The Effects of SGLT2 Inhibitors on Cardiovascular Outcome and Renal Disease in Type 2 Diabetic Patients Established Cardiovascular Disease and Moderate Chronic Kidney Disease: Systematic Review and Meta Analysis

International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 The Effects of SGLT2 Inhibitors on Cardiovascular Outcome and Renal Disease in Type 2 Diabetic Patients Established Cardiovascular Disease and Moderate Chronic Kidney Disease: Systematic Review and Meta Analysis Vinodhini Selvaraj1*, Viha Vaishalee2 1Junior Doctor in Sri Lalithambikai Medical College & Hospital, India 2Pathologist Trainee at Sri Ramachandra Medical College & Hospital, India Citation: Vinodhini Selvaraj, Viha Vaishalee. The Effects of SGLT2 Inhibitors on Cardiovascular Outcome and Renal Disease in Type 2 Diabetic Patients Established Cardiovascular Disease and Moderate Chronic Kidney Disease: Systematic Review and Meta Analysis. 2025;4(11):1-18. Received Date: 05 November 2025; Accepted Date: 08 November 2025; Published Date: 10 November 2025 *Corresponding author: Vinodhini Selvaraj, Junior Doctor in Sri Lalithambikai Medical College & Hospital, India Copyright: © Vinodhini Selvaraj, Open Access 2025. This article, published in Int Clinc Med Case Rep Jour (ICMCRJ) (Attribution 4.0 International), as described by http://creativecommons.org/licenses/by/4.0/ ABSTRACT Background: Diabetes patients are at high risk for mortality due to cardiorenal cause. Although multiple pharmacological drugs are available but SGLT2 (sodium glucose transporter 2) inhibitors efficacy in reducing incidence of cardiovascular and renal outcome in diabetic patients with both CKD (chronic kidney disease) and established cardiovascular disease are not clearly demonstrated. This systematic review with meta-analysis will address this with following studies. Method: Studies for this meta-analysis was been searched with PubMed, Cochrane from 2010 till 2023. Studies were screened in accordance with PRISMA updated version. Statistical analysis was done in JAMOVI software. Risk ratio with 95%CI with fixed model effect was done to find the effects of SGLT2inhibitors across various studies in reducing the incidence of cardiorenal outcome. Results: In total, 8 studies were been included for this meta-analysis. Overall, 49,034 patients were been included; 27,069 participated in treatment group and 21,965 participated in control group. Across 8 studies, mean age is 63, mean follow-up was 2.6 years. overall, there was significant reduction in CV outcome with fixed effect model -0.1482, p = 0.0008 (95% CI: -0.2345 to -0.0618). In addition, SGLT2 inhibitors has reduced risk of all cause death -0.1203 (95% CI: -0.1869 to -0.0536), hospitalization for heart failure -0.3851 (95% CI: - 0.4623 to -0.3078) and composite renal outcome -0.4170 (95% CI: -0.5347 to -0.2994) with minimal risk of heterogeneity. Conclusion: The result of this systematic review suggests that SGLT2 inhibitors have significant efficacy in reducing the incident of cardiovascular death and composite renal outcome which proves the protective role of drug in both established cardiovascular disease and moderate CKD patients in type 2 diabetes. Keyword: Estimated glomerular filtration rate; Albuminuria; Cardiorenal outcome; Heart failure; Composite renal outcome International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 BACKGROUND Type 2 diabetes is one of the common metabolic disorder prevalent worldwide. It is characterized by elevated blood glucose level, impaired insulin secretion and high insulin resistance, which is diagnosed as per WHO by HbA1C ≥6.5% or fasting blood glucose ≥7 mmol/ liter [1]. As per international diabetes federation 12.8%(4.8million) of diabetic patients belong to age group 20-79 years old, which could increase to 15.7% by 2045(37). Diabetes is a serious chronic disease associated with substantial risk for multiple microvascular and macrovascular complications. Particularly, macrovascular complication like Myocardial infarction, stroke, end stage kidney disease .4.2 million death are happening in age group of 20 to 79 years old, which