Effect of Intestinal Flora on Hyperuricemia-Induced Chronic Kidney Injury in Type 2 Diabetic Patients and the Therapeutic Mechanism of New Anti-Diabetic Prescription Medications

Figures & data

Table 1 Summary of Epidemiological Studies

Author, Year	Methods	Result and Main Findings
Choi BG, Kim DJ, Baek MJ, Ryu YG, Kim SW, Lee MW et al 2018^Citation7	Meta-analysis studies: a total of 10,505 consecutive patients who visited the cardiovascular center of Korea University Guro Hospital (KUGH) from January 2004 to February 2014 were retrospectively enrolled using the electronic database of KUGH.((hyperuricemia group, n=1138; normal-range group, n=9367)	In the Cox-proportional hazard ratio analysis, when uric acid concentration increased by 1 mg/dL, the risks of T2DM increased by 13.8% (6.1% to 22.1%, p< 0.001), in crude population and increased by 18.7% [5.0% to 34.2%, p=0.006] in matched population. Hyperuricemia is a risk factor for type 2 diabetes
Su H, Liu T, Li Y, Fan Y, Wang B, Liu M et al 2012^Citation8	This study was based on the annual health check dataset Health Management Center of Tianjin Medical University General Hospital. A total of 9471 participants were included in the analysis, and they were followed up for physical examination.	Elevated uric acid was associated with a 36% (95% CI 1.01−1.85) increased risk of diabetes.Decreased uric acid was associated with a 24% (95% CI 0.63−0.98) reduction in the risk of diabetes. There is a close relationship between hyperuricemia and type 2 diabetes, and hyperuricemia is a risk factor for type 2 diabetes.
Krishnan E, Pandya BJ, Chung L, Hariri A et al 2012^Citation9	Using Cox proportional hazards regression models, the authors analyzed 15-year follow-up data on 5012 persons in 4 US cities who were aged 18–30 years and diabetes-free at the time of enrollment.	The hazard ratios for diabetes, insulin resistance, and prediabetes in patients with hyperuricemia were 1.87 (95% confidence interval (CI): 1.33, 2.62), 1.36 (95% CI: 1.23, 1.51), and 1.25 (95% CI: 1.04, 1.52), respectively. Hyperuricemia in the mid twenties is an independent marker for predicting diabetes and prediabetes among young adults in the subsequent 15 years.
Kodama S, Saito K, Yachi Y, Asumi M, Sugawara A, Totsuka K et al 2009^Citation10	A cohort study of 2518 patients with type 2 diabetes mellitus was enrolled and registered in the Japan Diabetes Registry. Cox proportional hazards model was used to analyze the independent association between serum uric acid and the occurrence or progression of diabetic nephropathy.	Uric acid levels are associated with the progression of nephropathy. After multivariate adjustment, the hazard ratio was 2.17 (95% confidence interval 1.15 to 4.08; p = 0.016), 3.04 (95% CI 1.67–5.53; p < 0.001) and 3.56 (95% CI 1.83–6.93; P < 0.0011). In patients with type 2 diabetes, hyperuricemia is closely related to the progression of diabetic nephropathy
Zeng Y, Guo M, Fang X, Teng F, Tan X, Li X et al 2021^Citation11	Meta regression and subgroup analysis were used to identify possible sources of heterogeneity. A total of 32 eligible studies were included, including 42,062 participants.	Advanced CKD was associated with a 67.9 μmol/L (95% CI: 52.7, 83.2; P < 0.01) increase in TMAO concentration, and subjects with high concentrations of TMAO had a 12.9 mL/(min·1.73 m2) (95% CI: −16.6, −9.14; P < 0.01) decrease in glomerular filtration rate (GFR). To reveal a negative correlation between circulating TMAO concentration and renal function.
Obermayr RP, Temml C, Gutjahr G et al 2008^Citation12	In this study, data from 21,475 healthy volunteers who were followed prospectively for a median of 7 yr were analyzed to examine the association between uric acid level and incident kidney disease.	A slightly elevated uric acid level (7.0 to 8.9 mg/dl) was associated with a nearly doubled risk for incident kidney disease (OR 1.74; 95% CI 1.45 to 2.09), and an elevated uric acid (> or =9.0 mg/dl) was associated with a tripled risk (OR 3.12; 95% CI 2.29 to 4.25). Elevated uric acid levels alone increase the risk of new kidney disease.
Xu X, Hu J, Song N, Chen R et al 2017^Citation13	This randomized effects meta-analysis analyzed 18 cohort studies involving 75,200 patients. Hyperuricemia is defined as SUA levels greater than 360–420 μmol/L (6–7 mg/dl).	The hyperuricemia group significantly exerted a higher risk of AKI compared to the controls (OR 2.24, 95% CI 1.76–2.86, p < 0.01). Furthermore, there is less difference of the pooled rate of AKI after cardiac surgery between hyperuricemia and control group (34.3% vs 29.7%, OR 1.24, 95% CI 0.96–1.60, p = 0.10), while the rates after PCI were much higher in hyperuricemia group than that in control group (16.0% vs 5.3%, OR 3.24, 95% CI 1.93–5.45, p < 0.01). Elevated SUA level showed an increased risk for AKI in patients
Zoppini G, Targher G, Chonchol M et al 2012^Citation14	A total of 1449 type 2 diabetic patients with normal renal function and without overt proteinuria were enrolled and followed for a 5-year incidence of CKD.	During 5 years of follow-up, 194 patients developed incident CKD. The cumulative incidence of CKD in the hyperuricemia group was significantly higher than that in the non-hyperuricemia group (29.5% vs 11.4%, P < 0.001). The risk of CKD in patients with hyperuricemia was increased by about 2 times (OR 2.55 95% CI 1.71–3.85 P < 0.001). In type 2 diabetic individuals with preserved kidney function, hyperuricemia seems to be an independent risk factor for the development of incident CKD.
