Research ArticleOriginal Research

Association Between Metformin Initiation and Incident Dementia Among African American and White Veterans Health Administration Patients

Jeffrey F. Scherrer, John E. Morley, Joanne Salas, James S. Floyd, Susan A. Farr and Sascha Dublin
The Annals of Family Medicine July 2019, 17 (4) 352-362; DOI: https://doi.org/10.1370/afm.2415

Article Figures & Data

Figures

  • Figure 1
    Figure 1

    Veterans Health Administration eligibility criteria.

    FY = fiscal year; HbA1c = hemoglobin A1c; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification; MET = metformin; nSES = neighborhood socioeconomic status; SU = sulfonylurea.

  • Figure 2a
    Figure 2a

    Covariate standardized mean difference (SMD), metformin vs sulfonylurea, white race.

    HbA1c = hemoglobin A1c; NSAIDs = nonsteroidal anti-inflammatory drugs; nSES = neighborhood socioeconomic status; PTSD = posttraumatic stress disorder; VHA = Veterans Health Administration.

  • Figure 2b
    Figure 2b

    Covariate standardized mean difference (SMD), metformin vs sulfonylurea, African American race.

    HbA1c = hemoglobin A1c; NSAIDs = nonsteroidal anti-inflammatory drugs; nSES = neighborhood socioeconomic status; PTSD = posttraumatic stress disorder; VHA = Veterans Health Administration

Tables

  • Table 1

    Characteristics of African American and White VHA Patients Aged ≥50 Years Who Received Either a New Metformin or a New Sulfonylurea Prescription Fill (N = 73,761)

    CovariateWhite (n = 63,202)African American (n = 10,559)P Value
    Medication initiated, no. (%)
     Metformin47,821 (75.7)8,038 (76.1).307
     Sulfonylurea15,381 (24.3)2,521 (23.9)
    Index year, no. (%)
     2002-20043,653 (5.8)486 (4.6)
     2005-200620,728 (32.8)3,250 (30.8)
     2007-200816,714 (26.4)2,636 (25.0)<.001
     2009-201013,016 (20.6)2,381 (22.5)
     2011-20129,091 (14.4)1,806 (17.1)
    Sociodemographic related
     Age, y, mean (±SD)61.3 (±8.6)58.2 (±7.5)<.001
     Age category, y, no. (%)
      50-6440,811 (64.6)8,325 (78.8)
      65-7416,414 (26.0)1,824 (17.3)<.001
      ≥755,977 (9.5)410 (3.9)
     Male sex, no. (%)61,353 (97.1)10,049 (95.2)<.001
     Married, no. (%)38,549 (61.0)5,062 (47.9)<.001
     Low nSES, no. (%)30,134 (47.7)6,865 (65.0)<.001
     VHA insurance only, no. (%)27,705 (43.8)6,044 (57.2)<.001
     High health care use, no. (%)15,378 (24.3)3,134 (29.7)<.001
    Diabetes related
     Diabetic nephropathy, no. (%)753 (1.2)132 (1.3).608
     Diabetic retinopathy, no. (%)3,275 (5.2)560 (5.3).602
     Diabetic neuropathy, no. (%)4,696 (7.4)618 (5.9)<.001
     HbA1c value, %, mean (±SD)7.2 (±1.4)7.4 (±1.7)<.001
     HbA1c category, no. (%)
      <7%32,895 (52.0)4,875 (46.2)
      7-8%19,439 (30.8)3,431 (32.5)<.001
      >8%10,868 (17.2)2,253 (21.3)
    Creatinine value, mg/dL, mean (±SD)1.0 (±0.2)1.1 (±0.2)<.001
    Other comorbidities
     Obesity, no. (%)38,216 (60.5)5,846 (55.4)<.001
     Hypertension, no. (%)57,326 (90.7)9,751 (92.3)<.001
     Hyperlipidemia, no. (%)55,918 (88.5)8,252 (78.2)<.001
     Stroke, no. (%)4,304 (6.8)696 (6.6).409
     Ischemic heart disease, no. (%)31,514 (49.9)3,828 (36.3)<.001
     Congestive heart failure, no. (%)11,609 (18.4)1,397 (13.2)<.001
     Atrial fibrillation, no. (%)9,091 (14.4)699 (6.6)<.001
     Traumatic brain injury, no. (%)3,993 (6.3)638 (6.0).280
     Vitamin B12 deficiency, no. (%)3,243 (5.1)377 (3.6)<.001
    Psychiatric and substance comorbidities
     Depression, no. (%)18,165 (28.7)2,946 (27.9).077
     PTSD, no. (%)11,704 (18.5)2,631 (24.9)<.001
     Other anxiety, no. (%)a9,076 (14.4)1,081 (10.2)<.001
     Bipolar disorder, no. (%)4,926 (7.8)823 (7.8).999
     Schizophrenia, no. (%)3,008 (4.8)1,063 (10.1)<.001
     Nicotine dependence/smoking, no. (%)33,240 (52.6)6,072 (57.5)<.001
     Alcohol abuse/dependence, no. (%)9,209 (14.6)2,620 (24.8)<.001
     Illicit drug abuse/dependence, no. (%)3,988 (6.3)2,012 (19.1)<.001
    Other medicationsb
     Statins, no. (%)45,061 (71.3)6,276 (59.4)<.001
     Anticholinergics, no. (%)28,035 (44.4)5,243 (49.7)<.001
     NSAIDs, no. (%)34,581 (54.7)6,794 (64.3)<.001
     Antihypertensives, no. (%)55,492 (87.8)9,273 (87.8).954

