Effects of Sodium Glucose Cotransporter-2 Inhibitors on Serum Uric Acid in Type 2 Diabetes Mellitus

Abstract

Hyperuricemia has been linked to metabolic syndrome, cardiovascular disease, and chronic kidney disease. Hyperuricemia and type 2 diabetes mellitus were inter-related, type 2 diabetes mellitus was more at risk of having a higher serum uric acid level, and also individuals with higher serum uric acid had higher risk of developing type 2 diabetes in the future. Insulin resistance seems to play an important role in the causal relationship between metabolic syndrome, type 2 diabetes, and hyperuricemia. Oral diabetic drugs that would have additional beneficial effects on reducing serum uric acid levels are of importance. Selective SGLT2 inhibitors were extensively studied in type 2 diabetes mellitus and were found to have improvement of glycemic control, in addition to their proven metabolic effects on weight and blood pressure. Additional beneficial effect of SGLT2 inhibitors on serum uric acid level reduction is investigated. Recently, data have been accumulating showing that they have additional beneficial effects on serum uric acid reduction. As for the postulated mechanism, serum uric acid decreased in SGLT2 inhibitor users as a result of the increase in the urinary excretion rate of uric acid, due to the inhibition of uric acid reabsorption mediated by the effect of the drug on the GLUT9 isoform 2, located at the collecting duct of the renal tubule.

Introduction

Uric acid is a by-product of metabolism of substances in the body and therefore is affected by diet, breakdown of cellular material, and impaired renal elimination.^1,2 Chronic hyperuricemia is a well-known established risk factor for the development of gout, kidney stones, and nephropathy.^1,2

Recent epidemiological study found that hyperuricemia is also linked to other conditions such as hypertension, atherosclerosis, cardiovascular disease, and chronic kidney disease.³ Several other studies supported that adult patients with high uric acid level frequently have a cluster of other metabolic abnormalities, such as abdominal obesity, glucose intolerance, insulin resistance, dyslipidemia, and hypertension.^3

–7 In a study by Pacifico et al., it was found that in obese children, hyperuricemia is not only associated with metabolic syndrome but also is a predictor of early atherosclerosis, as assessed by measurement of carotid intima-media thickness, and this was independent of other classical risk factors.⁵ Several other studies among adults also found an association of hyperuricemia with atherosclerosis.^8
–10 The role of serum uric acid as an independent risk factor for cardiovascular disease was investigated using a systematic review and meta-analysis, and showed that hyperuricemia does increase the risk of cardiovascular disease and mortality.¹¹ Many different studies showed that hyperuricemia was as well an independent risk factor for hypertension.^12
–14 Moreover an association also exists between hyperuricemia and other rheumatological diseases, other than gouty arthritis.¹⁵

Hyperuricemia and type 2 diabetes mellitus (T2D) were found to be inter-related. A study by Rathmann et al. looked at the association of hyperuricemia with different components of insulin resistance syndrome. This study revealed that body mass index (BMI), fasting insulin, and triglycerides were significantly higher in subjects with hyperuricemia, while high-density lipoprotein-cholesterol was significantly lower.¹⁶ People with higher fasting plasma insulin concentration are more likely to develop impaired glucose tolerance and diabetes mellitus.¹⁷ The link between hyperuricemia and T2D was found in a prospective study obtained from two generations of the Framingham Heart Study. This study found that individuals with higher serum uric acid were at a higher future risk of T2D independent of any other known risk factors.¹⁸ As for the main causes of hyperuricemia in diabetes mellitus patients, it was found despite that high blood sugar and high urine sugar excretion actually enhance renal excretion of uric acid, however, patients with diabetes mellitus were found to have a higher uric acid level when compared to nondiabetic individuals, and this has been strongly linked to the associated renal lesions and the overproduction of uric acid due to the high activity of xanthine oxidase, lipid peroxidation, and the high prevalence of obesity in these patients.¹⁹ It is well known that cause of hyperuricemia in patients is either due to overproduction of uric acid or under excretion.²⁰ In patients with diabetes specifically, the mechanism is most probably due to overproduction of uric acid.¹⁹

