From Classic to Contemporary, Evolving Therapies in Diabetic Kidney Disease: The Point of View of the Nephrologist and the Diabetologist

Abstract

Diabetes mellitus represents a global health concern, which is expected to worsen over the years. The prevalence is estimated to increase up to 642 million people by 2040. Almost half of diabetic patients are at a high risk of developing kidney involvement up to dialysis; moreover, macrovascular complication could be an obstacle to kidney transplant. Besides the classic albuminuric phenotype, non-albuminuric diabetic kidney disease was also discovered recently. Fortunately, compared with classic therapy with diet, oral hypoglycemic drugs, and insulin, current clinicians can rely on several new drugs that act with different pathways characterized by kidney and heart protection, as shown by several clinical trials and confirmed in clinical practice. Herein, we will review the therapies that nephrologist and diabetologist have available today and the future perspective.

1. Introduction

Diabetes mellitus represents a global health concern, which is expected to worsen over the years. The prevalence is estimated to increase up to 642 million people by 2040 [1]. There is an increase in global deaths and years of life lost in the 2040 forecast, showing both better and worse health scenarios for diabetes [2].

Despite the fact that it took over three millennia from the first description of diabetes to the association between diabetes and kidney disease [3], only several decades were needed for diabetic kidney disease to become the leading cause of end-stage kidney disease (ESKD) worldwide, involving, nowadays, 40% of new patients requiring dialysis [4]. It can develop in the course of type 1 or type 2 diabetes, despite the different pathogenesis. Type 1 is an autoimmune disease due to the presence of the antibody working directly against pancreatic islet cells, while type 2 is a result of insulin resistance and insulin deficiency.

Until now, chronic kidney disease (CKD), defined by international guidelines as abnormalities of kidney structure or function present for ≥3 months and with implications for health [5], caused by diabetes mellitus is identified as diabetic nephropathy (DN), which begins with microalbuminuria, followed by macroalbuminuria and a progressive decline in kidney function, characterized by defined histopathological findings, such as increased mesangial substrate, nodular lesions, and tubulointerstitial fibrosis [6].

Recently, the finding of cases of impaired renal function without albuminuria in diabetic patients have led to epidemiological surveys that have underlined the heterogeneity of the natural history of kidney involvement, using “diabetic kidney disease” as the definition to include all types of renal injury occurring in diabetic patients [7]: classical diabetic nephropathy (DN), vascular and ischemic glomerular changes, and other glomerulonephritis in the presence or absence of DN [8]. The prevalence of these entities is influenced by ethnicity, geography, and selection criteria for renal biopsy in the presence of diabetes [9]. The risk for DKD is the same for type 1 and type 2 diabetes.

The pathogenesis of DKD includes glomerular hypertension with the upregulation of the renin–aldosterone system (RAAS) and consequently, a change in kidney hemodynamics, ischemia and hypoxia, and oxidative stress. Overall, the full pathogenesis remains not completely understood [10].

Several experimental models have shown the persistence of the aberrant expression of fibrotic, antioxidant, and inflammatory genes in vascular cells and endothelial cells despite glucose normalization. Recently, this phenomenon, known as “metabolic memory”, has shown that patients with past exposure to high levels of glycemia will more frequently develop complications, including DKD, even after the normalization of blood glucose levels, due to the accumulation of advanced glycation end products (AGEs) and epigenetic changes, such as DNA methylation and histone modifications, which could contribute to the progression of DKD as a cellular memory [11]. Several complications of diabetes appear to have a genetic predisposition: genome-wide association studies (GWAS) have uncovered only limited possible loci, while the evaluation of epigenotypes by epigenome-wide association studies (EWAS) could provide new information about the pathogenesis of diabetic complications and metabolic memory, with the possibility of developing new therapeutic strategies and new biomarkers. Moreover, the most polymorphism seems to be in non-coding or other regulatory regions of the genome which can alter gene expression [11]. Molecular and cell-based therapies, such as miRNA modulators, stem cell therapy, and gene therapy, are in preclinical or early clinical phases, with the goal of promoting kidney repair [12]. This will result in precision medicine that, together with artificial intelligence, could help to stratify the risk of the progression of the disease and individualize therapy [13].

Moreover, the recently defined Cardio–Kidney–Metabolic (CKM) syndrome emphasizes the interconnectedness of cardiovascular, renal, and metabolic pathways. The American Heart Association (AHA) has formally described CKM syndrome as a systemic disorder characterized by pathophysiological interactions among metabolic risk factors (such as obesity and diabetes), chronic kidney disease (CKD), and cardiovascular disease (CVD), which collectively drive multiorgan dysfunction and substantially increase the risk of adverse cardiovascular outcomes [14,15].

The interconnectedness is rooted in shared mechanisms including chronic inflammation, oxidative stress, insulin resistance, the activation of the renin–angiotensin–aldosterone system, and neurohormonal dysregulation. For example, dysfunctional adipose tissue—especially visceral fat—releases pro-inflammatory and prooxidative mediators that contribute to vascular, cardiac, and renal injury, and further impair insulin sensitivity, amplifying metabolic dysfunction and systemic inflammation [14,16]. These processes create a vicious cycle in which the impairment of one organ system accelerates deterioration in the others.

The AHA emphasizes that CKM syndrome should be approached holistically, with integrated prevention, screening, and management strategies that address all three domains rather than treating them as isolated conditions because the presence of multiple CKM components confers additive risk for all-cause and cardiovascular mortality, as well as progression to end-stage kidney disease [17].

Herein, we will review the therapies in greater number that nephrologists and diabetologists have available today, with a focus on the results of the latest clinical trials, and the use of these new drugs in kidney transplant recipients and in subjects with an oncological pathology.

