Beneficial effect of sodium-glucose cotransporter 2 inhibitors on kidney function can be just a mirage

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors suppress glucose reabsorption in the kidney proximal tubule through the SGLT2 protein, leading to glucosuria and osmotic diuresis. Randomized placebo-controlled clinical trials show that SGLT2 inhibitors increase long-term estimated glomerular filtration rate (GFR), calculated with serum creatinine-based equations. However, this effect of SGLT2 inhibitors may not reflect an improvement of kidney function. Investigations conducted in healthy volunteers and patients with chronic kidney disease and population-based studies reveal a positive association between urinary osmolality and GFR, either measured or estimated, indicating that glucosuria and osmotic diuresis are associated with glomerular hyperfiltration. Further, glomerular hyperfiltration is magnified by animal meat consumption. Therefore, the elevation of estimated GFR observed in patients receiving SGLT2 inhibitors may represent an adaptive response to glucosuria and osmotic diuresis driven by these drugs rather than an improvement of kidney function. Additionally, SGLT2 inhibitors have been consistently associated with loss of skeletal muscle mass. Reduction of muscle mass lowers serum creatinine. Serum creatinine-based equations to evaluate GFR overestimate kidney function in patients with reduced muscle mass. In patients receiving SGLT2 inhibitors, estimation of GFR using serum creatinine formulas may yield misleading high values of GFR that do not reflect a beneficial effect on kidney function.

Key Words: Sodium-glucose cotransporter-2 inhibitors; Estimated glomerular filtration rate; Glomerular hyperfiltration; osmotic diuresis; Glucosuria; Skeletal muscle mass; Serum creatinine-based estimation of glomerular filtration rate; Kidney function overestimation

Core Tip: Sodium-glucose cotransporter-2 (SGLT2) inhibitors increase long-term serum creatinine-based estimated glomerular filtration rate (GFR), but this effect may not represent a kidney protective effect. Subjects undergoing osmotic diuresis exhibit glomerular hyperfiltration. In patients receiving SGLT2 inhibitors, the elevated estimated GFR may reflect an adaptive response to osmotic diuresis rather than an improvement of kidney function. In addition, loss of skeletal muscle mass has been consistently associated with use of SGLT2 inhibitors. In patients with reduced muscle mass, serum creatinine-based estimation of GFR produces a deceptive increase of estimated GFR. In patients receiving SGLT2 inhibitors, increased estimated GFR may represent an overestimation of the factual kidney function rather than an actual improvement.

INTRODUCTION

Randomized placebo-controlled clinical trials have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors increase long-term serum creatinine-based estimated glomerular filtration rate (GFR) in patients with and without type 2 diabetes (T2D)[1-3]. However, the increase in estimated GFR driven by SGLT2 inhibitors may not represent a kidney protective effect. Subjects undergoing glucosuria or osmotic diuresis of any cause exhibit glomerular hyperfiltration[4-10]. Therefore, the elevated GFR observed in patients receiving SGLT2 inhibitors may reflect an adaptive response to glucosuria and osmotic diuresis elicited by these drugs rather than an improvement of kidney function. In addition, loss of skeletal muscle mass has been consistently associated with SGLT2 inhibitors use. Reduction of skeletal muscle mass lowers serum creatinine concentration. Lower serum creatinine in patients with reduced muscle mass causes a spurious increase in the estimated GFR when the estimation is calculated with serum creatinine-based equations[1,2]. In the presence of loss of skeletal muscle mass, serum creatinine-based estimations of GFR overestimate kidney function. Therefore, the increase in serum creatinine-based estimated GFR observed in patients receiving SGLT2 inhibitors may represent an overestimation of kidney function rather than an actual improvement (Figure 1).

