Narrative literature review of antidiabetic drugs’ effect on hyperuricemia: elaborating actual data and mechanisms

To optimize the treatment plan for patients with type 2 diabetes mellitus (T2DM) and hyperuricemia, this narrative literature review summarizes the effect of antidiabetic drugs on serum uric acid (SUA) levels using data from observational studies, prospective clinical trials, post hoc analyses, and meta-analyses. SUA is an independent risk factor for T2DM, and evidence has shown that patients with both gout and T2DM exhibit a mutually interdependent effect on higher incidences. We find that insulin and dipeptidyl peptidase 4 inhibitor (DPP-4i) except linagliptin could increase the SUA and other drugs including metformin, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), linagliptin, sodium–glucose cotransporter 2 inhibitors (SGLT2i), and α-glucosidase inhibitors have a reduction effect on SUA. We explain the mechanisms of different antidiabetic drugs above on SUA and analyze them compared with actual data. For sulfonylureas, meglitinides, and amylin analogs, the underlying mechanism remains unclear. We think the usage of linagliptin and SGLT2i is the most potentially effective treatment of patients with T2DM and hyperuricemia currently. Our review is a comprehensive summary of the effects of antidiabetic drugs on SUA, which includes actual data, the mechanisms of SUA regulation, and the usage rate of drugs.


Introduction
According to recent statistics, 529 million people will have diabetes worldwide in 2021, and the global agestandardized total diabetes prevalence will be 6.1% (1).Type 2 diabetes mellitus (T2DM) is the most frequent form of diabetes, accounting for 90-95% of all patients with diabetes (2), and the number of patients with T2DM is predicted to reach 439 million by 2030 (3).Based on the National Health and Nutrition Examination Survey (NHANES), a survey estimated mean serum uric acid (SUA) levels as 6.0 mg/dL in men and 4.8 mg/dL in women.Hyperuricemia was diagnosed according to the clinical diagnostic criteria, and the SUA level cutoff was 420 μmol/L for males and 360 μmol/L for females (4), and hyperuricemia prevalence rates were 20.2% and 20.0% in men and women, respectively (5).In China, the overall prevalence of hyperuricemia was 11.1% in 2015-2016 and 14.0% in 2018-2019, reflecting an alarming 3-year increase (6).Similar trends have also been observed in many other countries (7,8).The combined prevalence of diabetes among patients with hyperuricemia and gout was 19.00% and 17.80%, respectively (9).A crosssectional survey reported that SUA of patients with diabetes was 344.05 ± 90.89 μmol/L (10).Moreover, several studies have reported an association between hyperuricemia and adverse cardiovascular outcomes.Two of the main effects of hypertension, stroke and heart failure, have been linked to elevated SUA levels (11,12,13).A recent investigation confirmed that SUA levels are an independent predictor of cardiovascular mortality (14).Diabetes-related complications, particularly cardiovascular diseases (CVDs), are the leading causes of morbidity and mortality among patients with T2DM (15,16).Thus, to optimize the treatment plan, antidiabetic drugs that can reduce SUA levels are required to achieve comprehensive control in patients with T2DM and hyperuricemia.Therefore, this review aimed to summarize how antidiabetic drugs affect SUA levels and to recommend drug use for patients with T2DM.

Effect of antidiabetic drugs on SUA levels
Antidiabetic drugs can be classified into the following two groups based on their distinct effects in decreasing blood sugar: those that increase insulin secretion and those that rely on other mechanisms.The former drugs mainly include sulfonylureas, meglitinides, dipeptidyl peptidase-4 inhibitors (DPP-4i), whereas the latter drugs that lower blood sugar through other mechanisms mainly include metformin, thiazolidinediones (TZDs) α-glucosidase inhibitors, and sodium-glucose cotransporter 2 inhibitors (SGLT2i).The formation of serum uric acid (SUA) is the ribose 5-phosphate, a pentose derived from glycidic metabolism, converted to phosphoribosyl pyrophosphate (PRPP) and then to phosphoribosyl amine, that will be transformed into inosine monophosphate (IMP).From this intermediate compound derive adenosine monophosphate (AMP), guanosine monophosphate (GMP), and inosine which will be degraded into hypoxanthine and xanthine and finally into SUA.( 17) SUA exists majorly as urate, so humans cannot oxidize SUA to the more soluble compound allantoin due to the lack of uricase enzyme.Normally, most daily SUA degradation occurs via the kidneys (18).The kidneys eliminate approximately two-thirds, while the gastrointestinal tract eliminates one-third of the uric acid load.Almost all uric acid is filtered from glomeruli, while post-glomerular reabsorption and secretion regulate the amount of uric acid excretion.The proximal tubule is the site of uric acid reabsorption and secretion, and approximately 90% is reabsorbed into blood (19).Therefore, we analyzed the overall pharmacological effects from the actual data and the specific mechanisms provided ahead.

