A New Hope on the Horizon for Kidney and Cardiovascular Protection with SGLT2 Inhibitors,GLP-1 Receptor Agonists,and Mineralocorticoid Receptor Antagonists in Type 2 Diabetic and Chronic Kidney Disease Patients

Introduction

Type 2 Diabetes (T2D) stands as a worldwide health epidemiological issue, posing a multifaceted challenge, especially to the health care frameworks of low and middle-income countries. This condition is marked mainly by its long-term complications, such as cardiovascular disease (CVD) and chronic kidney disease (CKD), which significantly enhance the likelihood of the disease and death among those affected. Cardiovascular (CV) complications are notably prevalent among individuals with type 2 diabetes, with a prevalence rate of ∼32.2%, ¹ and the mortality rate is reported to be twice as high as that in individuals without diabetes. ² Similarly, the development of CKD in people with T2D is considered as a combination of metabolic factors (poor glycemic control), hemodynamic factors (arterial hypertension and increased intraglomerular pressure), and overactivation of the mineralocorticoid receptor (MR), which promotes inflammation and fibrosis that in turn leads to changes at the cardiac, vascular, and renal levels.

Thus, the introduction of newer glucose-lowering agents and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) has prompted a paradigm shift in managing T2D, suggesting a possibility to mitigate these potentially severe complications. Nevertheless, the medical community stands at a crossroad regarding the utilization of these novel therapies, particularly in the reno- and cardioprotection. While recent studies have shed light on the multifactorial nature of responses to such treatments, there is still a substantial gap in our strategic application of these agents to optimize patient outcomes.

With this landscape in focus, this review aims to analyze a possible impact on the intensive modifiable risk factor management, coupled with the latest advancements in glucose-lowering medications and nsMRAs on the morbidity and mortality of patients with T2D at high risk for CVD and CKD. Finally, the question remains how these therapies can be effectively and efficiently implemented into the clinical practice.

CV Protection

Nowadays, the scientific community's interest in both sodium–glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) has significantly increased due to their favorably presented data on reduction of CV risk in diabetic cohorts. Many randomized controlled CV outcome trials have shown significant positive effects of SGLT2i on CV outcomes. A study involving the effects of empagliflozin medication at a dosage of 10 mg over about 2 years showed that there was a 21% decrease in the likelihood of experiencing a combined outcome consisting of CV mortality or hospitalization owing to heart failure (HHF). ³ Food and Drug Administration (FDA) approved dapagliflozin and empagliflozin as drugs reducing the risk of CV death or HHF in patients regardless of their diabetic status. ^4,5 A recent study investigated the comparative effects of SGLT2i and alternative oral antidiabetic medications in individuals with T2D who had acute myocardial infarction (MI) and subsequently received percutaneous coronary intervention.

Results showed that the SGLT2i use was associated with significantly better in-hospital and long-term outcomes, including lower CV events and HHF. ⁶ Remarkably, these CV benefits are not solely dependent on their ability to control glucose levels but rather stem from both direct and indirect actions on various organs. Specifically, the CV protection is associated with hemodynamic mechanisms and metabolic improvements within the lipid profiles, reduced blood pressure (BP), uric acid levels, visceral fat, body weight, and myocardial reduction of sympathetic activity ⁷ leading to decreased CV events and mortality. ⁸

SGLT2i demonstrates antiatherosclerotic effects by reducing inflammatory factors, relieving inflammation, handling insulin resistance, protecting from the vascular stress, inhibiting the development and progression of atherosclerosis. ⁹ Furthermore, SGLT2i promises to ameliorate abnormal electrophysiological changes in failing myocardium, which could potentially reduce the occurrence of sudden cardiac death (SCD) and ventricular arrhythmias (VAs). Conducting such clinical trials with well-defined criteria using SGLT2i may offer some answers on whether these drugs can effectively mitigate SCD and VAs.