Figure 1 The increase in the glomerular filtration rate induced by sodium-glucose cotransporter-2 inhibitors does not correspond to an improvement in kidney function. Sodium-glucose cotransporter-2 (SGLT2) inhibitors induce: (1) Adaptive glomerular hyperfiltration in response to glucosuria and subsequent osmotic diuresis; and (2) Loss of skeletal muscle mass that reduces serum creatinine concentration. Lower serum creatinine level leads to an overestimation of kidney function when estimated glomerular filtration rate (GFR) is calculated with serum creatinine-based equations. The increase in serum creatinine-based estimated GFR associated with SGLT2 inhibitors may be attributable to either one or both of these confounding processes and may not reflect a beneficial effect on kidney function. SGLT2: Sodium-glucose cotransporter-2; GFR: Glomerular filtration rate.

SGLT2 INHIBITORS INCREASE LONG-TERM SERUM CREATININE-BASED ESTIMATED GFR

In patients with chronic kidney disease (CKD), randomized placebo-controlled trials have shown that therapy with SGLT2 inhibitors increases estimated GFR (after an initial decline), calculated by serum creatinine-based formulas, irrespective of the presence or absence of diabetes (Table 1). In 2019, the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation study reported that canagliflozin (compared to placebo) reduced the risk of a composite of end-stage kidney disease (ESKD), doubling of the serum creatinine level, or death from renal or cardiovascular causes, in T2D patients with kidney disease (albuminuria and an estimated GFR of 30 to < 90 mL/minute/1.73 m²) treated with renin-angiotensin system blockade, over a median follow-up of 2.62 years. Kidney function was assessed by estimated GFR, calculated with a serum creatinine-based CKD-epidemiology collaboration (CKD-EPI) equation. In 2020, the Dapagliflozin and Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease study reported that dapagliflozin, compared to placebo, reduced the risk of a composite of sustained decline in the estimated GFR of at least 50%, ESKD, or death from renal or cardiovascular causes, in patients with kidney disease (estimated GFR of 25 to 75 mL/minute/1.73 m² and albuminuria), over a median follow-up period of 2.4 years, regardless of the presence of T2D. Kidney function was assessed by estimated GFR calculated with a serum creatinine-based CKD-EPI equation[2]. In 2023, the Study of Heart and Kidney Protection with Empagliflozin reported that empagliflozin, compared to placebo, reduced progression of kidney disease (defined as ESKD, sustained decrease in estimated GFR to < 10 mL/minute/1.73 m², sustained decrease in estimated GFR of ≥ 40% from baseline, or death from renal causes), in patients with CKD, regardless of the presence of diabetes, over a median follow-up of 2.0 years. Kidney function was assessed by estimated GFR calculated with a serum creatinine-based CKD-EPI formula[3]. Subsequent studies[4-6], systematic reviews and meta-analyses[7-12] and a Cochrane systematic review[13] confirmed that SGLT2 inhibitors reduced the rate of decline of estimated GFR in CKD patients with and without diabetes. In a systematic review and meta-analysis that included 9 studies involving patients with kidney disease (estimated GFR < 60 mL/minute/1.73 m² and/or albuminuria > 300 mg/g), overall, SGLT2 inhibitors reduced the risk of a composite of worsening kidney function, ESKD, or renal death[7]. In a systematic review and meta-analysis that included 5 studies reporting the mean change in estimated GFR from baseline values, dapagliflozin reduced chronic estimated GFR decline compared to placebo in 2 studies (a third long duration study was excluded due to difficulties in data extraction)[10]. In a systematic review and meta-analysis that included 13 randomized controlled trials (29614 patients) with follow-up ≥ 12 weeks, SGLT-2 inhibitors improved kidney outcomes in adults with CKD, although the absolute benefit was variable depending on the baseline risk of kidney complications[11]. In a systematic review and meta-analysis that included 16 randomized controlled trials involving 52306 patients, SGLT2 inhibitors improved the rate of change in estimated GFR after 64 weeks. No differences were observed in death due to kidney disease or events of estimated GFR < 15 mL/minute/1.73 m²[12]. In a Cochrane systematic review that included 53 randomized controlled trials comprising 65,241 patients with diabetes and any stage of CKD (from 1 to 5) excluding dialysis, SGLT2 inhibitors decrease the risk of kidney composite outcomes (kidney failure, kidney death with or without ≥ 40% decrease in estimated GFR) compared to placebo[13].

