metabolic and cardiovascular effects of switching thiazides to amlodipine in hypertensive patients with and without type 2 diabetes (the diuretics and diabetes control study).
      2020
      Parallel-group, single-blind, single-center RCT20 normal glucose tolerant, 20 prediabetic, 20 T2DM12.5-25 mg/d6 wk+0.1 vs baseline;

      +1.0 vs 6 wk of amlodipine
      <.001 vs 6 wk of amlodipine
      HydrochlorothiazideReyes,
      • Reyes A.J.
      Cardiovascular drugs and serum uric acid.
      2003
      Randomized, crossover, double-blind1125 mg/d4 d+0.76<.01
      HydrochlorothiazideMacKay et al,
      • MacKay J.H.
      • Arcuri K.E.
      • Goldberg A.I.
      • Snapinn S.M.
      • Sweet C.S.
      Losartan and low-dose hydrochlorothiazide in patients with essential hypertension: a double-blind, placebo-controlled trial of concomitant administration compared with individual components.
      1996
      Double-blind, placebo controlled703 hypertensive (n=118, hydrochlorothiazide 12.5 mg)12.5 mg/d12 wk+0.3<.01
      ChlorthalidonePollavini,
      • Pollavini G.
      • Comi D.
      • Grillo C.
      Multicentre randomized cross-over double-blind comparison between chlorthalidone and slow-release oxprenolol in mild-to-moderate hypertension.
      1984
      Multicenter, randomized, crossover, double-blind298 hypertensive25 mg/d4 wk+0.7<.05
      TorsemideReyes,
      • Reyes A.J.
      Cardiovascular drugs and serum uric acid.
      2003
      Randomized, crossover, double-blind1610 mg/d7 d+1.18<.01
      AtenololAndersen,
      • Andersen G.S.
      Atenolol versus bendroflumethiazide in middle-aged and elderly hypertensives.
      1985
      Randomized prospective136 (atenolol, n=67; bendroflumethiazide, n=69)50-100 mg/d12 wk+0.5<.001 vs baseline
      MetoprololJuraschek et al,
      • Juraschek S.P.
      • Appel L.J.
      • Miller III, E.R.
      Metoprolol increases uric acid and risk of gout in African Americans with chronic kidney disease attributed to hypertension.
      2017
      Randomized prospective630 (metoprolol, n=249; ramipril, n=265; amlodipine, n=116)NA12 mo+0.3.03 vs baseline
      PropranololCaptopril Research Group of Japan,
      Captopril Research Group of Japan
      Clinical effects of low-dose captopril plus a thiazide diuretic on mild to moderate essential hypertension: a multicenter double-blind comparison with propranolol.
      1985
      Multicenter, randomized, double-blind270 (propranolol, n=137; captopril, n=133; both on diuretic)60-120 mg/d12 wk+0.3<.01 vs baseline
      PyrazinamideInayat et al,
      • Inayat N.
      • Shah R.H.
      • Lakhair M.A.
      • Sahito R.
      Hyperuricemia & arthralgia during pyrazinamide therapy in patients with pulmonary tuberculosis.
      2016
      Prospective, case-control46NA8 wkBetween weeks 2-6: +4.6<.05 vs baseline
      EthambutolPostlethwaite et al,
      • Postlethwaite A.E.
      • Bartel A.G.
      • Kelley W.N.
      Hyperuricemia due to ethambutol.
      1972
      Retrospective712-19 mg/kg per day30 d+3.2NA
      Aspirin (low dose)Yu and Gutman,
      • Yu T.F.
      • Gutman A.B.
      Study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanisms for excretion of urate in man.
      1959
      Self-controlled, prospective41 g/d4 d–6%
(control range, 10.8-11.4 vs treatment range, 11.2-12.2)<.05 vs control
      CyclosporineKanbay et al,
      • Kanbay M.
      • Akcay A.
      • Huddam B.
      • et al.
      Influence of cyclosporine and tacrolimus on serum uric acid levels in stable kidney transplant recipients.
      2005
      Retrospective73NA24 mo+1.6<.001 vs baseline
      TacrolimusKanbay et al,
      • Kanbay M.
      • Akcay A.
      • Huddam B.
      • et al.
      Influence of cyclosporine and tacrolimus on serum uric acid levels in stable kidney transplant recipients.
      2005
      Retrospective47NA24 mo+1.5<.001 vs baseline
      InsulinMacFarlane et al,
      • MacFarlane L.A.
      • Liu C.C.
      • Solomon D.H.
      The effect of initiating pharmacologic insulin on serum uric acid levels in patients with diabetes: a matched cohort analysis.
      2015
      Retrospective46NANA+1.25.02
      TestosteroneYahyaoui et al,
      • Yahyaoui R.
      • Esteva I.
      • Haro-Mora J.J.
      • et al.
      Effect of long-term administration of cross-sex hormone therapy on serum and urinary uric acid in transsexual persons.
      2008
      Prospective69 total (n=47 female-to-male, n=22 male-to-female)250 mg IM every 2 wk or 5 mg/d patches1 y+1.16<.01
      TestosteroneKurahashi et al,
      • Kurahashi H.
      • Watanabe M.
      • Sugimoto M.
      • et al.
      Testosterone replacement elevates the serum uric acid levels in patients with female to male gender identity disorder.
      2013
      Dose-response analysis160125 or 250 mg IM, every 2 wk12 mo+1.3<.05 vs baseline
      IM = intramuscular; NA = not available; RCT = randomized controlled trial; T2DM = type 2 diabetes mellitus.

