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Aging and disease    2019, Vol. 10 Issue (1) : 37-48     DOI: 10.14336/AD.2017.1202
Orginal Article |
Metformin and the Risk of Dementia in Type 2 Diabetes Patients
Tseng Chin-Hsiao1,2,3,*
1Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
2Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
3Division of Environmental Health and Occupational Medicine of the National Health Research Institutes, Zhunan, Taiwan
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Abstract  

This retrospective cohort study investigated dementia risk associated with metformin use in type 2 diabetes patients by using the reimbursement database of the Taiwan’s National Health Insurance. The patients had new-onset diabetes during 1999-2005 and were followed up until December 31, 2011. An unmatched cohort of 147,729 ever users and 15,676 never users of metformin were identified, and a matched-pair cohort of 15,676 ever users and 15,676 never users was created by propensity score (PS). Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using PS. Results showed that in the unmatched cohort, 713 never users and 3943 ever users developed dementia with respective incidence of 1029.20 and 570.03 per 100,000 person-years. The overall hazard ratio was 0.550 (95% confidence interval: 0.508-0.596). The hazard ratio for the first (<27.0 months), second (27.0-58.1 months) and third (>58.1 months) tertile of cumulative duration of metformin therapy was 0.975 (0.893-1.066), 0.554 (0.506-0.607) and 0.286 (0.259-0.315), respectively. Analyses in the matched cohort showed an overall hazard ratio of 0.707 (0.632-0.791) and the hazard ratio for the respective tertile was 1.279 (1.100-1.488), 0.704 (0.598-0.829) and 0.387 (0.320-0.468). In conclusion, metformin use is associated with a reduced dementia risk.

Keywords dementia      diabetes mellitus      metformin      Taiwan     
Corresponding Authors: Chin-Hsiao Tseng   
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These authors contributed equally to work