Li CX, Liang S, Gao L et al 2021^Citation15	In 14 studies, including 3,157,259 patients, the primary outcome was MACE and all-cause mortality (ACM). Secondary outcomes were hospitalization for heart failure (HHF), atrial fibrillation (AF), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), unstable angina (UA), heart failure (HF). Odds ratio (OR) with 95% CIs were pooled across trials, and cardiovascular outcomes were stratified by baseline incidence of cardiovascular disease (CVD), usage rate of cardiovascular benefit drug, follow-up period and region.	SGLT-2i reduced MACE (OR, 0.71; 95% CI, 0.67 0.75, P < 0.001) and ACM (OR, 0.53; 95% CI, 0.49 0.57, P < 0.001). The SGLT - 2 I had significantly lowered the risk of HHF (OR, 0.56; 95% CI 0.46,0.68, P<0.001), MI (OR, 0.77; 95% CI 0.73,0.81, P<0.001), stroke (OR, 0.75; 95% CI 0.72,0.78, P<0.001), CVM (OR, 0.58; 95% CI, 0.49 0.69, P < 0.001) and HF (OR, 0.56; 95% CI 0.48,0.67, P<0.001), but there was no benefit from UA or AF. SGLT-2i significantly reduced the risk of severe hypoglycemia (OR, 0.78; 95% CI, 0.69 0.90, P < 0.001) and the lower limb amputation (OR, 0.83; 95% CI, 0.71 0.98, P < 0.001), but it may happens the risk of diabetic ketoacidosis.
David Fitchett, Silvio E Inzucchi et al 2019^Citation16	The participants were randomly divided into two groups. Patients received empagliflozin 10 mg, empagliflozin 25 mg, or placebo.	Of 7020 patients who received the study drug, 65% had a prior myocardial infarction or stroke, and 12%, 40%, 30%, and 18% were at low, intermediate, high, and highest estimated cardiovascular risk according to TIMI Risk Score for Secondary Prevention (≤2, 3, 4, and ≥5 points, respectively). In the placebo group, 3-point MACE occurred during the trial in 7.3%, 9.4%, 12.6%, and 20.6% of patients at low, intermediate, high, and highest estimated baseline risk, respectively. Empagliflozin can significantly reduce the incidence of cardiovascular events and heart failure in hospitalized patients
Zhao Y, Xu L, Tian D, Xia P, Zheng H, Wang L et al 2018^Citation17	A total of 62 Studies involving34941patients were included. Studies meeting the following criteria were included: (1) population: patients withT2DM; (2) intervention: SGLT2 inhibitor monotherapy or as add-on to other hypoglycemic therapy; (3) comparison: active or placebo control or standard care; (4) outcome: serum uric acid changes from baseline; and (5) design: randomized controlled trials (RCTs); (6) follow-up duration at least 4 weeks. We excluded observational studies, pooled-analyses, trials that were not randomized, and trials with no control.	SGLT2 inhibitors significantly decreased SUA levels compared with control (Total WMD –37.73 μmol/L, 95% CI [–40.51, –34.95], empagliflozin WMD –45.83 μmol/L, 95% CI [–53.03, –38.63], canagliflozin WMD –41.22 μmol/L, 95% CI [–45.03, –37.42], dapagliflozin WMD –36.99 μmol/L, 95% CI [–41.73, –32.25], luseogliflozin WMD –28.20 μmol/L, 95% CI[–34.73, –21.67], tofogliflozin WMD –21.48 μmol/L, 95% CI [–35.15, –7.81], and pragliflozin WMD –17.40 μmol/L, 95% CI [–23.78, –11.02]). The effect of SGLT2 inhibitors on uric acid reduction in patients with type 2 diabetes mellitus was systematically analyzed. After SLGT2 inhibition, SUA decreased by 17.4–45.8 μmol/L.
Hussain M, Elahi A, Hussain A, Iqbal J et al 2021^Citation18	In this double-blind randomized controlled trial, 70 patients with type 2 diabetes and elevated SUA levels were assigned to two treatment groups. Patients in group A received SGLT-2 inhibitors tablet dapagliflozin 5 mg to 10 mg and empagliflozin 10 mg to 25 mg. Group B patients received OADs such as glimepiride, metformin, sitagliptin, gliclazide, and glibenclamide as monotherapy or combination therapy.	We noted a significant reduction of mean SUA levels in the SGLT-2 inhibitor group from 7.5 ± 2.5 to 6.3 ± 0.8 mg/dl versus comparator group from 7.1 ± 1.8 to 6.8 ± 2.2 mg/dl (p = 0.001). Mean body weight was significantly reduced in the SGLT-2 group from 82 ± 10.4 to 78 ± 12.5 kg versus comparator group from 78 ± 13.2 to 79.2 ± 9.7 kg (p = 0.001). Similarly, the mean BMI of patients in the SGLT-2 group was significantly reduced from 25.7 ± 3.2 to 24.2 ± 3.2 kg/m2 versus comparator group from 27.5 ± 4.2 to 28 ± 3.6 kg/m2 (p = 0.002). SGLT-2 inhibitors have a strong potential to decrease SUA levels in patients with type 2 diabetes.
Najafi S, Bahrami M et al 2022^Citation19	Randomized controlled trials, observational studies, uncontrolled trials, and conference abstracts were included. Studies with insufficient data, unrelated types of studies, and studies with less than 1 month of follow-up were excluded. Finally, in the 1004 study to determine 17 conform to the conditions included in this system were summarized.	Pre- to post-administration analysis of GLP-1 RA effects on SUA demonstrated that GLP-1 RAs could significantly reduce SUA concentration (difference in means −0.341, SE 0.063, P value <0.001). However, when compared to placebo, GLP-1RAs did not perform any better in lowering SUA concentration (difference in means −0.455, SE 0.259, P value 0.079). Surprisingly, the active controls, which included insulin, metformin, sodium-glucose co-transporter 2 (SGLT-2) inhibitors and dipeptidyl-peptidase 4 inhibitors, did outperform GLP-1 RAs in reducing SUA concentration (difference in means 0.250, SE 0.038, P value <0.001).Administration of GLP-1 RAs can result in a significant reduction in SUA concentration.
Zhao Y, Wang H, Ke D et al 2021^Citation20	442 patients with type 2 diabetes mellitus (T2DM) were randomized to add-on sitagliptin or usual care. According to the serum uric acid level of all study population in the preface study, they were divided into hyperuricemia subgroup (n = 104) and non-hyperuricemia subgroup (n = 331).	In the hyperuricemia subgroup, compared with the conventional therapy group, the changes in the mean internal carotid artery (ICA)-IMT and max ICA-IMT at 24 months were significantly lower in the sitagliptin group [−0.233 mm, 95% confidence interval (CI) (−0.419 to 0.046), p = 0.015 and −0.325 mm, 95% CI (−0.583 to −0.068), p = 0.014], although there was no significant difference in the common carotid artery CIMT. The results of our analysis indicated that sitagliptin attenuated the progression of CIMT than conventional therapy in T2DM and hyperuricemia patients.