      Antihypertensives

      Loop and Thiazide Diuretics

      Loop and thiazide diuretics are well-known to cause iatrogenic hyperuricemia
      • Pak C.Y.
      • Tolentino R.
      • Stewart A.
      • Galosy R.A.
      Enhancement of renal excretion of uric acid during long-term thiazide therapy.
      and increase the risk of gout.
      • Bruderer S.
      • Bodmer M.
      • Jick S.S.
      • Meier C.R.
      Use of diuretics and risk of incident gout: a population-based case-control study.
      Diuretics increase sU concentration in a dose-dependent manner,
      • Bengtsson C.
      • Johnsson G.
      • Sannerstedt R.
      • Werkö L.
      Effect of different doses of chlorthalidone on blood pressure, serum potassium, and serum urate.
      and increases in the sU level can be seen as early as 24 hours after initiating treatment.
      • Leary W.P.
      • Reyes A.J.
      • Wynne R.D.
      • van der Byl K.
      Renal excretory actions of furosemide, of hydrochlorothiazide and of the vasodilator flosequinan in healthy subjects.
      Effects have ranged from a 6% to 21% sU increase (0.3-1.1 mg/dL) above baseline after 10 weeks of treatment.
      • Carlsen J.E.
      • Køber L.
      • Torp-Pedersen C.
      • Johansen P.
      Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects.
      ,
      • Reyes A.J.
      Cardiovascular drugs and serum uric acid.
      Diuretic effects on sU levels are reversible
      • Freis E.D.
      • Thomas J.R.
      • Fisher S.G.
      • et al.
      Effects of reduction in drugs or dosage after long-term control of systemic hypertension.
      and in one study returned from a mean of 7.5 mg/dL to 6.5 mg/dL 3 weeks after discontinuation (P<.0005).
      • Freis E.D.
      • Calabresi M.
      • Castle C.
      Return of elevated blood pressure after withdrawal of antihypertensive drugs.
      ,
      • Takata Y.
      • Yoshizumi T.
      • Ito Y.
      • et al.
      Comparison of withdrawing antihypertensive therapy between diuretics and angiotensin converting enzyme inhibitors in essential hypertensives.
      Diuretics raise sU levels through effects on renal UA transporters. Loop and thiazide diuretics enter proximal tubular cells through organic anion transporters and then are transported into the lumen in exchange for UA by organic anion transporter 4, resulting in UA retention.
      • Sica D.A.
      • Carter B.
      • Cushman W.
      • Hamm L.
      Thiazide and loop diuretics.
      • Palmer B.F.
      Metabolic complications associated with use of diuretics.
      • Hasannejad H.
      • Takeda M.
      • Taki K.
      • et al.
      Interactions of human organic anion transporters with diuretics.
      • Hagos Y.
      • Stein D.
      • Ugele B.
      • Burckhardt G.
      • Bahn A.
      Human renal organic anion transporter 4 operates as an asymmetric urate transporter.
      Diuretics also increase UA reabsorption via intravascular volume contraction.