Table 1 Randomized placebo-controlled clinical trials revealing that sodium-glucose cotransporter-2 inhibitors increase serum creatinine-based estimated glomerular filtration rate.

	Ref.	Study design	Sodium-glucose cotransporter-2 inhibitor	Formula used to estimate GFR	Study population	Number of participants	Primary outcome	Median surveillance period	Estimated GFR change	Main results on kidney disease
Canagliflozin and renal outcomes in type 2 diabetes and nephropathy	Perkovic et al[1], 2019	Randomized, double-blind, placebo-controlled trial	Canagliflozin (100 mg/day) vs placebo	CKD-EPI equation	Patients with T2D treated with renin-angiotensin system blockade, estimated GFR 30-90 mL/min/1.73 m2, and albuminuria	4401	Composite of ESKD (sustained estimated GFR of < 15 mL/minute/1.73 m2, transplantation or dialysis), a doubling of the serum creatinine level, or death from renal or cardiovascular causes	2.62 years	After 3 weeks, the decline in the estimated GFR was slower in the canagliflozin group than in the placebo group (-1.85 ± 0.13 vs -4.59 ± 0.14 mL/minute/1.73 m2 per year)	The relative risks of the primary outcome, the renal-specific composite (ESKD, a doubling of the creatinine level, or death from renal causes), and ESKD were all lower in the canagliflozin group than in the placebo group, by 30%, 34% or 32%, respectively
Dapagliflozin in patients with chronic kidney disease	Heerspink et al[2], 2020	Randomized, double-blind, placebo-controlled trial	Dapagliflozin (10 mg/day) vs placebo	CKD-EPI equation	Patients with CKD with or without diabetes, estimated GFR 25-75 mL/min/1.73 m2 and albuminuria	4304	Composite of a sustained decline in the estimated GFR of at least 50%, ESKD, or death from renal or cardiovascular causes	2.4 years	After 2 weeks, the annual change in the estimated GFR was smaller with dapagliflozin than with placebo (-1.67 ± 0.11 and -3.59 ± 0.11 mL/minute/1.73 m2, respectively)	The risk of a composite of a sustained decline in the estimated GFR of at least 50%, ESKD, or death from cardiovascular or renal causes was significantly lower with dapagliflozin than with placebo. The effects were similar in participants with and without T2D
Empagliflozin in patients with chronic kidney disease	Herrington et al[3], 2023	Randomized, double-blind, placebo-controlled trial	Empagliflozin (10 mg/day) vs placebo	CKD-EPI equation	Patients with CKD and either estimated GFR 20-45 mL/minute/1.73 m2 or estimated GFR 45-90 mL/minute/1.73 m2 and albuminuria	6609	Composite of progression of kidney disease (ESKD, sustained decrease in estimated GFR to < 10 mL/minute/1.73 m2, sustained decrease in estimated GFR of ≥ 40% from baseline, or death from renal causes) and death from cardiovascular causes	2 years	After 2 months, there was a between-group (empagliflozin vs placebo) difference of 1.37 mL/minute/1.73 m2 (95%CI: 1.16-1.59) per year	Empagliflozin therapy led to a lower risk of the composite of progression of CKD and death from cardiovascular causes compared to placebo. The effects were similar in participants with and without T2D

GFR: Glomerular filtration rate; T2D: Type 2 diabetes; ESKD: End-stage kidney disease; CKD-EPI: Chronic kidney disease-epidemiology collaboration.

