Efficacy of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists on proteinuria and weight in a diabetes cohort

Abstract

BACKGROUND

With accumulating evidence showing a benefit in the renal and cardiovascular systems, diabetes guidelines recommend that patients with diabetes and chronic kidney disease (CKD) be treated with sodium-glucose cotransporter-2 inhibitor (SGLT2i) and/or glucagon like peptide-1 receptor agonists (GLP-1RAs) for renal protection. The real-world efficacy of the two medications on the urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) remains to be explored.

AIM

To evaluate the SGLT2i and GLP-1RA application rates and UACR alterations after intervention in a real-world cohort of patients with diabetes.

METHODS

A cohort of 5482 patients with type 2 diabetes were enrolled and followed up at the Integrated Care Clinic for Diabetes of Peking University First Hospital for at least 6 months. Propensity score matching was performed, and patients who were not recommended for GLP-1RA or SGLT2i with comparable sex categories and ages were assigned to the control group at a 1:2 ratio. Blood glucose, body weight, UACR and eGFR were evaluated after 6 months of treatment in real-world clinical practice.

RESULTS

A total of 139 (2.54%) patients started GLP-1RA, and 387 (7.06%) received SGLT2i. After 6 months, the variations in fasting blood glucose, prandial blood glucose, and glycosylated hemoglobin between the GLP-1RA group and the SGLT2i and control groups were not significantly different. UACR showed a tendency toward a greater reduction compared with the control group, although this difference was not statistically significant (GLP-1RA vs control, -2.20 vs 30.16 mg/g, P = 0.812; SGLT2i vs control, -20.61 vs 12.01 mg/g, P = 0.327); eGFR alteration also showed no significant differences. Significant weight loss was observed in the GLP-1RA group compared with the control group (GLP-1RA vs control, -0.90 vs 0.27 kg, P < 0.001), as well as in the SGLT2i group (SGLT2i vs control, -0.59 vs -0.03 kg, P = 0.010).

CONCLUSION

Compared with patients who received other glucose-lowering drugs, patients receiving SGLT2i or GLP-1RAs presented significant weight loss, a decreasing trend in UACR and comparable glucose-lowering effects in real-world settings.

Key Words: Type 2 diabetes; Chronic kidney disease; Body weight; Sodium-glucose cotransporter-2 inhibitors; Glucagon-like peptide-1 receptor agonists

Core Tip: In this study, a cohort of 5482 patients with type 2 diabetes were enrolled and followed up for at least 6 months. After propensity score matching, patients who received glucagon like peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose cotransporter-2 inhibitor (SGLT2i) were compared with those who did not receive either treatment. Patients with increased body mass index were predisposed to treatment with GLP-1RAs, and those with higher urinary albumin-creatinine ratio (UACR) were more likely to be treated with SGLT2is. Patients on SGLT2i or GLP-1RAs showed significant weight loss, a decreasing trend in UACR and comparable glucose-lowering effects compared with patients who received glucose-lowering drugs other than SGLT2i or GLP-1RA in real-world settings.

INTRODUCTION

Diabetes has imposed a heavy burden on the global social economic status, with the prevalence increasing to 12.8% among adults in China, 95% of whom were diagnosed with type 2 diabetes (T2D)[1]. Prior to 2015, either individual glucose-lowering medications or combined therapy with insulin failed to improve renal outcomes. The situation persisted until the publication of the results of the DAPA-chronic kidney disease (CKD) (Dapagliflozin and Prevention of Adverse Outcomes in CKD trial)[2] and trials investigating canagliflozin and empagliflozin in CKD[3,4], which provided robust evidence of the renoprotective and proteinuria-reducing effects of sodium-glucose cotransporter-2 inhibitors (SGLT2is). In addition to SGLT2i, glucagon like peptide-1 receptor agonists (GLP-1RAs) have been suggested to reduce the urinary albumin-creatinine ratio (UACR) in multiple trials involving liraglutide and semaglutide, among others[5]. On the basis of strong evidence of benefit, diabetes guidelines recommend that patients with diabetes and CKD should be treated with SGLT2i and/or GLP-1RAs for renal protection, even if the glucose level target has been reached[6].

In addition to their glucose-lowering and renal-protective effects, GLP-1RAs and SGLT2i exhibit weight loss effects in patients with diabetes. In a meta-analysis, GLP-1RAs resulted in weight loss of 5.79% of the baseline body weight, and SGLT2is resulted in weight loss of 2.07% of the baseline body weight[7]. Therefore, diabetes guidelines recommend that patients with diabetes and overweight or obesity should be treated with SGLT2i and/or GLP-1RAs for the purpose of weight loss[6].