2. Role and Importance of Kidney Biopsy for the Diagnosis of DKD

The true incidence of CKD and ESKD from diabetes is difficult to estimate because kidney biopsies have not always been performed due to the prevailing notion among nephrologists that CKD in the context of diabetes is attributed to DN [18]. Most nephrologists would agree that a kidney biopsy is needed when its result may change treatment [19].

Therefore, biopsy has been performed in defined clinical conditions such as the absence of diabetic retinopathy, an expected decrease in kidney function, the sudden onset of proteinuria, an unexpected increase in albuminuria, and the new onset of other signs of systemic disease.

The new clinical phenotype of DKD highlights the importance of performing kidney biopsy: patients with normo-albuminuric kidney disease show a predominance of macrovascular and tubule interstitial changes compared with classical DN [20].

The treatment strategy of DKD is still represented by a multidisciplinary approach starting with lifestyle modifications treating overweight, when present, smoke cessation, the improvement of blood glucose levels, and dyslipidemia and blood pressure control. To the pillar of therapy represented by RAAS inhibitors, sodium–glucose cotransporter 2 inhibitors (SGLT2is) have also been added as the new drug of choice for the treatment of DKD since 2019. In addition to these drugs, there are other emerging therapies aimed at slowing the progression of kidney disease towards ESKD.

In this new “pharmacological era”, histopathology provides the roadmap for tailoring treatment and reducing the progression of the disease [9]. The transition from a one-size-fits-all medical approach to personalized medicine is supported by the information unlocked through kidney biopsies [9].

In our experience, of sixty diabetic patients biopsied in fifteen years in our Kidney Unit, 63% showed histological lesions in line with diabetic kidney disease, 11% had other glomerulonephritis, while 26% exhibited lesions due to diabetes and associated glomerulonephritis. The therapeutic management of this last group of patients represents a challenge for clinicians, showing the importance of kidney biopsy for identifying the prevalent lesions and personalizing the therapy by weighing up the risks and benefits (for example the risk of worsening diabetes if steroid therapy is needed).

3. Metformin-Associated Lactic Acidosis (MALA)

Metformin is a biguanide drug commonly used for the initial treatment of type 2 diabetes. It works on gluconeogenesis, decreasing hepatic glucose production and increasing the glucose uptake in peripheral tissue.

Due to its pharmacokinetic features (high volume distribution, negligible plasma protein binding, primarily renal excretion), the risk of accumulation and toxicity is higher in acute or chronic renal failure and caution must be used in patients with CKD. In fact, for eGFR > 45 and <60 mL/min, no dosage adjustment is necessary (but the frequent monitoring of renal function is recommended), while eGFR lower than 30 mL/min represents one of the major contraindications to the use of metformin by the Food and Drug Administration (FDA) indications, which recommend avoiding starting use with a glomerular filtration rate (GFR) between 30 and 45 mL/min [20,21].

The most feared complication related to drug intoxication is metformin-associated lactic acidosis (MALA), defined as pH < 7.3 and lactate > 5 mmol/L when drug plasmatic concentrations are >5 mg/L. Some medical conditions (like dehydratation due to gastroenteritis or fever and infections) are known as precipitating causes of MALA, predisposing to the development of acute kidney injury (AKI). The co-therapy with drugs acting on RAAS can often also contribute to decreased renal function.

MALA is a potentially life-threatening disease, characterized by a high mortality rate (reported to be between 30 and 50% [22,23]), for which no antidote is available. For this reason, in cases of oligoanuric AKI, severe lactic acidosis, or hyperkalaemia, when medical therapy is ineffective, kidney replacement therapy as emergency treatment could be necessary.

As regards the best treatment, no conclusive data are available to guide specialists in the choice of kidney replacement therapy (KRT) modality. Between 1 January 2022 and 30 September 2024, we treated 20 patients admitted at Piacenza “Guglielmo da Saliceto” Hospital with a diagnosis of MALA (Table 1, based on personal unpublished data.

Table 1. Clinical and laboratory data and the start and end of dialysis session (mean and standard deviation values of 20 patients).

Values	Dialysis Start	Dialysis End
Serum creatinine (mg/dL)	7.41 ± 2.97	3.42 ± 1.83
GFR (mL/min/1.73 mq, EPI-CKD)	6.52 ± 2.93
Serum metformin (mg/L, ref. value < 2)	24.39 ± 16.35	9.81 ± 5.57
Blood pH	7.10 ± 0.2	7.35 ± 0.05
Serum lactate (mg/dL)	103.15 ± 60.51	28.7 ± 19.81
HCO3-(mmol/L)	11.1 ± 5.6	19.36 ± 3.88
Serum potassium (mEq/L)	6 ± 1.25	4.5 ± 0.26

At dialysis start, metformin levels were toxic for all patients (mean range 7–61.01 mg/L, normal value 0–1.99 mg/L). After the first dialysis session, a drug reduction rate occurred in about 50% (44.8% for intermittent hemodialysis (IHD)) and 55.2% for sustained low-efficiency daily diafiltration (SLEDD-f) with a slight rebound in eleven patients. Two patients died after the first treatment (one received a SLEDD-f session and one IHD); all other patients received two or more dialysis sessions to avoid potential drug rebound. The other two patients died during hospitalization due to infectious complications several days after dialysis interruption (which occurred due to the normalization of electrolytes, acid–base disorders, and restored kidney function). After discharge, one patient continued ambulatory hemodialysis three times/week, with treatment interruption after 30 days for partial renal recovery function (residual stage 3b CKD).

Some authors have suggested sustained low-efficiency dialysis (SLED) as the best type of treatment in patients with MALA and AKI [24] but in our experience, both IHD and SLEDD-f were effective in patients with acute kidney injury and lactic acidosis caused by metformin intoxication.

