Daily low-dose aspirin and incident type 2 diabetes in community-dwelling healthy older adults: a post-hoc analysis of efficacy and safety in the ASPREE randomised placebo-controlled trial

Summary

Background

Inflammation has been implicated in the pathogenesis of diabetes. This study investigated the randomised treatment effect of low-dose aspirin on incident type 2 diabetes and fasting plasma glucose (FPG) concentrations among older adults.

Methods

ASPREE was a double-blind, placebo-controlled trial of daily oral low-dose aspirin. The study population included community-dwelling individuals aged 70 years or older (≥65 years for US minority ethnic groups) in the USA and Australia who were free of cardiovascular disease, independence-limiting physical disability, or dementia. For the post-hoc analysis, we excluded participants with diabetes at baseline or with incomplete or missing incident diabetes data during follow-up. Participants were randomly assigned 1:1 to oral 100 mg daily enteric-coated aspirin or placebo. Incident diabetes was defined as self-reported diabetes, commencement of glucose-lowering medication, or a FPG concentration of 7·0 mmol/L or more assessed at annual follow-up visits among participants with no diabetes at baseline. We used Cox proportional hazards models and mixed-model repeated measures to assess the effect of aspirin on incident diabetes and FPG concentrations in the intention-to-treat population. We assessed major bleeding in participants who had taken at least one dose of study medication.

Findings

Between March 10, 2010, and Dec 24, 2014, a total of 16 209 participants were included (8086 [49·9%] randomly assigned to aspirin and 8123 [50·1%] randomly assigned to placebo). During a median follow-up of 4·7 years (IQR 3·6–5·7), 995 (in 6·1% individuals) incident cases of type 2 diabetes were recorded (459 in the aspirin group and 536 in the placebo group). Compared with placebo, the aspirin group had a 15% reduction in risk of incident diabetes (hazard ratio 0·85 [95% CI 0·75 to 0·97]; p=0·013) and a slower rate of increase in FPG concentration at year 5 (between-group difference estimate –0·048 mmol/L [95% CI –0·079 to –0·018]; p=0·0017). Major bleeding (major gastrointestinal bleeding, intracranial bleeding, and clinically significant bleeding at other sites) occurred in 510 (3·2%) of 16 104 participants (300 [3·7%] in the aspirin group and 210 [2·6%] in the placebo group). Compared with placebo, the aspirin group had a 44% increase in risk of major bleeding (hazard ratio 1·44 [95% CI 1·21 to 1·72]; p<0·0001).

Interpretation

Aspirin treatment reduced the incidence of type 2 diabetes and slowed the increase in FPG concentration but increased major bleeding among community-dwelling older adults. Given the increasing prevalence of type 2 diabetes among older adults, the potential for anti-inflammatory agents such as aspirin to prevent type 2 diabetes or improve glucose levels warrants further study with a comprehensive assessment of all potential safety events of interest.

Funding

US National Institute on Aging, US National Cancer Institute, National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency

Introduction

The world is undergoing a demographic transition towards an older population. Older adults (aged 65 years and older) are at high risk of developing type 2 diabetes and the glucometabolic derangements that precede it. The 2021 International Diabetes Federation report¹ on the global prevalence of diabetes estimated that 537 million people had diabetes in 2021, with almost one in five people aged older than 70 years affected. Projections for the US population suggest that there has been a 4·5-fold increase in the number of cases of diabetes in people older than 75 years (compared with a 2-fold increase in the total US population) between 2005 and 2050.²

The mechanisms that underpin type 2 diabetes in older age can include loss of muscle mass and declines in insulin sensitivity and secretion, and can differ from those observed at younger ages including those younger han 45 years and those aged 45–65 years.^3,4 Experimental and epidemiological data have suggested that subclinical inflammation might contribute to metabolic diseases, insulin resistance, and type 2 diabetes.^5–7 For example, increases in the concentrations of inflammatory markers, such as C-reactive protein (CRP), interleukin-6, and fibrinogen, have been associated with poor health outcomes in older adults.^8–10

