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Aging and disease
Orginal Article |
Dementia Risk in Type 2 Diabetes Patients: Acarbose Use and Its Joint Effects with Metformin and Pioglitazone
Chin-Hsiao Tseng1,2,3,*
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 population-based retrospective cohort study investigated dementia risk associated with acarbose in patients with type 2 diabetes mellitus by using Taiwan’s National Health Insurance database. A cohort of 15,524 matched pairs of ever and never users of acarbose based on propensity score matching was enrolled from new-onset type 2 diabetes patients from 1999 to 2006. Patients who were alive on January 1, 2007, were followed up for dementia until December 31, 2011. Adjusted hazard ratios were estimated using Cox proportional hazards models. The results revealed that the incident case numbers (incidence rates) of dementia were 264 (407.19 per 100,000 person-years) for never users and 231 (337.94 per 100,000 person-years) for ever users. The hazard ratio for ever users versus never users was 0.841 (95% confidence interval, 0.704-1.005) and 0.918 (0.845-0.998) for every 1-year increment of cumulative duration of acarbose therapy. Subgroup analyses showed that the reduced risk associated with acarbose was only observed in women (adjusted hazard ratio, 0.783; 95% confidence interval, 0.618-0.992) and in non-users of metformin (adjusted hazard ratio, 0.635; 95% confidence interval, 0.481-0.837). A model comparing different combinations of acarbose, metformin, and pioglitazone suggested that users of all three drugs had the lowest risk of dementia (hazard ratio, 0.406; 95% confidence interval, 0.178-0.925). In conclusion, reduced risk of dementia associated with acarbose is observed in the female sex and in non-users of metformin. Moreover, users of all three drugs (acarbose, metformin, and pioglitazone) have the lowest risk of dementia.

Keywords acarbose      dementia      diabetes mellitus      metformin      pioglitazone      Taiwan     
Corresponding Authors: Chin-Hsiao Tseng   
About author:

These authors contributed equally to this work.