The choice of treatment type was guided by patients’ hemodynamic status, hospitalization setting, and the availability of different dialysis machine types. Our 10% mortality rate for MALA treated with dialysis is lower than the mortality rates commonly reported in the medical literature [25,26], but still, it remains clinically significant. The mortality rate was low for both treatment types and renal recovery was not related to the initial choice of renal replacement therapy.

4. Contemporary Therapies

The role of kidney in the management of diabetic kidney disease is underlying by the mechanism of action of several drugs applied in this disease, that acting in several part of the nephron. (Figure 1).

Figure 1. Antidiabetic drugs’ target within the nephron.

4.1. Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker

The oldest and most pre-eminent drug for DKD treatment is RAS inhibition. RAS inhibitors have been shown to be effective in treating DKD in many clinical trials. In 1993, the Captopril Collaborative Study published by Lewis et al. showed that captopril, an angiotensin-converting enzyme inhibitor (ACE-I), inhibited the progression of nephropathy inpatients with type 1 diabetes mellitus [27]. Thereafter, large randomized controlled trials showed a reduction in the progression from microalbuminuria to proteinuria [10], as reported in Table 2.

RAASi are also able to prevent the development of microalbuminuria in normotensive patients; for this reason they should be used either in patients with hypertension or nephropathy [28].

Despite some studies reporting clinical benefits [29], such as the better control of albuminuria, better cellular sensitivity to insulin, and also reducing the risk of developing de novo diabetes [30] and improving diabetic nephropathy and heart failure, the combination therapy of ACE-I and angiotensin II receptor blocker (ARB) is not recommended based on ONTARGET and VA Nephron D trials [20,21]. These studies did not show significant differences in the efficacy for DKD, reporting on the other side, a higher number of adverse events, such as hyperkalemia and acute kidney injury (AKI), despite a substantial reduction in albuminuria. Moreover, in the ONTARGET patients a low risk of progression to ESKD was shown with a low urine albumin–creatinine ratio (7.2 mg/g) and an average eGFR of 73.6 mL/min/1.73 mq. Only 263 patients out of 25,620 were affected by CKD and stages 4 and 5 (eGFR < 30 mL/min/1.73 mq) and only 0.4% of the patients developed ESKD during the study [31,32]. The incidence of ESKD in the group of patients treated with ACEi or ARB overlapped with the group treated with both drugs [27]. Nevertheless, in selected patients, the risk of hyperkaliemia could be often better managed with diet with a low amount of potassium and with the use of new oral K⁺-binding agents.

Table 2. Clinical trials with the use of ACEi and ARBs in diabetic patients with kidney disease. UACR: urine albumin–creatinine ratio; ESKD: end-stage kidney disease.

Trial	Treatment	Population	Follow Up	Results
RENAAL (2001) [33]	Losartan	- type 2 diabetes - nephropathy - UACR of at least 300 mg/g - serum creatinine between 1.3 and 3.0 mg/dL	3.4 years	Significant reduction in the progression of diabetic nephropathy, slowing the onset of ESKD and doubling serum creatinine. It did not have a significant impact on overall mortality or cardiovascular events, however.
INDT (2005) [33]	Irbestartan	- vascular hypertension - age 30–70 years - 24 h urinary protein excretion of >900 mg - serum creatinine 1.0–3.0 mg/dL in women and 1.2–3.0 mg/dL in men	2.6 years	Effectiveness in slowing the progression of diabetic nephropathy in patients with type 2 diabetes and hypertension, independent of the effect on blood pressure.
INNOVATION (2007) [34]	Telmisartan	- type 2 diabetes - early-stage nephropathy - UACR between 100 and 300 mg/g - serum creatinine under 1.5 mg/dL for men and 1.3 mg/dL for women	2 years	Efficacy in delaying the worsening of diabetic kidney disease in patients with type 2 diabetes who had microalbuminuria; inhibition of the progression from microalbuminuria to overt proteinuria by approximately 60% compared with placebo.
IRMA-2 (2001) [35]	Irbesartan	- vascular hypertension - type 2 diabetes - UACR between 20 e 200 µg/min in 2 of 3 consecutive samples - serum creatinine under 1.5 mg/dL for men and 1.1 mg/dL for women	2 years	Inhibition of the progression from microalbuminuria to overt proteinuria by approximately 70%.
MARVAL (2002) [36]	Valsartan	- type 2 diabetes - microalbuminuria (urinary albumin excretion rate between 20 and 200 µg/min) - renal function preserved	6 months	The comparison between an ARB with a calcium channel blocker showed that only ARB was effective in lowering microalbuminuria, indicating that RAS inhibitors have an inhibitory effect on nephropathy and a blood pressure-lowering ability.
BENEDICT (2004) [37]	Tradolapril	- vascular hypertension - type 2 diabetes (less than 25 years) - normal urinary albumin excretion rate (less than 20 µg per minute)	3.6 years	ARBs reduced the incidence of microalbuminuria among patients who did not present with microalbuminuria.
ROADMAP (2011) [38]	Olmesartan	- type 2 diabetes - UACR ≤ 35 mg/g for women and ≤25 mg/g for men in 2 consecutives samples - at least 1 cardiovascular risk factor	5 years	ARBs reduced the incidence of microalbuminuria among patients who did not present with microalbuminuria.

Table 2. Clinical trials with the use of ACEi and ARBs in diabetic patients with kidney disease. UACR: urine albumin–creatinine ratio; ESKD: end-stage kidney disease.