is attributed to.11.3% of death worldwide are due to diabetes particularly below 60 years old [2]. More premature death happening in diabetes patient, which are due to diabetic complication rather than diabetes alone[3]. Elevated blood glucose is associated with 15% of all cause death due to cardiovascular disease, renal disease and diabetes [4]. Therefore, essential part in diabetes is to prevent such premature death in diabetes by early detection of type 2 Diabetes or diabetic complications. The presence of diabetes and cardiovascular disease has shown to increase the risk of mortality [5]. The characteristics metabolic impairment in diabetic patients are hyperglycemia , excessive free fatty acid, insulin resistance ,which end up in reduced nitric Oxide production and activation of reninangiotensin system ,leads to endothelial dysfunction [6] .This contributes to hypertension or arterial stiffness, which partially explain the risk of vascular events in diabetic patients[7] .The risk of heart failure(HF) in diabetic patients are multifactorial ,few studies shown that heart failure are independent of coronary artery disease and studies are lacking in appropriate pharmacological intervention to tackle cardiovascular outcome in diabetic patients[8,9]. Hence, drugs determined for diabetic treatment should not only focus on diabetes but also to prevent cardiac mortality in diabetic patients [10,11]. However, there are also few studies concerned that intensive glucose lowering agents or specific group of anti-diabetic agents are associated with adverse cardiac outcome [12], which emphasize the importance of evaluating the cardiovascular safety of anti-diabetic medication [13]. SGLT2 inhibitors are becoming popular as they have shown some benefit in diabetic patients with cardiovascular disease risk. SGLT2 inhibitors are dapagliflozin, empagliflozin, ertugliflozin, Sota gliflozin, canagliflozin. These drugs act by reducing resorption of glucose in kidney proximal tubules, which leads to excessive excretion of glucose in urine [5]. This mechanism of action is independent of insulin .SGLT2 inhibitors has shown significant reduction in BP and weight, which is considered to be vital action of SGLT2 inhibitors in reducing the vascular events in diabetes [13,14]. In addition, reduction in intraglomerular pressure, reducing albuminuria are proving the protective mechanism against cardiorenal outcome [15]. But still studies are lacking to prove protective effect of SGLT2 inhibitors on diabetic patients with both established cardiovascular disease and moderate chronic kidney disease. In addition, SGLT2 inhibitors were reluctant to use among type 2 diabetic patients with chronic kidney disease patients and older patients due to their adverse events on renal system. But , in recent time there are multiple studies involving chronic kidney disease with type 2 diabetes are treated with SGLT2 inhibitors and long-term follow-up done, which has shown insignificant progression of CKD and similar beneficial effect as seen in patients without CKD on composite renal outcome like renal death, new onset of end stage kidney disease (ESKD) ,≥40% of eGFR reduction [16-18]. Few studies International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 has shown similar effects on cardiovascular outcome in both younger and older patients treated with SGLT2 inhibitors for reducing cardiovascular outcome. As the effect of SGLT2 inhibitors are on renal proximal tubule, they are directly dependent on glomerular filtration rate. Therefore, their efficacy was assumed to be reduced with reducing eGFR rate. Recently systematic review with meta-analysis [19] was done using various SGLT2inhibitors on cardiorenal outcome irrespective of diabetes. Totally 13trial were selected for analysis, 82.7% participants were diabetic and 17.3% were non-diabetic. Results showed SGLT2 inhibitors reduced progression of renal disease by 37%, reduced risk of acute kidney injury by 23%, reduced risk if cardiovascular death or hospitalization for heart failure by 23% but risk of non-cardiac death rate was not significantly reduced. All the