Metformin Treatment Is Associated with a Decreased Risk of Nonproliferative Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus: A Population-Based Cohort Study

Table 4

Multivariate analysis for NPDR development in DM patients ().

	Model 1	Model 2	Model 3	Model 4	Model 5
	Crude HR (95% CI)	Adjusted HR (95% CI)	Adjusted HR^§ (95% CI)	Adjusted HR^¶ (95% CI)	Adjusted HR^$ (95% CI)
Sex
Female	Reference	Reference	Reference	Reference	Reference
Male	0.84 (0.75–0.94)	0.81 (0.72–0.91)	0.80 (0.71–0.90)	0.80 (0.71–0.90)	0.80 (0.71–0.91)
Age (years)
<45	1.26 (1.04–1.52)	1.24 (1.01–1.52)	1.30 (1.06–1.6)	1.32 (1.07–1.62)	1.25 (1.02–1.54)
45–54	1.59 (1.36–1.86)	1.62 (1.38–1.91)	1.68 (1.43–1.98)	1.70 (1.44–2.00)	1.63 (1.38–1.92)
55–64	1.50 (1.28–1.76)	1.54 (1.31–1.81)	1.56 (1.33–1.83)	1.57 (1.34–1.85)	1.53 (1.30–1.80)
≥65	Reference	Reference	Reference	Reference	Reference
Comorbidities
Hypertension	0.88 (0.78–0.99)	1.20 (0.96–1.51)	1.18 (0.94–1.47)	1.18 (0.95–1.48)	1.19 (0.95–1.49)
Cerebrovascular accidents (CVA)	0.81 (0.72–0.92)	0.74 (0.58–0.94)	0.76 (0.60–0.96)	0.75 (0.59–0.95)	0.74 (0.59–0.94)
Diabetic polyneuropathy (DPN)	1.80 (1.08–2.99)	1.78 (1.07–2.97)	2.14 (1.28–3.58)	2.10 (1.26–3.50)	1.90 (1.14–3.16)
Diabetic nephropathy (DN)	1.19 (0.82–1.73)	1.14 (0.78–1.67)	1.20 (0.82–1.76)	1.19 (0.81–1.74)	1.14 (0.78–1.66)
Dyslipidemia	0.89 (0.73–1.08)	0.96 (0.78–1.17)	0.90 (0.74–1.10)	0.90 (0.73–1.10)	0.94 (0.77–1.16)
Medication
Antihypertensive drugs	0.68 (0.58–0.79)	0.75 (0.63–0.90)	0.80 (0.67–0.95)	0.80 (0.67–0.95)	0.78 (0.65–0.93)
Antihyperlipidemic drugs	0.76 (0.68–0.86)	0.76 (0.67–0.86)	0.86 (0.76–0.98)	0.86 (0.76–0.97)	0.82 (0.72–0.93)
aDCSI score
0	Reference	Reference	Reference	Reference	Reference
1	1.04 (0.89–1.22)	1.21 (1.02–1.43)	1.22 (1.03–1.45)	1.21 (1.02–1.44)	1.23 (1.04–1.45)
≥2	1.04 (0.90–1.19)	1.36 (1.16–1.60)	1.37 (1.17–1.61)	1.35 (1.15–1.59)	1.37 (1.17–1.62)
Metformin use
Yes	0.65 (0.58–0.73)		0.76 (0.68–0.87)
No	Reference		Reference
Sulfonylurea
Yes	1.28 (1.04–1.58)		1.30 (1.05–1.61)
No	Reference		Reference
Mitiglinide
Yes	0.79 (0.67–0.92)		0.91 (0.78–1.06)
No	Reference		Reference
Acarbose
Yes	0.74 (0.65–0.85)		0.87 (0.75–1.01)
No	Reference		Reference
TZD
Yes	0.84 (0.73–0.97)		1.10 (0.94–1.28)
No	Reference		Reference
DPP-4i
Yes	0.38 (0.31–0.48)		0.41 (0.33–0.52)
No	Reference		Reference
Metformin and DPP-4i use
Neither metformin nor DPP-4i				Reference
Metformin alone				0.76 (0.67–0.86)
DPP-4i alone				0.36 (0.22–0.60)
Both metformin and DPP-4i				0.32 (0.25–0.41)
Metformin and sulfonylurea use
Neither metformin nor sulfonylurea					Reference
Metformin alone					0.98 (0.65–1.46)
Sulfonylurea alone					1.56 (1.15–2.11)
Both metformin and sulfonylurea					1.02 (0.75–1.39)

Adjusted for gender, age at DM diagnosis, comorbidities, medication use, and aDCSI scores. ^§Adjusted for gender, age at DM diagnosis, comorbidities, medication use, aDCSI scores, and antidiabetic drug use. ^¶Adjusted for gender, age at DM diagnosis, comorbidities, medication use, aDCSI scores, and metformin or DPP-4i use. ^$Adjusted for gender, age at DM diagnosis, comorbidities, medication use, aDCSI scores, and metformin or sulfonylurea use. NPDR: nonproliferative diabetic retinopathy; aDCSI scores: adapted Diabetes Complications Severity Index scores; DM: diabetes mellitus; HR: hazard ratio.