      • Cappuccio F.P.
      • Strazzullo P.
      • Farinaro E.
      • Trevisan M.
      Uric acid metabolism and tubular sodium handling: results from a population-based study.
      ,
      • Weinman E.J.
      • Eknoyan G.
      • Suki W.N.
      The influence of the extracellular fluid volume on the tubular reabsorption of uric acid.
      More recently, diuretics were found to inhibit multidrug resistance protein 4
      • El-Sheikh A.A.
      • van den Heuvel J.J.
      • Koenderink J.B.
      • Russel F.G.
      Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4.
      and the human voltage-driven drug efflux transporter NPT4
      • Jutabha P.
      • Anzai N.
      • Wempe M.F.
      • et al.
      Apical voltage-driven urate efflux transporter NPT4 in renal proximal tubule.
      at the proximal tubule.
      In patients treated for 7 days with torsemide 10 mg daily, sU levels were elevated by 1.18 mg/dL vs patients treated with placebo for 7 days.
      • Reyes A.J.
      Cardiovascular drugs and serum uric acid.
      Hydrochlorothiazide 12.5 mg at week 12 increased the sU level by 0.3 mg/dL.
      • MacKay J.H.
      • Arcuri K.E.
      • Goldberg A.I.
      • Snapinn S.M.
      • Sweet C.S.
      Losartan and low-dose hydrochlorothiazide in patients with essential hypertension: a double-blind, placebo-controlled trial of concomitant administration compared with individual components.
      Reyes
      • Reyes A.J.
      Cardiovascular drugs and serum uric acid.
      found that 4 days of treatment with hydrochlorothiazide 25 mg increased the sU level by 0.76 mg/dL.
      • Reyes A.J.
      Cardiovascular drugs and serum uric acid.
      Chlorthalidone 25 mg at week 4 was associated with a 0.7-mg/dL increase in sU level.
      • Pollavini G.
      • Comi D.
      • Grillo C.
      Multicentre randomized cross-over double-blind comparison between chlorthalidone and slow-release oxprenolol in mild-to-moderate hypertension.
      Overall, it is difficult to directly compare the effects of the various thiazides on sU level, but all seem to have a potentially significant impact.
      Given the availability of other antihypertensives (including those that lower the sU concentration), altering hypertension therapy in patients with gout or AH seems reasonable. Accordingly, the 2020 ACR gout treatment guideline conditionally recommends “switching hydrochlorothiazide to an alternate hypertensive when feasible … for patients with gout.”
      • FitzGerald J.D.
      • Dalbeth N.
      • Mikuls T.
      • et al.
      2020 American College of Rheumatology guideline for the management of gout.
      In contrast, diuretics are the mainstay for treatment of fluid retention and/or congestive heart failure, with no reasonable alternatives. In such patients, or in those for whom diuretics are essential for blood pressure management, using the lowest effective dose diminishes hyperuricemic effects.