Despite the robust evidence of benefit, the utilization of SGLT2i or GLP1RA was relatively less than the expectations of most health care providers[8]. A single-center study in a real-world setting confirmed the benefit of SGLT2i on CKD progression, but data concerning proteinuria were lacking[9]. Although real-world evidence is accumulating to supplement the strong data from randomized clinical trials (RCTs), more comprehensive real-world studies could contribute to the utilization of these two medications. In this study, we aimed to evaluate the application rates of SGLT2i and GLP-1RA, the alterations in UACR and estimated glomerular filtration rate (eGFR) after treatment, and the factors associated with differential use, including patient demographics and baseline complications, in a real-world cohort of patients with diabetes.

MATERIALS AND METHODS

Settings

A cohort of 6998 patients with T2Ds were regularly followed up at the Integrated Care Clinic for Diabetes of Peking University First Hospital from October 2016 to October 2023. The study protocol was approved by the clinical research ethics committees of Peking University First Hospital and by the institutional review board (No. 2018104). All participants provided written informed consent at the first visit. Patients met the diagnostic criteria of diabetes for T2Ds (American Diabetes Association, 2018)[10] and were followed up at the Integrated Care Clinic for Diabetes for at least 6 months. Patients with type 1 diabetes, who were incapable of regular follow-up, or who were comorbid with severe complications, including diabetic foot or end-stage renal disease (ESRD) and impaired cognitive function, and who were currently in use of SGLT2i or GLP-1RAs at the first visit, were excluded from the study cohort.

At the first visit, 1183 (16.9%) patient who were currently in use of SGLT2i and 497 (7.1%) in use of GLP-1RAs were ruled out. Subsequently, a total of 5482 patients with T2Ds were enrolled in the study cohort. Among them, 139 (2.54%) patients were started on an GLP-1RA, and 387 (7.06%) were treated with SGLT2i after enrollment in the Integrated Care Clinic for Diabetes. Propensity score matching (PSM) was performed, and patients who were not recommended for GLP-1RA or SGLT2i with comparable sex categories, ages, and the duration of diabetes were assigned to the control group at a 1:2 ratio. Demographic data, complications, family history and medications were collected at the first visit. Participants in the GLP-1RA group, SGLT2i group or control group were evaluated every 3 months, and fasting blood glucose (FBG), prandial blood glucose (PBG), glycosylated hemoglobin (HbA_1c), body weight, body mass index (BMI), UACR and eGFR were collected and evaluated at each visit. The treatment of all participants was modified on the basis of diabetes subspecialists in real-world clinical practice.

Statistical analysis

Continuous variables are presented as the means ± SD or medians and were analyzed via paired t tests or Wilcoxon rank sum tests if the variables were normally distributed. Categorical endpoints are presented as percentages and were assessed via χ² analysis. PSM was performed for comparable sex categories, ages, and the duration of diabetes between the treatment and control groups at a 1:2 ratio using logistic regression model with the nearest neighbor matching method in a non-replacement matching manner, and the allowed range difference between the two groups was set at 0.05. After matching, we evaluated the balance of covariates using SMD, and the SMDs of all covariates were less than 0.1, indicating that the differences between groups were small after PSM. Since the UACR was highly discrete, logarithmic analysis was performed. All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, United States), and P < 0.05 was considered to indicate statistical significance.

RESULTS

Baseline characteristics

Patients on GLP-1RA (n = 139, 2.54%) had an age of 52.52 years, among which 55.4% were male and the duration of diabetes onset was 10.25 years. The baseline FBG was 7.81 mmol/L, 2hPBG was 8.55 mmol/L, HbA_1c was 6.91%, UACR was 170.16 mg/g and eGFR was 85.51 mL/min/1.73 m² in the GLP-1RA group. Patients with greater body weight and BMI were predisposed to GLP-1RA treatment (body weight, GLP-1RA group vs control group, 79.66 vs 71.18 kg, P < 0.001; BMI, GLP-1RA group vs control group, 28.11 vs 25.08 kg/m², P < 0.001), whereas other variables were comparable between the GLP-1RA group and the control group (Table 1).

Table 1 Baseline characteristics of the glucagon like peptide-1 receptor agonist group and control group, n (%).