SGLT2 INHIBITORS INDUCE GLUCOSURIA AND OSMOTIC DIURESIS

SGLT2 inhibitors suppress glucose (and sodium) reabsorption in the kidney proximal tubule via the SGLT2 protein, (Figure 2) provoking glucosuria and subsequent increase in urine osmolality, osmotic diuresis, and reduction of the free water clearance (Figure 3). In addition, SGLT2 inhibitors induce a two-phase change in estimated GFR. An initial drop (estimated GFR dip) has been very consistently observed following administration of these drugs. After this transitory decline, SGLT2 inhibitors induce a sustained increase in the estimated GFR[1-3,14-22]. Two meta-analyses show that the magnitude of the acute dip in estimated GFR is generally mild (about 3-6 mL/minute/1.73 m²) and short-lived, having a duration of approximately 1-6 weeks[20,21]. The transient fall in estimated GFR that follows SGLT2 administration has been attributed to the tubuloglomerular feedback, an acute kidney adaptation that induces vasoconstriction of the afferent glomerular arteriole in response to increased amount of sodium reaching the distal tubule (macula densa). In order to maintain plasma volume and GFR, adaptive mechanisms take place following SGLT2 inhibition, including activation of the renin-angiotensin-aldosterone system (increased plasma renin and angiotensin II and urinary aldosterone concentration) and increased plasma copeptin level, a surrogate of plasma vasopressin[15,23-25]. These compensatory mechanisms tend to normalize in the long term. At 6 months of therapy, plasma copeptin, renin, and aldosterone concentrations have been reported similar between patients receiving dapagliflozin and control individuals[25].

Figure 2 The sodium glucose cotransporter-2 protein conveys glucose and sodium from the lumen of the kidney proximal tubule to the blood. SGLT2: Sodium-glucose cotransporter-2.

Figure 3 Sodium glucose cotransporter-2 inhibitors induce glucosuria and subsequent osmotic diuresis. SGLT2: Sodium-glucose cotransporter-2.

Due to their effect inducing osmotic diuresis, SGLT2 inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death[13,26,27]. However, a beneficial effect of SGLT2 inhibitors on the risk of atherosclerotic cardiovascular disease (myocardial infarction or stroke) has not been consistently found[13,27,28]. In a randomized trial that treated 7020 T2D patients with either empagliflozin or placebo for a median time of 3.1 years, no differences in the rate of myocardial infarction or stroke were observed, although lower rates of hospitalization for heart failure and cardiovascular death were identified in the empagliflozin group[28]. In a meta-analysis that included 11 trials involving 78607 patients (42568 with diabetes, 20725 with heart failure, and 15314 with CKD), SGLT2 inhibition reduced the rate of cardiovascular death across the three population groups. However, the benefit for cardiovascular death was driven by a reduction in heart failure death and sudden cardiac death while no significant beneficial effect for myocardial infarction or stroke was observed[27]. In a systematic review and meta-analysis of 13 randomized controlled trials involving 90413 participants, SGLT2 inhibitors reduced the risk of hospitalization for heart failure, but no statistical difference was observed in the risk for cardiac death or stroke in T2D patients[29]. In a Cochrane systematic review that included 53 randomized controlled trials comprising 65241 patients with diabetes and any stage of CKD excluding dialysis, SGLT2 inhibitors decreased the risk of hospital admission due to heart failure and cardiovascular death, but had little or no beneficial effect on the risk of myocardial infarction or stroke[13]. Likewise, in an observational study comparing empagliflozin with dipeptidyl peptidase-4 inhibitors, no differences were observed in the risk of myocardial infarction and stroke between the two groups[26]. Accordingly, SGLT2 inhibitors fail to show a beneficial effect on atherosclerotic vascular injury, such as arterial stiffening[30] or increased intima-media thickness[31].

OSMOTIC DIURESIS IS INDEPENDENTLY ASSOCIATED WITH GLOMERULAR HYPERFILTRATION

An acute reduction in plasma volume leads to kidney vasoconstriction and acute decline in the GFR. However, persistent osmotic diuresis (that may result in mild and continuous reduction in plasma volume) induces glomerular hyperfiltration in order to support the mandatory urinary loss of water imposed by osmotic diuresis (Figure 4). Glomerular hyperfiltration in the presence of persisting osmotic diuresis may be enabled by vasoconstriction of the efferent glomerular arteriole to increase the filtration fraction in the setting of subclinical dehydration. In healthy volunteers under low hydration conditions, a positive correlation between urine osmolality and GFR (measured by inulin clearance) has been observed. In subjects with subclinical dehydration, high urine osmolality is associated with glomerular hyperfiltration[32,33].