Trial	Treatment	Population	Follow Up	Results
RENAAL (2001) [33]	Losartan	- type 2 diabetes - nephropathy - UACR of at least 300 mg/g - serum creatinine between 1.3 and 3.0 mg/dL	3.4 years	Significant reduction in the progression of diabetic nephropathy, slowing the onset of ESKD and doubling serum creatinine. It did not have a significant impact on overall mortality or cardiovascular events, however.
INDT (2005) [33]	Irbestartan	- vascular hypertension - age 30–70 years - 24 h urinary protein excretion of >900 mg - serum creatinine 1.0–3.0 mg/dL in women and 1.2–3.0 mg/dL in men	2.6 years	Effectiveness in slowing the progression of diabetic nephropathy in patients with type 2 diabetes and hypertension, independent of the effect on blood pressure.
INNOVATION (2007) [34]	Telmisartan	- type 2 diabetes - early-stage nephropathy - UACR between 100 and 300 mg/g - serum creatinine under 1.5 mg/dL for men and 1.3 mg/dL for women	2 years	Efficacy in delaying the worsening of diabetic kidney disease in patients with type 2 diabetes who had microalbuminuria; inhibition of the progression from microalbuminuria to overt proteinuria by approximately 60% compared with placebo.
IRMA-2 (2001) [35]	Irbesartan	- vascular hypertension - type 2 diabetes - UACR between 20 e 200 µg/min in 2 of 3 consecutive samples - serum creatinine under 1.5 mg/dL for men and 1.1 mg/dL for women	2 years	Inhibition of the progression from microalbuminuria to overt proteinuria by approximately 70%.
MARVAL (2002) [36]	Valsartan	- type 2 diabetes - microalbuminuria (urinary albumin excretion rate between 20 and 200 µg/min) - renal function preserved	6 months	The comparison between an ARB with a calcium channel blocker showed that only ARB was effective in lowering microalbuminuria, indicating that RAS inhibitors have an inhibitory effect on nephropathy and a blood pressure-lowering ability.
BENEDICT (2004) [37]	Tradolapril	- vascular hypertension - type 2 diabetes (less than 25 years) - normal urinary albumin excretion rate (less than 20 µg per minute)	3.6 years	ARBs reduced the incidence of microalbuminuria among patients who did not present with microalbuminuria.
ROADMAP (2011) [38]	Olmesartan	- type 2 diabetes - UACR ≤ 35 mg/g for women and ≤25 mg/g for men in 2 consecutives samples - at least 1 cardiovascular risk factor	5 years	ARBs reduced the incidence of microalbuminuria among patients who did not present with microalbuminuria.

4.2. SGLT2 Inhibitors

SGLT2 inhibitors (SGLT2is) were originally developed to treat type 2 diabetes and have demonstrated protective cardiorenal benefits in people with diabetes and in patients with known kidney disease [39,40], emerging as a pivotal class of medications in the management of CKD, especially for patients with DKD [39,40]. These drugs have been shown to significantly slow down the progression of kidney disease, reduce proteinuria, decrease the risk of end-stage kidney failure, and improve overall kidney function in patients with type 2 diabetes, as well as those with non-diabetic CKD [39,40,41].

The main mechanism whereby SGLT2is provide their nephroprotective effects is reducing the workload on the kidneys [41]. In CKD, the kidneys undergo hyperfiltration to compensate for the loss of functioning nephrons. This increased filtration can worsen kidney damage, according to Brenner’s hyperfiltration hypothesis. SGLT2is counteract this mechanism by promoting the excretion of glucose, sodium, and water, leading to a reduction in intraglomerular pressure, which improves kidney hemodynamics and consequently protects the kidneys from further damage and slows the progression of kidney disease. [40,41].

In in vitro and in vivo models, SGLT2is have been shown to improve pathological processes involved in the development and progression of kidney aging, including inflammation, fibrosis, cellular senescence, endothelial disfunction, and mitochondrial injury, through both blood glucose-dependent and independent mechanisms [42,43].

Clinical studies (see Table 3) have shown that SGLT2is, such as empagliflozin, canagliflozin, and dapagliflozin, reduce albuminuria (a marker of kidney damage) and improve the eGFR, a key indicator of kidney function (the reversible decrease in eGFR on initiation is generally not an indication to discontinue therapy) [44,45]. Furthermore, they reduce the risk of major adverse kidney events, including the need for dialysis or kidney transplant [40,46,47,48]. The CREDENCE trial, the DAPA-CKD trial, and the EMPA-KIDNEY trial have been instrumental in demonstrating the efficacy of these drugs in non-diabetic CKD as well, proving that their benefits extend beyond diabetes-related kidney disease to other forms of chronic kidney impairment [45].

SGLT2 inhibitors have revolutionized the treatment of CKD, offering significant nephroprotective effects and reducing the progression of kidney disease in both diabetic and non-diabetic subjects [5]. By improving kidney hemodynamics, reducing albuminuria, and providing cardiovascular benefits, these medications are now considered a first-line option in managing CKD, particularly in patients at a high risk of progression [5].

Moreover, SGLT2 inhibitors have shown significant cardioprotective effects [47]. Large clinical studies such as EMPA-REG OUTCOME, CANVAS, and DAPA-HF have shown that these agents reduce the risk of hospitalization for heart failure and cardiovascular death, while improving outcomes in heart failure, regardless of their glucose-lowering effects [48,49,50]. Their benefits are attributed to many mechanisms including osmotic diuresis, a reduction in blood pressure, an improvement of myocardial energy efficiency, and a reduction in inflammation [51,52]. Consequently, SGLT2 inhibitors are now recommended for diabetic patients with cardiovascular disease or at high cardiovascular risk [47].

Regarding adverse effects, SGLT2 inhibitors are associated with an increased risk of genital infections due to the loss of glucose in urine, acute kidney injury, and diabetic ketoacidosis (DKA), which is a potentially life-threatening complication; indeed SLGT2is are contraindicated in patients with type 1 diabetes [53].