A study by Ito et al. confirmed that hyperuricemia prevalence is high among patients with T2D, where one-fourth of T2D patients had also been associated with hyperuricemia. He went on further to document that hyperuricemia in patients with T2D was further associated with diabetic microangiopathy excluding neuropathy.²¹ In this study as well, high serum uric acid was found to be an independent risk factor for diabetic macroangiopathy, where the hazard ratio for coronary heart disease was 2.81, even after adjustment for sex, treatment of diabetes mellitus, BMI, hyperlipidemia and hypertension, and the estimated glomerular filtration rate.²¹ This was again confirmed in a meta-analysis which showed that hyperuricemia in patients with T2D was an independent predictor of vascular complications and mortality. This pooled analysis showed that for each increase in serum uric acid by 0.1 mmol/L, there was an associated 28% increase in diabetic complications and a 9% increase in the mortality risk due to diabetes.²²

In addition, a retrospective case-matched cohort study was conducted, trying to assess the impact of urate-lowering therapy (ULT) on all-cause and cardiovascular mortality, and showed that after adjustment, hyperuricemic patients who did not receive ULT had increased risks of all-cause (hazard ratio, 1.24; 95% confidence interval 0.97–1.59) and cardiovascular disease (2.13; 1.34–3.39) mortality relative to the matched reference subjects. On the contrary, patients who had ULT had a lower risk of all-cause death (0.60; 0.41–0.88) relative to those hyperuricemic patients who did not receive ULT.²³

Given these associated clinical disorders with hyperuricemia, it is advantageous and beneficial to lower serum uric acid in patients with T2D, who are already at increased risk of microvascular and macrovascular disease.

The aim of this review is to characterize the effects that the new class of oral antidiabetics, the SGLT2 inhibitors, have on serum uric acid levels in patients with T2D.

Efficacy of SGLT2 Inhibitors in T2D

SGLT2 inhibitors control blood glucose level and improve glycemic control in patients with T2D in an insulin-independent method.²⁴

The first agent among these selective agents was dapagliflozin, later followed by canagliflozin and empagliflozin. Ipragliflozin, tofogliflozin, and luseogliflozin are three other drugs that have been approved in Japan, and there are still other compounds in the advanced stages of clinical development (including ertugliflozin).

All these SGLT2 inhibitors led to sustained urinary glucose loss of around 40–80 g/day, and were found to be associated with good blood glucose-lowering efficacy in T2D in addition to other beneficial effects such as lowering of body weight.^25
–27

SGLT2 inhibitors have clearly proven their efficacy in many different placebo-controlled trials in patients with T2D and were found to be as active or even superior to other glucose-lowering agents (sulfonylureas or sitagliptin).^28

–31 In the review article by Scheen et al., SGTL2 inhibitors demonstrated consistent effect on reduction in HbA1c and body weight, whatever the background of glucose-lowering therapy and the nature of the SGLT2 inhibitor used.³²

Moreover, SGLT2 inhibitors are characterized by their added benefits to address unmet clinical needs, such as weight loss, blood pressure control, and possible lipid-lowering effect.^25,26,33,34