Figure 4 Glucosuria induces osmotic diuresis and subsequent glomerular hyperfiltration. A: In healthy humans with blood glucose concentration below the kidney threshold for glucose reabsorption (approximately 180-200 mg/dL or 10-11 mmol/L), glucose is reabsorbed in the proximal tubule and no glucose is detectable in urine; B: Glucosuria occurs when glucose reabsorption in the proximal tubule is inhibited or when the plasma glucose concentration exceeds the kidney threshold for glucose reabsorption. The presence of glucose in urine requires concomitant elimination of water (osmotic diuresis). Glomerular hyperfiltration may be an adaptive response that arises in order to supply the obligatory loss of water in urine in the setting of glucosuria and osmotic diuresis.

In normal subjects, glucose infusion to induce hyperglycemia above the kidney threshold for glucose reabsorption (around 180-200 mg/dL or 10-11 mmol/L) increases GFR, measured by ¹²⁵I-iothalamate clearance. In contrast, no change in GFR is observed following oral glucose administration that rises plasma glucose below the kidney threshold for glucose reabsorption, suggesting that the presence of glucosuria may contribute to increase GFR[34,35].

Similar responses have been noted in patients with type 1 diabetes (T1D). A rise in blood glucose values from 4.6 to 16.0 mmol/L elevates GFR (measured by ¹²⁵I-iothalamate clearance) in T1D patients[35,36]. Likewise, a glucose infusion to achieve plasma glucose concentration of 15.5 mmol/L increases GFR, measured by polyfructosan (inulin analogue) clearance, in T1D patients with diabetic kidney disease[37]. Accordingly, in a study that included 637 patients with diabetes and hyperglycemia (blood glucose levels > 11 mmol/L), higher glucose reabsorption in the kidney proximal tubule (resulting in lower amount of glucose in urine) is associated with lower estimated GFR, calculated by the CKD-EPI equation[38].

Large population-based investigations conducted in different ethnic groups reveal a positive association between urine osmolality (or urine specific gravity) and estimated GFR, after multivariable adjustment. Increased urine osmolality (or increased urine specific gravity) is independently associated with higher estimated GFR in the general population[39-41]. In a cross-sectional study that included 28342 community-dwelling participants in the Korea National Health and Nutrition Examination Surveys, multivariate linear regression analyses indicate that the urine specific gravity unit, defined as (urine specific gravity − 1.0) × 100, is positively associated with estimated GFR, calculated using a CKD-EPI equation, independently of confounding. In the general population, increased urine specific gravity (reflecting increased concentration of solutes in urine) is associated with glomerular hyperfiltration. The relationship between urine specific gravity and estimated GFR is J-shaped, so that estimated GFR rises as urine specific gravity unit increases[40]. Comparable findings have been obtained in the United States general population. Urine concentration is positively associated with estimated GFR, after multivariable adjustment. In a cross-sectional analysis of National Health and Nutrition Examination Surveys (NHANES) data, lower fasting urine concentration (urine specific gravity in 2007-2008 NHANES or urine osmolality in 2009-2010 NHANES) is independently associated with lower estimated GFR, calculated with a CKD-EPI formula. Compared to the highest quintile, estimated GFR is lower in the lowest quintile of urine specific gravity. Likewise, compared to the highest quintile, estimated GFR is lower in the lowest quintile of fasting urine osmolality in 2009-2010 NHANES[39].