SGLT2is should not be started in patients with a history of urinary infection, while DKA is more common in the presence of precipitating factors, such as starvation, acute illness, and surgical procedure, so it is mandatory to hold the drug during this time, particularly in elderly and oncology patients [54].

Table 3. Clinical trials about the use of SGLT2is in diabetic patients with kidney disease.

Trial	Treatment	Population	Follow Up	Results
EMPA-REG OUTCOME (2015) [50]	Empaglifozin	- T2D - pre-existing cardiovascular disease - eGFR ≥ 30 mL/min/1.73 m2	3.1 years	Significant reduction in cardiovascular events in type 2 diabetes mellitus patients with pre-existing cardiovascular disease and in progression of nephropathy
CANVAS (2017) [48]	Canaglifozin	- cardiovascular disease - eGFR ≥ 30 mL/min/1.73 m2 - HbA1c between 7.0% and 10.5%	4.3 years	Reduction in cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke by 14% compared with placebo 33% reduction in hospitalization for heart failure 40% reduction in the risk of a composite renal outcome
CREDENCE (2019) [55]	Canaglifozin	- T2D: HbA1c between 6.5% and 12.0% - eGFR 30 to 90 mL/min/1.73 m2 - UACR between 300 and 5000 mg/g	2.6 years	Significant reduction in the risk of ESKD or cardiovascular death (30%) compared with placebo
DAPA-CKD (2020) [56]	Dapaglifozin	- eGFR between 25 and 75 mL/min/1.73 m2 - UACR between 200 and 5000 mg/g - stable use of an ACE inhibitor or ARB for at least 4 weeks	2.4 years	Significant reduction in the risk of ESKD, ≥50% sustained decline in eGFR or cardiovascular death
EMPA-KIDNEY (2023) [45]	Empaglifozin	- eGFR between 20 and <45 mL/min/1.73 m2, OR - eGFR ≥ 45 mL/min/1.73 m2 with UACR ≥ 200 mg/g - with and without T2D - stable use of an ACE inhibitor or ARB unless contraindicated	2 years	Reduction in risk of CKD progression or cardiovascular death by 28% with empagliflozin compared with placebo Reduction in the risk of all-cause hospitalization by 14%

Table 3. Clinical trials about the use of SGLT2is in diabetic patients with kidney disease.

Trial	Treatment	Population	Follow Up	Results
EMPA-REG OUTCOME (2015) [50]	Empaglifozin	- T2D - pre-existing cardiovascular disease - eGFR ≥ 30 mL/min/1.73 m2	3.1 years	Significant reduction in cardiovascular events in type 2 diabetes mellitus patients with pre-existing cardiovascular disease and in progression of nephropathy
CANVAS (2017) [48]	Canaglifozin	- cardiovascular disease - eGFR ≥ 30 mL/min/1.73 m2 - HbA1c between 7.0% and 10.5%	4.3 years	Reduction in cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke by 14% compared with placebo 33% reduction in hospitalization for heart failure 40% reduction in the risk of a composite renal outcome
CREDENCE (2019) [55]	Canaglifozin	- T2D: HbA1c between 6.5% and 12.0% - eGFR 30 to 90 mL/min/1.73 m2 - UACR between 300 and 5000 mg/g	2.6 years	Significant reduction in the risk of ESKD or cardiovascular death (30%) compared with placebo
DAPA-CKD (2020) [56]	Dapaglifozin	- eGFR between 25 and 75 mL/min/1.73 m2 - UACR between 200 and 5000 mg/g - stable use of an ACE inhibitor or ARB for at least 4 weeks	2.4 years	Significant reduction in the risk of ESKD, ≥50% sustained decline in eGFR or cardiovascular death
EMPA-KIDNEY (2023) [45]	Empaglifozin	- eGFR between 20 and <45 mL/min/1.73 m2, OR - eGFR ≥ 45 mL/min/1.73 m2 with UACR ≥ 200 mg/g - with and without T2D - stable use of an ACE inhibitor or ARB unless contraindicated	2 years	Reduction in risk of CKD progression or cardiovascular death by 28% with empagliflozin compared with placebo Reduction in the risk of all-cause hospitalization by 14%

4.3. Glucagon-like Peptide-1 Receptor Agonists

Glucagon-like Peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), or incretin mimetics, bind to GLP-1 receptors, which are expressed in different tissues, including pancreatic β-cells, the brain, and kidneys [57,58]. They are effective in glucose control, weight loss, and CV risk reduction in subjects with diabetes [59,60,61,62]. Since obesity and T2DM present major global health challenges with an increasing prevalence worldwide, GLP-1RAs have emerged as a pivotal treatment option for both conditions [63].

With regard to renal function, firstly, they are safe and maintain their efficacy also in subjects with low eGFR. Moreover, recent studies suggest that GLP-1 RAs also provide renal protective effects in subjects with diabetes, namely reducing albuminuria, improving GFR, and potentially slowing the progression of CKD [64,65]. Dulaglutide provided adequate glycemic control irrespective of CKD stage and was associated with a reduced decline in eGFR in a CKD population [66,67]; semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and CKD [64,68]

Retatrutide (LY3437943), a dual (GLP1-GIP) receptor agonist, showed substantial body weight reduction in adults with obesity [69]; a post hoc analysis of phase 2 trials suggested possible benefits for kidney function [70] and another specifically designed trial is currently ongoing (NCT05936151). In a post hoc analysis of the SURPASS-4 trial [71], tirzepatide, a dual (GLP1-GIP) receptor agonist, reduced a composite kidney endpoint by 42%, compared with insulin glargine.