    • HbA1c = hemoglobin A1c; NSAID = nonsteroidal anti-inflammatory drug; nSES = neighborhood socioeconomic status; PTSD = posttraumatic stress disorder; VHA = Veterans Health Administration.

    • ↵a Other anxiety disorders = panic disorder, obsessive-compulsive disorder, social phobia, generalized anxiety disorder, anxiety not otherwise specified.

    • ↵b Other medications = sustained use before metformin or sulfonylurea (at least 2 fills in a 6-month period).

    • NSAID = nonsteroidal anti-inflammatory drug; PTSD = posttraumatic stress disorder; VHA = Veterans Health Administration.

  • Table 2

    Characteristics of Patients Who Received Either a New Metformin or a New Sulfonylurea Prescription Fill, Stratified by Race (N = 73,761)

    CovariateWhite (n = 63,202)African American (n = 10,559)
    Metformin (n = 47,821)Sulfonylurea (n = 15,381)P ValueMetformin (n = 8,038)Sulfonylurea (n = 2,521)P Value
    Index year, no. (%)
     2002-20042,274 (4.8)1,379 (9.0)286 (3.6)200 (7.9)
     2005-200613,899 (29.1)6,829 (44.4)2,209 (27.5)1,041 (41.3)
     2007-200812,999 (27.2)3,715 (24.2)<.0012,034 (25.3)602 (23.9)<.001
     2009-201010,805 (22.6)2,211 (14.4)1,948 (24.2)433 (17.2)
     2011-20127,844 (16.4)1,247 (8.1)1,561 (19.4)245 (9.7)
    Sociodemographic related
     Age, y, mean (±SD)60.4 (±8.1)64.1 (±9.4)<.00157.6 (±7.0)59.9 (±8.5)<.001
     Age category, y, no. (%)
      50-6432,914 (68.8)7,897 (51.3)6,543 (81.4)1,782 (70.7)
      65-7411,633 (24.3)4,781 (31.1)<.0011,276 (15.9)548 (21.7)<.001
      ≥753,274 (6.8)2,703 (17.6)219 (2.7)191 (7.6)
     Male sex, no. (%)46,352 (96.9)15,001 (97.5).00017,603 (94.6)2,446 (97.0)<.001
     Married, no. (%)29,057 (60.8)9,492 (61.7).0363,888 (48.4)1,174 (46.6).114
     Low nSES, no. (%)22,544 (47.1)7,590 (49.3)<.0015,171 (64.3)1,694 (67.2).009
     VHA insurance only, no. (%)21,703 (45.4)6,002 (39.0)<.0014,626 (57.6)1,418 (56.2).248
     High health care use, no. (%)11,500 (24.0)3,878 (25.2).0032,353 (29.3)781 (31.0).102
    Diabetes related
     Diabetic nephropathy, no. (%)506 (1.1)247 (1.6)<.00189 (1.1)43 (1.7).018
     Diabetic retinopathy, no. (%)2,267 (4.7)1,008 (6.6)<.001393 (4.9)167 (6.6).001
     Diabetic neuropathy, no. (%)3,332 (7.0)1,364 (8.9)<.001433 (5.4)185 (7.3).0003
     HbA1c value, %, mean (±SD)7.1 (±1.3)7.4 (±1.5)<.0017.4 (±1.6)7.7 (±1.9)<.001
     HbA1c category, no. (%)
      <7%25,738 (53.8)7,157 (46.5)3,891 (48.4)984 (39.0)
      7-8%14,519 (30.4)4,920 (32.0)<.0012,598 (32.3)833 (33.0)<.001
      >8%7,564 (15.8)3,304 (21.5)1,549 (19.3)704 (27.9)
    Creatinine value, mg/dL, mean (±SD)1.0 (±0.2)1.1 (±0.2)<.0011.0 (±0.2)1.1 (±0.2)<.001
    Other comorbidities
     Obesity, no. (%)30,193 (63.1)8,023 (52.2)<.0014,684 (58.3)1,162 (46.1)<.001
     Hypertension, no. (%)43,223 (90.4)14,103 (91.7)<.0017,427 (92.4)2,324 (92.2).726
     Hyperlipidemia, no. (%)42,570 (89.0)13,348 (86.8)<.0016,417 (79.8)1,835 (72.8)<.001