Similarly to community-living subjects, urine osmolality is positively associated with GFR (either measured or estimated) in CKD patients, regardless of confounding[41,42]. In the French NephroTest Cohort Study, a cross-sectional analysis of baseline data involving 1796 patients with CKD (median GFR of 40.2 mL/minute/1.73 m², measured by ⁵¹Cr-EDTA clearance), fasting urine osmolality is strongly and independently associated with measured GFR. CKD patients with higher urine osmolality show higher measured GFR compared to CKD patients with lower urine osmolality[42]. Likewise, in a cross-sectional investigation of the 2009-2012 NHANES that analyzed data from 7373 participants, a positive and independent correlation between urine osmolality and estimated GFR (calculated with a CKD-EPI equation) is identified in patients with CKD (estimated GFR < 60 mL/minute/1.73 m²). Higher urine osmolality is associated with increased estimated GFR among adults with CKD[41].

Furthermore, glomerular hyperfiltration induced by osmotic diuresis may be magnified by animal meat consumption[32,33,43]. In healthy volunteers under low hydration conditions, intake of animal meat induces an increase in the GFR (measured by inulin clearance) compared to high hydration conditions. In normal humans, subclinical dehydration magnifies the increase in GFR induced by animal meat consumption[32].

IN PATIENTS TREATED WITH SGLT2 INHIBITORS, ONGOING GLUCOSURIA AND SUBSEQUENT OSMOTIC DIURESIS MAY INDUCE GLOMERULAR HYPERFILTRATION

Patients receiving SGLT2 inhibitors experience persistent glucosuria and ongoing osmotic diuresis. Hemoconcentration[44] and a reduction in body water[45] have been detected among these patients. As mentioned, increased urine osmolality (or increased urine specific gravity) is associated with glomerular hyperfiltration in subjects from the general population and in patients with CKD. Therefore, in patients receiving SGLT2 inhibitors, the observed rise in estimated GFR may be caused by an adaptive response to glucosuria and osmotic diuresis that does not represent an improvement of kidney function. Accordingly, a patient with severe familiar renal glucosuria (virtually complete absence of tubular glucose reabsorption) has been shown to experience glomerular hyperfiltration, with a GFR (measured by inulin clearance) of 148-153 mL/minute/1.73 m²[46]. Mutations in the SLC5A2 gene, that encodes the SGLT2 protein, cause familial renal glucosuria, a condition reminiscent of the status that follows administration of SGLT2 inhibitors, particularly in non-diabetic subjects. Patients with familial renal glucosuria experience normal blood glucose levels and isolated persistent glucosuria[47].

Furthermore, SGLT2 inhibitors increase estimated GFR (following the initial dip) regardless of the degree of estimated GFR prior to therapy, so that the rise in estimated GFR driven by SGLT2 inhibitors takes place not only in patients with CKD (estimated GFR < 60 mL/minute/1.73 m²), but also in subjects with estimated GFR 60-90 mL/minute/1.73 m² or estimated GFR > 90 mL/minute/1.73 m². T2D patients with estimated GFR > 90 mL/minute/1.73 m² treated with SGLT2 inhibitors experience an increase in estimated GFR, suggesting that these drugs induce glomerular hyperfiltration[16-20]. In a retrospective cohort study that enrolled 648 T2D patients (216 on SGLT2 inhibitors and 432 matched control subjects) with an average estimated GFR of 84.7 mL/minute/1.73 m², calculated using the serum creatinine-based CKD-EPI 2009 equation, patients receiving SGLT2 inhibitors showed an annual increase in estimated GFR during the surveillance period (4 years), unlike control subjects[17]. In a longitudinal cohort study that enrolled 13666 matched pairs of T2D patients using either SGLT2 inhibitors or other glucose-lowering drugs (2300 patients with estimated GFR < 60 mL/minute/1.73 m², 5705 subjects with estimated GFR 60-90 mL/minute/1.73 m², and 5509 subjects with GFR > 90 mL/minute/1.73 m²), T2D patients on SGLT2 inhibitors showed an increase in the estimated GFR, calculated with a serum creatinine-based modification of diet in renal disease (MDRD) equation, compared to other antidiabetic agents. In stratified analysis, SGLT2 inhibitors increased estimated GFR irrespective of baseline GFR. Over a follow-up period of 12 months, an average monthly increase in estimated GFR of 0.84 mL/minute/1.73 m² was observed after the initial dip[16]. Similar results have been obtained in other longitudinal studies. T2D patients with estimated GFR > 90 mL/minute/1.73 m² receiving SGLT2 inhibitors experienced an increase in estimated GFR (calculated by serum creatinine-based equations, either MDRD or CKD-EPI) compared to other glucose-lowering medications[18,19]. In a systematic review and meta-analysis that included 25 studies involving 43721 participants, SGLT2 inhibitors induced an elevation in estimated GFR across categories of baseline estimated GFR levels in patients with T2D, compared to placebo[20].