Insulin
Type 1 diabetes mellitus (T1DM) is an endocrine disorder in which pancreatic β cells do not secrete insulin, typically due to autoimmune destruction.Thus, insulin replacement is vital for its management (12).In T2DM, despite the availability of oral glucose-lowering drugs, insulin supplementation is often required to achieve favorable glucose control (13).A matched-cohort study (20) (n = 223 patients with gout and DM) showed that insulin therapy led to a significant mean increase in SUA levels (Table 1).Meanwhile, another investigation found that the baseline hyperinsulinemia follow-up hyperuricemia group had the greatest incidence risk of T2DM (27.9%) and that the follow-up SUA level had a 5.5% mediation effect on the insulin-T2DM connection.This phenomenon may be increased by renal urate reabsorption via the stimulation of GLUT9 (21) (encoded bySLC2A9), urate transporter 1 (URAT-1), and the sodium-dependent anion cotransporter in the proximal tubule (22) (Fig. 1).Furthermore, acute hyperinsulinemia during insulin clamp significantly decreases the urinary excretion of uric acid (UE UA ) (23).In conclusion, hyperinsulinemia causes hyperuricemia and insulin could increase SUA levels.

Metformin
Metformin is the most widely used and intensively studied drug recommended as a first-line therapy, accounting for 55.6% of patients with T2DM worldwide (24).A survey of the treatment patterns of oral drug users in China shows that 53.7% of patients with T2DM used metformin.As shown by an investigation, SUA levels were higher in experiments (n = 64 patients with T2DM) than those in controls (n = 47 patients with T2DM).Similarly, SUA levels increased after 18 weeks of metformin treatment (n = 16 patients with T2DM) (Table 1) (25).Nevertheless, a 1996 trial (n = 76 patients with T2DM) demonstrated that adding low-dose metformin to sulfonylurea treatment led to significant improvements in blood lipids and blood sugar, as well as a considerable reduction in SUA and body weight (26).In another trial, 26 patients with gout and insulin resistance (IR) were treated with metformin.Follow-up after 6 months later revealed that 12 patients had significantly lower SUA levels and 11 had normal SUA levels (27).The same result was reported in that the incidence of hyperuricemia significantly decreased (n = 10 patients with T2DM) although SUA levels did not significantly decrease (28).In addition to reducing SUA levels through weight loss (Fig. 1), metformin may also have a notable impact on appetite.This resulted in a low-purine diet and helped control SUA levels.More importantly, by reducing IR, which minimizes the risk of gout (29), metformin may lower SUA synthesis, and increase SUA excretion.Metformin also promoted the phosphorylation of AMPactivated protein kinase (AMPK) and restored insulinstimulated glucose uptake in hyperuricemia-induced IR cardiomyocytes.It could delay the development of atherosclerosis and inflammation through this effect (30).Metformin enhances IR and glucose tolerance in a rat model of acute hyperuricemia.Additionally, it is associated with the increased phosphorylation of protein kinase B, AMPK, and GLUT4 in the myocardial https://doi.org/10.1530/EC-24-0070Z Liu et al. tissues (31,32).Moreover, some studies have indicated that a reduction in BMI, SUA levels at baseline, and metformin therapy are all independent predictors of a decline in SUA levels.However, the physiological mechanisms that affect SUA levels remain unclear.