     Stroke, no. (%)3,029 (6.3)1,275 (8.3)<.001489 (6.1)207 (8.2).0002
     Ischemic heart disease, no. (%)22,979 (48.1)8,535 (55.5)<.0012,851 (35.5)977 (38.8).003
     Congestive heart failure, no. (%)7,797 (16.3)3,812 (24.8)<.001989 (12.3)408 (16.2)<.001
     Atrial fibrillation, no. (%)6,158 (12.9)2,933 (19.1)<.001504 (6.3)195 (7.7).01
     Traumatic brain injury, no. (%)3,045 (6.4)948 (6.2).366489 (6.1)149 (5.9).75
     Vitamin B12 deficiency, no. (%)2,370 (5.0)873 (5.7).0004292 (3.6)85 (3.4).538
    Psychiatric and substance comorbidities
     Depression, no. (%)14,231 (29.8)3,934 (25.6)<.0012,334 (29.0)612 (24.3)<.001
     PTSD, no. (%)9,357 (19.6)2,347 (15.3)<.0012,089 (26.0)542 (21.5)<.001
     Other anxiety, no. (%)a7,022 (14.7)2,054 (13.4)<.001847 (10.5)234 (9.3).07
     Bipolar disorder, no. (%)3,909 (8.2)1,017 (6.6)<.001650 (8.1)173 (6.9).045
     Schizophrenia, no. (%)2,335 (4.9)673 (4.4).01809 (10.1)254 (10.1).988
     Nicotine abuse/dependence, no. (%)25,423 (53.2)7,817 (50.8)<.0014,630 (57.6)1,442 (57.2).722
     Alcohol abuse/dependence, no. (%)7,190 (15.0)2,019 (13.1)<.0012,008 (25.0)612 (24.3).474
     Illicit drug abuse/dependence, no. (%)3,139 (6.6)849 (5.5)<.0011,524 (19.0)488 (19.4).658
    Other medicationsb
     Statins, no. (%)34,418 (72.0)10,643 (69.2)<.0014,896 (60.9)1,380 (54.7)<.001
     Anticholinergics, no. (%)21,443 (44.8)6,592 (42.9)<.0014,035 (50.2)1,208 (47.9).046
     NSAIDs, no. (%)26,919 (56.3)7,662 (49.8)<.0015,272 (65.6)1,522 (60.4)<.001
     Antihypertensives, no. (%)41,827 (87.5)13,665 (88.8)<.0017,057 (87.8)2,216 (87.9).887

    • HbA1c = hemoglobin A1c; NSAID = nonsteroidal anti-inflammatory drug; nSES = neighborhood socioeconomic status; PTSD = posttraumatic stress disorder; VHA = Veterans Health Administration.

    • ↵a Other anxiety disorders = panic disorder, obsessive-compulsive disorder, social phobia, generalized anxiety disorder, anxiety not otherwise specified.

    • ↵b Other medications = sustained use before metformin or sulfonylurea (at least 2 fills in a 6-month period).

  • Table 3

    Results From Cox Proportional Hazards Models Estimating the Association Between Receipt of a New Metformin vs a New Sulfonylurea Prescription Fill and Incident Dementia for FY 2002 to 2015, Stratified by Race, Among African American and White VHA Patients Aged ≥50 Years (N = 73,761)

    Model 1
    Crudea    		Model 2
    Weightedb    		Model 3
    Weighted + AMGBc    		Model 4
    Weighted + Hypoglycemiad
    RaceMET vs SU, HR (95% CI)MET vs SU, HR (95% CI)MET vs SU, HR (95% CI)MET vs SU, HR (95% CI)
     Whitee0.67 (0.63-0.71)0.96 (0.9-1.03)0.92 (0.86-0.99)0.98 (0.92-1.05)
     African Americane0.6 (0.51-0.71)0.73 (0.6-0.89)0.72 (0.58-0.88)0.77 (0.64-0.94)
     Race * drug, P valuef.207.008.026.022

    • AMGB = average monthly glycemic burden; FY = fiscal year; HbA1c = hemoglobin A1c; HR = hazard ratio; MET = metformin; SU = sulfonylurea; VHA = Veterans Health Administration.

