Higher diversity of anti-diabetic therapy is associated with lower risk of major adverse kidney events in diabetes

Table 1 Baseline characteristics of participants in UK Biobank and Chongqing Diabetes Registry cohorts after propensity score matching, n (%)

Characteristic	UK biobank			Chongqing diabetes registry
	Monotherapy (n = 3475)	Combination therapy (n = 3475)	SMD	Monotherapy (n = 261)	Combination therapy (n = 808)	SMD
Age, year	61.00 (55.00, 65.00)	61.00 (55.00, 65.00)	-0.014	59.78 (48.56, 67.42)	58.41 (52.21, 66.79)	0.028
Female sex	1270 (36.5)	1311 (37.7)	0.025	107 (41.0)	322 (39.9)	0.034
Ethnicity (White)	2991 (86.1)	2983 (85.8)	-0.006	-	-	-
Diabetes duration, year	8.89 (5.05, 16.76)	9.00 (5.16, 14.16)	0.018	8.86 (2.13, 15.12)	9.95 (4.05, 15.02)	0.000
Current smoker	1591 (45.8)	1611 (46.4)	-0.012	107 (41.0)	340 (42.1)	-0.007
Current drinker	1641 (47.2)	1619 (46.6)	-0.013	61 (23.4)	186 (23.0)	-0.006
Hypertension	2317 (66.7)	2303 (66.3)	-0.009	93 (35.6)	343 (42.5)	-0.019
CVD	691 (19.9)	663 (19.1)	-0.020	6 (2.3)	24 (3.0)	0.004
CeVD	294 (8.5)	290 (8.3)	-0.004	9 (3.4)	25 (3.1)	0.017
BMI, kg/m2	31.00 (27.67, 35.18)	31.31 (28.10, 35.33)	0.048	23.51 (20.81, 25.50)	24.03 (22.13, 26.12)	-0.006
HbA1c %	7.85 (7.36, 8.65)	7.89 (7.39, 8.70)	0.009	9.30 (7.80, 11.30)	9.25 (8.00, 10.80)	0.044
Cholesterol, mmol/L	4.28 (3.76, 4.93)	4.25 (3.73, 4.91)	-0.019	4.23 (3.47, 5.10)	4.27 (3.62, 5.00)	-0.012
Triglycerides, mmol/L	1.93 (1.29, 2.78)	1.96 (1.35, 2.80)	0.000	1.34 (0.96, 2.04)	1.48 (1.02, 2.28)	-0.029
HDL cholesterol, mmol/L	1.11 (0.94, 1.31)	1.10 (0.95, 1.30)	-0.015	1.13 (0.93, 1.39)	1.08 (0.90, 1.29)	-0.011
LDL cholesterol, mmol/L	2.54 (2.15, 3.02)	2.53 (2.13, 3.01)	-0.017	2.53 (1.89, 3.20)	2.56 (2.01, 3.26)	-0.012
Uric acid, μmol/L	305.20 (254.60, 369.05)	309.00 (258.95, 363.95)	-0.006	304.00 (245.00, 381.00)	311.00 (251.00, 385.25)	-0.034
eGFR, mL/minute/1.73 m2	93.76 (81.60, 100.92)	93.66 (79.82, 101.03)	0.018	85.38 (64.66, 101.54)	87.07 (68.50, 100.30)	-0.003
RAS inhibitors	680 (19.6)	685 (19.7)	0.004	47 (18.0)	206 (25.5)	-0.028
Diuretic	720 (20.7)	733 (21.1)	-0.022	10 (3.8)	45 (5.6)	-0.048
MRA	56 (1.6)	47 (1.4)	-0.004	1 (0.4)	2 (0.2)	-0.014

Continuous variables are presented as median (25^th and 75^th percentiles) and categorical variables as n (%). SMD: Standardized mean difference; CVD: Cardiovascular disease; CeVD: Cerebrovascular disease; BMI: Body mass index; HbA1c: Glycated hemoglobin A1c; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; eGFR: Estimated glomerular filtration rate; RAS: Renin-angiotensin system; MRA: Mineralocorticoid receptor antagonist.

Table 2 Effects of combination anti-diabetic therapy vs monotherapy on risk of major adverse kidney events.

Characteristic	Case/total		HR (95%CI)
	Monotherapy	Combination therapy
UK Biobank: Intention-to-treat analysis
Unadjusted model	83/3475	54/3475	0.65 (0.46-0.92)
Adjusting for ACEI/ARB and MRA use at baseline	83/3475	54/3475	0.65 (0.46-0.92)
Excluding ACEI/ARB users at baseline	68/2795	40/2790	0.65 (0.46-0.93)
Excluding MRA users at baseline	78/3419	51/3428	0.59 (0.40-0.87)
Chongqing Diabetes Registry: Per-protocol analysis
Unadjusted model	19/261	13/808	0.24 (0.11-0.55)
Adjusting for ACEI/ARB, MRA, SGLT2i, and GLP-1RA use at baseline or during follow-up	19/261	13/808	0.37 (0.16-0.88)
Excluding ACEI/ARB users at baseline or during follow-up	9/157	4/373	0.25 (0.07-0.95)
Excluding MRA users at baseline or during follow-up	19/258	12/797	0.24 (0.11-0.55)
Excluding SGLT2i users at baseline or during follow-up	19/203	6/288	0.30 (0.10-0.87)
Excluding GLP-1RA users at baseline or during follow-up	19/251	9/640	0.22 (0.09-0.56)

The major adverse kidney events are a composite of end-stage renal disease (defined as estimated glomerular filtration rate ≤ 15 mL/minute/1.73 m², initiation of dialysis, or undergoing kidney transplantation) or death attributed to kidney disease. Monotherapy: With a single anti-diabetic medication. Combination therapy: With ≥ 2 anti-diabetic medications. HR: Hazard ratio; CI: Confidence interval; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; MRA: Mineralocorticoid receptor antagonist; SGLT2i: Sodium-glucose cotransporter-2 inhibitor; GLP-1RA: Glucagon-like peptide-1 receptor agonist.