A recent retrospective study showed the real-world effectiveness of GLP-1 RAs for T2D and CKD [72]: GLP-1 RAs provided a higher reduction both in HbA1c and weight and greater kidney protection, compared with basal insulin, among adults with T2DM and CKD already treated with an SGLT2i. Interestingly, semaglutide improved kidney outcomes also in people without diabetes [73]. Clinical studies have shown the effects of weight loss on kidney function: caloric restriction can reduce proteinuria, even by more than 80% of the baseline values [74]. Moreover, evidence suggests that the antiproteinuric effect could be directly induced by caloric restriction by itself, even with the achievement of a significant weight loss [75]. The use of GLP-1 could be used therefore also in patients without diabetes but with obesity, which represents itself a risk condition to develop diabetes.

GLP-1 RAs improve endothelial function and vasodilation in the glomerulus, potentially reducing glomerular hyperfiltration; furthermore, they may reduce inflammation and oxidative stress in the kidney, both of which contribute to the pathogenesis of albuminuria and renal fibrosis [57,76]. GLP-1 RAs have also been shown to reduce intraglomerular pressure and influence renal hemodynamics by improving renal blood flow, which may help preserve GFR [57,58,76]. Their nephroprotective properties may therefore be related to both metabolic and non-metabolic mechanisms.

KDIGO Guidelines [77] strongly recommends long-acting GLP-1 Ras, with documented cardiovascular benefits for people with T2D and CKD who have not achieved individualized glycemic targets despite the use of SGLT2is, with or without metformin, or who are unable to use those medications. Incretin mimetics may also have a role in the treatment of people with CKD who do not have T2D. As for SGLT2is, initial studies of incretin mimetics focused on people with T2D, but as benefits were observed and suggested to be independent of glycemia control, inclusion criteria should be broadened to other CKD groups.

Therefore, these drugs are increasingly being considered in the management of CKD, particularly in patients with concomitant diabetes and other risk factors for CKD progression [5,77,78].

It is recognized that dialysis patients with a higher BMI show better survival, probably because it helps against protein–energy wasting and inflammation. This phenomenon is called the “obesity paradox”, which appears in conflict with the use of GLP-1 in this population. On the other hand, weight loss in these patients could represent the possibility of kidney transplant eligibility. The weight loss and sarcopenia must be associated with the preservation of muscle mass with a specific diet and physical exercise. However, long-term clinical data are still needed to fully understand their role in the management of CKD. Meta-analysis did not show serious adverse events, but in clinical practice there are some side effects, in particular, gastrointestinal (nausea, reduction in appetite, vomiting, and diarrhea). GLP1-RA may cause injection site reactions and an increase in heart rate, which is usually transient [79].

4.4. Mineralocorticoids Receptor Antagonists (MRAs)

In the past years, the renewed interest in aldosterone as a mediator of cardiovascular and renal disease, through its blood pressure effects, has resulted in a greater interest in using mineralcorticoid receptor antagonists (MRAs) to reduce proteinuria and delay CKD progression [80]. A 2009 meta-analysis, updated in 2014, demonstrated that the addition of MRAs to RAS blockade reduced blood pressure and proteinuria in CKD patients [81].

Elevated levels of steroid hormones, such as aldosterone and cortisol, may increase inflammation by inducing the pathological overactivation of the mineralocorticoid receptor (MR) in the kidneys and the heart. However, elevated aldosterone release or high salt intake can activate the MR with an inflammatory response that may ultimately lead to organ damage [82].

There are two distinct groups of MRAs: steroidal MRAs (such as spironolactone and eplerenone), and the newer, different, nonsteroidal MRAs.

The use of spironolactone in treating patients with cardiovascular disease has been shown in several clinical studies [83,84], and they represent one of the cornerstones in patients with heart failure due to the improvements in survival, as documented in the Randomized Aldactone Evaluation Study (RALES) trial [85]. Subsequently, good results were obtained using eplerenone, a more selective steroidal MRA, which improved survival and reduced the rate of hospitalizations for heart failure. These drugs appear to also have beneficial effects on the kidney, improving albuminuria [86].

Therefore, inhibiting the receptor with an MRA could reduce the progression of kidney disease. The main problem with MRAs is an increase in plasma potassium, which in people with CKD often leads to hyperkalemia and sexual side effects (such as gynecomastia). Nonsteroidal MRAs (nMRAs), instead, showed a protection of the kidney and the heart with a better side effect profile, compared with steroidal MRAs. The most developed nMRAs approved are finerenone and esaxerenone. The clinical benefits of the former were evaluated in two randomized, double-blind, place-controlled clinical trials: FIDELIO-DKD and FIGARO-DKD [87,88] (Table 4).

Table 4. Clinical trials about the use of nMRAs in diabetic patients with kidney disease.

Trial	Treatment	Population	Follow Up	Results
FIGARO-DKD (2021) [88]	Finerenone	- T2D - UACR 30–300 mg/g and eGFR 25–90 mL/min/1.73 m2 - UACR 300–5000 mg/g and eGFR ≥ 60 mL/min/1.73 m2 - maximum tolerated dose of a RAS inhibitor	3.4 years	Reduction in risk of cardiovascular events compared with placebo and occurrence of a trend toward reduced kidney-related outcomes in patients with T2D and early to moderate stages of CKD
FIDELIO-DKD (2020) [89]	Finerenone	- T2D - UACR 30–300 mg/g and eGFR 25–60 mL/min/1.73 m2, with diabetic retinopathy - UACR 300–5000 mg/g and eGFR 25–75 mL/min/1.73 m2 - maximum tolerated dose of a RAS inhibitor - serum potassium ≤ 4.8 mmol/L.	2.6 years	Reduction in risk of a composite of kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death, compared with placebo

The FIDELIO-DKD trial [87,89] assessed the long-term efficacy and safety of finerenone vs. placebo in patients with CKD (stage 3 to 4 with eGFR of 25–75 mL/min/1.73 m²) and type 2 diabetes. Patients treated with finerenone experienced an 18% lower risk compared with patients treated with a placebo in the rate of the primary kidney endpoint, which is defined as a composite of time to kidney failure, a sustained decrease of ≥40% in eGFR from baseline over ≥4 weeks, or death from renal causes. The safety profile of finerenone was comparable to that of the placebo, except for hyperkalemia, which occurred at a higher incidence with finerenone (18.3%) than with the placebo (9.0%), but regardless, the levels of hyperkalemia were lower compared with those reported in the literature using RAS blockade in CKD patients.