A new diagnosis of type 2 diabetes might have substantial implications for older adults, who often have other medical conditions, functional decline, polypharmacy, other treatment costs, and a high risk of adverse effects from drugs. Anti-inflammatory and anti-platelet agents, such as aspirin, have been proposed to improve glucose handling and insulin resistance.¹¹ However, results from randomised trials of aspirin for diabetes prevention have not been consistent and randomised trials exclusively in older adults are absent.^12–15 Given that small decreases in the risk of type 2 diabetes can result in substantial benefits at a global population level, simple, low-cost, and safe preventive approaches are urgently needed.^16,17

The Aspirin in Reducing Events in the Elderly (ASPREE) trial was a primary prevention trial that investigated whether a daily use of 100 mg of enteric-coated aspirin would prolong the healthy life span of older adults (older than 70 years).^18–20 The trial was conducted in Australia and the USA and recruited 19 114 older people from community settings. The primary endpoint, survival free from dementia and persistent physical disability, did not differ significantly in the aspirin group compared with the placebo group after a median of 4·7 years of follow-up. However, the risks of major bleeding and death from cancer were higher in the aspirin group than in the placebo group, raising concerns about the safety of aspirin use as a preventive therapy for healthy older people.

Using the comprehensive data collected in the ASPREE trial, we sought to further investigate the randomised treatment effects of aspirin on incident diabetes and fasting plasma glucose (FPG) concentrations in a large, community-based cohort of older adults We hypothesised that treatment of healthy older adults with 100 mg daily of enteric-coated oral aspirin would not reduce incident diabetes or slow the increase in FPG concentration over time when compared with treatment with placebo.

Methods

Study design and participants

The study design, rationale, and principal findings of the ASPREE trial have been previously detailed.^18–21 In brief, ASPREE was an international, prospective, double-blind, randomised placebo-controlled trial examining whether daily oral low-dose aspirin (enteric-coated 100mg) versus a matching placebo would extend the trial’s primary endpoint of survival that is free from dementia and persistent physical disability in community-dwelling older adults. In this study, we report a post-hoc analysis of the ASPREE trial examining the effect of low-dose aspirin on incident diabetes. The trial included 19 114 participants aged 70 years or older (≥65 years among participants in US minority race or ethnic groups) with no previous cardiovascular events, dementia, or independence-limiting physical disability. Participants were recruited between March 10, 2010, and Dec 24, 2014, in Australia (87% of participants) and the USA (13%).^18–21 To be eligible for the ASPREE trial, participants did not have any serious intercurrent illness that was likely to cause death within the next 5 years, did not have a condition known to be associated with a high risk of major bleeding, had a score of 78 or more for the Modified Mini-Mental State Examination test, and had no major physical disability, defined as severe difficulty in any one of the six basic activities of daily living (bathing, dressing, toileting, transferring, walking, and feeding).²² The trial was conducted in accordance with the criteria of the International Conference on Harmonisation for the conduct of clinical trials. The institutional review board at each participating institution approved the trial and all the participants provided written informed consent. The study was registered with ClinicalTrials.gov, NCT01038583.

For this post-hoc study, two additional exclusion criteria were applied: participants with diabetes at baseline (self-report use of glucose-lowering medication, or FPG ≥7.0 mmol/L) and participants with incomplete or missing incident diabetes data during follow-up—ie, those who did not self-report diabetes and did not have FPG concentration and glucose-lowering medication data collected at all annual follow-up visits.

Randomisation and masking

Participants who met the eligibility criteria at a screening visit were enrolled in a 4-week placebo run-in phase for compliance checking. Participants who took 80% or more of the placebo pills during a 4-week run-in phase were randomly assigned, in a 1:1 ratio, to receive daily low-dose aspirin (enteric-coated aspirin 100 mg) or matching placebo. Participants were randomly assigned remotely by study staff via the ASPREE web portal according to a computer-generated randomisation schedule in a ratio of 1:1 to receive aspirin or matching placebo. Randomisation was stratified for general practice in Australia, for regional site in the USA, and for age (65–69 years, 70–79 years, and ≥80 years). Randomisation was blocked within strata, using variable-sized blocks of sizes two, four, or six. ASPREE participants, staff, and trial investigators were masked to study group allocation during follow-up.