Thiazolidinediones
The guideline indicated (34) that thiazolidinediones (TZDs) mainly reduce blood sugar by increasing target cell sensitivity.Most likely because of safety issues, use of TZDs has decreased (34).Pioglitazone and rosiglitazone are the two main TZDs.After 12 weeks of pioglitazone treatment (n = 68 patients with T2DM), SUA changes depended on baseline SUA levels.In particular, the higher the baseline SUA level, the greater the decrease.
When the baseline SUA level was greater than 6.0 mg/dL, the SUA levels decreased (Table 1), but did not change in individuals whose baseline SUA was between 3.8 and 5.9 mg/dL (35).Notably, 24-week pioglitazone treatment reduced the acid load in the kidneys of 36 patients with idiopathic uric acid nephrolithiasis, resulting in a significantly greater urine pH (36).This leads to enhanced urinary uric acid excretion and, consequently, reduced SUA levels.Similar results have been reported previously (36).Rosiglitazone treatment (n = 16 patients with T2DM) had similar effects (25).Animal experiments have shown that TZD drugs indirectly regulate the expression of UAT and URAT1 mRNA by improving IR and reducing blood insulin levels, thereby reducing hyperuricemia caused by hyperinsulinemia.In rats, the brush-border membrane Na+/H+ exchanger 3 (NHE3) had lower expression and activity, which is the principal mediator of proximal tubule ammonium excretion, had lower expression and activity (37).NHE3 increases SGLT2 expression Pioglitazone modestly, but significantly, increased urine pH, the fraction of net acid excretion carried by NH 4+ (NH4+/NAE) and the ammoniagenic response (Δ NH 4+ /creatinine) after an acid load (Fig. 1).TZDs can reduce SUA levels (38).Pioglitazone also reduced net acid excretion and increased urine pH (5.37-5.59), the proportion of net acid excreted as ammonium, and ammonium excretion in response to an acute acid load (36).

Glucagon-like peptide-1 receptor agonists
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exert hypoglycemic effects by activating the GLP-1 receptor in a glucose concentration-dependent manner, stimulating insulin secretion and inhibiting glucagon secretion, while increasing glucose uptake in muscle and adipose tissue and inhibiting liver glucose production, gastric emptying, and appetite.In the USA, a survey reported that GLP-1 RA use increased by 8.5% in 2019 (39).SUA levels remained unchanged (  lixisenatide, liraglutide, and reference group) (41).In contrast to previous findings, the analysis (42) showed that, based on 20 studies, GLP-1 RA might considerably lower the SUA levels by 0.34 mg/dL.Even when analyzed in subgroups of clinical trials and observational studies, the reductions remained significant.In T2DM patients and overweight healthy men, immediate exenatide infusion raised UE UA , most likely through blocking Na+/H+-exchanger type 3 in the renal proximal tubule (41).In addition, GLP-1 RA has been shown to suppress NHE3 activity (Fig. 1), a major route of fluid, NaCl, and bicarbonate reabsorption located in the apical membrane of the proximal tubule and thick ascending limb of Henle (43).Additionally, it improves cardiovascular health by lowering blood pressure and thus the risk of hypertension (44,45).Accordingly, the administration of GLP-1 RAs can significantly reduce SUA levels (42).
It catalyzes the oxidation of inosine to hypoxanthine, xanthine, and uric acid (Fig. 1).Therefore, linagliptin reduces SUA levels in patients with T2DM (50).The mechanism of DPP-4i except linagliptin increasing SUA levels remains unclear.Under certain conditions, linagliptin is better than other DPP-4i medications for patients with T2DM and hyperuricemia.

Sodium-glucose cotransporter 2 inhibitors
SGLT2i is a novel oral antidiabetic drug that has received considerable attention in recent years.It can reduce the renal glucose threshold, prevent the kidneys from reabsorbing glucose, and promote the excretion of sugar in the urine.In the USA, the use of SGLT2i has increased from 4.3% in 2015 to 18.5% in 2019 (39).SGLT2i also prevents the development of gout (51).Gout incidence was shown to be 64% lower in patients taking SGLT2i compared to those taking GLP-1 RA (4.9 vs 7.8 events/1000 patients/year) based on a U.S. nationwide insurance database encompassing 295,907 patients with T2DM ( 52).An interview revealed The mechanisms of the effect of antidiabetic drugs on SUA.