The FIGARO-DKD trial [88,90] evaluated a wider spectrum of CKD patients (eGFR between 25 and 90 mL/min/1.73 m²) with persistent moderately or elevated albuminuria levels. In this trial 61.7% of patients exhibited mild CKD, showing beneficial effects also in this group of patients.

In a pre-specified individual patient analysis of the FIDELITY-DKD trial [91] patients included in the FIGARO and FIDELIO trials were evaluated over a median follow up of 3 years: a 14% lower risk of the composite CV outcome was reported as well as a reduction in the risk of the composite kidney outcome. Moreover, finerenone decreased the incidence of dialysis initiation by 20%.

Currently, finerenone is recommended in patients with CKD associated with type 2 diabetes to decrease the risk of sustained eGFR decline, ESKD, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure [89]. Esaxerenone, instead, has been clinically available in Japan since 2019 for treating hypertension and has been proved to have a higher incidence of urinary albumin remission in patients with type 2 diabetes with high levels of albuminuria treated with a RAS inhibitor [92].

Recently, aldosterone synthase inhibitors (ASis) have emerged as an alternative to MRAs. A phase II clinical study showed a significant improvement of the urine albumin-to-creatinine ratio compared with a placebo with vicadrostat, with or without SGLT2i therapy [93]. Currently, a large-scale randomized trial, the EASi-KIDNEY trial (NCT06531824), is ongoing to evaluate the cardiorenal efficacy and safety of vicadrostat in combination with empaglifozin in patients with CKD with or without diabetes. The composite primary outcomes are kidney disease progression and cardiovascular death from heart failure needing hospitalization [94].

4.5. SGLT-1 Inhibitors

SGLT1i improves glucose metabolism through the reduction in intestinal glucose absorption and increases the release of gastrointestinal incretins. In the kidney, SGLT1i is expressed in the macula densa where it affects glomerular hemodynamics and blood pressure. Evidence has shown the expression of SGLT1 also in the parotid, liver, lung, heart, brain, pancreatic alpha cells, and salivary glands, and the possible effects of SGLT1i on these organs are not fully known [95].

Sotaglifozin is a dual sodium–glucose co-transporter 1 and 2 inhibitor. The SCORED trial has shown a reduction in heart failure complications in patients with type 2 diabetes and CKD. Data from a secondary analysis [96], recently published from the SCORE trial, confirmed the reduction in major adverse cardiovascular events, with the reduction in myocardial infarction and stroke in this group of patients reflecting a possible unique role of SGLT1i compared with SGLT2i alone. Moreover, the drug reduced the risk of the composite of the first event of sustained reduction in eGFR, dialysis, or kidney transplant compared with the placebo, while the incidence of acute kidney injury was similar between the two groups [97].

The adverse events described include diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis. These data confirm the need for more studies to better define the therapeutic potential of SGLT1i inhibition alone or in combination with SGLT2i [95].

4.6. Endothelin Receptor Antagonists

Endothelin-1 promotes mesangial cell proliferation, sclerosis, and direct podocyte injury through the activation of endothelin type A and B receptors, which drive the progression of glomerulosclerosis in diabetic kidney disease [98].

Endotelin receptor antagonists (ERAs), including agents like atrasentan, are under investigation for their anti-fibrotic and hemodynamic effects, with ongoing trials assessing their impact on renal outcomes. Atrasentan antagonizes the vasoconstrictive action of endothelin A receptors within the smooth muscle cells of blood vessels [99].

Clinical trials have studied the effect of the drug in DKD patients with type 2 diabetes, showing an improvement of kidney function, a relative risk reduction in eGFR decline, [100,101] and an improvement of albuminuria levels [102]. However, fluid retention and an increased risk of heart failure associated with ERAs need careful consideration with further trials to optimize dosing and patient selection.

In conclusion, DM and its severe complications, especially DKD, represent an arduous and exciting challenge in the management of the disease and its treatment. Undoubtably, today we have in our hands several effective weapons that can help us in the best management of this disease and its often-dramatic complications. Probably, in the short term, other new drugs will be on the way, providing clinicians with new opportunities that were unthinkable until a few years ago.

5. Special Populations

5.1. Kidney Transplant Recipients

Diabetes mellitus (DM) is a prevalent and complex issue among kidney transplant recipients, as the prevalence of pre-existing DM in kidney transplant patients is estimated to be 17.5–30% [46] and represents a growing concern, affecting both the immediate post-transplant period and long-term outcomes [103]. It can be classified into two main types: pre-existing diabetes, which is diagnosed prior to transplantation, and post-transplant diabetes (PTDM), which occurs after the transplant intervention [103]. While pre-transplant diabetes remains associated with an increased risk for mortality after kidney transplantation, mortality outcomes associated with PTDM are time dependent and likely to mature with time [104]. Moreover, PTDM is particularly concerning, as it is closely linked to the use of immunosuppressive medications [105]. The use of immunosuppressive agents, such as steroids, calcineurin inhibitors (e.g., tacrolimus and cyclosporine), and mTOR inhibitors (e.g., sirolimus), significantly contributes to insulin resistance, beta-cell dysfunction, and impaired glucose metabolism [106]. These medications, which are essential to prevent graft rejection, on the other hand, can exacerbate or trigger the development of PTDM [107].

The development of diabetes in kidney transplant recipients increases the risk of various complications, including cardiovascular disease, graft dysfunction, and an increased susceptibility to infections [108]. On the other hand, diabetes often results in an increased acute rejection rate [109]. Furthermore, diabetes exacerbates the risk of CKD progression, placing additional strain on already-compromised renal function. Data show that up to 20–40% of kidney transplant recipients may develop PTDM, depending on various risk factors such as age, ethnicity, obesity, and a history of impaired glucose tolerance [107].

Managing diabetes in kidney transplant recipients is particularly challenging due to the need for a careful balance between blood glucose levels and, at the same time, minimizing the side effects of immunosuppressive therapy. Moreover, treatment strategies must account for the unique pharmacokinetics of immunosuppressive drugs and their potential interactions with antidiabetic medications. Consequently, a multifaceted approach to address both glycemic control and the prevention of complications, while also minimizing the negative effects of immunosuppressive drugs, is required [110,111].

While pharmacologic agents are crucial for glycemic control, adjusting immunosuppressive therapy is equally important. The use of steroid-sparing regimens, such as tacrolimus monotherapy or the use of mycophenolate mofetil instead of steroids, can help minimize the hyperglycemic effects of corticosteroids. Transitioning to sirolimus (an mTOR inhibitor) in select patients may also improve glucose metabolism but requires careful monitoring due to its potential nephrotoxic effects, especially in those with pre-existing kidney dysfunction [111].

In addition to pharmacologic treatment, lifestyle modifications, including dietary counseling and exercise, play a pivotal role in managing diabetes in kidney transplant recipients.

5.2. Pharmacologic Management

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Insulin therapy: Insulin remains the cornerstone of diabetes management in kidney transplant recipients, especially in those with significant hyperglycemia or advanced stages of PTDM. Given the altered pharmacokinetics of insulin in renal failure, dosing adjustments are necessary to avoid hypoglycemia, especially in patients with impaired kidney function [107].

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Oral hypoglycemic agents: The use of oral agents is considered in patients with mild PTDM and preserved renal function. Metformin is generally avoided in patients with significant renal dysfunction due to the risk of lactic acidosis. Sulfonylureas and thiazolidinediones can be used cautiously, but their use is often limited by their side effects, including weight gain and fluid retention, which can exacerbate cardiovascular risks [110].

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Glucagon-like Peptide-1 (GLP-1) Receptor Agonists: They are increasingly being used in kidney transplant recipients, especially in those with mild to moderate PTDM, especially for the benefit of weight loss [77].

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SGLT2 inhibitors: Their positive cardiovascular and kidney effects make them an attractive option for PTDM in kidney transplant recipients [111,112,113]. A multicenter study involving 750 KTRs recently reported that SGLT2 inhibitors significantly reduced the risk of major adverse cardiovascular events (MACEs), including myocardial infarction and cardiovascular mortality, without increasing the incidence of urinary tract infections (UTIs). Furthermore, a systematic review of 18 studies reported that SGLT2 inhibitors led to modest reductions in HbA1c and body weight, without a significant impact on eGFR or systolic blood pressure [114]. Despite these benefits, concerns remain regarding the potential risk of UTIs, in immunosuppressed patients, and the long-term effects on graft function [114].

6. Future Perspective

Emerging cellular approaches for diabetes management include stem cell therapy, microRNA modulation, gene therapy, and islet transplantation. These advanced therapies are being developed to address the limitations of conventional treatments, particularly the inability to restore endogenous insulin production and the progressive decline of β-cell mass and function seen in both type 1 and type 2 diabetes [115].

Stem cell therapy utilizes pluripotent stem cells, mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs) to generate insulin-producing β-like cells or to support endogenous β-cell regeneration. MSCs, especially those derived from adipose tissue, have shown immunomodulatory and anti-inflammatory effects, facilitated β-cell regeneration, and improved insulin sensitivity [116]. Cell-free derivatives such as exosomes are also under investigation for their therapeutic potential [117]. Challenges include immune rejection, tumorigenesis, and ensuring long-term cell survival and function.

Gene therapy and microRNA modulation are being explored to enhance β-cell proliferation, protect against apoptosis, and improve insulin secretion. Gene editing technologies, such as CRISPR/Cas9, are used to correct genetic defects or engineer stem cells for improved therapeutic efficacy [118,119].

Islet transplantation remains a viable option for selected patients with type 1 diabetes but is limited by donor availability and immune-mediated rejection [120]. The use of stem cell-derived islet-like clusters and MSC co-transplantation is being investigated to overcome these barriers and improve graft survival [117,120]

Precision medicine and artificial intelligence (AI) are being increasingly integrated with these approaches. The AI-driven analysis of multi-omics data (including miRNA profiles) and clinical parameters enables improved risk stratification, the identification of therapeutic targets, and the prediction of individual responses to therapy, which is particularly relevant in CKM syndrome given the complex interplay of cardiovascular, renal, and metabolic pathways [121].

In the context of Cardio–Kidney–Metabolic (CKM) syndrome, these cellular therapies have the potential to not only restore glycemic control but also mitigate downstream cardiovascular and renal complications by addressing the root cause—β-cell dysfunction and systemic metabolic dysregulation. The integration of these therapies into clinical practice will require multidisciplinary care models and a careful consideration of their impact on interconnected organ systems [115,116,117].