Procedures

Recruitment of ASPREE participants commenced on March 10, 2010, and ended on Dec 24, 2014. The interventional phase of the trial was ended on June 12, 2017, by the US National Institute on Aging (funder) after data reviewed by the data safety and monitoring board showed similar rates of the primary endpoint in the two groups that made it very unlikely that continuation of the trial until its scheduled end date of Dec 31, 2017, would show a significant treatment effect for the primary endpoint. Participants were followed up through annual in-person study visits with study staff at their local clinic and a range of physical and cognitive health measures were done, pathology samples collected, and questionnaires on health behaviours, health events, and medications were completed.

Outcomes

The primary outcome of this post-hoc analysis was incident diabetes. The presence of diabetes was determined on the basis of self-report of diabetes in response to a specific question about diabetes, use of glucose-lowering medication, or FPG concentration on annual clinical testing of 7·0 mmol/L or higher (American Diabetes Association [ADA]²³ and WHO criteria²⁴). Participants were asked to bring all currently used prescription medications or a list of these to their baseline and annual study visits. When this request was not possible, medication use was self-reported and, subsequently, confirmed via review of primary care practice records, where possible. Blood samples for measurement of FPG concentrations were collected from participants after an overnight fast at baseline and each annual follow-up visit in a clinic or local pathology centre. Self-reported diabetes was captured at baseline and follow-up visits. The timing of incident diabetes was the date of the annual follow-up visit at which a participant first had any one of self-reported diabetes, commencement of glucose-lowering medication, or FPG of 7 mmol/L or more.

The secondary outcome was the change in FPG concentration over time. FPG concentrations were recorded by collecting a single FPG concentration annually from baseline to the end of follow-up or to the initiation of any glucose-lowering medication, whichever occurred first.

Major bleeding was the safety outcome (a prespecified endpoint in the ASPREE trial) and was defined as the composite of major gastrointestinal bleeding, intracranial bleeding, or clinically significant bleeding at other sites (defined as bleeding that led to transfusion, hospitalisation, prolongation of hospitalisation, surgery, or death). Non-serious safety events were not collected and thus could not be reported for this analysis.

Statistical analysis

The sample size of the ASPREE trial was originally determined for the primary trial endpoint of survival free of both dementia and persistent physical disability. With 995 diabetes cases recorded during the follow-up in 16 209 participants (in the main analysis cohort), our post-hoc study of incident diabetes had at least 80% power to detect hazard ratios (HRs) less than 0·84 or greater than 1·19.

All statistical analyses were conducted on an intention-to-treat basis except for the safety analysis for major bleeding, which included all randomly assigned participants who had taken at least one dose of study medication, as assessed by pill counts. The number of events and incidence rates (events per 1000 person-years) for diabetes in the aspirin and placebo groups were calculated separately. We used Cox proportional hazards regression models with Efron’s method of tie handling to calculate cause-specific HRs with 95% CIs comparing incident diabetes between aspirin and placebo groups in the main analysis cohort. We assessed the proportional hazards assumption by Schoenfeld residual tests and found no violations. Cumulative incidence curves for incident diabetes were plotted, considering the competing risk of death. We investigated effect modification by baseline characteristics, which were sex, median age (<74 and ≥74 years), country of residence, race and ethnicity, previous regular aspirin use, BMI, statin use, smoking, hypertension, frailty,²⁵ and prediabetes status (ADA²³ and WHO²⁴ criteria), by adding an interaction term between the randomisation group and stratifying variable.

To investigate the treatment effect on the change in FPG concentration at each annual visit (year 1 to 5), we used mixed-model repeated measures, including randomised treatment, the year of glucose assessment (0 [baseline] to 5), and year-by-treatment interaction. Restricted maximum likelihood estimation with a Kenward-Roger correction and an unstructured variance-covariance matrix generated parameter estimates with 95% CIs. We also estimated the least-squares means and corresponding 95% CIs at each timepoint for within-group change in FPG concentration and differences between groups.

Four sensitivity analyses were done for the primary outcome of incident diabetes. First, we considered more liberal criteria for diabetes data completeness than the main analysis. Of 860 participants who were originally excluded due to incomplete data on self-reported diabetes, commencement of glucose-lowering medication, or having an FPG of 7 mmol/L or more during follow-up, 799 had at least self-reported not having diabetes at all visits and were included for a sensitivity analysis. Second, a more objective definition of incident diabetes than in the main analysis was assessed by excluding self-reported incident diabetes from the main analysis. Third, the intermittent nature of the ascertainment of incident diabetes was accounted for in analyses using discrete time proportional hazards regression models instead of Cox models. Fourth, we used the Fine-Gray sub-distribution hazard model to further calculate the sub-distribution HR (sHR) for incident diabetes between aspirin and placebo groups, where all-cause death was considered a potential competing event.²⁶

No imputation of missing data or adjustment for multiple comparisons of the primary outcome were considered. There is no allowance for multiplicity for the secondary outcomes. All statistical tests were two-sided, and we considered a p value of 0·05 or less to be statistically significant. Analyses were conducted using Stata (SE 17·0).

Role of the funding source

The funders of the ASPREE study had no role in study design, data collection, data analysis, data interpretation, or writing of this report.

Results

Between March 10, 2010 and Dec 24, 2014, 83 376 participants were screened by telephone with 23 163 entering the run-in phase. A total of 19 114 participants were randomly assigned, with 9525 assigned to receive aspirin and 9589 assigned to receive placebo (figure 1). Of 19 114 participants, 2045 (10·7%) with diabetes at baseline were excluded. Participants who had incomplete incident diabetes data at any annual visits (415 in the aspirin group and 445 in the placebo group) were also omitted, leaving 16 209 participants included in the main analysis cohort. Of these, 8086 were in the aspirin group and 8123 in the placebo group, and there was a median of 4·7 (IQR 3·6–5·7) years of follow-up. The participants in each treatment group were evenly matched for mean FPG concentrations, age, and other cardiovascular disease risk factors at baseline (table 1). The median age was 73·9 (IQR 71·7–77·6) years, mean weight was 76·1 (SD 14·5; IQR 65·8–85·1) kg, mean BMI was 27·8 (4·6; 24·7–30·3) kg/m², and mean FPG concentration of the trial population was 5·3 (0·6; 4·9–5·6) mmol/L. Hypertension was present in 11 796 (72·8%) of 16 209 participants and dyslipidaemia was present in 10 496 (64·8%) of 16 209 participants at baseline. Previous regular aspirin use was self-reported by 1582 (9·8%) of 16 209 participants at baseline. The baseline characteristics of participants with missing data (860 [4·5%] of 19 114) were similar to those included in the main analysis cohort, except for a greater proportion of participants residing in the USA in the missing data cohort (appendix p 1).

Figure 1: Trial profile.

FPG=fasting plasma glucose. *Presence of diabetes at baseline was defined as self-report, being on glucose-lowering medication, or having an FPG concentration of 7 mmol/L or more (≥126 mg/dL).

Table 1:

Baseline characteristics of participants in the full analysis set randomly assigned to aspirin or placebo

	Aspirin (n=8086)	Placebo (n=8123)
Median age at baseline (IQR), years	74·0 (71·7–77·7)	73·9 (71·6–77·5)
Sex, n (%)  Female	4622 (57·2%)	4634 (57·0%)
Male	3464 (42·8%)	3489 (43·0%)
Race or ethnicity, n (%)  White	7568 (93·6%)	7611 (93·7%)
Black	277 (3·4%)	256 (3·2%)
Hispanic or Latino	146 (1·8%)	144 (1·8%)
Other	95 (1·2%)	112 (1·4%)
Country, n (%)  Australia	7264 (89·8%)	7330 (90·2%)
USA	822 (10·2%)	793 (9·8%)
Education (>12 years of education), n (%)	4414 (54·6%)	4434 (54·6%)
Mean weight (SD), kg	76·0 (14·5)	76·3 (14·5)
Mean BMI (SD), kg/m2	27·8 (4·5)	27·8 (4·6)
Mean abdominal circumference (SD), cm  Male	101·2 (10·4)	101·4 (10·4)
Female	92·4 (12·5)	92·6 (12·7)
Hypertension, n (%)	5866 (72·5%)	5930 (73·0%)
Dyslipidaemia, n (%)	5192 (64·2%)	5304 (65·3%)
Chronic kidney disease, n (%)	1895 (23·4%)	1877 (23·1%)
Smoking status, n (%)  Non-smoker	4549 (56·3%)	4564 (56·2%)
Previous smoker	3259 (40·3%)	3282 (40·4%)
Current smoker	278 (3·4%)	277 (3·4%)
Frailty, n (%)  None	4902 (60·6%)	4967 (61·1%)
Pre-frail	3029 (37·5%)	3015 (37·1%)
Frail	155 (1·9%)	141 (1·7%)
Previous regular aspirin use	800 (9·9%)	782 (9·6%)
Current use of medications, n (%)  Angiotensin-converting-enzyme inhibitor	1228 (15·2%)	1240 (15·3%)
Angiotensin II receptor blocker	1944 (24·0%)	2003 (24·7%)
Diuretics	1435 (17·7%)	1394 (17·2%)
β-blocker	610 (7·5%)	584 (7·2%)
Calcium channel blocker	1321 (16·3%)	1256 (15·5%)
Statin	2290 (28·3%)	2278 (28·0%)
Other lipid-lowering agents	339 (4·2%)	314 (3·9%)
Non-steroidal anti-inflammatory drugs	1263 (15·6)	1254 (15·4)
Mean fasting plasma glucose (SD), mmol/L	5·27 (0·57)	5·28 (0·58)

In the race or ethnicity row, the other category includes Aboriginal or Torres Strait Islander, Native American, mixed race, Native Hawaiian or Pacific Islander, and those who were not Hispanic and who did not state their ethnicity or race. Hypertension was defined as being on treatment for high blood pressure or having a blood pressure of more than 140/90 mm Hg at study entry. Dyslipidaemia was defined as taking cholesterol-lowering medications or having a serum cholesterol of 212 mg/dL or more (≥5 mmol/L in Australia) and 240 mg/dL or more (≥6·2 mmol/L in the USA) or low-density lipoprotein cholesterol of more than 160 mg/dL (>4·1 mmol/L). Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min per 1·73m² or urinary albumin-to-creatinine ratio of 3 mg/mmol or more. Previous regular aspirin use was self-reported regular use of aspirin immediately before first baseline visit with a 4-week run-in before random assignment to study medication. Pre-frail included anyone with one or two criteria and frail included anyone with three or more criteria of the adapted Fried frailty criteria,²⁵ including bodyweight, strength, exhaustion, walking speed, and physical activity.

At the final in-trial follow-up visit, concomitant medication use, including anti-hypertensive drug classes, statins, other lipid-lowering medications, and non-steroidal anti-inflammatory drugs remained well balanced between the randomised aspirin and placebo groups. Compared with baseline, the use of all medications had increased modestly at the final visit, more so in participants who developed diabetes than in those who did not (appendix p 2).

During the entire follow-up, 11 787 (72·7%) of 16 209 participants had an average adherence rate of 50% or more and 8368 (51·6%) of 16 209 had an average adherence rate of 85% or more by pill count in both treatment groups (appendix p 3).

During the follow-up, 995 (6·1% of the study population) incident diabetes events were reported, including 459 in the aspirin group (12·7 [11·5–13·9] cases per 1000 person-years) and 536 in the placebo group (14·8 [13·6–16·1] cases per 1000 person-years; table 2). The types of glucose-lowering medications used by participants during the follow-up consisted mostly of oral agents, particularly metformin, DPP-4 inhibitors, and sulfonylureas (appendix p 4).

Table 2:

Hazard ratios of incident diabetes for aspirin versus placebo groups in the main analysis set and by subgroups defined by baseline characteristics

	Aspirin (n=8086)	Placebo (n=8123)	Hazard ratio (95% CI)	p value
Total	12·7 (11·5–13·9); 459	14·8 (13·6–16·1); 536	0·85 (0·75–0·97)	0·013
Sex  Female	11·2 (9·9–12·7); 236	12·0 (10·6–13·6); 251	0·93 (0·78–1·12)	0·17
Male	14·6 (12·8–16·7); 223	18·5 (16·5–20·8); 285	0·78 (0·66–0·94)	..
Age  <74 years	12·5 (11·0–14·2); 225	14·7 (13·0–16·6); 266	0·85 (0·71–1·01)	0·93
≥74 years	12·8 (11·3–14·6); 234	14·8 (13·2–16·7); 270	0·86 (0·72–1·02)	..
Country  Australia	11·7 (10·6–13·0); 378	14·3 (13·1–15·7); 464	0·82 (0·71–0·94)	0·11
USA	19·8 (15·9–24·6); 81	18·2 (14·5–22·9); 72	1·10 (0·80–1·51)	..
Race  White	11·8 (10·7–13·0); 400	14·2 (13·0–15·5); 485	0·83 (0·72–0·94)	0·42
Black	30·7 (22·2–42·3); 37	24·0 (16·3–35·2); 26	1·26 (0·76–2·08)	..
Hispanic or Latino	25·2 (15·4–41·1); 16	26·0 (15·9–42·4); 16	0·96 (0·48–1·91)	..
Other	14·2 (6·4–31·5); 6	18·9 (9·8–36·4); 9	0·76 (0·27–2·13)	..
Previous regular aspirin use  No	12·5 (11·3–13·8); 404	14·3 (13·1–15·7); 465	0·87 (0·76–0·99)	0·45
Yes	13·9 (10·7–18·1); 55	18·5 (14·7–23·3); 71	0·75 (0·53–1·07)	..
BMI  <25 kg/m2	6·3 (5·0–8·1); 66	8·9 (7·3–11·0); 90	0·71 (0·52–0·98)	0·11
25–29.9 kg/m2	10·9 (9·4–12·6); 178	13·7 (12·0–15·6); 226	0·79 (0·65–0·96)	..
≥30 kg/m2	22·9 (20·0–26·2); 215	22·6 (19·7–25·8); 216	1·01 (0·84–1·22)	..
Statin use  No	11·2 (10·0–12·5); 292	13·2 (11·9–14·7); 347	0·84 (0·72–0·98)	0·72
Yes	16·5 (14·1–19·1); 167	18·7 (16·2–21·6); 189	0·88 (0·72–1·09)	..
Smoking  Never	11·7 (10·3–13·2); 240	12·7 (11·2–14·3); 260	0·91 (0·77–1·09)	0·57
Past	13·6 (11·8–15·6); 197	16·9 (14·9–19·2); 248	0·80 (0·66–0·97)	..
Current	18·5 (12·2–28·2); 22	23·9 (16·5–34·6); 28	0·78 (0·44–1·36)	..
Hypertension  No	8·3 (6·7–10·3); 83	10·4 (8·6–12·6); 103	0·79 (0·59–1·06)	0·55
Yes	14·3 (12·9–15·8); 376	16·4 (14·9–18·0); 433	0·87 (0·76–1·00)	..
Frailty  None	10·4 (9·2–11·9); 229	13·2 (11·7–14·7); 292	0·79 (0·66–0·94)	0·28
Pre-frail	16·0 (14·1–18·3); 219	17·0 (14·9–19·3); 229	0·95 (0·79–1·14)	..
Frail	16·2 (9·0–29·3); 11	25·1 (15·1–41·6); 15	0·65 (0·30–1·42)	..
Prediabetes (American Diabetes Association criteria: FPG ≥5·6 mmol/L)
No	5·0 (4·2–5·9); 139	6·7 (5·8–7·8); 188	0·74 (0·59–0·92)	0·12
Yes	39·1 (35·0–43·7); 310	42·9 (38·6–47·7); 339	0·91 (0·78–1·06)	..
Prediabetes (WHO criteria: FPG ≥6·1 mmol/L)
No	8·2 (7·3–9·3); 275	9·4 (8·4–10·5); 314	0·87 (0·74–1·03)	0·69
Yes	77·1 (66·5–89·5); 174	92·5 (80·9–105·8); 213	0·84 (0·68–1·02)	..

Data are in rate per 1000 person-years; n, unless stated. Each variable, except total, shows a p value for interaction. FPG=fasting plasma glucose.