      β-Blockers

      The β-blockers propranolol,
      • Berglund G.
      • Andersson O.
      • Larsson O.
      • Wilhelmsen L.
      Antihypertensive effect and side-effects of bendroflumethiazide and propranolol.
      ,
      • Weber M.A.
      • Drayer J.I.
      • Kaufman C.A.
      The combined alpha- and beta-adrenergic blocker labetalol and propranolol in the treatment of high blood pressure: similarities and differences.
      atenolol,
      • Andersen G.S.
      Atenolol versus bendroflumethiazide in middle-aged and elderly hypertensives.
      metoprolol,
      • Juraschek S.P.
      • Appel L.J.
      • Miller III, E.R.
      Metoprolol increases uric acid and risk of gout in African Americans with chronic kidney disease attributed to hypertension.
      ,
      • Andersson O.
      • Berglund G.
      • Descamps R.
      • Thomis J.
      Sotalol and metoprolol comparison of their anti-hypertensive effect.
      and sotalol
      • Andersson O.
      • Berglund G.
      • Descamps R.
      • Thomis J.
      Sotalol and metoprolol comparison of their anti-hypertensive effect.
      have all been found to modestly increase sU levels.
      • Ueno S.
      • Hamada T.
      • Taniguchi S.
      • et al.
      Effect of antihypertensive drugs on uric acid metabolism in patients with hypertension: cross-sectional cohort study.
      In a trial of hypertensive patients treated with atenolol (50-100 mg once daily; n=67) for 12 weeks, the mean sU level increased from 5.2 mg/dL to 5.7 mg/dL.
      • Andersen G.S.
      Atenolol versus bendroflumethiazide in middle-aged and elderly hypertensives.
      The addition of propranolol to the antihypertensive regimen of 137 patients increased the mean sU level by 0.3 mg/dL after 12 weeks.
      Captopril Research Group of Japan
      Clinical effects of low-dose captopril plus a thiazide diuretic on mild to moderate essential hypertension: a multicenter double-blind comparison with propranolol.
      Metoprolol increased sU by 0.3 mg/dL after 12 months.
      • Juraschek S.P.
      • Appel L.J.
      • Miller III, E.R.
      Metoprolol increases uric acid and risk of gout in African Americans with chronic kidney disease attributed to hypertension.
      β-Blockers overall were found to have less hyperuricemic effect than were diuretics. The mechanism of β-blockers on sU concentration is unknown, but in one study β-blockers were found to modify neither renal clearance nor 24-hour urinary excretion of UA.
      • Weber M.A.
      • Drayer J.I.
      • Kaufman C.A.
      The combined alpha- and beta-adrenergic blocker labetalol and propranolol in the treatment of high blood pressure: similarities and differences.