Just Accepted Date: 02 October 2019  
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Chin-Hsiao Tseng. Dementia Risk in Type 2 Diabetes Patients: Acarbose Use and Its Joint Effects with Metformin and Pioglitazone[J]. Aging and disease, 10.14336/AD.2019.021
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http://www.aginganddisease.org/EN/10.14336/AD.2019.021     OR     http://www.aginganddisease.org/EN/Y/V/I/0
Figure 1.  Flowchart for the procedures in selecting a propensity score-matched cohort of acarbose ever users and never users.
VariableNever usersEver users
(n=15524)(n=15524)P-valueStandardized difference
n%n%
Demographic data
Age (years)59.7610.1059.759.950.9225-0.13
Sex (men)835853.84844354.390.33301.15
Diabetes duration (years)5.422.415.452.270.24441.26
Occupation
I674943.47678243.690.6102
II368723.75360923.25-1.24
III251516.20258016.621.14
IV257316.57255316.45-0.34
Living region
Taipei592338.15588437.900.6517
Northern185911.98178511.50-1.55
Central185911.98273617.620.80
Southern196212.64199012.820.61
Kao-Ping and Eastern308919.90312920.160.70
Major comorbidities
Hypertension1079669.541077769.420.8149-0.34
Dyslipidemia1151574.181149874.070.8256-0.35
Obesity10366.679596.180.0747-2.08
Diabetes-related complications
Nephropathy271717.50272917.580.85790.23
Eye disease386424.89386124.870.96860.01
Ischemic heart disease525333.84523433.720.8197-0.34
Peripheral arterial disease264217.02261416.840.6718-0.51
Potential risk factors of cancer
Chronic obstructive pulmonary disease565736.44559736.050.4787-0.84
Tobacco abuse3852.483852.480.3738-1.07
Alcohol-related diagnoses7474.817344.730.7292-0.45
Potential factors that may affect the prescription of acarbose
Gallstone13358.6012938.330.3918-1.06
Diseases of the digestive system1533298.761533798.800.79610.25
Helicobacter Pylori infection and/or Helicobacter Pylori eradication therapies290418.71288818.600.8157-0.36
Hepatitis B virus infection3552.293522.270.9091-0.24
Hepatitis C virus infection5603.615533.560.8308-0.37
Liver cirrhosis4212.714923.170.01712.64
Other chronic non-alcoholic liver diseases14829.5515089.710.61690.59
Antidiabetic drugs
Insulin7404.777815.030.28101.10
Sulfonylurea1074569.221084569.860.21751.19
Metformin937460.38937060.360.9630-0.48
Meglitinide11147.1811047.110.8256-0.27
Rosiglitazone13818.9014079.060.60580.54
Pioglitazone13979.0014159.110.72190.34
Medications commonly used in diabetes patients
Angiotensin converting enzyme inhibitor/angiotensin receptor blocker960461.87957061.650.6913-0.55
Calcium channel blocker727846.88726246.780.8556-0.24
Statin897057.78881056.750.0664-2.12
Fibrate582337.51587037.810.58200.59
Aspirin706545.51705045.410.8643-0.30
Table 1  Characteristics in never and ever users of acarbose.
Table 1  shows the characteristics of never users and ever users of acarbose. None of the calculated values of standardized difference between the two groups was found to be > 10%, suggesting that the two groups were well matched in these covariates. However, the proportion of liver cirrhosis in ever users was slightly higher than that in never users (3.17% versus 2.71%, P-value = 0.0171).
ModelsnNPerson-yearsIncidence rate (per 100,000 person-years)Adjusted hazard ratio95% Confidence intervalP-value
All patients
Acarbose never users2641552464834.36407.191.000
Acarbose ever users2311552468355.38337.940.841(0.704-1.005)0.0561
Cumulative duration of acarbose therapy treated as a continuous variable
For every 1-year increment of acarbose use0.918(0.845-0.998)0.0444
Men
Acarbose never users101835834603.53291.881.000
Acarbose ever users107844337111.21288.320.934(0.710-1.228)0.6252
Cumulative duration of acarbose therapy treated as a continuous variable
For every 1-year increment of acarbose use0.983(0.871-1.110)0.7840
Women
Acarbose never users163716630230.84539.181.000
Acarbose ever users124708131244.17396.870.783(0.618-0.992)0.0425
Cumulative duration of acarbose therapy treated as a continuous variable
For every 1-year increment of acarbose use0.870(0.775-0.976)0.0180
Table 2  Incidence rates of dementia and hazard ratios by acarbose exposure in all patients and in different sexes.
Figure 2.  Kaplan-Meier curves comparing dementia-free probability in different subgroups of acarbose exposure. Kaplan-Meier curves comparing dementia-free probability between ever users and never users of acarbose in both sexes together (A) and in separate sexes (B: men, C: women). (D) compares the respective curves in subgroups of patients with different combinations of use (+) and non-use (-) of metformin (M), pioglitazone (P) and acarbose (A). The 95% confidence intervals are shown in shaded areas. HR: hazard ratio; CI: confidence interval.
ModelsnNPerson-yearsIncidence rate (per 100,000 person-years)Adjusted hazard ratio95% Confidence intervalP-value
1.Patients with metformin
Acarbose never users131937439407.59332.421.000
Acarbose ever users127937040996.20309.781.023(0.798-1.312)0.8559
2.Patients without metformin
Acarbose never users133615025426.78523.071.000
Acarbose ever users104615427359.18380.130.635(0.481-0.837)0.0013
3.Patients with pioglitazone
Acarbose never users2713976101.85442.491.000
Acarbose ever users1314156098.01213.180.598(0.303-1.180)0.1382
4.Patients without pioglitazone
Acarbose never users2371412758732.51403.521.000
Acarbose ever users2181410962257.37350.160.877(0.728-1.055)0.1644
5.Joint effects of metformin, pioglitazone and acarbose
Group 0: Metformin (-) / Pioglitazone (-) / Acarbose (-)126564723323.77540.221.000
Group 1: Metformin (-) / Pioglitazone (-) / Acarbose (+)97560024953.18388.730.643(0.489-0.845)0.0015
Group 2: Metformin (-) / Pioglitazone (+) / Acarbose (-)75032103.01332.860.635(0.295-1.369)0.2466
Group 3: Metformin (-) / Pioglitazone (+) / Acarbose (+)75542405.99290.940.603(0.281-1.295)0.1945
Group 4: Metformin (+) / Pioglitazone (-) / Acarbose (-)111848035408.74313.480.596(0.457-0.779)0.0002
Group 5: Metformin (+) / Pioglitazone (-) / Acarbose (+)121850937304.19324.360.691(0.535-0.893)0.0048
Group 6: Metformin (+) / Pioglitazone (+) / Acarbose (-)208943998.85500.141.104(0.683-1.784)0.6870
Group 7: Metformin (+) / Pioglitazone (+) / Acarbose (+)68613692.01162.510.406(0.178-0.925)0.0320
Table 3  The effects of acarbose on dementia risk with regards to exposure to metformin and/or pioglitazone.
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