Issue Date: 20 October 2017
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Chin-Hsiao Tseng
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Chin-Hsiao Tseng. Metformin and the Risk of Dementia in Type 2 Diabetes Patients[J]. Aging and disease, 2019, 10(1): 37-48.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.1202     OR     http://www.aginganddisease.org/EN/Y2019/V10/I1/37
Figure 1.  Flowchart showing the procedures followed in creating the unmatched original cohort and a cohort of 1:1 matched-pairs of metformin ever and never users from the reimbursement database of the National Health Insurance.
VariableUnmatched original cohortMatched cohort
Never usersEver usersNever usersEver users
(n=15676)(n=147729)PSD(n=15676)(n=15676)PSD
n%n%n%n%
Demographic data
Age* (years)63.4±10.461.6±10.0<0.01-17.8363.4±10.463.5±9.90.301.67
Sex (men)900957.478012354.24<0.01-7.18900957.47898557.320.78-0.56
Occupation
I614239.185806639.31<0.01614239.18608438.810.92
II312219.923411223.098.28312219.92315320.110.51
III330121.063060020.71-0.65330121.06331621.150.45
IV311119.852495116.89-8.58311119.85312319.920.02
Living region
Taipei521133.244651231.48<0.01521133.24529633.780.31
Northern158610.121657711.223.71158610.1214999.56-1.86
Central276917.662711518.351.88276917.66269117.17-1.27
Southern274617.522509816.99-1.49274617.52278017.730.65
Kao-Ping and Eastern336421.463242721.951.35336421.46341021.750.81
Major comorbidities
Hypertension1280481.6812073181.720.890.271280481.681283681.880.640.69
Dyslipidemia1129972.0812254982.96<0.0128.631129972.081129072.020.910.26
Obesity4242.7066764.52<0.019.964242.703892.480.21-1.29
Nephropathy535634.174010127.14<0.01-17.32535634.17529633.780.47-1.31
Eye diseases294218.774780332.36<0.0131.61294218.77266216.98<0.01-4.94
Stroke499631.874210128.50<0.01-8.08499631.87488531.160.18-1.49
Ischemic heart disease738447.106701845.37<0.01-3.60738447.10734846.870.68-0.30
Peripheral arterial disease355022.653774225.55<0.016.98355022.65355022.651.00-0.12
Antidiabetic drugs
Insulin12828.1834522.34<0.01-29.9012828.1810486.69<0.01-6.59
Sulfonylurea1146873.1610789673.040.755.131146873.161176875.07<0.015.32
Meglitinide12838.1857673.90<0.01-19.1712838.1812598.030.62-0.50
Acarbose174311.1280885.47<0.01-20.10174311.12169710.830.41-1.42
Rosiglitazone4642.9673885.00<0.0110.944642.964672.980.92-0.06
Pioglitazone3872.4739432.670.14-20.103872.473982.540.69-1.42
Commonly encountered comorbidities
COPD767548.967104448.090.03-2.12767548.96780749.800.141.86
Tobacco abuse4422.8259434.02<0.016.834422.824692.990.361.06
Alcohol-related diagnoses12317.85104907.10<0.01-4.1612317.8510876.93<0.01-3.77
Head injury5383.4355243.740.051.445383.435233.340.64-0.63
Parkinson’s disease5043.22
3349
2.27<0.01-6.26
504
3.22
504
3.221.000.10
Commonly used medications in diabetes patients
ACEI/ARB1085469.2410791173.05<0.018.811085469.241087969.400.76-0.30
Calcium channel blocker977162.338808359.62<0.01-5.62977162.33976762.310.960.41
Statin842853.769735865.90<0.0126.59842853.76830052.950.150.06
Fibrate533834.056381743.20<0.0120.06533834.05517032.98<0.05-1.41
Aspirin887156.599040061.19<0.019.87887156.59879756.120.40-2.07
Table 1  Characteristics of metformin never users and ever users in the unmatched original cohort and in the propensity, score matched cohort.
Metformin usenNPerson-yearIncidence rate (per 100,000 person-years)HR95% CIP value
Unmatched original cohort
Never users7131567669277.311029.201.000
Ever users3943147730691712.02570.030.550(0.508-0.596)<0.0001
Tertiles of cumulative duration of metformin therapy (months)
Never users7131567669277.311029.201.000
<27.0165748645168899.36981.060.975(0.893-1.066)0.5819
27.0-58.1136348872237111.30574.840.554(0.506-0.607)<0.0001
>58.192350213285701.36323.060.286(0.259-0.315)<0.0001
Matched cohort
Never users7131567669277.311029.201.000
Ever users5311567672593.50731.470.707(0.632-0.791)<0.0001
Tertiles of cumulative duration of metformin therapy (months)
Never users7131567669277.311029.201.000
<26.6226517117707.201276.321.279(1.100-1.488)0.0014
26.6-57.8180517524707.24728.530.704(0.598-0.829)<0.0001
>57.8125533030179.07414.190.387(0.320-0.468)<0.0001
Table 2  Incidence rates of dementia and hazard ratios by metformin exposure
ModelsnNHR95% CIP value
Excluding two consecutive prescriptions of metformin spanning more than 4 months
Never users713156761.000
Ever users1046497040.467(0.425-0.514)<0.0001
Tertiles of cumulative duration of metformin therapy (months)
Never users713156761.000
<27.0392160430.937(0.826-1.064)0.3174
27.0-58.1325136650.528(0.463-0.603)<0.0001
>58.1329199960.261(0.229-0.298)<0.0001
Excluding two consecutive prescriptions of metformin spanning more than 6 months
Never users713156761.000
Ever users1448659760.469(0.429-0.513)<0.0001
Tertiles of cumulative duration of metformin therapy (months)
Never users713156761.000
<27.0512194460.966(0.860-1.085)0.5606
27.0-58.1482190130.541(0.482-0.607)<0.0001
>58.1454275170.259(0.230-0.292)<0.0001
Excluding patients treated with incretin-based therapies during follow-up
Never users692147501.000
Ever users36151130900.655(0.604-0.711)<0.0001
Tertiles of cumulative duration of metformin therapy (months)
Never users692147501.000
<27.01580410311.072(0.979-1.173)0.1318
27.0-58.11241371530.650(0.592-0.713)<0.0001
>58.1794349060.349(0.315-0.387)<0.0001
Table 3  Sensitivity analyses estimating hazard ratios for dementia for ever versus never users of metformin in the original cohort.
YearEver users
Never users
HR95% CIP value
nNnN
Unmatched original cohort
1999793210337313350.562(0.442-0.714)<0.0001
2000704213097014730.588(0.460-0.752)<0.0001
2001639220898517260.514(0.410-0.645)<0.0001
20025352162410021100.485(0.392-0.600)<0.0001
20035022199710424110.511(0.414-0.632)<0.0001
20043972043012428730.456(0.373-0.558)<0.0001
20053761924715737480.507(0.420-0.611)<0.0001
Matched cohort
19999023047313350.588(0.432-0.801)0.0008
20008423297014730.659(0.480-0.906)0.0101
20019624208517260.725(0.541-0.971)0.0309
200259223110021100.529(0.383-0.730)0.0001
200369222310424110.697(0.514-0.945)0.0200
200455214212428730.611(0.445-0.840)0.0024
200549202715737480.624(0.453-0.861)0.0041
Table 4  Hazard ratios for dementia for ever versus never users of metformin estimated for each specific year from 1999 to 2005
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