Addressing these inquiries has the potential to enhance current approaches to preventing SCD. ¹⁰ An extensive research utilizing animal models has tried to uncovered the cardioprotective effects of SGLT2i, revealing three key remodeling outcomes: cardiac, ionic, and metabolic improvements. Cardiac benefits are linked to anti-inflammatory properties and pathways such as TGF-β and Nrf-2. Ionic enhancements involve an improved ionic homeostasis, while metabolic shifts favor ketones over glucose, with potential mechanisms, including AMP-activated protein kinase and monocarboxylate transporter 1. These insights pave the way for further understanding SGLT2i's positive impact on the heart condition. ¹¹

Nevertheless, based on evidence clinical trials evaluating SGLT2i (involving 57,000 diabetic patients on SGLT2i, including empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, and sotagliflozin with CV conditions) provided diverse outcome results. In the EMPA-REG trial, empagliflozin was noninferior to placebo but significantly reduced CV death. Canagliflozin in the CANVAS program showed nonsignificant results for the primary major adverse cardiovascular events (MACE) endpoint. Dapagliflozin in DECLARE-TIMI demonstrated noninferiority for safety but only reduced HHF. Ertugliflozin in VERTIS was noninferior but not superior at the MACE endpoint. Finally, sotagliflozin in SCORED trial reduced significantly the primary endpoint, mainly driven by HF effects. ^8,12 Recently a comprehensive metanalysis underlined that SGLT2i have shown significant efficacy in reducing the risk of CV death and HHF, establishing their fundamental role in the treatment of HF, irrespective of ejection fraction or care setting. ¹³

Besides SGLT2i, GLP-1RA has emerged as a promising class of drugs in diabetic patients. These agents improve blood sugar control and target other critical CV risk factors, including high BP, dyslipidemia, and obesity. They achieve this by targeting α cells and β cells to regulate glucagon and insulin, slowing gastric emptying, promoting weight loss, and improving endothelial cell function through anti-inflammatory and vasodilatory effects. Additionally, GLP-1RAs exhibit antiproliferative and anti-inflammatory effects on smooth muscle cells and macrophages, potentially preventing atherosclerosis. ¹⁴ GLP-1RAs have also been observed to suppress platelet activity in laboratory tests, suggesting an additional cardioprotective mechanism. ¹⁵ While the GLP-1 receptor-dependent effects are well understood, further research is needed to explore GLP-1 receptor-independent pathways, such as anti-inflammatory, antioxidant, and direct vasodilatory effects, contributing to their cardioprotective properties.

Consequently, CV outcome studies have shown the safety and potential for CV benefits with drugs like liraglutide, semaglutide, dulaglutide, and albiglutide. In the analysis based on time-to-event, individuals with T2D who received liraglutide experienced a reduced incidence of CV-related death, nonfatal MI, or nonfatal stroke compared with those who received placebo. ¹⁶ Similarly, semaglutide, administered once weekly, showed superiority over standard therapy in reducing CV events among T2D patients at risk for CVD. ¹⁷ Dulaglutide, another weekly treatment, reduced the primary composite (first occurrence of the composite endpoint of nonfatal MI, nonfatal stroke, or death from CV causes) outcome by 12% compared with standard care. ¹⁸ Although albiglutide also exhibited CV protective effects in trials, ¹⁹ it was withdrawn from the market for economic reasons. Patients without T2D who had HF or CKD were shown to benefit from SGLT2i's cardiorenal effects, whereas patients with obesity and T2D were shown to benefit from treatment with GLP-1RA associated with reduction of CV events.

In the absence of an RCT comparing the 2 classes of drugs, a recent meta-analysis of 11 RCTs included 98,572 patients, tried to guide cardiologists and diabetologists on their usefulness for cardiorenal protection. ²⁰ At a medium follow-up of about 3.0 ± 1.3 years, there was no difference in the rates of reduction of the composite primary outcome between the two classes of drugs. Compared with optimal medical care, both drugs reduced MI rates and CV and all-cause mortality. Recent study, ²¹ “Coordinated Care to Improve Cardiovascular Therapies in Type 2 Diabetes,” conducted across 43 U.S. clinics, highlighted the success of a team-based, education-focused intervention. This approach significantly boosted the prescription of evidence-based therapies in adults with T2D and atherosclerotic cardiovascular disease (AVSCD). Notably, the intervention group has had a substantial increase in the prescription of all three recommended therapies (high-intensity statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers [ACEis/ARBs], and SGLT2i/GLP-1RAs), with a remarkable 23.4% difference compared with the standard care group (P < 0.001).

Although it did not affect CV risk factors, it holds promise for reducing CV risk in this population.