Variables	GLP-1RA group (n = 139)	Control group (n = 278)	P value
Age (years)	52.52 ± 12.65	51.96 ± 13.20	0.872
Sex (male/female, male %)	77/62, 55.40	166/112, 59.71	0.431
Duration of diabetes (years)	10.25 ± 9.15	9.70 ± 8.51	0.726
FBG (mmol/L)	7.81 ± 2.18	7.72 ± 1.97	0.993
2hPBG (mmol/L)	8.55 ± 2.50	8.56 ± 2.21	0.914
HbA1c (%)	6.91 ± 1.20	6.88 ± 1.21	0.956
UACR (mg/g)	170.16 ± 560.78	116.68 ± 408.78	0.053
eGFR (mL/min/1.73 m2)	85.51 ± 23.60	85.91 ± 22.91	0.937
Body weight (kg)	79.66 ± 13.77	71.18 ± 13.83	< 0.001
BMI (kg/m2)	28.11 ± 4.17	25.08 ± 3.65	< 0.001
UACR grades
< 30 mg/g	53 (66.25)	94 (79.66)	0.072
30-300 mg/g	8 (10.00)	10 (8.47)
> 300 mg/g	19 (23.75)	14 (11.86)
BMI grades
18-24 kg/m2	0 (0.00)	6 (3.02)	< 0.001
24-28 kg/m2	20 (14.39)	69 (34.67)
28-35 kg/m2	55 (39.57)	85 (42.71)
> 35 kg/m2	64 (46.04)	39 (19.60)

FBG: Fasting blood glucose; PBG: Prandial blood glucose; HbA_1c: Glycosylated hemoglobin; UACR: Urinary albumin-creatinine ratio; eGFR: Estimated glomerular filtration rate; BMI: Body mass index; GLP-1Ras: Glucagon like peptide-1 receptor agonists.

Patients who were treated with SGLT2is after enrollment (n = 387, 7.06%) had an age of 56.26 years, of which 66.15% were male, and had a mean duration of diabetes of 9.2 years. The baseline FBG of the SGLT2i group was 7.92 mmol/L, 2hPBG was 8.94 mmol/L, and eGFR was 85.79 mL/min/1.73 m², which were not significantly different from those of the control group (n = 774). Patients who tended to be treated with SGLT2is presented with elevated UACR (SGLT2i group vs control group, 96.82 vs 50.54 mg/g, P < 0.001), HbA_1c (SGLT2i group vs control group, 6.85 vs 6.66%, P < 0.001), body weight (SGLT2i group vs control group, 73.38 vs 71.16 kg, P = 0.017), and BMI (SGLT2i group vs. control group, 25.68 vs 25.08 kg/m², P = 0.007) (Table 2). At the end of the study, the utilization rate of SGLT2i reached 22.4% (1570/6998) and GLP-1RA achieved the prevalence of 9.1% (636/6998) at the research site.

Table 2 Baseline characteristics of the sodium-glucose cotransporter-2 inhibitor group and control group, n (%).

Variables	SGLT2i group (n = 387)	Control group (n = 774)	P value
Age (years)	56.26 ± 11.56	56.07 ± 12.47	0.992
Sex (male/female, male %)	256/131, 66.15	511/263, 66.02	0.987
Duration of diabetes (years)	9.20 ± 7.82	9.06 ± 8.29	0.334
FBG (mmol/L)	7.92 ± 1.97	7.88 ± 1.88	0.675
2hPBG (mmol/L)	8.94 ± 2.39	8.75 ± 2.52	0.367
HbA1c (%)	6.85 ± 0.98	6.66 ± 1.02	< 0.001
UACR (mg/g)	96.82 ± 299.39	50.54 ± 257.55	< 0.001
eGFR (mL/min/1.73 m2)	85.79 ± 19.33	85.46 ± 19.48	0.534
Body weight (kg)	73.38 ± 12.88	71.16 ± 12.43	0.017
BMI (kg/m2)	25.68 ± 3.47	25.08 ± 3.48	0.007
UACR grades
< 30 mg/g	156 (65.82)	269 (83.80)	0.009
30-300 mg/g	19 (8.02)	9 (2.80)
> 300 mg/g	62 (26.16)	43 (13.40)
BMI grades
18-24 kg/m2	4 (1.04)	6 (1.13)	0.143
24-28 kg/m2	115 (29.79)	194 (36.47)
28-35 kg/m2	183 (47.41)	239 (44.92)
> 35 kg/m2	84 (21.76)	93 (17.48)

FBG: Fasting blood glucose; PBG: Prandial blood glucose; HbA_1c: Glycosylated hemoglobin; UACR: Urinary albumin-creatinine ratio; eGFR: Estimated glomerular filtration rate; BMI: Body mass index; SGLT2i: Sodium-glucose cotransporter-2 inhibitor.