Efficacy of SGLT2 Inhibitors on Uric Acid

SGLT2 inhibitors have been reported to have beneficial extra-glycemic effects.^33,34 Recently, beneficial effects on uric acid lowering have also been noted (Table 1). A post hoc analysis, including pooled data obtained from four randomized, phase III, 26-week multinational trials, assessed the effect of canagliflozin on serum uric acid level in type 2 diabetes mellitus patients.³⁵ Serum uric acid was evaluated in a total of 2313 patients with T2D, taking canagliflozin (100 or 300 mg), as monotherapy, or dual or triple combination therapy (add-on to metformin, metformin and sulfonylurea, or metformin and pioglitazone), when compared to placebo. The changes in uric acid levels were evaluated in the overall pooled cohort and in a subset of patients (n = 115), whose baseline serum uric acid levels were evaluated to start with, indicating hyperuricemia [serum uric acid level ≥8 mg/dL].³⁵ Canagliflozin was shown to be able to decrease serum uric acid levels in these patients and in those having hyperuricemia, where 20%–30% of those with hyperuricemia were able to achieve normal serum uric acid levels (<6 mg/dL) when treated with canagliflozin,³⁵ and this was linked to the increased fractional excretion of uric acid within the first weeks of treatment.³⁶

Table 1.

Studies Evaluating the Effect of SGLT2 Inhibitors on Serum Uric Acid

Study reference and methods	Drug and dose	Effects on uric acid	Conclusion
Davies et al.³⁷ Post hoc analysis of pooled data from randomized, phase III, multinational trials	Canagliflozin 100 and 300 mg compared to placebo	At week 26, both doses of canagliflozin (100 and 300 mg) led to around 13% reduction in levels of serum uric acid compared with placebo. Patients who had hyperuricemia had a serum uric acid level of <6 mg/dL, 23.5% with canagliflozin 100 mg and 32.4% with 300 mg compared to 3.1% with placebo.	Canagliflozin decreased serum uric acid in T2DM, including those who had baseline high uric acid level
		Incidences of gout and kidney stones were low and similar across groups
List et al.³⁹ Prospective, 12-week, randomized, parallel-group, double-blind, placebo-controlled study, with a 2-week diet/exercise placebo lead-in and 4-week follow-up	Dapagliflozin (2.5, 5, 10, 20, or 50 mg), metformin XR (750 mg force-titrated at week 2 to 1500 mg) or placebo	A larger relative decrease of 1.0 mg/dL below the baseline mean (5.5 mg/dL) in serum uric acid was observed, where there was a reduction of −1.03 ± 0.81 with dapagliflozin 2.5 mg, −1.12 ± 0.84 with dapagliflozin 5 mg, −0.98 ± 0.66 with dapagliflozin 10 mg, −1.13 ± 0.78 with dapagliflozin 20 mg, −1.14 ± 1.15 with dapagliflozin 50 mg, −0.16 ± 0.75 with placebo and an increase of 0.18 ± 0.54 with metformin	Serum uric acid did decrease more with dapagliflozin treatment when compared to placebo and metformin therapy, but this decrease discontinued on the discontinuation of dapagliflozin treatment
Bailey et al.⁴⁰ Long-term extension (total 102 weeks) of a 24-week phase III, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial	Dapagliflozin 2.5 mg versus dapagliflozin 5 mg versus dapagliflozin 10 mg versus placebo on top of metformin	Dapagliflozin when added to metformin led to a significant reduction in uric acid of −0.6 versus −0.5 versus −0.6 versus −0.02 mg/dL, with the dapagliflozin 2.5, 5, 10 mg, and placebo, respectively	Serum uric acid significantly dropped with different doses of dapagliflozin when compared to placebo
Jabbour et al.⁴¹ Multicenter, randomized, double-blind, placebo-controlled 24-week study	Dapagliflozin 10 mg versus placebo on top of sitagliptin ± metformin	Dapagliflozin led to a reduction in uric acid at 24 weeks (−0.75 [0.06] mg/dL) and at 48 weeks (−0.76 [0.07] mg/dL) when compared to placebo, where there was an increase of 0.03 [0.06] mg/dL at 24 weeks and 0.10 [0.07] mg/dL at 48 weeks	There was a decrease in serum uric acid with dapagliflozin 10 mg dose when compared to placebo
Strojek et al.⁴² A 24-week, randomized, double-blind, placebo-controlled, parallel-group, international, multicenter trial (ClinicalTrials.gov NCT00680745)	Patients uncontrolled receiving sulfonylurea monotherapy were randomly assigned to placebo or dapagliflozin (2.5, 5, or 10 mg/day) added to open-label glimepiride 4 mg/day for 24 weeks	Dapagliflozin led to a reduction in uric acid (−0.36 mg/dL for 2.5 mg dose vs. −0.44 mg/dL for 5 mg dose vs. −0.44 mg/dL for 10 mg dose vs. +0.02 mg/dL for placebo, P not mentioned)	Dapagliflozin led to a reduction in uric acid versus placebo
Wilding et al.⁴³ A randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial	Dapagliflozin 2.5 mg versus dapagliflozin 5 mg versus dapagliflozin 10 mg versus placebo on top of insulin plus oral antidiabetic drugs	Dapagliflozin led to a reduction in uric acid (−0.13 mg/dL for 2.5 mg dose vs. −0.14 mg/dL for 5 mg dose vs. −0.16 mg/dL for 10 mg dose) versus +0.04 mg/dL for placebo, P not mentioned)	Dapagliflozin led to a reduction in uric acid versus placebo