      Antibiotics: Antitubercular Drugs

      Multidrug treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol was reported to result in marked hyperuricemia, increasing the sU level by a mean ± SD of 9.78±3.21 mg/dL (P<.001) after 2 weeks of treatment and beginning as early as 24 hours after a single dose.
      • Louthrenoo W.
      • Hongsongkiat S.
      • Kasitanon N.
      • Wangkaew S.
      • Jatuworapruk K.
      Effect of antituberculous drugs on serum uric acid and urine uric acid excretion.
      Most hyperuricemic effects from the treatment are likely from pyrazinamide and ethambutol. Pyrazinamide, a synthetic analogue of nicotinamide with potent mycobactericidal activity, was first reported by Cullen et al to result in hyperuricemia. It was later discovered to be a strong UA retention agent, causing a more than 80% reduction in renal clearance of UA at a 300-mg therapeutic daily dose.
      • Gutman A.B.
      • Yü T.F.
      • Berger L.
      Renal function in gout, 3: estimation of tubular secretion and reabsorption of uric acid by use of pyrazinamide (pyrazinoic acid).
      ,
      • Cullen J.H.
      • Early L.J.
      • Fiore J.M.
      The occurrence of hyperuricemia during pyrazinamide-isoniazid therapy.
      Pyrazinamide reversibly increased the sU level by 4.6 mg/dL between weeks 2 and 6 of treatment, generally remaining stable thereafter, and returning to baseline 2 weeks after discontinuation.
      • Inayat N.
      • Shah R.H.
      • Lakhair M.A.
      • Sahito R.
      Hyperuricemia & arthralgia during pyrazinamide therapy in patients with pulmonary tuberculosis.
      Pyrazinamide promotes UA reabsorption via URAT1, which has the highest affinity for aromatic organic anions such as nicotinate and pyrazinoic acid.
      • Bahn A.
      • Hagos Y.
      • Reuter S.
      • et al.
      Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13).
      • Enomoto A.
      • Kimura H.
      • Chairoungdua A.
      • et al.
      Molecular identification of a renal urate–anion exchanger that regulates blood urate levels.
      • Mandal A.K.
      • Mount D.B.
      The molecular physiology of uric acid homeostasis.
      Patients with homozygous loss-of-function mutations in the gene for URAT1 lack a full response to pyrazinamide, providing further evidence for its mechanism through URAT1. Similar to pyrazinamide, ethambutol was reported to reversibly increase sU by a mean of 3.2 mg/dL after 1 month of therapy
      • Postlethwaite A.E.
      • Bartel A.G.
      • Kelley W.N.
      Hyperuricemia due to ethambutol.
      and can precipitate gout flares,
      • Khanna B.K.
      Acute gouty arthritis following ethambutol therapy.
      with sU level returning to baseline after withdrawal of ethambutol. Overall, antitubercular treatment particularly results in increased risk of gout attacks in patients at higher risk for hyperuricemia, including those with higher body mass index, CKD, and higher baseline hyperuricemia,
      • Ha Y.-J.
      • Chung S.W.
      • Lee J.H.
      • et al.
      Clinical features and risk factors for gout attacks during anti-tuberculosis treatment: a case-control study in South Korea.
      and the effect on sU level can be dramatic, particularly when pyrazinamide and ethambutol are used together. In one group of high-risk patients, the mean ± SD sU level was increased to 8.4±3.1 mg/dL (P<.001) at 2 months from pretreatment levels of 5.5±1.9 mg/dL.
      • Ha Y.-J.
      • Chung S.W.
      • Lee J.H.
      • et al.
      Clinical features and risk factors for gout attacks during anti-tuberculosis treatment: a case-control study in South Korea.
      Mean ± SD time from treatment initiation to gouty attack was 4.13±4 months, and half of the attacks occurred during the first 2 months of treatment.
      • Ha Y.-J.
      • Chung S.W.
      • Lee J.H.
      • et al.
      Clinical features and risk factors for gout attacks during anti-tuberculosis treatment: a case-control study in South Korea.

      Anti-inflammatories and Immunosuppressives

      Low-Dose Aspirin

      As noted previously herein, low doses of aspirin and other salicylates may raise sU levels by promoting renal UA reabsorption. Caspi et al,
      • Caspi D.
      • Lubart E.
      • Graff E.
      • et al.
      The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients.
      testing the effects of 1 week of cardiac-level low-dose aspirin (ie, 75 mg/d), observed renal UA retention and a mean increase in sU concentration of 6.2% (P=.009) in a group of 49 elderly inpatients. Interestingly, aspirin-induced decreases in UA excretion were largely confined to a subset of patients with low serum albumin levels in whom UA excretion decreased by a mean ± SD of 105±199 mg/d compared with increased mean ± SD UA excretion of 23±167 mg/d for the normal albumin group (P=.009).
      • Caspi D.
      • Lubart E.
      • Graff E.
      • et al.
      The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients.
      Because the sU-raising effects of low-dose aspirin are modest and manageable with adjustment of urate-lowering therapy, whereas the cardiovascular benefit of aspirin is unequivocal in patients with appropriate indications, the 2020 ACR gout treatment guideline conditionally recommends against discontinuing cardiac-indicated aspirin for the management of hyperuricemia in patients with gout.
      • FitzGerald J.D.
      • Dalbeth N.
      • Mikuls T.
      • et al.
      2020 American College of Rheumatology guideline for the management of gout.