Improvements in glucose levels

After 6 months of treatment, patients in the GLP-1RA group showed similar values for FBG, 2hPBG and HbA_1c compared with those in the control group, in which patients received medications other than GLP-1RA and SGLT2i (GLP-1RA group vs control group, FBG, 7.91 vs 8.03 mmol/L, P = 0.924; PBG, 9.13 vs 8.75 mmol/L, P = 0.274; HbA_1c, 6.73 vs 7.03%, P = 0.367). The variation in HbA_1c between the two groups was not significantly different (GLP-1RA group vs control group, -0.09 vs 0.18%, P = 0.120) (Table 3). Defining overweight or obesity subgroup as patients with BMI > 24 kg/m² and normal weight subgroup as BMI of 20-24 kg/m², the variation of FBG was insignificant between GLP-1RA group and the control group (overweight or obesity subgroup, GLP-1RA vs control, -0.29 vs -0.65 mmol/L, P = 0.465; normal weight subgroup, 1.32 vs 0.15, P = 0.119), nor was found in PBG (overweight or obesity subgroup, GLP-1RA vs control, 0.10 vs -0.32 mmol/L, P = 0.243; normal weight subgroup, 1.89 vs -0.18, P = 0.144). Defining high glucose subgroup as baseline HbA_1c > 8.0% and moderate glucose subgroup as baseline HbA_1c ≤ 8.0%, FBG in GLP-1RA group showed no significant difference compared with the control group (high glucose subgroup, GLP-1RA vs control, -2.32 vs -1.32 mmol/L, P = 0.938; moderate glucose subgroup, -0.05 vs -0.01, P = 0.976), nor was in PBG (high glucose subgroup, GLP-1RA vs control, -0.18 vs -0.12 mmol/L, P = 0.511; moderate glucose subgroup, 0.52 vs -0.04, P = 0.117).

Table 3 Glucose, renal function and body weight changes after 6 months of treatment in the glucagon like peptide-1 receptor agonist and control groups, n (%).

Variables	GLP-1RA group (n = 139)	Control group (n = 278)	P value
FBG (mmol/L)	7.91 ± 1.68	8.03 ± 2.10	0.924
Variation of FBG (mmol/L)	0.12 (-1.00, 0.97)	0.10 (-0.66, 0.58)	0.857
2hPBG (mmol/L)	9.13 ± 1.92	8.75 ± 2.29	0.274
Variation of 2hPBG (mmol/L)	0.81 (-0.65, 1.58)	-0.25 (-1.00, 0.85)	0.053
HbA1c (%)	6.73 ± 1.09	7.03 ± 1.78	0.367
Variation of HbA1c (%)	-0.09 ± 0.76	0.18 ± 1.63	0.120
UACR (mg/g)	73.60 ± 217.18	143.57 ± 513.87	0.331
Variation of UACR (mg/g)	-2.20 ± 54.36	30.16 ± 277.64	0.812
Logarithm of the variation of UACR	-0.08 ± 0.84	0.18 ± 0.94	0.416
eGFR (mL/min/1.73 m2)	83.63 ± 23.84	86.41 ± 22.56	0.659
Variation of eGFR (mL/min/1.73 m2)	-0.77 ± 10.50	0.00 ± 11.76	0.637
Body weight (kg)	77.94 ± 12.64	71.28 ± 13.80	< 0.001
Variation of body weight (kg)	-0.90 ± 3.30	0.27 ± 3.55	< 0.001
BMI (kg/m2)	27.64 ± 4.06	25.02 ± 3.70	< 0.001
Variation of BMI (kg/m2)	-0.33 ± 1.17	0.08 ± 1.26	0.001
UACR grades
< 30 mg/g	47 (72.31)	82 (78.85)	0.273
30-300 mg/g	4 (6.15)	10 (9.62)
> 300 mg/g	14 (21.54)	12 (11.54)
Renal composite outcome	0 (0.00)	2 (0.72)	0.637
BMI grades
18-24 kg/m2	0 (0.00)	4 (2.19)	< 0.001
24-28 kg/m2	16 (14.29)	67 (36.61)
28-35 kg/m2	52 (46.43)	73 (39.89)
> 35 kg/m2	44 (39.29)	39 (21.31)

FBG: Fasting blood glucose; PBG: Prandial blood glucose; HbA_1c: Glycosylated hemoglobin; UACR: Urinary albumin-creatinine ratio; eGFR: Estimated glomerular filtration rate; BMI: Body mass index; GLP-1RA: Glucagon like peptide-1 receptor agonist.