outcome were similar in diabetic as well as non-diabetic patients. Results were produced irrespective of baseline eGFR. This analysis has included participants with chronic kidney disease. Therefore, they have proved better cardiorenal risk reduction even in presence of chronic kidney disease patients irrespective of diabetes. The current meta-analysis will evaluate similar effect in presence of diabetes and moderate chronic kidney disease. Among SGLT2 inhibitors, empagliflozin was the first drug approved to use in patients with history of cardiovascular disease. A study by Anker et al., 2021 [20] has used empagliflozin in patients with NYHA class 2-4 stage of heart failure with an ejection fraction >40% has shown reduction in rate of incidence of cardiac death and hospitalization for heart failure in treatment group. To our best of knowledge, there were no systematic review with meta-analysis were conducted to evaluate the efficacy of SGLT2 inhibitors in reducing cardiorenal outcome like cardiac death, all cause death, hospitalize for heart failure or composite renal outcome among type 2 diabetic patients with both risk factors like established cardiovascular disease and moderate chronic kidney disease. Therefore, this systematic review with meta-analysis will address the risk reduction caused by this drug on cardiorenal outcome in type 2 diabetes patients with both established cardiovascular disease and moderate CKD patients. Through such meta-analysis results, we could suggest recommendations on individualizing the treatment plan based on patients profile in type 2 diabetic patients with risk factors. METHODOLOGY The current systematic review with meta-analysis has followed PRISMA guideline [21] Data source Two electronic database (Cochrane, PubMed) was used to search clinical trials published in English from the year 2010 till July 2023. Data search done on 28/07/2023 with advanced keyword search (((((((cardiorenal outcome)) AND (SGLT2inhibitor)) OR (empagliflozin)) OR (dapagliflozin)) OR (ertugliflozin)) OR (canagliflozin)) OR (Sota gliflozin) AND (type 2diabetes mellitus) OR (non-insulin dependent diabetes) OR (Diabetes mellitus) in different combination PubMed. In Cochrane diabetes mellitus" in All Text AND SGLT2inhibiotrs in Title Abstract Keyword AND cardiorenal outcome in Title Abstract Keyword – (Word variations have been searched). Filters used which include only Randomized clinical trial conducted between 2010 to July 2023, with full free text, published in English, only studies conducted in humans. International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 Study selection Inclusion criteria 1) Only randomized controlled trials are included 2) Studies involving human subjects 3) Studies examining SGLT2inhibitors with placebo are involved 4) ≥18years with T2DM defined as per WHO characterized by HbA1c ≥6.5% or fasting blood glucose ≥7 mmol/liter [22]. 5) Study Patient should has established cardiovascular disease or high risk for cardiac outcome (1) and should have chronic kidney disease. 6) Study duration should be more than 6month 7) Studies outcome should explore on cardiorenal outcome. Exclusion criteria 1) Exclude studies if language other than English 2) Exclude case studies, case series 3) Patients with type 1 diabetes, Gestational diabetes, severe chronic kidney disease <30ml /min/1.73m² are excluded. 4) Sub analysis of involved trials and duplicate studies are excluded 5) Studies comparing other drugs except for placebo will be excluded. Quality assessment Each study’s methodology was carefully assessed using JADAD score [23]. It is a 5-point scale for measuring quality of randomized trials .1) randomization is mentioned 2) method of randomization is appropriate 3) blinding mentioned 4) method of blinding is appropriate 5) outcome of all participant including number of dropout and reason for dropouts are mentioned. Score of 3or more indicate high quality studies [4,11], which denote that we are very confident that the true effect is close to the estimate effect. Data extraction From all the selected studies, detailed information on characteristics, study