      Calcineurin Inhibitors

      Hyperuricemia is more common in transplant recipients than in healthy persons, in part due to the immunosuppressants required after transplant.
      • Clive D.M.
      Renal transplant-associated hyperuricemia and gout.
      ,
      • Schlitt H.J.
      • Barkmann A.
      • Böker K.H.
      • et al.
      Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study.
      Cyclosporine, a calcineurin inhibitor, can promote hyperuricemia through decreased renal urate clearance,
      • Lin H.Y.
      • Rocher L.L.
      • McQuillan M.A.
      • et al.
      Cyclosporine-induced hyperuricemia and gout.
      ,
      • Perico N.
      • Codreanu I.
      • Caruso M.
      • Remuzzi G.
      Hyperuricemia in kidney transplantation.
      and gout develops in 4% to 10% of all cyclosporine-treated patients. Compared with patients who develop AH, those with gout induced by cyclosporine are mostly men, are also taking diuretics, and have more advanced CKD. In one study, the onset of gout occurred after a mean of less than 1.5 years of AH, with progression to polyarticular tophaceous gout in nearly half the patients within 3 years.
      • Burack D.A.
      • Griffith B.P.
      • Thompson M.E.
      • Kahl L.E.
      Hyperuricemia and gout among heart transplant recipients receiving cyclosporine.
      Tacrolimus is another calcineurin inhibitor that causes hyperuricemia. In one study, mean ± SD sU levels in patients starting cyclosporine or tacrolimus therapy rose from 6.3±1.6 mg/dL to 7.9±1.9 mg/dL (cyclosporine) and from 6.5±1.8 mg/dL to 8.0±1.8 mg/dL (tacrolimus) from pretreatment to 24 months (P<.001 for each). Changing between the 2 inhibitors resulted in no alteration in sU levels (P>.05), indicating that tacrolimus offers no advantage over cyclosporine for minimizing sU elevations in renal transplant recipients.
      • Kanbay M.
      • Akcay A.
      • Huddam B.
      • et al.
      Influence of cyclosporine and tacrolimus on serum uric acid levels in stable kidney transplant recipients.
      Other studies have investigated substitutions for calcineurin inhibitors. One found that when switching from a calcineurin inhibitor to the mTOR inhibitor sirolimus after cardiac transplant,
      • Raichlin E.
      • Khalpey Z.
      • Kremers W.
      • et al.
      Replacement of calcineurin-inhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients.
      the mean ± SD sU level decreased from 7.6±2.4 mg/dL to 6.2±1.9 mg/dL (P=.0007), with no difference in cardiac rejection or cardiac allograft function. In contrast, the use of mycophenolate mofetil, although improving renal function and lowering sU concentration compared with calcineurin inhibitors, increased risk of rejection in liver transplant recipients.
      • Schlitt H.J.
      • Barkmann A.
      • Böker K.H.
      • et al.
      Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study.
      Compared with renal transplant patients receiving cyclosporine (80%), there was decreased incidence of hyperuricemia with the use of azathioprine (55%; P<.002),
      • West C.
      • Carpenter B.J.
      • Hakala T.R.
      The incidence of gout in renal transplant recipients.
      ,
      • Marcén R.
      • Gallego N.
      • Orofino L.
      • et al.
      Impairment of tubular secretion of urate in renal transplant patients on cyclosporine.
      which provides an alternative to cyclosporine without significant differences in live donor kidney transplant rejection rates.
      • Gheith O.A.
      • Bakr M.A.
      • Fouda M.A.
      • et al.
      Comparative analysis of azathioprine versus cyclosporine-based therapy in primary haplo-identical live-donor kidney transplantation: a 20-year experience.
      However, in patients with gout taking allopurinol, azathioprine should be used with caution because their interaction may result in bone marrow suppression. One case report of 4 patients showed that mycophenolate mofetil, when substituted for azathioprine, enabled safe use of allopurinol in kidney transplant patients.
      • Jacobs F.
      • Mamzer-Bruneel M.F.
      • Skhiri H.
      • et al.
      Safety of the mycophenolate mofetil-allopurinol combination in kidney transplant recipients with gout.
      Alternatively, the uricosuric agent probenecid may be substituted for allopurinol, but probenecid is ineffective in patients with marked CKD (typically, estimated GFR <50 mL/min). The alternative uricosuric benzobromarone (not approved for use in the United States) can be used to lower sU levels in those with creatinine clearance greater than 25 mL/min /1.73 m2 (to convert to mL/s/m2, multiple by 0.0167) but requires hepatic function monitoring.
      • Omar E.K.
      • Khan S.
      E19. Rapid response to benzbromarone for gout in a renal transplant patient.
      • Stamp L.
      • Searle M.
      • O'Donnell J.
      • Chapman P.
      Gout in solid organ transplantation: a challenging clinical problem.
      • Lee M.H.
      • Graham G.G.
      • Williams K.M.
      • Day R.O.
      A benefit-risk assessment of benzbromarone in the treatment of gout: was its withdrawal from the market in the best interest of patients?.