Pathophysiological mechanisms underlying glomerular hyperfiltration in subjects with osmotic diuresis are unclear. It has been proposed that enhanced vasopressin secretion in response to subclinical dehydration may play a role increasing GFR. In patients with familial renal glucosuria, the suppression of glucagon secretion that normally follows glucose ingestion has been found absent, so that these patients exhibit increased glucagon secretion during the post-prandial period[48]. Glucagon induces glomerular hyperfiltration and may contribute to increase GFR among these subjects. However, the role of these hormones increasing GFR in subjects with osmotic diuresis requires further elucidation.

SGLT2 INHIBITORS INDUCE A REDUCTION IN SKELETAL MUSCLE MASS

Therapy with SGLT2 inhibitors has been consistently associated with a reduction of skeletal muscle mass[44,45,49-60]. Longitudinal investigations performed in different ethnic groups receiving varied SGLT2 inhibitors associate these drugs with loss of skeletal muscle mass, independently of confounding variables[44,50-52,54-57,60]. In a prospective study that followed Japanese T2D patients treated with SGLT2 inhibitors for a year, the skeletal muscle mass index (skeletal muscle mass/height²) was reduced at and after week 36[54]. In a longitudinal study that recruited T2D patients treated with SGLT2 inhibitors as an add-on therapy to metformin for 52 weeks, skeletal muscle mass was reduced, particularly at 12 months, compared to baseline values[56]. In a retrospective cohort study with a mean follow-up period of 4.4 years that enrolled T2D patients treated with SGLT2 inhibitors for more than two years, a reduction in skeletal muscle mass was observed compared to baseline values. Older individuals receiving SGLT2 inhibitors experienced loss of skeletal muscle mass earlier than younger patients[57]. In a prospective study that followed CKD patients (with and without T2D) treated with dapagliflozin for 24 weeks, skeletal muscle index decreased at 12 weeks and even more at 24 weeks[60].

In a randomized controlled trial aimed to compare the effects of dapagliflozin and vitamin E on metabolic dysfunction-associated steatotic liver disease in patients with T2D, dapagliflozin therapy was associated with a clinically significant decline in the skeletal muscle index, absent in the vitamin E group[58].

In 2022, a systematic review and meta-analysis that included 18 randomized controlled trials with 1430 participants, revealed that SGLT2 inhibitors reduced lean mass and skeletal muscle mass, increasing the risk of sarcopenia[53].

In 2023, two systematic reviews and meta-analyses of randomized controlled trials corroborate the detrimental effect of SGLT2 inhibitors on skeletal muscle mass[45,55]. In a meta-analysis that included 25 randomized controlled trials involving 2286 T2D patients, SGLT2 inhibitors reduced lean mass, skeletal muscle mass, and skeletal muscle index[45]. In a systematic review and meta-analysis that included 19 randomized controlled trials involving 1482 T2D patients, participants treated with SGLT2 inhibitors demonstrated a reduction in lean body mass and skeletal muscle mass, compared to the control group. In addition, SGLT2 inhibitors may lead to a reduction in muscle strength[55].

