The complex interplay between obesity and diabetes leads to overall kidney damage. This damage primarily emerges from neurohormonal shifts in the cardiovascular system, characterized by increased sympathetic activity, accelerating heart rate, and spiking blood pressure levels (7). Central to this is the role of angiotensin II, synthesized in adipose tissue, which interfaces with diverse pathways to induce endothelial dysfunction, inflammation, and fibroblast proliferation (8, 9). Another exacerbator of obesity is related to the growth in the body surface, which often outpaces renal mass expansion, facilitating conditions like hyperfiltration within the glomerular filtration barrier focal and segmental glomerulosclerosis, and glomerulomegaly. Consequently, obesity is considered to be a main risk factor for diabetes and its progression to DKD (10–12).

Hyperglycemia, or elevated blood sugar levels, is a primary factor in kidney damage. Several theories have been proposed to explain the relationship between high glucose levels and renal impairment. The main ones include sorbitol formation, oxidative stress escalation, protein kinase C activation, and hexosamine pathway activation (13, 14). However, the most widely accepted theory centers around advanced glycation end products (AGEs). AGEs are complex compounds that form when the residuals of the reduction of sugars are bound to proteins. AGEs can damage cells in several ways. First, they can generate reactive oxygen species (ROS), which can damage DNA. Second, AGEs can activate transcription factors that can produce inflammatory cytokines (15, 16). Third, they can bind to growth factors, such as transforming growth factor β (TGF-β), which can promote fibrosis, and the vascular endothelial growth factor (VEGF), an influential angiogenic mediator (17). In the next sections, we will mention the role of managing blood glucose and how it is an essential factor in reducing the risk of progression to DKD.

Arterial hypertension in patients living with diabetes has unique physiopathological features (18–20). These patients tend to experience higher elevations in systolic blood pressure, wider pulse pressures, increased blood pressure variability, heightened salt sensitivity, a tendency toward hyperkalemia, and orthostatic hypotension, among others. These processes are combined with specific CKD-related mechanisms, such as the activation of the renin-angiotensin-aldosterone system (RAAS), stress on the renal microvasculature and the endoplasmic reticulum, mitochondrial dysfunction, and apoptosis, which ultimately promote endothelial cell damage, thickening of the glomerular basement membrane, podocyte effacement, and pedicel fusion (21). Therefore, blood pressure targets are one of the main protective factors to the onset of DKD. In this context, patients’ optimal blood pressure targets are a topic of ongoing debate. Some guidelines and studies recommend aiming for a blood pressure below 140/90 mmHg, while others advocate for even lower targets, such as 130/80 mmHg or a systolic pressure of less than 120 mmHg (22, 23). In terms of pharmacological treatment, medications that have been shown to be effective in lowering blood pressure in the context of DKD include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) (23–25). Based on individual patient conditions, diuretics or calcium channel blockers may serve as second-line treatments, with spironolactone positioned as a potential fourth-line option (26, 27). Some clinical trials have highlighted the potential benefit of using chlorthalidone as an alternative to spironolactone for people with refractory hypertension and decreased glomerular filtration rate (28). In patients with absolute or relative contraindications to use ARBs or ACEIs, non-dihydropyridine Calcium Channel Blockers, whose beneficial effect on proteinuria is documented in clinical studies, may be considered (29).

Dyslipidemia is highly prevalent in Mexico. In national surveys, hypoalphalipoproteinemia is the most frequent dyslipidemia in Mexico, followed by hypertriglyceridemia (30). The co-existence of dyslipidemia and diabetes is also extremely high. In some studies from other countries, rates have been reported up to 85.3%, with a higher prevalence in females and the elderly (31). The pathophysiological mechanism of kidney damage due to dyslipidemia is linked with lipotoxicity, which generates an exacerbated inflammatory process. Free fatty acids (FFAs) are triacylglycerols stored in adipose tissue, primarily as abdominal fat. When abdominal fat increases, there is a rise in blood FFAs, which exceeds the maximum lipid storage capacity of adipose tissue, releasing lipid mediators that cause insulin resistance and accumulation of fatty acids in other tissues, such as the heart, blood vessels, kidneys, liver, and pancreas. This leads to an increase in the expression of inflammatory cytokines, oxidative stress, lipid peroxidation, and vesicular transport dysfunction, causing endoplasmic reticulum and lysosomal stress. All these alterations promote atherogenesis in renal vasculature and the progression of kidney damage (32). Moreover, it has also been reported that dyslipidemia increases the values of oxidized low-density lipoprotein cholesterol in plasma and renal parenchyma, which are cytotoxic to kidney cells, inducing apoptosis of tubular cells (33). Currently, the term “fatty kidney” has been coined. This condition is characterized by the ectopic accumulation of lipids in kidney tissue, causing lesions at the level of podocytes, proximal tubule epithelial cells, and tubulointerstitial tissue (34).