Compared with placebo, assignment to aspirin resulted in a 15% reduction in risk of incident diabetes (HR 0·85 [95% CI 0·75–0·97]; table 2). The difference in the rate of diabetes was –2·1 per 1000 person-years in the total study population, and –3·9 per 1000 person-years for male participants and –0·8 per 1000 person-years for female participants. A divergence in case numbers beginning after the second year of aspirin or placebo treatment was shown in curves that plotted the cumulative incidence of diabetes (figure 2). The risk reduction was generally consistent in all pre-specified subgroups considered, including sex, age, country of residence, race and ethnicity, previous regular aspirin use, BMI, statin use, smoking, hypertension, frailty, and prediabetes status at baseline (all p values for interaction >0·10; table 2).

Figure 2: Cumulative incidence of diabetes in participants randomised to aspirin or placebo .

The plots were constructed from the cumulative incidence of diabetes predicted using separate models in participants assigned to aspirin (red solid line) and participants assigned to placebo (blue solid line), taking into account the competing risk of death. Data are not shown after year 6 because only a small number of participants reached year 7. HR=hazard ratio.

Mean FPG concentration was 5·3 (SD 0·6) mmol/L at baseline and increased over time in both assigned treatment and placebo groups. The mean FPG concentrations increased from baseline to year 5 in both treatment groups, with least squares mean change of 0·061 (95% CI 0·040 to 0·083) mmol/L in the aspirin group and of 0·109 (0·088 to 0·131) mmol/L in the placebo group. In addition, at year 5, the difference in the least squares mean change between aspirin and placebo groups was –0·048 mmol/L (–0·079 to –0·018; p=0·0017; appendix p 5). The mean FPG concentration increased less in the aspirin group than in the placebo group at all annual follow-up visits (figure 3).

Figure 3: The effect of aspirin on change in mean fasting plasma glucose over time.

The changes in raw mean fasting glucose with aspirin assignment (red solid line) versus placebo assignment (blue solid line). Error bars indicate 95% CIs. Fasting glucose was set as missing at annual visits at which glucose-lowering medication use was reported.

The safety analysis set included 16 104 participants, with 8040 in the aspirin group and 8064 in the placebo group. Major bleeding occurred in 300 (3·7%) participants in the aspirin group and 210 (2·6%) participants in the placebo group, with incidence rates of 8·2 events per 1000 person-years in the aspirin group and 5·7 events per 1000 person-years in the placebo group. Compared with placebo, aspirin treatment increased the risk of major bleeding by 44% (HR 1·44 [95% CI 1·21–1·72]; p<0·0001) including major gastrointestinal bleeding, intracranial bleeding, and other clinically significant bleeding (table 3).

Table 3:

Major bleeding events in aspirin versus placebo group in the safety population

	Aspirin (n=8040)	Placebo (n=8064)	Hazard ratio (95% CI)	p value
Total major bleeding	8·2 (7·3–9·2); 300	5·7 (5·0–6·5); 210	1 44(1.21–1.72)	<0·0001
Subgroups
Gastrointestinal bleeding	3·6 (3·1–4·3); 133	2·1 (1·7–2·6); 77	..	..
Intracranial bleeding	2·2 (1·8–2·7); 81	1·5 (1·1–1·9); 54	..	..
Other bleeding sites	2·4 (1·9–2·9); 86	2·1 (1·7–2·7); 79	..	..

Data are in rate per 1000 person-years; n, unless stated.

When analyses were repeated for incident diabetes to additionally include participants who did not have incident diabetes based on self-report alone (n=799) or exclude participants with incident diabetes based on self-report alone (n=161), the results were similar to those in the full analysis set (HRs 0·86 [95% CI 0·76–0·97] for aspirin vs 0·85 [95% CI 0·75–0·97] for placebo). When a discrete time proportional hazards regression model was used instead of a Cox model, the results were also similar (0·86 [0·76–0·97]). Finally, in analyses taking account of all cause death as a competing risk, the results were unchanged (sHR 0·85 [0·75–0·97]).