      Metabolism Modulators

      Lactate

      Lactate infusion, used in resuscitation of critically ill patients, increases sU levels. URAT1 is a urate-lactate exchanger, where UA is reabsorbed in exchange for lactate, and thus a high lactate level stimulates UA uptake, promoting hyperuricemia.
      • Mount D.B.
      • Kwon C.Y.
      • Zandi-Nejad K.
      Renal urate transport..
      ,
      • Burch R.E.
      • Kurke N.
      The effect of lactate infusion on serum uric acid.
      Similarly, sU levels rise in lactic acidosis or ketoacidosis, as organic anions compete with UA for proximal secretion.

      Insulin

      Insulin decreases the urinary excretion of UA and significantly increases the sU level (mean, 1.25 mg/dL; P=.02).
      • MacFarlane L.A.
      • Liu C.C.
      • Solomon D.H.
      The effect of initiating pharmacologic insulin on serum uric acid levels in patients with diabetes: a matched cohort analysis.
      The effect of insulin is likely due to increased UA reabsorption via URAT1 or through the sodium-dependent anion cotransporter in the proximal tubule.
      • Choi H.K.
      • Mount D.B.
      • Reginato A.M.
      Pathogenesis of gout.
      This suggests that insulin’s increase of the sU level by 1.25 mg/dL may confer an increased gout risk
      • Choi H.K.
      • Atkinson K.
      • Karlson E.W.
      • Willett W.
      • Curhan G.
      Alcohol intake and risk of incident gout in men: a prospective study.
      ,
      • Choi H.K.
      • Curhan G.
      Beer, liquor, and wine consumption and serum uric acid level: the Third National Health and Nutrition Examination Survey.
      that could potentially be avoided by selecting alternative therapies, where possible, for treatment of T2DM.