Patients with detected DKD experience an average annual decrease in GFR of 10 to 20 mL/min/1.73m^2, which can lead to End-Stage Renal Disease (ESRD) within 7–8 years (47, 48). Therefore, GFR is an important marker in determining the progression of DKD and predicting the onset of ESRD. In clinical practice, the most commonly used equations to determine the estimated GFR (eGFR) in patients aged 18 to 70 years are the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease by Isotope-Dilution Mass Spectrometry (MDRD-IDMS) (49). MDRD-IDMS and CKD-EPI equations effectively estimate GFR levels below 60 mL/min/1.73m², but CKD-EPI is superior for rates between 60 and 120 mL/min/1.73m² (50). However, efforts to standardize both formulas for specific populations have yielded varied results. A 2021 systematic review from Latin American countries found no significant differences between the CKD-EPI and MDRD-4-IDMS equations. However, most of these studies focused on Brazilian populations, which limits regional extrapolation (49).

A specific situation arises when managing older adults living with DKD. Two new equations based on serum creatinine and cystatin C have emerged for this specific population. The equation using serum creatinine is called BIS-1, while the one that includes CysC is called BIS-2. Both equations were more accurate than MDRD-IDMS and CKD-EPI within older adults (51, 52). In 2016, a novel equation emerged specifically for patients over 70 years: the FAS (Full Age Spectrum). The FAS equation was better than CKD-EPI in classifying CKD stages, especially when GFR ranged from 15 to 60 mL/min/1.73 m2 (53), and it provided similar results to the BIS-1 equation. Therefore, it has been suggested that using the FAS and BIS formulas is a better approach to measuring the eGFR in older adults.

It has been reported that serum Cystatin C (CysC) is a more accurate indicator of kidney function compared to creatinine (54). As CysC measurements become more widely available in clinical labs, it may be beneficial to consider using CysC-based equations for more accurate estimations whenever possible, particularly in cases where creatinine-based equations might produce inaccurate results due to fluctuating creatinine concentrations, muscle mass/diet changes, or when GFR is between 45 and 59 mL/min/1.73 m² without other damage markers (55). However, the current KDIGO guidelines advise against using CysC routinely due to its potential cost and the need for specialized equipment (47, 48). Therefore, its use may be potentially reserved in a context with high resources.

The pediatric population presents a challenging scenario when it comes to measuring the eGFR, as several equations have been proposed. Among them, the Schwartz equation is the most recommended formula. However, it tends to overestimate the eGFR since it is based on the Jaffé method for measuring creatinine (56). To achieve better results, it has been suggested that the 2012 Schwartz equation is a better approach as it incorporates serum creatinine, cystatin C, blood urea nitrogen, height, and gender (56, 57).

Regarding glycemic control, ADA guidelines propose an HbA1c target of ≤7% in patients living with CKD to decrease the risk of CVD complications (68–70). Previous studies suggest that patients living with diabetes with HbA1c levels between 6.5–7.0% experience a reduced risk of micro and macro-albuminuria and the onset of advanced CKD (71). Similarly, other studies have highlighted the benefits of intensive glycemic control in slowing the risk of progression to DKD (72, 73). However, reaching a threshold <6.5% did not result in a significant benefit for the reduction of CVD (74). Overall, both ADA and KDIGO recommend a personalized approach to setting glycemic targets. In Figure 2, we summarize the main factors to consider individualized HbA1c goals in the context of DKD. These strategies need a collaborative effort between patients and healthcare professionals, ensuring that individual risk factors and the potential benefits of glycemic control are adequately considered. Although a general agreement leans toward maintaining HbA1c levels ≤7.0%, dropping toward a Hba1c <6.5% might inadvertently increase hypoglycemia risk. Additionally, the ADA suggests slightly elevated targets (HbA1c <8%) for specific patient groups, especially those with a limited lifespan, severe complications, multiple comorbidities, or a history of hypoglycemic incidents (75).

A challenging scenario in diabetes care emerges when managing glycemic control in patients living with diabetes with advanced stages of CKD, specifically stages 4 & 5 (68, 76). The discussion becomes even more pronounced for patients undergoing renal replacement therapy (RRT). To achieve optimal glucose management within these populations, there are several factors that need to be taken into account. These include the reduction of renal gluconeogenesis due to a decrease in renal tissue volume, slower metabolism and excretion of insulin and oral diabetic medications, which prolongs the half-life of these drugs, and the development of anorexia, decreased food intake, and subsequent weight loss due to the uremic condition (77).

Another important consideration is the reliability of HbA1c as a marker of glycemic control in patients with GFR <30 mL/min/1.73 m² and anemia due to a curtailed accumulation of glycosylation products and hemoglobin carbamylation (78). These spontaneous processes result from the binding of urea metabolism to protein amino groups. Therefore, carbamylation in the context of CKD may artificially increase and fluctuate HbA1c levels (71, 79). In these scenarios, when GFR falls <30 mL/min/1.73 m², HbA1c measurements might be underestimated by 0.5 to 1.0%. Therefore, adjusting observed values of HbA1c within this range could lead to more accurate estimations to evaluate glycemic control in this population. Another potential option is the use of glycated albumin since it’s not influenced by anemia or other CKD-related treatments. Furthermore, it reflects blood glucose status in an average of 2 to 3 weeks (80). Nevertheless, its application may be restricted to its cost and accessibility in several primary care settings.