It is recommended to provide either GLP-1RA or SGLT2i to individuals diagnosed with T2D who also have AVSCD or a significant risk of CVD. However, it was shown that only GLP-1RA reduced strokes ²² and in patients with HF, regardless of LVEF, SGLT2i should be the primary therapeutic choice. ^{23 –25} However, in cases where SGLT2i are contraindicated or not tolerated, GLP-1RA may exert the same effect on HHF. For individuals with CKD and an estimated glomerular filtration rate (eGFR) above 20 mL/min/1.73 m², SGLT2i are the preferred treatment. However, if SGLT2i are contraindicated or not well tolerated, GLP-1RA may be considered. ²⁶ While combining SGLT2 inhibitors with GLP-1RA may offer benefits in terms of lowering HbA1C, low-density lipoprotein cholesterol, body weight, and systolic BP compared with monotherapy, it also increases the risk of discontinuation due to adverse effects like diarrhea and vomiting and was associated with a higher risk of hypoglycemic events, particularly when used alongside other hypoglycemic agents.

Notably, no significant improvement in CV outcomes was observed, suggesting the need for further research in this area. ²⁷ Therefore, a personalized approach to treatment should be emphasized in the clinical practice.

Furthermore, in a recent retrospective study, both drugs reduced the 10-year risk for CVD in T2D patients in primary CV prevention, ²⁸ while SGLT2i had a more significant cardioprotective benefit for secondary prevention. ²⁹ Nonetheless, the optimal clinical management of T2D remains to be determined, considering the antiglycemic targets with variety of available drugs as first and subsequent drug choice, risk factors with regard to the vascular complications prevention, and achieved treatment outcomes (surrogate vs. clinical).

The existing treatment guidelines still need to provide the desired clarity for clinicians. ³⁰ Because of the variety of possible treatment combinations and lack of evidence-based algorithms due to insufficient comparative studies, physicians often need clarification, resulting in clinical inertia when dealing with these medications. ^30,31 To address this confusion and enhance treatment outcomes, recently released guidelines by the American Diabetes Association ²⁶ offered a coordinated approach, particularly for managing T2D patients with CVD and CKD with SGLT2i and GLP-1RA. This is especially important in view of the recent reports about worsened glycemic control and a consequent rise in vascular diabetic complications over the past decade. ^32,33

In addition, MRAs have effectively reduced morbidity and mortality in chronic HF. The ongoing development of novel nsMRA requires a comprehensive pharmacological assessment compared with traditional steroidal MRAs. The novel nsMRA, finerenone, is a potent and selective MRA known to reduce the presence of proinflammatory and profibrotic mediators, effectively preventing MR overactivation. ³⁴ Notably, finerenone has demonstrated the capacity to diminish the activity of specific genes associated with fibrosis in the heart. However, its effect is comparatively less robust when compared with eplerenone and spironolactone. ³⁵ Consequently, this translates into a significantly more substantial antifibrotic impact within the left ventricle.

The FIDELIO-DKD and FIGARO-DKD trials ^36,37 were published recently. They looked at the safety and effectiveness of finerenone when used with renin–angiotensin–aldosterone system inhibitors and how it affected cardiorenal endpoints in people with diabetic kidney disease (DKD). These trials featured complementary designs, encompassing similar patient demographics and shared objectives.

Finerenone significantly lowered the risk of a major CV event in the FIGARO-DKD trial, which included 7437 people. This was seen in people with CKD stages 2 to 4 who had moderately elevated albuminuria or those with CKD stages 1 or 2 who had severely elevated albuminuria. As anticipated, owing to its mechanism of action, both trials reported an increase in hyperkalemia associated with finerenone compared with the placebo (2.3% vs. 0.9% in FIDELIO-DKD and 1.2% vs. 0.4% in FIGARO-DKD).

In the FIDELIO-DKD trial (with 5734 participants), finerenone importantly reduced the risk of the primary kidney composite outcome, which included kidney failure, a sustained reduction of 40% in eGFR from baseline, or death from renal causes. In addition, it lowered the risk of the primary and secondary CV composite outcome, which is made up of death from heart disease, MI, stroke, and hospitalization for HF, in people with CKD stages 3 or 4, most of whom had moderate-to-severe albuminuria. ³⁶

Combining participants from both studies allowed for a predetermined pooled analysis known as FIDELITY (Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Program Analysis). The purpose of this predetermined individual participant study of 13,026 individuals was to more precisely estimate the effectiveness and safety of finerenone across the range of CKD and T2D patients. According to the recent study by FIDELITY2, finerenone significantly reduced the composite CV outcome (death from CV causes, nonfatal MI, nonfatal stroke, and HHF), with a hazard ratio (HR) of 0.86 (95% confidence interval [CI] 0.78–0.95). HHF decreased (HR 0.78; 95% CI 0.66–0.92), and appeared as primary contributing factor. Additionally, finerenone had a 2.2% lower absolute risk of the CV composite outcome after 3 years of treatment. ³⁸