Dapagliflozin treatment was also found to cause a reduction in serum uric acid levels, and this was found to be dose related in one of the studies, where there was a noted reduction of −1.03 ± 0.81 with dapagliflozin 2.5 mg, −1.12 ± 0.84 with dapagliflozin 5 mg, −0.98 ± 0.66 with dapagliflozin 10 mg, −1.13 ± 0.78 with dapagliflozin 20 mg, −1.14 ± 1.15 with dapagliflozin 50 mg, −0.16 ± 0.75 with placebo, and, on the contrary, an increase in uric acid of 0.18 ± 0.54 was noted with metformin treatment alone. However, this reduction in uric acid was not maintained after discontinuation of dapagliflozin treatment.³⁷ In another long-term extension (total 102 weeks) of a 24-week phase III, multicenter, randomized, placebo-controlled, parallel-group trial, dapagliflozin, in its different doses, when added to metformin, led to a significant reduction in uric acid of −0.6 versus −0.5 versus −0.6 versus −0.02 mg/dL, with dapagliflozin 2.5, 5, and 10 mg and placebo, respectively.³⁸ The same noted reduction in uric acid with dapagliflozin treatment, in its different doses, when compared to placebo, was established in four other trials.^37

–41

This benefit in serum uric acid reduction was also again noted with another SGLT2 inhibitor drug, empagliflozin, where in a review of the peer-reviewed articles and abstracts describing preclinical studies and clinical trials, including empagliflozin in the treatment of patients with T2D, a small decrease was noted with empagliflozin treatment, of approximately the same level seen in another study that assessed the addition of empagliflozin as add-on to metformin plus sulfonylurea.⁴²

Mechanism of Reduction of Serum Uric Acid by SGLT2 Inhibitor Drugs

The mechanism by which SGLT2 inhibitors reduce serum uric acid has not been clearly understood, however, speculations have shown that it may possibly involve the renal SLC2A9 (GLUT9) transporter. The SLC2A9 gene encodes a facilitative glucose transporter and has two splice variants that are highly expressed in the apical membrane of the proximal tubule in nephron, a key site for urate handling in the kidney, found to transport both uric acid and d-glucose. SGLT2 inhibitor treatment leads to an increase in glucose excretion in the urine, which could eventually lead to an increased exchange of uric acid in the apical membrane of tubular cells leading to an increased release of uric acid from blood into the urine, thus decreasing serum uric acid levels.^43
–45

A study was done to elucidate the mechanism that may lead to this reduction, where serum uric acid and urinary excretion rate of uric acid were analyzed after the oral administration of luseogliflozin, an SGLT2 inhibitor, to healthy subjects, and this study confirmed that serum uric acid decreased as a result of the increase in the urinary excretion rate of uric acid, which correlated with the increase in urinary glucose excretion.⁴⁵ This increase in urinary excretion rate of uric acid was not due to a direct effect of the drug on the renal handling of uric acid, but may be attributed to glycosuria caused by SGLT2 inhibitors on the GLUT9 isoform 2 or any other transporter(s) at the proximal tubule and may inhibit uric acid reabsorption mediated by GLUT9 isoform 2 at the collecting duct of the renal tubule.^43
–45