SGLT2i act by blocking glucose reabsorption in the proximal convoluted tubule via the SGLT-2 co-transporter, thus leading to glycosuria. By inhibiting the SGLT-2 cotransporter, these drugs also reduce sodium reabsorption, which is typically elevated in patients with diabetes due to excessive tubular glucose loads, thus resulting in natriuresis and decreased intravascular volume and blood pressure. Additionally, natriuresis increases sodium supply to the macula densa by normalizing the tubuloglomerular feedback (82). Therefore, it has been described that SGLT2i reduces intraglomerular pressure by constricting abnormally dilated afferent arterioles, thus mitigating glomerular hyperfiltration and delaying the progression of kidney disease. Other pleiotropic effects that explain the renal benefits of SGLT2i include blood pressure reduction, weight loss, and decreased serum uric acid levels. Additionally, SGLT2i possesses anti-inflammatory and antifibrotic properties, which may counteract renal hypoxia and thus reduce systemic inflammation (83). Nevertheless, their effect depends on renal function, which may lead to pharmacodynamic changes in individuals with reduced kidney function (84). Thus, initiating SGLT2i in patients with GFR <20 mL/min/1.73 m² may not be effective and may even increase the risk for adverse events (85).

SGLT2i have shown a clear benefit in reducing CKD progression and preventing ESRD onset (82). Although the absolute risk reduction is higher among cases with severe albuminuria, the relative risk reduction of renal failure is similar among patients with and without this condition. Several clinical trials have found that canagliflozin, dapagliflozin, and empagliflozin can reduce the risk of ESRD, serum creatinine doubling, heart failure hospitalization, CVD death, and all-cause mortality in patients with diabetes and certain levels of GFR and albuminuria/creatinine ratios (86–88). Ertugliflozin has also been studied and was found to have a slower decline in eGFR and a decrease in urine ACR, thus proving efficacy and safety among patients living with diabetes (89, 90). Other SGLT2i, such as ipragliflozin and luseogliflozin, have been studied in smaller trials with diverse renal outcomes, thus leading to inconclusive results for clinical practice (91, 92).

Side effects of SGLT2i include genital fungal infections, for which approximately 10% of women and 1–2% of uncircumcised men had reported. Other studies have reported an increased rate of orthostatic hypotension, especially when combined with diuretics, and an increase in the risk of euglycemic diabetic ketoacidosis (93). An increased risk of below-the-knee amputations was observed with canagliflozin, whil this was not reported for empagliflozin, dapagliflozin, or ertugliflozin as an adverse outcome in their respective trials (94).

GLP-1 RA have emerged as novel and efficient hypoglycemic agents with significant benefits on cardiovascular and renal outcomes (95). Therefore, for patients living with diabetes and CKD who have not attained glycemic control despite initial glucose-lowering therapy or SGLT2i use, GLP-1 RA represent an attractive alternative. This option not only enhances glycemic control but also offers added renal advantages. GLP-1 RA promote a glucose-dependent insulin response by targeting GLP-1 receptors. These are found in the gastrointestinal tract and other tissues, including glomerular endothelial cells. When administered subcutaneously, GLP-1 RA amplify glucose-dependent insulin secretion, diminish glucagon release, decelerate gastric emptying, and suppress appetite. This multifaceted action can lead to substantial weight loss. Furthermore, GLP-1 RA mitigate albuminuria and mesangial expansion by inhibiting TGF-β signaling (96).

Several clinical trials have assessed the long-term impacts of liraglutide on the composite of diverse clinical outcomes, including improved GFR and decreased risk for CKD onset, kidney disease-related mortality, and CVD mortality. Furthermore, patients treated with liraglutide experienced fewer adverse outcomes compared with conventional treatment (97–99). However, no discernible cardiovascular or CKD benefits were observed with the extended release of either exenatide or lixisenatide (100, 101).

A series of systematic reviews focusing on these two drug groups and their effects on ACR in patients living with diabetes concluded that over extended periods, both canagliflozin and empagliflozin decreased ACR by 19–22% compared with control groups, while GLP-1 RA led to a 17–33% reduction in ACR (102). In patients without diabetes, two multicentric clinical trials found that SGLT2i consistently lowers ACR compared to control groups, irrespective of initial albuminuria status (103). In contrast, GLP-1 RA exhibited diverse impacts on ACR reduction based on initial albuminuria status. Compared to placebo, liraglutide led to ACR reductions of 14, 24, and 13% in patients with normo, micro, and macroalbuminuria, respectively (102).

Based on the research and clinical insights related to glucose management in patients living with DKD, we present the following suggestions tailored for the Mexican context: