Aspirin Use and Risk of Type 2 Diabetes in Apparently Healthy Men

Article Outline

• Abstract
• Materials and Methods
  • Study Population
  • Questionnaires
  • Assessment of Aspirin and NSAID Use
  • Statistical Analysis
• Results
• Discussion
• Study Limitations
• Conclusions
• Acknowledgements
• References
• Copyright

Abstract 

Background

Epidemiologic data on aspirin use and the risk of diabetes are limited. The Physician's Health Study has accumulated 22 years of follow-up data, including 5 years of randomized data, from 22,071 apparently healthy men.

Methods and Results

At baseline and in yearly follow-up questionnaires, participants self-reported a history of diabetes, aspirin use, and various lifestyle factors. To evaluate the association between aspirin use and risk of subsequent diabetes, we used a Cox proportional hazards model with time-varying regression coefficients. During the 22 follow-up years, 1719 cases of diabetes were reported. The multivariable-adjusted hazard ratio of developing diabetes was 0.86 (95% confidence interval [CI], 0.77-0.97) for those who self-selected any aspirin. During the 5 years of randomized treatment, 318 cases of diabetes were observed, with a hazard ratio of 0.91 (95% CI, 0.73-1.14) for those randomized to aspirin.

Conclusion

Our data suggest a small but not significant decrease in the risk of diabetes during 5 years of randomized comparison of 325 mg of aspirin every other day. This trend was continued during 22 years of follow-up, indicating that self-selection of any use of aspirin is associated with a significant, approximately 14% decrease in the risk of diabetes. Decreased risk of type 2 diabetes may be added to the list of the clinical benefits of aspirin.

Keywords: Aspirin, Cohort study, Diabetes, Epidemiology, Incidence, Men

Type 2 diabetes mellitus is one of the most prevalent chronic diseases, affecting more than 13.3 million people in the United States alone, a number that has doubled during the past 20 years.¹ Diabetes imposes a substantial social and economic burden and is the leading cause of nontraumatic lower-extremity amputation, renal failure, and blindness in working-age adults, as well as a major cause of mortality through cardiovascular disease, stroke, and peripheral artery disease.² Because of its preventive effect on cardiovascular events, the use of aspirin is recommended by the American Diabetes Association and American Heart Association for individuals with type 2 diabetes who have experienced cardiovascular disease or show atherogenic risk factors.³ The association between aspirin and glycemic control, however, is still under investigation. Several earlier clinical studies suggested that aspirin improves insulin sensitivity and glycemic control in patients with type 2 diabetes,⁴, ⁵, ⁶, ⁷ whereas 3 other studies suggested that aspirin impairs insulin sensitivity in healthy volunteers.⁸, ⁹, ¹⁰

A causal association between aspirin and the incidence of diabetes appears biologically plausible because of the suggested partial role of chronic low-grade inflammation in atherosclerosis,¹¹ which possibly shares the same inflammatory basis as diabetes.¹², ¹³, ¹⁴ In recent studies in rodents, high-dose aspirin was shown to reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents, as well as lower blood glucose concentration by inhibiting the IκB kinase-β pathway, which is not inhibited by other nonsteroidal anti-inflammatory drugs (NSAIDs).¹⁵, ¹⁶ Despite these findings, analytic studies on aspirin or non-aspirin NSAIDs and the risk of diabetes in free-living human populations are limited.

We thus investigated the relationship between aspirin or non-aspirin NSAIDs and the subsequent risk of type 2 diabetes mellitus. Analysis was carried out using randomized data from the Physicians' Health Study, which included 22,071 apparently healthy male physicians treated with 325 mg aspirin every 2 days for 5 years, followed by analysis of prospective observational data, in which a variety of doses were self-selected for an additional 17 years.

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Materials and Methods 

Study Population 

The Physicians' Health Study was a randomized, double-blind, placebo-controlled trial designed to test the risk and benefits of low-dose aspirin and β-carotene assignment on the risk of cardiovascular disease and cancer in apparently healthy men.¹⁷, ¹⁸ A detailed description of the subjects and methods has been published.¹⁷, ¹⁸, ¹⁹ Briefly, 22,071 male physicians, aged 40 to 84 years at baseline in 1982, who were free of cardiovascular disease, cancer, or other major disease and had no indication or contraindications to aspirin or non-aspirin NSAID treatment were randomly assigned to active aspirin (325 mg on alternate days), active beta carotene (50 mg every other day), both active agents, or both placebos.

In January 25, 1988, the randomized aspirin component of the study was prematurely terminated on the basis of the unanimous recommendation of the external data monitoring board, primarily because of the emergence of a statistically extreme 44% reduction in risk of first myocardial infarction after aspirin administration.¹⁷ After this termination, physicians were allowed to request an aspirin pill replacement containing active aspirin instead of placebo. The randomized β-carotene component of the study continued uninterrupted until its scheduled termination on December 31, 1995, which was followed by post-trial experimental follow-up.²⁰ A total of 638 men who reported having diabetes before participating in the study were excluded from the analysis.

Questionnaires 

Information on height and weight, previously diagnosed medical conditions, including diabetes mellitus, hypertension history, high cholesterol levels, parental history of myocardial infarction, and lifestyle factors, such as cigarette smoking (never, past, currently smoking), frequency of alcohol intake and frequency of vigorous exercise was collected at baseline by mailed questionnaires.

Every 6 months for the first year and annually thereafter, participants were mailed follow-up questionnaires inquiring about compliance with the randomized treatment, nonstudy use of aspirin and non-aspirin NSAIDs, and any new medical diagnosis, including diabetes. Given the age structure of the population sample, all incident cases of diabetes were diagnosed after age 40 years and classified as type 2 diabetes mellitus. The vital status of all physicians also was known.

Assessment of Aspirin and NSAID Use 

During the randomized and post-trial observational period, participants completed annual questionnaires inquiring about compliance with study medication, as well as outside use of aspirin and non-aspirin NSAIDs. This information was used to consistently group subjects by aspirin or NSAID use, in terms of no use (0 days), 1 to 60 days of use, and more than 60 days of use. Details of this categorization have been comprehensively described elsewhere.²¹

Statistical Analysis 

The association of aspirin and NSAID use with diabetes incidence was evaluated using Cox proportional hazards models with time-varying exposure information. Person-time was calculated from the date of randomization to that of diabetes, death, or receipt of the last questionnaire, whichever occurred first.

First, we investigated the association between randomized aspirin assignment and the risk of diabetes on an intention-to-treat basis until the end of the aspirin arm of the trial. Next, we investigated the association between self-selection of aspirin (0 d/y or any use of aspirin) and risk of diabetes by multivariable-adjusted model analyses based on data from the combined aspirin categories, which were collected from randomization until the end of the 22-year follow-up period. We also performed the analysis by stratifying aspirin dose (0 d/y vs 1-60 d/y or >60 d/y) using age- and multivariable-adjusted models. In addition, the association between non-aspirin NSAIDs and diabetes was analyzed by calculating age- and multivariable-adjusted hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs). The multivariable models controlled for variables considered potential confounders: age (in 5-year increments); body mass index (BMI) (<25, 25-29.9, ≥30 kg/m²); smoking history (never, past, currently smoking); history of hypertension (self-reported systolic blood pressure≥140 mm Hg, diastolic pressure≥90 mm Hg, or use of antihypertensive medication); history of hypercholesterolemia (serum cholesterol≥240 mg/dL or use of cholesterol-lowering medication); history of hypercholesterolemia (serum cholesterol ≥240 mg/dL or use of cholesterol-lowering medication); parental history of myocardial infarction before age 60 years; alcohol use (daily, weekly, monthly, rarely, or never); and exercise. Linear trends were analyzed across aspirin and NSAID intake categories. To evaluate the rational of treating study and nonstudy use of aspirin as having the same effect, the interaction of study and nonstudy use on the risk of diabetes was evaluated using indicator variables for each aspirin category combination. Further, we evaluated effect modification of the association between aspirin use and diabetes by age (<60 or ≥60 years), obesity (BMI<30 or≥30 kg/m²), smoking (currently smoking or not), or hypertension history (yes, no). Statistical interactions were analyzed using likelihood ratio tests, which compared the −2 log (likelihood) between 2 nested models: one considering the main effects alone and one considering the main effects and additional interaction terms. All analyses were conducted using SAS version 8.2 (SAS Institute Inc, Cary, NC).