Figure 1 Literature inclusion process for the study.

Abbreviations: DN, diabetic nephropathy; VIP, vip database; CNKI, China national knowledge infrastructure; SGLT-2, Sodium-glucose cotransporter 2; GLP-1, glucagon-like peptide-1; DPP-4, Dipeptidyl peptidase-4; MRA, mineralocorticoid receptor antagonist; GKA, glucokinase antagonist.

Figure 2 The mechanism of aggravated kidney injury in patients with type 2 diabetes mellitus and hyperuricemia.

Notes: These novel antidiabetic medicines, including SGLT2 inhibitors, GLP-1 receptor agonists, DDP-4 inhibitor, Glucokinase enzyme activator (GK agonist), and mineralocorticoid receptor antagonist (MRA), may have a multifaceted approach to treating hyperuricemia-induced kidney impairment in diabetic patients; nevertheless, additional study is required to establish their efficacy and comprehend their specific mechanisms.

Abbreviations: T2D, type 2 diabetes; HUA, hyperuricemia; PYY, peptide YY; RAAS, renin-angiotensin-aldosterone system; SCFA, Short-chain fatty acids; TMAO, trimethylamine N-oxide; GLP-1, glucagon-like peptide- 1; GK, glucokinase; TNF-a, tumor necrosis factor-α; IL-6, interleukin-6; SGLT-2i, Sodium-glucose cotransporter 2 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonists; DPP-4i, Dipeptidyl peptidase-4 inhibitors; MRA, mineralocorticoid receptor antagonist.

Figure 3 The therapeutic mechanism of new antidiabetic medicines on hyperuricemia-induced chronic kidney injury in the patients with T2D.

Notes: It is unclear whether the GKA and MRA could contribute to the reduction of uric acid. SGLT2i, sodium-glucose cotransporter 2 inhibitors, GLP-1RA, glucagon like peptide-1 receptor agonist, DDP-4i, DDP-4 inhibitor, GKA, glucokinase activator, MRA, mineralocorticoid antagonist.

Abbreviations: SGLT-2i, Sodium-glucose cotransporter 2 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonists; DPP-4i, Dipeptidyl peptidase-4 inhibitors; MRA, mineralocorticoid receptor antagonist; GKA, glucokinase antagonist.

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