In 2025, a study aimed to investigate the association between antidiabetic drugs and sarcopenia analyzed reports of the World Health Organization international pharmacovigilance database from 1967 to 2023. Overall, antidiabetic drugs show significant associations with sarcopenia. Among them, SGLT2 inhibitors exhibit the strongest association[59].

In patients treated with SGLT2 inhibitors, loss of skeletal muscle mass can result in overestimation of kidney function when estimated GFR is calculated with serum creatinine-based equations.

Serum creatinine concentration is related with skeletal muscle mass. A decline in skeletal muscle mass lowers serum creatinine, leading to a deceptively elevated estimated GFR when calculated with serum creatinine-based equations. In patients with reduced skeletal muscle mass, serum creatinine-based estimations of GFR overestimate kidney function[61]. Therefore, in patients receiving SGLT2 inhibitors, estimations of GFR based on serum creatinine formulas may yield a misleadingly increased value of estimated GFR due to reduced skeletal muscle mass that does not represent an improvement of kidney function. In the setting of SGLT2 inhibitors use, increased estimated GFR calculated with serum creatinine-based equations may reflect an overestimation of kidney function rather than a kidney protective effect. Therefore, creatinine-based estimation of GFR is not reliable to determine GFR decline among patients receiving SGLT2 inhibitors[62-64]. In a case-control study that recruited 180 T2D patients (90 receiving SGLT2 inhibitors and 90 matched controls), those on SGLT2 inhibitors had lower plasma creatinine concentration and correspondingly higher creatinine-based estimated GFR (calculated by a CKD-EPI formula), compared to T2D patients free of these drugs. In contrast, plasma cystatin C level and cystatin C-based estimated GFR (calculated by a CKD-EPI equation) did not differ between the two groups. Accordingly, the difference between creatinine-based estimated GFR and cystatin C-based estimated GFR was higher in patients receiving SGLT2 inhibitors compared to control subjects, suggesting that the overestimation of creatinine-based estimated GFR compared to cystatin C-based estimated GFR is higher among patients receiving SGLT2 inhibitors. Creatinine-based estimation of GFR overestimates GFR in patients receiving SGLT2 inhibitors[63].

FUTURE RESEARCH DIRECTIONS

A causal relationship between glucosuria and glomerular hyperfiltration cannot be established based on cross-sectional studies, but it is highly suggested by investigations performed in healthy volunteers and patients with diabetes. The increase in estimated GFR observed in subjects with GFR > 90 mL/minute/1.73 m² receiving SGLT2 inhibitors seems to indicate that these drugs induce glomerular hyperfiltration. In addition, given the robust limitation of serum creatinine-based equations to accurately estimate GFR among subjects with loss of skeletal muscle mass (such as patients receiving SGLT2 inhibitors), human research is warranted in order to confirm the beneficial effect of these antidiabetic drugs on kidney function.

LIMITATIONS

The literature search was performed only in the PubMed database and restricted to articles published in English concerning human beings. Other medical databanks, books, conference proceedings, theses, artificial intelligence, or other types of dissertations that may contain information related to the topic of the review were not examined. As a result, some degree of selection bias may have occurred. In addition, some of the reviewed studies had an observational design, limiting their ability to demonstrate causality.

CONCLUSION

SGLT2 inhibitors attenuate glucose reabsorption in the kidney proximal tubule, inducing glucosuria and osmotic diuresis. The elevated GFR observed in patients receiving SGLT2 inhibitors may reflect adaptive glomerular hyperfiltration in the setting of persistent glucosuria and osmotic diuresis rather than a protective effect on kidney function. In addition, the loss of skeletal muscle mass associated with use of SGLT2 inhibitors makes unreliable the estimation of GFR based on serum creatinine formulas. In the presence of loss of skeletal muscle mass, serum creatinine-based estimation of GFR overestimates kidney function and renders a misleading high value of estimated GFR. Therefore, the increased serum creatinine-based estimated GFR observed in patients receiving SGLT2 inhibitors may represent a spurious overestimation of GFR rather than an improvement of kidney function.