methodology, intervention, control group and follow-up period were been collected. In patient characteristics, mean age, total number of participants in control and intervention group, follow-up period, duration of diabetes disease and mean HbA1C levels were been noted across studies. In terms of cardiorenal risk factors like [25], number of participants with established cardiovascular disease, heart failure, NTproBNP level, angina, hypertension, chronic kidney disease status, albuminuria, estimated glomerular filtration rate (eGFR) are been compared across studies. Most of the studies had explored outcome like cardiac death, all cause death, hospitalization of heart failure, composite renal outcome, hence these 4 outcomes [1,31,25-30] were used in this analysis for better comparison and to find appropriate results pertaining to it. Other outcome like non-fatal myocardial infarction, non-fatal International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 stroke, silent MI, different albuminuria level was not broadly studied in most of studies therefore those outcomes were been rejected from analysis. Moreover, they are not associated with more mortality [10,12] when compared to 4 principal outcomes selected for this Meta analysis. Composite renal outcome is defined as sustained reduction of >40% eGFR calculated by means of chronic kidney disease epidemiology collaboration equation to <60ml /min / 1.73m² of body surface area, new end stage renal disease, or death from renal or cardiovascular causes [7]. Data analysis Each study will be screened for above mentioned inclusion, exclusion criteria, outcome. Meta analysis is conducted using JAMOVI software. Initially heterogeneity is assessed by Q statistic and I² test (18). I² test range from 0-100%; where <25% is minimal risk for heterogeneity, 25-75% with moderate amount of risk for heterogeneity and >75% are associated with high risk for heterogeneity. If heterogeneity is found to be high across studies, then sub group analysis will be performed to detect true effect value. Separate meta-analysis for each outcome (Cardiovascular death, all cause death, hospitalization for heart failure, composite renal outcome) were been done using Fixed effect method if most of results were consistent or random effect model if heterogeneity is high and forest plot with 95%CI are reported. P<0.05 are considered significant difference beyond chance in heterogeneity test. Publication bias was reported using Egger’s regression test [6] and funnel plot presented. RESULTS Study selection Systematic search strategy was used in accordance with PRISMA updated version 2021[2]. Two databases were used PubMed and Cochrane. Totally 1660 studies were been retrieved from PubMed (495), Cochrane (1165). EndNote was used to do screening for duplicate studies, 128 duplicate studies were been removed, 1119 studies are been excluded based upon text and abstract, 126 studies excluded as they do not have access to free full text. Remaining 287 studies were been evaluated, based upon exclusion criteria 221 studies removed as they involved severe CKD, type1diabetes and other exclusion criteria. 5 studies removed as the study duration was <6month, 38 studies removed as they have used different comparator (GLP1 agonist, pioglitazones, insulin, sulfonylureas), 15studies provided irrelevant outcome. Therefore, 8 studies matching inclusion criteria were been finalized and included in this meta-analysis. (Screening procedure detailed in figure 1) International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 Figure 1: PRISMA FLOW CHART Table 1: Characteristics of studies included in meta-analysis AUTHOR & DATE STUDY DESIGN NUMB ER OF SUBJE CT IN TREAT MENT /CONT ROL GROU P MEAN AGE IN TREATMENT /CONTROL GROUP TREATMENT DOSE CONTROL GROUP FOLLOW UP PATIENT CHARACT ERISTICS JADAD score Quality Zinman et al., 2015 (1) RCT 4687/ 2333 63.1/63.2 Empagliflozin 10mg or 25mg once daily Placebo 3.1 year T2DM CV risk CKD 3 High Wiviott et al.,2018(2) RCT 8582/ 8578 63.9/64.0 Dapagliflozin 10mg once daily Placebo 4.2 years T2DM CV risk 4 high Perkovic et al., 2019(3) RCT 2202/ 2199 62.9/63.2 Canagliflozin 100mg once daily Placebo 2.62 years T2DM CV risk CKD 3 high Cannon et al., 2020(4) RCT 5499/ 2747 64.4/64.4 Ertugliflozin 5mg or 15mg once daily Placebo 3.5years T2DM CV risk CKD 5 High Bhatt et al., 2021 .1(5) RCT 5292/ 5292 69/69 Sotagliflozin 200mg once daily Placebo 30month T2DM CV risk CKD 4 High Bhatt et al.,2021 .2(6) RCT 608/6 14 69/70 Sotagliflozin 200mg once daily Placebo 18month T2DM CV risk CKD 4 high International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 Adel et al., 2022(7) RCT 45/48 55/57 Empagliflozin 10mg once daily Placebo 6month T2DM CV risk CKD 4 high Wada et al.,2022(8) RCT 154/1 54 62.5/62.4 Canagliflozin 100mg once daily Placebo 30month T2DM CV risk CKD 3 high RCT -randomized control trial, T2DM – type 2 diabetes mellitus, eGFR – estimated glomerular filtration rate, CV risk – cardiovascular risk, HF – heart failure CKDchronic kidney disease Table 2: Established cardiorenal risk factors in included studies AUTHOR AND DATE CARDIOVSCULAR RISK Number of affected patients in T/ C RENAL DISEASE (CKD/ eGFR) Number if affected patients in T/ C DIABETES (mean duration or Mean HbA1C) T/ C OUTCOME MEASURED Zinman et al.,2015 Coronary artery disease – 2732/1340 eGFR<60ml1212/607 HbA1C <8.5%- 3212/1607 CV death, HHF Wiviott et al.,2018 Established CV disease3474/3500 HF852/872 - HbA1C-8.3/8.3 Duration of T2DM11/10 CV death, All cause death, HHF, composite renal outcome Perkovic et al.,2019 Established CV disease – 1113/1107 HF-329/323 eGFR-56/56 Duration of T2DM15/16 CV death, All cause death, HHF, composite renal outcome Cannon et al., 2020 Coronary artery disease4144/2112 HF1286/672 MI2625/1329 eGFR76.1/75.7 HbA1c – 8.2/8.2 Duration of T2DM12.9/13.1 CV death, All cause death, HHF, composite renal outcome Bhatt et al.,2021.1 CVS risk factor at least one major – 4682/4699 History of HF – 1640/1643 eGFR44/44 HbA1C8.3/8.3 CV death, All cause death, HHF, composite renal outcome Bhatt et al.,2021.2 Mean EF35/35% Mean NT ProBNP1816/1741 eGFR – 49/50 HbA1C – 7.1/7.2 CV death, All cause death, HHF Adel et al.,2022 STEMI – 27/23 NSTEMI2/4 Unstable angina – 16/21 HTN26/32 CKD – 4/3 Duration of T2DM – 6/6 CV death Wada et al.,2022 HTN -154/154 eGFR – 56.3/55.2 HbA1C7.75/7.77 Duration of T2DM – 15.43/16.49 All cause death, Composite renal outcome T2DM – type 2 diabetes mellitus, eGFR – estimated glomerular filtration rate, CV risk – cardiovascular risk, HF – heart failure CKDChronic kidney disease, HHF – hospitalization for heart failure, STEMI – ST elevate Myocardial infarction, MImyocardial infarction, HTN – hypertension, EF – ejection fraction, Ttreatment group, Ccontrol group International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 Characteristics of studies Totally eight placebo controlled randomized studies of five SGLT2 inhibitors( Dapagliflozin[8] , canagliflozin [27,17], empagliflozin [1,7],ertugliflozin[4], sotagliflozin [5,6])in T2DM patients with high risk for cardiovascular disease and renal disease were been identified and cohort characteristics illustrated in Table 1&2. Overall, from eight studies 49,034 patients were been included; 27,069 participated in treatment group and 21,965 participated in control group. Across 8 studies, mean age is 63, mean follow-up was 2.6 years. Six studies have mentioned the mean HbA1c, average HbA1c level range from 8%-8.3% and five studies show T2DM duration with average range around 11years. All the studies had placebo as comparator. All the 8 studies show established or high risk for cardiovascular disease and renal disease .7 studies shows majority of participants with established cardiovascular disease [26-32], high risk for cardiovascular disease [5,8]. Five studies have shown established chronic kidney disease [5-8,3], other studies show eGFR <60ml /min / 1.73m² of body surface area which indicate mild CKD. Outcome of four studies [27-31] have shown CV death, all cause death, HHF, composite renal outcome, only CV death reported in [7]. All the 8 studies have shown CV death. Table 1: Characteristics of studies included in meta-analysis Cardiovascular death (CV death) A total of eight studies were included in this meta-analysis. The observed log risk ratios ranged from -0.6286 to 1.0986, with the majority of estimates being negative (88%). The estimated average log risk ratio based on the fixed-effects model was -0.1482 (95% CI: -0.2345 to -0.0618). Therefore, the average outcome differed significantly from zero (z = -3.3640, p = 0.0008) Figure 2A. The Q-test for heterogeneity was not significant, but some heterogeneity may still be present in the true outcomes (Q =13.3589, p = 0.0638, I² = 47.6005%). An examination of the studentized residuals revealed that one study (zinman et al., 2015) had a value larger than ± 2.7344 and may be a potential outlier in the context of this mode. The 95%CI of wiviott et al.,2018; cannon et al.,2020; Bhatt et al.,2021.2; Adel et al.,2022; Wada et al., 2022 cross the line of no effect which reveals that the results of those individual studies may not be significant. But, 95% CI of other studies does not cross null effect, those results are significant. Although majority of studies had crossed null effect but pooled effect of risk ratio shows significant reduction -0.1482, p = 0.0008 (95% CI: -0.2345 to -0.0618) in treatment group than in placebo group. All cause death Total of seven studies are included in this analysis. The observed log risk ratios ranged from -0.3708 to 0.0000, with the majority of estimates being negative (71%). The estimated average log risk ratio based on the fixedeffects model was = -0.1203 (95% CI: -0.1869 to -0.0536). Therefore, the average outcome differed significantly from zero (z = -3.5370, p = 0.0004) which shows that SGLT2 inhibitors have significantly reduced incidence of all cause death compared to placebo (Figure 2B). The Q-test for heterogeneity was not significant, but some heterogeneity may still be present in the true outcomes (Q = 10.9061, p = 0.0913, I² = 44.9849%). An examination of the studentized residuals revealed that one study (zinman et al., 2015) had a value larger than ± 2.6901 and may be a potential outlier in the context of this model. 95%CI of all studies are crossing the line of International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 null effects, which denote non-significant results of individual studies. But overall pooled effect shows significant reduction of incidence of all cause death in SGLT2 inhibitor than in placebo group. FIGURE 2A: FOREST PLOT COMPARING EFFECT OF SGLT2 INHIBITORS WITH PLACEBO IN INCIDENCE OF CARDIOVASCULAR DEATH, BASED UPON FIXED EFFECT MODEL WITH 95% CONFIDENCE INTERVAL. B IS FOREST PLOT COMPARING THE EFFECT OF SGLT2INHIBITORS AND PLACEBO ON INCIDENCE OF ALL CAUSE DEATH, BASED UPON FIXED EFFECT MODEL EFFECT WITH 95% CONFIDENCE INTERVAL. Hospitalization for heart failure A total of seven studies were included in this analysis. The observed log risk ratios were ranging from -1.0986 to -0.2999, with the majority of estimates being negative (100%). The estimated average log risk ratio based on the fixed-effects model was -0.3851 (95% CI: -0.4623 to -0.3078). Therefore, the average outcome differed significantly from zero (z = -9.7729, p < 0.0001). According to the Q-test, there was no significant amount of heterogeneity across studies in the true outcomes (Q = 1.9195, p = 0.9270, I² = 0.0000%). Overall, SGLT2 inhibitors significantly reduced the hospitalization for heart failure in comparison to placebo with no heterogeneity across studies (Figure 3A) .95% CI of all studies except wads et al., 2022 does not cross the line of null effect., this denote that he results of each individual study results shows significant reduction of incidence of hospitalization for heart failure in treatment group than placebo group. Therefore, this overall result proves to have supportive evidence for risk reduction 0.3851 (95% CI: -0.4623 to -0.3078) in patient treated with SGLT2 inhibitors. International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 14. Häring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Woerle HJ, Broedl UC: Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. 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