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Results 

During the 5 years of randomized aspirin treatment (105,625 person years), 318 incident cases of diabetes were reported. A total of 1719 cases were reported during the 22 years from randomization until the end of the follow-up. The age-adjusted baseline characteristics with respect to diabetes incidence after study enrollment are summarized in Table 1. Participants who developed diabetes during the follow-up period were more likely to be obese, to be hypertensive, to have high cholesterol, and to report a parental history of myocardial infarction before age 60. Further, they were more likely to be current smokers and less physically active, and to drink less alcohol.

Table 1. Age-adjusted Baseline Characteristics of Participants According to Diabetes^a

	Diabetes (n=1719)	No Diabetes (n=19,714)
Age (SD), y	54.1 (8.7)	53.5 (9.5)
BMI, %
<25 kg/m2	32.9	60.1
25-29.9 kg/m2	52.9	36.7
≥30 kg/m2	14.2	3.2
Hypertension, %b	36.0	21.9
High cholesterol, %c	14.9	11.5
Parental history of myocardial infarction before age 60 y, %	11.1	9.2
Smoking, %
Never	43.9	50.2
Past	40.3	39.2
Currently smoking	15.8	10.6
Physical activity, %d
<1 time/wk	36.0	26.6
≥1 time/wk	64.0	73.4
Alcohol, %
Daily	19.8	25.4
Weekly	47.6	49.6
Monthly	14.5	10.7
Rarely or never drink	18.2	14.3

SD=standard deviation; BMI=body mass index.

Table 2 shows the number of person-years in each combined aspirin category for the 60-month interval subsequent to aspirin use. Because participants were not allowed to use additional aspirin at baseline, fewer person-years were spent in the 1 to 60 days of aspirin use/year category than in the 0 and more than 60 days/year categories between baseline and the 60-month follow-up period. In addition, participants were more likely to frequently use aspirin as the study progressed; between 120 months and 180 months, results show 63,812 person-years in the more than 60 days/year category, whereas 10,904 person-years were not classified in any category.

Table 2. Aspirin Use and Subsequent Risk of Diabetes Mellitus during Follow-up Periods

	0 d/y			1-60 d/y			>60 d/y			Cumulative Deceased
Follow-up Periods	PY	DM	Incidence Ratea	PY	DM	Incidence Ratea	PY	DM	Incidence Ratea
			(95% CI)			(95% CI)			(95% CI)
Baseline to 60 mo	37,825	133	3.5(2.9-4.2)	17,802	53	3.0(2.2-3.9)	49,649	141	2.8(2.4-3.3)	408
61-120 mo	17,186	70	4.1(3.2-5.1)	16,501	49	3.0(2.2-3.9)	65,014	246	3.8(3.3-4.3)	822
121-180 mo	10,904	58	5.3(4.0-6.9)	9893	50	5.1(3.8-6.7)	63,812	336	5.3(4.7-5.9)	1254
181 mo	19,540	117	6.0(5.0-7.2)	16,767	70	4.2(3.3-5.3)	65,135	318	4.9(4.4-5.4)	2207

PY=person-years; DM=diabetes mellitus; CI=confidence interval.

During the 5 years of randomized treatment, intention-to-treat analysis revealed an HR for diabetes development of 0.91 for the aspirin group (95% CI, 0.73-1.14) compared with the aspirin placebo group. Observational comparisons over 22 years showed a multivariable-adjusted HR for diabetes of 0.86 (95% CI, 0.77-0.97) for subjects who self-selected any aspirin. Further, stratification by aspirin dose revealed that compared with non-aspirin users, multivariable-adjusted HRs for diabetes in men who used aspirin for 1 to 60 days/year and more than 60 days/year were 0.83 (95% CI, 0.71-0.98) and 0.87 (95% CI, 0.78-0.98), respectively (Table 3). The likelihood ratio test showed no significant interaction between study and additional aspirin use in reducing the risk of type 2 diabetes. Contrary to the aspirin findings, we did not observe a decrease in risk of developing diabetes by non-aspirin NSAIDs: Compared with subjects who did not use non-aspirin NSAIDs, the age-adjusted HRs for diabetes in men who used non-aspirin NSAIDs for 1 to 60 days/year and more than 60 days/year were 0.97 (95% CI, 0.87-1.08) and 1.11 (95% CI, 0.93-1.32), respectively. This association remained nonsignificant after adjustment for a large number of confounders, including age, BMI, history of smoking, hypertension, high cholesterol, parental myocardial infarction before age 60 years, alcohol use, and exercise.

Table 3. Hazard Ratios and 95% Confidence Intervals According to Time-varying Combined Aspirin and Non-aspirin Nonsteroidal Anti-inflammatory Drug Use During 22 Years of Follow-up

	DM, n	Age-adjusteda HR (95% CI)	Multivariable-adjustedb HR (95% CI)
Combined Aspirin
None	456	1.00	1.00
1-60 d/y	222	0.79(0.67-0.93)	0.83(0.71-0.98)
>60 d/y	1041	0.85(0.76-0.95)	0.87(0.78-0.98)
P for trend		0.0049	0.0329
Non-aspirin NSAIDs
None	1039	1.00	1.00
1-60 d/y	536	0.97(0.87-1.08)	0.95(0.85-1.06)
>60 d/y	144	1.11(0.93-1.32)	0.99(0.83-1.18)
P for trend		0.3429	0.6552

DM=diabetes mellitus; HR=hazard ratio; CI=confidence interval; NSAID=nonsteroidal anti-inflammatory drug.

To examine the possible effect modification of the association between aspirin and diabetes incidence based on diabetes risk factors for which an association with inflammation has been reported, a stratified analysis by these risk factors was performed (Table 4). Results showed no statistically significant effect modification by hypertension, BMI, smoking status, or age at randomization.

Table 4. Multivariable-adjusted Hazard Ratios and 95% Confidence Intervals According to Combined Aspirin Categories^a

	Combined Aspirin Categories
	0	1-60	>60	P for Interaction
Age				.58
<60 y	1.00	0.78(0.65-0.94)	0.83(0.73-0.95)
≥60 y	1.00	0.98(0.69-1.40)	0.96(0.76-1.21)
Obesity				.46
BMI<30 kg/m2	1.00	0.83(0.69-0.99)	0.85(0.75-0.96)
BMI≥30 kg/m2	1.00	0.82(0.52-1.32)	1.03(0.75-1.42)
Smoking				.06
Never or past	1.00	0.77(0.65-0.93)	0.83(0.73-0.94)
Currently smoking	1.00	1.22(0.82-1.83)	1.19(0.88-1.62)
Hypertensionb				.09
No	1.00	0.71(0.58-0.88)	0.79(0.69-0.92)
Yes	1.00	1.12(0.85-1.48)	1.04(0.85-1.26)

BMI=body mass index.

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Discussion 

Results from randomized comparisons over 5 years suggest a small but nonsignificant reduction in the risk of diabetes after administration of 325 mg aspirin on alternate days. This trend continued during 22 years of observational follow-up, indicating a significant approximately 14% reduction in relative risk, which remained significant after adjustment for a large number of potential confounders. We observed no beneficial association between the use of non-aspirin NSAIDs and risk of diabetes.

Our findings are consistent with those from a number of previous clinical studies that evaluated the association between salicylates and glycemic control. In 1877 and 1902, Ebstein⁴ and Williamson and Loud⁵ showed that high-dose salicylate treatment reduced the severity of glycosuria in diabetic patients. In 1957, Reid et al⁶ also observed a decrease in glycosuria and blood glucose in a diabetic patient treated with aspirin for acute rheumatism and further demonstrated an improvement in test results for the oral glucose tolerance in diabetic patients after 10 to 14 days of aspirin treatment.⁶, ²² A randomized trial in type 2 diabetic patients treated for 2 weeks with high-dose aspirin reported a significant decrease in hepatic glucose production, fasting plasma glucose, fatty acids, and triglycerides.⁷

Our findings, which show that aspirin, but not non-aspirin NSAIDs, reduces the risk of developing diabetes, are also consistent with plausible biological mechanisms. A recent finding suggests that salicylates inhibit inflammation through a pathway different from cyclooxygenase inhibition. Salicylate affects a key pathway in tissue inflammation by inhibiting nuclear factor κB and its upstream activator, IκB kinase-β,²³ which is activated by inflammatory mediators (eg, tumor necrosis factor-α, interleukin-1β), high glucose, and obesity.¹⁵, ²⁴, ²⁵ Further, activated IκB kinase-β induces the synthesis of tumor necrosis factor-α and interleukin-1β, resulting in a cycle that induces insulin resistance and perpetual tumor necrosis factor-α production initiation. This pathway, however, is not associated with non-aspirin NSAIDs.²³ Our negative result for non-aspirin NSAIDs may indirectly suggest that the cyclooxygenase-mediated inflammatory pathway does not play an important role in the development of type 2 diabetes.