    • ↵a Unweighted data.

    • ↵b Inverse probability of treatment weighted data with robust, sandwich-type variance estimators.

    • ↵c Additional adjustment for glycemic burden from MET/SU initiation to end of follow-up among a subset of 69,918 African American and white VHA patients with at least 2 HbA1c values after MET/SU initiation.

    • ↵d Additional adjustment for time-dependent hypoglycemia episode after MET/SU initiation.

    • ↵e Proportional hazard assumption P value: white = .244; African American = .07.

    • ↵f Interaction P value testing differential effect of race on MET vs SU for each model.

  • Table 4

    Association Between a New Metformin vs a New Sulfonylurea Prescription Fill and Incident Dementia for FY 2002 to 2015, Stratified by Age Within Race Group, Among African American and White VHA Patients Aged ≥50 Years (N = 73,761)

    Model 1
    Cox Model Weighted    		Model 2
    Cox Model Weighted + AMGB    		Model 3
    Cox Model Weighted + Hypoglycemia
    White raceMET vs SU, HR (95% CI)MET vs SU, HR (95% CI)MET vs SU, HR (95% CI)
     50-64 years of age0.94 (0.81-1.09)0.93 (0.8-1.09)0.97 (0.84-1.13)
     65-74 years of age0.9 (0.82-0.99)0.89 (0.8-0.99)0.92 (0.84-1.02)
     ≥75 years of age1.01 (0.91-1.13)1.01 (0.89-1.14)1.03 (0.92-1.15)
     Age * drug, P value.315.314.351
    African American raceMET vs SU, HR (95% CI)MET vs SU, HR (95% CI)MET vs SU, HR (95% CI)
     50-64 years of age0.6 (0.45-0.81)0.56 (0.41-0.77)0.63 (0.47-0.85)
     65-74 years of age0.71 (0.53-0.94)0.79 (0.58-1.08)0.77 (0.57-1.03)
     ≥75 years of age1.17 (0.73-1.85)1.18 (0.7-1.98)1.39 (0.83-2.36)
     Age * drug, P value.055.038.036

    • AMGB = average monthly glycemic burden from MET/SU start to end of follow-up; FY = fiscal year; HR = hazard ratio; hypoglycemia = time-dependent hypoglycemia episode from MET/SU start to end of follow-up; MET = metformin; SU = sulfonylurea; VHA = Veterans Health Administration.

Additional Files

  • Supplemental Appendixes

    Supplemental Appendixes

    Files in this Data Supplement:

  • The Article in Brief

    Association Between Metformin Initiation and Incident Dementia Among African American and White Veterans Health Administration Patients

    Jeffrey F. Scherrer , and colleagues

    Background African American patients are more likely than white patients to experience cognitive decline following type 2 diabetes mellitus. While metformin use has been associated with a lower risk of dementia compared with sulfonylurea, evidence for whether this association differs by race is sparse.

    What This Study Found A large observational cohort study examining male veterans aged over 50 years with type 2 diabetes found that metformin use was associated with a significantly lower risk of dementia in African American patients. The study included data from 73,500 patients who received care through the Veteran�s Health Administration from 2000-2015 and were diabetes- and dementia-free at baseline and who subsequently developed type 2 diabetes and began treatment with either metformin or sulfonylurea. Cox proportional hazards models, using propensity scores and inverse probability treatment to balance confounding factors, were computed to measure the association of both drugs and incident dementia across race and age groups. For African American patients aged 50-64 years, the hazard ratio for developing dementia was 0.60 (CI, 0.45-0.81), and for African American patients aged 65-74 years, the hazard ratio was 0.71 (CI, 0.53-0.94). The study showed modest to no association between metformin and lower risk for dementia in white patients 65-74 and no association in other age groups.

    Implications

    • The present results may point to a novel approach for reducing dementia risk in African American patients with type 2 diabetes mellitus.
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Get Permissions

Jump to section

Subjects

Keywords