In light of the new evidence, we can certainly consider the new perspective opened for treatment of CKD that postpone disease progression and development of end-stage kidney disease (ESKD) and the need for renal replacement therapy (RRT). This effect certainly goes along with the CVD prevention and prolonged survival of CKD patients. In the last two decades, mainstream therapy for preventing CKD progression in patients with and without T2D was either ACEi and/or ARB. However, the holistic treatment approach would also include a decreased risk of all-cause mortality in these CKD patients regardless of the presence of diabetes as a significant risk factor.

Kidney Function Preservation

Initial findings from CV safety trials conducted in individuals with T2D suggest potential improvements in renal function associated with SGLT2i, such as canagliflozin, dapagliflozin, and empagliflozin. These promising results emerged from the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOMES trials. Also, early research shows that SGLT2i therapy is linked to lower albuminuria, a slower decline in eGFR, and a lower risk of renal-related events such as ESKD, death from renal causes, and a doubling of serum creatinine (or a 40% drop in eGFR) even in people who are thought to have a lower risk for kidney disease. ^38,39

Subsequent clinical trials involving SGLT2i incorporated a primary composite kidney outcome into their study designs, encompassing renal and CV mortality. For example, in the CREDENCE study, following a median follow-up period of 2.6 years, the daily administration of canagliflozin at 100 mg demonstrated a marked decline in the incidence of the primary outcome within a cohort characterized by eGFR levels ranging from 30 to 90 mL/min/1.73 m² and urine albumin/creatinine ratio (UACR) values >34, up to 565 mg/mmol. ⁴⁰

Similarly, within a population comprising individuals with or without T2D but exhibiting comparable degrees of kidney impairment (eGFR between 25 and 75 mL/min/1.73 m² and UACR values >22.6–565 mg/mmol), the DAPA-CKD trial showcased a reduction in the primary composite kidney outcome associated with the daily administration of 10 mg dapagliflozin over a median period of 2.4 years. ²³ This effect persisted regardless of T2D status. In the recently concluded EMPA-KIDNEY study, individuals with kidney disease (eGFR 20–45 mL/min/1.73 m² or 45–90 mL/min/1.73 m²) and UACR <22.6 mg/mmol were analyzed, and the critical composite outcome was significantly reduced with daily 10 mg empagliflozin treatment. ⁴¹

In conclusion, SGLT2i therapy has been shown to lower the risk of ESKD and significantly slow down the loss of eGFR over the long-term treatment phases in the CREDENCE, DAPA-CKD, and EMPA-KIDNEY studies. ^23,25,40 Patients receiving SGLT2i maintained significantly higher mean eGFR levels compared with those on placebo at the conclusion of their respective studies, despite an initial drop in eGFR upon initiation of SGLT2i therapy. Notably, most of the patients in the CREDENCE and DAPA-CKD studies and a good number of those in the EMPA-KIDNEY studies were taking ACEi or ARBs at the highest doses that were safe for them. ^23,25,40

A comprehensive meta-analysis aggregated data from all placebo-controlled trials involving SGLT2i, including the EMPA-KIDNEY trials, further substantiated their efficacy. This extensive analysis incorporated a substantial cohort of 90,413 participants drawn from 13 trials. The findings indicated that SGLT2i treatment was associated with a 37% reduction in the risk of kidney disease progression compared with the placebo, as denoted by a relative risk of 0.63, within a 95% CI of 0.58–0.69. Notably, these risk reduction trends remained consistent across patient groups, encompassing individuals with and without diabetes.

Also, when the analysis was limited to four studies that only looked at CKD, those included the three trials we talked about earlier in this section, as well as SCORED with sotagliflozin, the risk reduction ratios were the same across all subgroups. These subgroups were categorized based on primary kidney diagnosis, the presence or absence of diabetes, and baseline eGFR. ⁴¹

Real-world population studies, such as CVD-REAL 3, have reaffirmed the effectiveness of SGLT2i in everyday clinical settings. This study, involving 35,561 patients, confirmed that individuals initiating gliflozin therapy experienced better renal outcomes compared with those initiating other antihyperglycemic drugs. These findings suggest that the start of SGLT2i therapy is correlated with a decelerated yearly decline in the eGFR, estimated at ∼1.53 mL/min/1.73 m². Additionally, it is associated with a decreased likelihood of encountering significant renal-related events. ⁴²

These observations highlight two crucial aspects of the utilization of SGLT2i in managing DKD. First, the positive effects on kidney outcomes appear to be significant irrespective of T2D status or baseline A1C levels, indicating that these benefits extend beyond glycemic effects. The mechanisms of kidney protection by SGLT2i involve receptor- and nonreceptor-mediated pathways. Receptor-mediated effects include the restoration of tubuloglomerular feedback, resulting in reduced glomerular hyperfiltration through adenosine-mediated hemodynamic changes.

Some effects not caused by receptors are changes in the metabolism, like slower glycolysis and mTORC1 pathway suppression, which affect different parts of the nephron. Comprehending the complexities of these sophisticated pathways holds significant importance in translating SGLT2i research into efficacious therapies for DKD. However, it is essential to acknowledge the limits of the studies and the presence of confounding variables that should be considered in future investigations. Furthermore, the renal benefit of SGLT2i complements the existing standard-of-care treatment regimen, including BP management, glycated hemoglobin control, and ACEi or ARBs.

Hence, a new hope on the horizon appeared in view of the SGLT2i treatment of early CKD patients with or without diabetes. Notably, 60%–70% of people have a transient decrease in eGFR of 3–4 mL/min/1.73 m² after starting an SGLT2i, although, this impact is not associated with an Acute Kidney Injury (AKI) or increasing long-term kidney function loss. Hence, most patients with an eGFR >45 mL/min/1.73 m² typically do not necessitate regular blood tests to monitor electrolyte levels or kidney function unless there are particular clinical indications of volume depletion. These indications may include patients with BP readings of 120/70 mmHg, signs or symptoms suggesting volume depletion (such as orthostatic symptoms), individuals taking high-dose diuretics, or potentially elderly patients. ⁴³ Additionally, a recent metaanalysis of randomized controlled trials on SGLT2i in CKD patients revealed that SGLT2i sustainably reduced UACR, prevented macroalbuminuria, and showed a mixed effect on eGFR with a decrease before 24 weeks and continuous increase after 24 weeks.

Thus, SGLT2i exhibited renoprotective effects independent of glycemic effects, reduced morbidity rates of related adverse events, and did not increase the occurrence of urinary tract infection, bone fractures, amputation, or acute pancreatitis compared with the control group. ⁴⁴

Based on the findings of the studies mentioned above, the FDA has expanded the approval of canagliflozin for T2D patients with diabetic nephropathy (albuminuria ≥300 mg/day and an eGFR ≥30 mL/min/1.73 m², ⁴⁰ and for dapagliflozin in patients with CKD with an eGFR ≥25 mL/min/1.73 m² at risk of CKD progression. ⁴⁵ Finally, it is recommended that patients with an eGFR ≥20 mL/min/1.73 m² could start SGLT2i, which can be maintained until the person starts RRT. ⁴⁶

GLP-1RAs have a significant role in the treatment of DKD as well. The GLP-1RAs have been linked to a decrease in 3-point MACE, comprising CV death, nonfatal MI, or nonfatal stroke, and these advantages seem to persist in individuals with impaired renal function. GLP-1RA lowers albuminuria, but an additional research is needed to determine how it affects “hard” renal outcomes, such as doubling of serum creatinine or a severe decline in eGFR, progression to ESKD, or kidney death. ¹⁶

Pooled analysis of 12,637 participants analyzing the data from SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; n = 3297) and LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; n = 9340) found that semaglutide and liraglutide reduced albuminuria by 24% from baseline to 2 years after randomization when compared with placebo. Compared with placebo, both drugs showed risks of 40% and 50% eGFR decline from baseline, and slowed down the predicted GFR decline. In individuals with eGFR levels between 30 and 60 mL/min/1.73 m², as opposed to those with eGFR >60 mL/min/1.73 m², the chance of delaying the eGFR decrease was higher. ⁴⁷

The antioxidant, anti-inflammatory, and antifibrotic actions in the diabetic kidney supported by GLP-1 signaling are among the suggested mechanisms by which GLP-1RAs lower the incidence of macroalbuminuria and limit eGFR decline. ⁴⁸ Other characteristics of GLP-1RAs include that they continue to lower A1C levels in individuals with renal impairment and do not require dosage modifications in those with low eGFRs. Notably, most patients who utilize GLP-1RA experience considerable weight reduction (>5% of original weight). ⁴⁹

In addition to ACE inhibition, aldosterone blockade has the additional benefit of preventing organ damage. The newer and novel approaches to counteract this aldosterone breakthrough while emphasizing these agents' antihypertensive, antiproteinuric, anti-inflammation, and antifibrotic effects would be perfect, and MRAs look to fit in this settings quite well, especially in CKD and diabetic nephropathy. Besides in CKD, Aldosterone and angiotensin II stimulate the production of FGF-23 in bone tissue, leading to an elevation in circulating FGF-23 levels. Strategies to diminish aldosterone activation make sense, and drugs that interfere with the binding of aldosterone to its receptor to affect CKD are a relatively novel concept. ^50,51

The analysis of Fidelity showed that the risk of the renal composite outcome (renal mortality, sustained 57% decline in eGFR from baseline, or kidney failure) was considerably lower when finerenone was used. ³⁴ Recently, Bakris and colleagues in the detailed analysis of Fidelity showed an HR of 0.77 (95% CI 0.67–0.88) in the study population where finerenone decreased the renal composite outcome, which included kidney failure (i.e., dialysis, transplantation, or a sustained fall in eGFR to 15 mL/min/1.73 m²), sustained 57% eGFR decline, and kidney death. ⁵²

Using an SGLT2i along with finerenone has been shown to improve the reduction of renal-related outcomes. This is shown by a combined subanalysis of data from the FIDELIO-DKD and FIGARO-DKD trials. Nevertheless, it is important to note that any potential superiority of this combination over either drug used individually has yet to be conclusively demonstrated. ⁵³ In the population covered by the finerenone trials, SGLT2i is recommended in class IA by the 2020 KDIGO Diabetes Management in CKD Guideline. ⁵⁴ Besides lowering renal and CV outcomes, SGLT2i has been demonstrated to decrease potassium and reduce the risk of hyperkalemia. Furthermore, finerenone appeared to reduce the CV composite (HR 0.67; 95% CI 0.42–1.07), and renal composite outcome (HR 0.42; 95% CI 0.16–1.08); among patients taking SGLT2i at baseline (n = 877; 6.7%) with wide CI. However, further investigation into combination treatments involving SGLT2i is warranted, and future research should aim to substantiate these findings.

In a recent meta-analysis, the aim was to compare the effectiveness of SGLT2is, GLP-1RAs, and nsMRAs in T2D and CKD patients. ⁵⁵ In this study were included 29 trials with nearly 51,000 participants, and was found that SGLT2is were associated with superior cardiorenal protection compared with GLP-1RAs and nsMRAs in the patient population. The risk of composite renal outcomes was lower with SGLT-2is than with GLP-1RAs and nsMRAs. The risk of HHF was also lower with SGLT-2is compared with GLP-1RAs and nsMRAs by 31% and 22%, respectively. However, SGLT-2is did not significantly reduce MACE or other secondary outcomes. No significant differences were observed between GLP-1RAs and nsMRAs regarding these outcomes.

Nowadays, SGLT2i and GLP-1RA reduce CVD and CKD risks while controlling glycemia in patients with T2D. On top of it, SGLT2i may be beneficial even in nondiabetic patients with HF, with or without preserved ejection fraction. However, further investigation into combination treatments involving SGLT2i is warranted, and future research should aim to substantiate these findings. Finally, the Medicare system should incorporate these treatment possibilities as a regular support through the health insurance system for both (with or without T2D) patient groups at risk or with established CVD and CKD, to have a greater possibility for an early CV disease protection. A summary of main Clinical Trials Investigating the effects of SGLT2i, GLP-1RA, and nsMRAs in Patients with T2D and Kidney Outcomes is presented in Table 1.

Conclusions

Based on the evidence shown, nephrologists in low- and middle-income countries should be aware of this new added value in slowing down the progression of CKD in people with or without diabetes. Despite the apparent need for new pharmaceutical agents, it frequently takes longer in the current clinical practice. Clinical inertia, as widespread condition, contributes to polypharmacy combination of the current therapies, worsening the patient's quality of life, which causes excessive expenses without satisfactory outcomes. Hence, we should make authorities and health care providers aware of the SGLT2is cost-effectiveness in the treatment of CKD patients. Finally, we should work on the implementation of these new classes of renoprotection (SGLT2i and nsMRA) into our clinical practice for the ultimate benefit of our patients and health care system.

Ethics Approval Statement

NA (the article is a review and do not need ethics approval statement).