Patients treated with SGLT2i for 6 months had FBG and 2hPBG values comparable to those in the control group, and the alteration in HbA_1c was similar between the two groups (SGLT2i group vs control group, -0.00 vs 0.07%, P = 0.219; Table 4). In BMI subgroup analysis, the alteration of FBG displayed no significance between SGLT2i group and the control group (overweight or obesity subgroup, SGLT2i vs control, -0.33 vs -0.14 mmol/L, P = 0.471; normal weight subgroup, 0.22 vs 0.23, P = 0.956), nor was found in PBG (overweight or obesity subgroup, SGLT2i vs control, -0.08 vs -0.11 mmol/L, P = 0.832; normal weight subgroup, 0.28 vs 0.35, P = 0.641). When stratified with baseline HbA_1c, FBG in SGLT2i group had no significant difference compared with the control group (high glucose subgroup, SGLT2i vs control, -1.54 vs -0.41 mmol/L, P = 0.533; moderate glucose subgroup, -0.09 vs 0.01, P = 0.791), nor was in PBG (high glucose subgroup, SGLT2i vs control, -1.92 vs -0.76 mmol/L, P = 0.575; moderate glucose subgroup, 0.13 vs 0.08, P = 0.826).

Table 4 Glucose, renal function and body weight variation after 6 months of treatment in the sodium-glucose cotransporter-2 inhibitor and control groups, n (%).

Variables	SGLT2i group (n = 387)	Control group (n = 774)	P value
FBG (mmol/L)	7.83 ± 1.62	7.94 ± 1.90	0.769
Variation of FBG (mmol/L)	-0.13 (-0.75, 0.56)	-0.02 (-0.73, 0.64)	0.642
2hPBG (mmol/L)	8.83 ± 2.07	8.87 ± 2.21	0.951
Variation of 2hPBG (mmol/L)	0.17 (-0.90, 0.92)	-0.01 (-1.00, 0.83)	0.623
HbA1c (%)	6.86 ± 1.00	6.72 ± 1.06	0.004
Variation of HbA1c (%)	-0.00 ± 0.81	0.07 ± 0.67	0.219
UACR (mg/g)	89.18 ± 285.30	84.57 ± 423.05	0.001
Variation of UACR (mg/g)	-20.61 ± 283.92	12.01 ± 156.68	0.327
Logarithm of the variation of UACR	-0.02 ± 0.71	0.01 ± 0.91	0.482
eGFR (mL/min/1.73 m2)	86.22 ± 19.04	84.60 ± 18.91	0.297
Variation of eGFR (mL/min/1.73 m2)	-1.01 ± 10.44	0.25 ± 10.74	0.068
Body weight (kg)	72.23 ± 12.31	71.35 ± 12.64	0.479
Variation of body weight (kg)	-0.59 ± 3.83	-0.03 ± 4.07	0.010
BMI (kg/m2)	25.31 ± 3.35	25.15 ± 3.46	0.461
Variation of BMI (kg/m2)	-0.21 ± 1.40	-0.03 ± 1.55	0.013
UACR grades
< 30 mg/g	135 (69.59)	240 (81.63)	0.009
30-300 mg/g	13 (6.70)	12 (4.08)
> 300 mg/g	46 (23.71)	42 (14.29)
Renal composite outcome	4 (1.03)	2 (0.26)	0.169
BMI grades
18-24 kg/m2	4 (1.26)	5 (1.04)	0.682
24-28 kg/m2	105 (33.02)	173 (36.12)
28-35 kg/m2	154 (48.43)	211 (44.05)
> 35 kg/m2	55 (17.30)	90 (18.79)

FBG: Fasting blood glucose; PBG: Prandial blood glucose; HbA_1c: Glycosylated hemoglobin; UACR: Urinary albumin-creatinine ratio; eGFR: Estimated glomerular filtration rate; BMI: Body mass index; SGLT2i: Sodium-glucose cotransporter-2 inhibitor.