Adverse Effects of SGLT2 Inhibitors

Up till now, the data presented on SGLT2 inhibition are very promising, but still caution needs to be exercised as the duration of the available studies are limited.^46
–48 Moreover, SGLT2 inhibitors are not without side effects. The most important symptomatic side effects are genitourinary, including vaginal infections and discomfort with urination, which may affect up to 30% of women and a lower proportion of men.^47,48 A less commonly reported adverse event is symptomatic hypotension, due to its effects on sodium depletion.³⁶ SGLT2 inhibitors are known to reduce the glucose available for energy utilization. Therefore, in the event of any extra demand for glucose, the SGLT2-inhibited body may not be able to maintain its homeostasis, thus leading to a ketogenic metabolic pathway.⁴⁹ The alteration of insulin to glucagon ratio also plays a role in the pathogenesis of euglycemic diabetic ketoacidosis (DKA).⁴⁹ The subsequent relative insulinopenia will manifest as ketonuria when challenged with stress, and high glucagon levels are associated with nausea, which may precipitate or worsen loss of appetite.^50
–52 This has led the U.S. Food and Drug Administration (FDA) to warn against this increased risk of euglycemic DKA associated with SGLT2 inhibitors.⁵³ There is currently an ongoing review, started by European Medicines Agency (EMA), trying to evaluate the risk of euglycemic DKA among T2D patients, utilizing dapagliflozin, canagliflozin, or empagliflozin.⁵⁴ In addition, recently there has been concern with SGLT2 inhibitors as increased risk of lower limb amputation (mostly affecting the toes) has been observed in patients taking canagliflozin, a medicine from this group, in two of the ongoing clinical trials, CANVAS and CANVAS-R, compared to patients taking placebo.^55–56

Conclusion

In conclusion, SGLT2 inhibitors were found in general to reduce serum uric acid levels in patients with T2DM. This of course is of importance especially that type 2 diabetes mellitus and hyperuricemia are interlinked, and this by itself increases risk for many other clinical disorders, among which are atherosclerosis and mortality. Given the associated clinical disorders with hyperuricemia, it is of course beneficial to lower serum uric acid in T2D patients, who are already at increased risk of microvascular and macrovascular disease, and therefore, given the beneficial effects that SGLT2 inhibitors were found to have on serum uric acid reduction, this would give them an advantage over other oral antidiabetic agents. As for the mechanism for this decrease in serum uric acid concentration, it is still not very clearly understood, but has been speculated to be possibly attributed to the inhibition of sodium-coupled uric acid reabsorption in the renal proximal tubule. There are encouraging data on SGLT2 inhibition, however, caution needs to be exercised as the duration of the available studies is limited in addition to the associated reported adverse events so far.

Key Points

1. Hyperuricemia is linked to many conditions such as hypertension, atherosclerosis, cardiovascular disease, and chronic kidney disease.

2. Hyperuricemia and type 2 diabetes mellitus are inter-related and linked together.

3. SGLT2 inhibitors were found in general to reduce serum uric acid levels in patients with T2DM.

4. The reduction in uric acid by SGLT2 inhibitors is possibly attributed to the inhibition of sodium-coupled uric acid reabsorption in the renal proximal tubule.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of JNJ-28431754 on Cardiovascular Outcomes in Adult Subjects with Type 2 Diabetes Mellitus: CANVAS—CANagliflozin cardioVascular Assessment Study (CANVAS). ClinicalTrials.gov Identifier: NCT01032629.

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A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with Type 2 Diabetes Mellitus. A Study of the Effects of Canagliflozin (JNJ-28431754) on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus (CANVAS-R). ClinicalTrials.gov Identifier: NCT01989754.