      Sex Hormones: Testosterone

      Often used in patients with female-to-male gender identity disorder, and occasionally in older men, testosterone can increase the sU level in a dose-dependent manner. In one study, 3 months of intramuscular testosterone use increased the sU level by 29% and 43% at dosages of 125 and 250 mg every 2 weeks, respectively.
      • Kurahashi H.
      • Watanabe M.
      • Sugimoto M.
      • et al.
      Testosterone replacement elevates the serum uric acid levels in patients with female to male gender identity disorder.
      Testosterone reduces renal excretion of UA by upregulating a sodium-dependent anion cotransporter in the proximal tubule that collaborates with URAT1 to increase UA reabsorption.
      • Hosoyamada M.
      • Takiue Y.
      • Shibasaki T.
      • Saito H.
      The effect of testosterone upon the urate reabsorptive transport system in mouse kidney.
      Another mechanism for sU elevation may relate to increased muscle mass—and, therefore, purine turnover—after testosterone treatment.
      • Kurahashi H.
      • Watanabe M.
      • Sugimoto M.
      • et al.
      Testosterone replacement elevates the serum uric acid levels in patients with female to male gender identity disorder.
      This is consistent with findings that men have higher baseline sU levels than age-matched women
      • Nicholls A.
      • Snaith M.L.
      • Scott J.T.
      Effect of oestrogen therapy on plasma and urinary levels of uric acid.
      and that sU levels increase in men after puberty.
      • Mikkelsen W.M.
      • Dodge H.J.
      • Valkenburg H.
      The distribution of serum uric acid values in a population unselected as to gout or hyperuricemia: Tecumseh, Michigan 1959-1960.
      Women with polycystic ovary syndrome also have been found to have higher sU levels, likely as a result of testosterone,
      • Mu L.
      • Pan J.
      • Yang L.
      • et al.
      Association between the prevalence of hyperuricemia and reproductive hormones in polycystic ovary syndrome.
      and postmenopausal women have increased sU levels, likely due to decreased estrogen levels.
      • Adamopoulos D.
      • Vlassopoulos C.
      • Seitanides B.
      • Contoyiannis P.
      • Vassilopoulos P.
      The relationship of sex steroids to uric acid levels in plasma and urine.
      Mean ± SD differences in mean sU levels among males, females of child-bearing age, and postmenopausal women were 5.22±1.1 mg/dL, 3.45±1.1 mg/dL, and 4.2±0.9 mg/dL, respectively,
      • Russo C.
      • Olivieri O.
      • Girelli D.
      • Guarini P.
      • Corrocher R.
      Relationships between serum uric acid and lipids in healthy subjects.
      consistent with a recent study in which postmenopausal women had higher sU levels than premenopausal women by 0.34 mg/dL (95% CI, 0.19 to 0.49 mg/dL) and 0.36 mg/dL (95% CL, 0.14 to 0.57 mg/dL), respectively.
      • Hak A.E.
      • Choi H.K.
      Menopause, postmenopausal hormone use and serum uric acid levels in US women: the Third National Health and Nutrition Examination Survey.

      Conclusion

      Drugs increase or decrease the sU level largely by affecting renal proximal tubule transporters to increase UA reabsorption or decrease secretion. There are no published guidelines on the prevention of drug-induced hyperuricemia. Yet, lowering the sU level is an essential part of gout treatment and may have a role in reducing associated metabolic comorbidities associated with AH, including hypertension, T2DM, CKD, and hyperlipidemia. By selecting agents with inherent sU-decreasing rather than sU-increasing properties, one can potentially increase medication compliance and reduce polypharmacy while treating multiple indications simultaneously. Ultimately, withdrawal or substitution of any drug should be based on benefit-risk ratio. In patients with hyperlipidemia and/or requiring statins for primary prevention, atorvastatin and fenofibrates have been shown to have greater sU-lowering effects than most other agents. In patients with hypertension, specific ARBs (losartan) and CCBs (dihydropyridines) may have consistent sU-lowering effects that could affect the risk of gout. If thiazide or loop diuretics are necessary to control blood pressure, using the lowest effective dose can be considered because drug-induced hyperuricemia by diuretics is dose-dependent. β-Blockers tend to elevate sU levels minimally, but their cardiovascular benefits likely outweigh their adverse effects on sU levels, a consideration that also applies to cardiac aspirin. Among antidiabetic agents, SGLT2 inhibitors (especially empagliflozin) decrease the sU concentration, whereas insulin raises it. In posttransplant patients who develop cyclosporine- or tacrolimus-induced hyperuricemia or gouty arthritis with tophi, allopurinol or a uricosuric agent can be added to control the sU level. Alternatively, non–urate-raising immunosuppressants such as sirolimus, mycophenolate, or azathioprine can be considered after accounting for efficacy in suppressing transplant rejection. However, co-administration of allopurinol and azathioprine is relatively contraindicated. In kidney transplant patients requiring allopurinol, mycophenolate mofetil can be considered as an alternative for azathioprine.

      Potential Competing Interests

      Dr Pillinger is on the data safety monitoring board and advisory board of Horizon Therapeutics. He is also a consultant for Sobi and Fortress Bioscience. Dr Toprover is on the advisory board of Horizon Therapeutics. The other authors report no competing interests.

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