Changes in UACR and eGFR

After treatment with GLP-1RA for 6 months, UACR displayed a greater reduction compared with the control group, although this difference was not statistically significant (GLP-1RA group vs control group, -2.20 vs 30.16 mg/g, P = 0.812). Owing to the large extent of dispersion, the logarithm of the alteration in UACR was compared between the two groups, but no significant difference was revealed (GLP-1RA group vs control group, -0.08 vs 0.1, P = 0.416). Similar to those before GLP-1RA treatment, the proportions of patients with UACRs of < 30 mg/g, 30–300 mg/g, and > 300 mg/g were comparable between the two groups (P = 0.273, Table 3). The renal composite outcome was defined as an increase in eGFR exceeding 50%, new-onset UACR over 300 mg/g, or receiving renal replacement therapy. There was no significant difference in the renal composite outcome between the two groups (GLP-1RA group vs control group, 0 vs 2 patients, P = 0.637).

Compared with patients in the control group, patients receiving SGLT2i for 6 months presented a decrease in UACR, but the difference was not statistically significant (variation in the UACR between the SGLT2i group and the control group: -20.61 vs 12.01 mg/g, P = 0.327). The logarithm of the UACR change was compared between the two groups to diminish the degree of dispersion, but it still failed to show statistical significance (SGLT2i group vs control group, -0.02 vs 0.01, P = 0.482). Renal function was evaluated based on the eGFR, which was not significantly different between the SGLT2i group and the control group after treatment (SGLT2i group vs control group, -1.01 vs 0.25 mL/min/1.73 m², P = 0.068). Similar to that before SGLT2i treatment, the proportion of patients with UACRs of 30-300 mg/g and > 300 mg/g was greater in the SGLT2i group than in the control group (P = 0.009, Table 4). The renal composite outcome did not differ between the two groups (SGLT2i group vs control group, 4 vs 2 patients, P = 0.169).

Improvements in body weight

Significant weight loss was observed in the GLP-1RA group compared with the control group (GLP-1RA group vs control group, alteration of body weight, -0.90 vs 0.27 kg, P < 0.001; alteration of BMI, -0.33 vs 0.08 kg/m², P = 0.001) (Table 3).

Compared with the control group, the SGLT2i group demonstrated greater weight reduction (SGLT2i group vs control group, variation in body weight, -0.59 vs -0.03 kg, P = 0.010; variation in BMI, -0.21 vs -0.03 kg/m², P = 0.013) (Table 4).

DISCUSSION

In this study, comprehensive management, including glucose levels, renal function, and body weight, was evaluated after 6 months of treatment with GLP-1RAs or SGLT2is in a real-world diabetes cohort. Compared with other glucose-lowering medications, GLP-1RAs or SGLT2is were associated with significant weight loss and a trend toward a reduction in UACR, while the alteration in glucose levels was similar between the two groups. Our study provides valuable insights into the application and efficacy of SGLT2i and GLP-1RAs in a real-world setting, which supplements the real-world evidence supporting the utility of these two new medications beyond data from RCTs.

Among the 5482 patients with T2Ds enrolled in the study cohort, 139 (2.54%) patients were started on a GLP-1RA, and 387 (7.06%) were started on an SGLT2i at enrollment, which increased the utilization rate of SGLT2i to 22.4% and GLP-1RAs to 9.1% at the end of the study. In the global observational study DISCOVER, 8.7% of diabetic patients were receiving an SGLT2i and 2.2% were receiving GLP-1RA at enrollment, and the application rate of SGLT2i or GLP-1RA was relatively low in Asia compared with that in the Americas and Europe[11]. The utilization rate was substantially higher than the global average report, which is related to the high accessibility of medications in Beijing and the physicians in the research site were endocrinologists who keeping up with updated guidelines. Since data from mainland China were not included in the above study, we supplemented the utilization data for the two glucose-lowering medications in our study with benefits to the cardiovascular and renal systems in mainland China.