To date, randomized controlled trials have demonstrated the efficacy of 3 types of medication in the prevention or delay of type 2 diabetes.²⁶, ²⁷, ²⁸ These trials were conducted in subjects with impaired glucose tolerance who were consequently a high-risk population for diabetes incidence. The Diabetes Prevention Program (DPP), Study TO Prevent Non-Insulin-Dependent Diabetes Mellitus (STOPN-IDDM), and Troglitazone in the Prevention of Diabetes (TRIPOD) studies showed a 31%, 32%, and 56% decrease in diabetes risk using biguanide metformin, the α-glucosidase inhibitor acarbose, and the thiazolidinedione troglitazone, respectively.²⁶, ²⁷, ²⁸ However, the American Diabetes Association does not recommend the use of these drugs for the prevention of type 2 diabetes, because of their required monitoring, association with significant adverse side effects, and contraindication in a few individuals, as well as the absence of studies on these drugs showing an effect on coronary vascular diseases or other clinical benefits to nondiabetic individuals. Although the reduction in diabetes risk by aspirin should be carefully evaluated, its use is potentially valuable in the prevention of this condition because of its beneficial effect even in nondiabetic populations if they have a high risk of coronary artery disease, and aspirin is already recommended by the US Preventive Services Task Force. Aspirin also is currently used in nondiabetic populations for the prevention of coronary vascular disease.²⁹

The strengths of our study include its prospective design, large number of outcome events and high participant follow-up rate, detailed assessment of aspirin and NSAIDs, and use of physicians as study subjects, which may have reduced confounding caused by variability in medical care access, as well as educational and socioeconomic status. In addition, we controlled for a large number of potential confounding factors. On enrollment in the Physicians' Health Study, participants had no indication or contraindication for aspirin or NSAID use, which have reduced residual confounding by prior use.

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Study Limitations 

Several limitations of the study also warrant mention. First, our cohort was not screened at baseline for glucose tolerance, fasting glucose, or hemoglobin-A1c. Further, the clinical diagnosis of diabetes was self-reported, resulting in possible underdiagnosis of type 2 diabetes cases.³⁰ However, underdiagnosis of diabetes would be expected to be lower among physicians than in the general population. Furthermore, such nondifferential misclassification would likely lead to an underestimation of effect. Second, only data on the number of days of aspirin or NSAIDs use were available, as opposed to data on actual drug dose. Further, the absence of variation in the association of aspirin dosage and risk of diabetes is possibly due to misclassification bias or, alternatively, to residual and uncontrollable confounding, despite controlling for a large number of potential confounding factors. Third, participants in the Physicians' Health Study were predominantly white. Nevertheless, on the basis of current knowledge, differential biological effects of aspirin and NSAIDs on diabetes among different male populations seem unlikely. Recent data from the Women's Health Study indicate no significant association of participants randomly assigned to receive 100 mg of aspirin every other day when compared with a corresponding placebo. Whether this lack of association remains during further follow-up remains to be established.³¹

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Conclusions 

Our data suggest a small but not significant decrease in the risk of diabetes during 5 years of a randomized comparison of 325 mg of aspirin every other day. This trend was continued during 22 years of follow-up, indicating that self-selection of aspirin is associated with a significant approximately 14% decrease in the risk of diabetes. Decreased risk of type 2 diabetes may be added to the list of clinical benefits of aspirin. Future studies are warranted to further investigate this association.

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Acknowledgements 

We are indebted to the participants in the Physicians' Health Study for outstanding commitment and cooperation, to the entire Physicians' Health Study staff for expert and unfailing assistance, and to Eunjung Kim for programming assistance.

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