α-Glucosidase inhibitors
α-Glucosidase inhibitors are appropriate for patients with elevated postprandial (in diets that is primarily constituted of carbs) blood sugar because they lower postprandial blood sugar by preventing the upper section of the small intestine from absorbing carbohydrates.Owing to its ease of administration and high tolerance, it can be used as an adjunct to lifestyle modification for T2DM prevention (66).Glucosidase accounted for 35.9% in the OAD treatment.This effect was observed in 18% of monotherapies had this effect (67).One study (68) measured SUA and UEUA levels in six healthy participants (Table 1) before and after administering sucrose, with and without co-administration of acarbose.Sucrose increased the SUA levels by 10% (P < 0.01).However, the uric acid excretion and fractional clearance remained unaltered.Sucrose and acarbose co-administration also increased UEUA, but less than sucrose alone, without changes in urinary excretion and fractional clearance of uric acid (68).Sucrose is converted into fructose and glucose, which can increase SUA levels through increased purine degradation and/or decreased UEUA.By preventing sucrose absorption, acarbose can reduce the SUA increase caused by sucrose consumption (Fig. 1) (68,69).In summary, acarbose alleviates the increase in the plasma concentration of uric acid induced by sucrose by inhibiting its absorption (68,69).

Sulfonylureas
Sulfonylureas are classified as insulin-secreting agents.Their primary pharmacological function was to increase the amount of insulin secreted by pancreatic islets β cells, hence lowering blood sugar and boosting insulin levels.Sulfonylureas constitute 7.7% of firstline therapies worldwide (24,67).A study (70) (n = 29 patients with T2DM) with gliclazide reported no change in SUA levels.Similar results have been reported in another study (71).At present, the mechanism is unclear, and there is no evidence suggesting a connection between sulfonylureas and uric acid.

Other drugs
There have been no relevant studies on the mechanisms or clinical data related to SUA levels for meglitinides and amylin analogs.

Discussion
Notably, a part of patients with T2DM use more than two antidiabetic drugs to treat.Since the usage of in requires different renal functions which could affect SUA metabolism, we should conduct a more detailed and comprehensive analysis of such clinical results.It should be considered as a confounding factor in Table 1.Moreover, some studies (72,73) suggest SUA levels decrease with increasing blood glucose levels.This is mainly attributed to the compensatory effect of the kidney via ultrafiltration.So in the listed data which come from all long-term studies, blood glucose is stable.
Based on it, this compensatory effect will not affect the overall effect.

Conclusion
Elevated SUA levels have been implicated in T2DM development and in CVD in patients with T2DM.SUA levels have been recognized as a predictor of DM development.Numerous pathways associated with lipid and glucose dysmetabolism, such as insulin resistance, oxidative stress, and inflammation, have been implicated in these relationships.Moreover, patients with DM with micro-or macrovascular complications had higher SUA levels than those without complications.SUA is the main component of renal stones in patients with T2DM.In light of these intricate and multifaceted interactions, further research are required to delineate the clinical implications of SUA measurements in the management and follow-up of patients with DM.In this literature review, we find that insulin and DPP-4i, with the exception of linagliptin, increases SUA levels.We think the usage of linagliptin and SGLT2i is the potentially effective treatment of patients with T2DM and hyperuricemia currently, while more RCT researches are required for a recommendation.Metformin, TZDs, GLP-1 RAs, and α-glucosidase inhibitors could decrease SUA.However, whether they can be used as potentially recommended drugs still requires further research for the treatment of patients with T2DM and hyperuricemia.

Table 1
Effect of antidiabetic drugs on SUA.

Table 1
(40)ter 52 weeks of exenatide treatment (n = 36 patients with T2DM and overweight)(40).A similar outcome was observed in a post hoc analysis of four clinical trials (exenatide,