Despite several trials indicating encouraging results and guidelines and position papers recommending broader use[12], GLP-1RA or SGLT2i utilization is still suboptimal in clinical practice, as presented in the secondary analysis of the multinational CAPTURE study[13]. Despite the renoprotective effects of these two medications, CKD is associated with lower use, and cardiovascular disease is associated with greater use by mainly cardiologists[11]. Urogenital infections, postural hypotension and ketosis prevent the continuation of SGLT2i use[14,15]. Gastrointestinal discomfort, including nausea and vomiting, and fear of injection limit the extensive utilization of GLP-1RA[16-19]. In a national survey in China, patients with T2Ds prioritized medications with high efficacy, no risk of hypoglycemia and cardiovascular benefits instead of weight reduction[20]. In the TriMaster, randomized, double-bind, three-way crossover trial, canagliflozin was the most preferred drug with better efficacy and fewer side effects than other once-daily second-line glucose-lowering drugs, including sitagliptin and pioglitazone (preference, canagliflozin 38%, sitagliptin 35%, pioglitazone 25%)[21]. These studies suggest that endocrinologists should be more proactive in promoting these two medications due to their high efficacy and lower risk of adverse events than the expectations of most physicians. In our study, patients with higher BMIs were more likely to be treated with GLP-1RAs, and those with higher UACR tended to be treated with SGLT2is. In clinical practice, patients who are obese or overweight could benefit from weight reduction in addition to the glucose-lowering effect of GLP-1RAs, which contributes to the choice of GLP-1RAs by clinicians.

Our study suggested that the glucose-lowering effect of GLP-1RAs or SGLT2is was comparable to that of other medications in a real-world cohort. In a meta-analysis, GLP-1RAs decreased HbA1c by 0.98%-1.48%, and SGLT2is decreased HbA1c by 0.83%-1.02%[22]. In the real-world setting of our study, patients in the control group receiving medications, including insulin rather than GLP-1RA or SGLT2i, achieved similar glucose-lowering efficacy. Additionally, the relatively small sample size might influence the difference in glucose levels between the groups.

In terms of renal indicators, UACR decreased by 14.3% in the SGLT2i group in our study, which might be explained by the fact that the majority of patients in the diabetes cohort were in the normal UACR range, and it might be related to the small sample size and the relatively high degree of UACR data dispersion. The UACR reduction of SGLT2i was 29.3% in RCTs[23], while real-world evidence provided support to CKD protection and delayed ESRD, without sufficient data for UACR alteration after SGLT2i initiating[9,24]. According to our study, the UACR reduced insignificantly after SGLT2i treatment, and the UACR lowering effect diminished a small proportion in the real-world settings compared with RCTs. In addition, UACR, eGFR and renal composite outcomes were not significantly different because of the limited follow-up period of 6 months.

Body weight was significantly lower in the SGLT2i (0.59 kg) and GLP-1RA (0.90 kg) groups than in the randomized controlled trials[25,26], where GLP-1RA and SGLT2i resulted in weight losses of 3-7 kg and 2-3 kg, respectively. The diminished weight reduction efficacy of the two medications was observed, which might be explained by the baseline BMI of 25-28 kg/m², which indicated that most of the patients in the diabetes cohort were normal or overweight, with a small proportion of obese individuals, and the weight loss effect and willingness were attenuated in this situation. Second, the real-world setting of our study led to lower adherence compared with RCTs, and concomitant medications, including insulin or sulfonylureas, increased body weight in the context of GLP-1RAs and SGLT2is.

Although the weight reduction effect of GLP-1RAs or SGLT2is has been confirmed even in real-world studies and cardiovascular or renal protection has been confirmed in RCTs[2-5], clinicians should pay greater attention to adverse effects, especially gastrointestinal (GI) adverse events associated with GLP-1RAs and urogenital infection associated with SGLT2is. Semaglutide 0.5 mg or 1 mg once weekly was reported to result in 38% GI adverse events in the treatment group, although most of the events were mild or moderate[27]. Dapagliflozin 10 mg once daily led to urinary tract infection in 5.7% of patients and genital infection in 12.9% of patients[28].

There are limitations to our study. As a real-world, single-center, cohort study, the power of our conclusions was inevitably limited because of the preference of physicians at the research site or other regional factors and the heterogeneity of the baseline characteristics of the study cohort. The follow-up period was short, which diminished the possibility of significant changes in UACR and eGFR. A multicenter study with a prolonged follow-up period and expanded sample size could provide more precise real-world data on new glucose-lowering drugs.

CONCLUSION

Patients on SGLT2i or GLP-1RAs showed significant weight loss, a decreasing trend in UACR and comparable glucose-lowering effects compared with other patients receiving glucose-lowering drugs in real-world settings.

ACKNOWLEDGEMENTS

We appreciate all the patients who participated during the follow-up study.