Discussion

In this analysis of data from a large-scale, two-country, randomised trial of community-dwelling healthy older adults without previous cardiovascular events, dementia, or independence-limiting physical disability, the use of low-dose aspirin (100 mg per day for a median of 4·7 years) reduced the risk of incident diabetes and slowed the age-associated increase in FPG concentrations. The effects did not significantly differ by sex, age, BMI, country of recruitment, statin use, or previous regular use of aspirin; however, the largest absolute effects were observed among male participants. The effects were also robust in sensitivity analyses considering minor changes to the definition of incident diabetes and the competing risk of death.

Given the proposed role of chronic subclinical inflammation in the development of insulin resistance or deficiency, which can increase an individual’s susceptibility to glucometabolic disorders, it is important to further understand any effect of aspirin on incident diabetes using a contemporary cohort of older adults who can be at greater risk due to age alone. Our finding of a 15% reduction in risk of incident diabetes was very similar to that of the Physicians’ Health Study,¹² which reported that aspirin (randomised treatment and then self-use) reduced the risk of incident diabetes by 14% (HR 0·86 [95% CI 0·77–0·97]) in healthy men aged 40–84 years (mean age 54 years) followed up for up to 22 years. In contrast, the Women’s Health Study¹⁵ reported that 100 mg aspirin every other day did not modify the risk of incident diabetes in women older than 45 years (61% in women aged 45–54 years, 29% in women aged 55–64 years, and 10% in women aged ≥65 years) given aspirin over 10 years (rate ratio 1·01 [95% CI 0·91–1·11]). Of note, these trials^12,15 were conducted more than 20 years ago and in younger participants, whose use of background preventive therapies, such as statins, and absolute risk would have substantially differed from that of our trial population. It is also of interest that we observed greater absolute treatment effects in male than in female participants, suggesting possible sex differences in responses. Indeed, previous studies have proposed that variation in the bioavailability of low-dose aspirin (which can differ by gender, formulation, dosing frequency and timing, or bodyweight) might explain differences in efficacy, particularly when used for the prevention of vascular disease.^27–29

Preclinical and clinical studies have provided a good rationale for targeting inflammation to improve the action of insulin and improve blood glucose levels.¹¹ Moreover, studies of salicylate treatment have reported anti-inflammatory effects at both low and high doses, albeit through different mechanisms of action. In an experimental model of cantharidin-induced acute inflammation, low-dose aspirin (75 mg) administered for 10 days to healthy men inhibited innate immune-mediated responses by reducing total leukocyte as well as neutrophil and macrophage accumulation in skin blisters. These effects were dependent on 15-epi-lipoxin A4 synthesis and signalling, which triggered anti-adhesive nitric oxide release, a crucial determinant of extravascular leukocyte accumulation and inhibition of prostacyclin production through the cyclooxygenase pathway.³⁰ In contrast, high-dose salicylates, such as salsalate (the non-acetylated dimer of salicylic acid), have been shown to be potent inhibitors of IκB kinase and the NF-κB cascade.³¹ In studies of high-risk populations with prediabetes or populations with diabetes, high-dose salsalate improved insulin sensitivity, as well as increased insulin release and peripheral glucose disposal.^32–35 A 4-week randomised, placebo-controlled study of 4 g/day of salsalate in people with obesity reported a 14% reduction in fasting glucose as well as reductions in C-peptide levels.³⁵ Similarly, a 12-week randomised, placebo-controlled study of up to 4 g/day of salsalate in people with impaired fasting glucose or impaired glucose tolerance reported a 6% reduction in fasting glucose and reduced adipose tissue NF-κB activity. Mean salicylate concentrations correlated inversely with the change in fasting glucose concentrations, suggesting that reductions in glucose were related to an individuals’ salicylic acid levels.³⁶ Future work using the biobanked samples of the ASPREE cohort might help to explain the putative mechanisms for our findings.

Although our findings are from a post-hoc analysis of a trial designed to address primary and secondary outcomes that did not include diabetes, it is worth noting that our analyses of changes in FPG over time were consistent with our analysis of incident diabetes. As has been reported by other observational studies of ageing populations, the FPG concentration trajectory increased modestly over time in both treatment groups, but the increase was lower with aspirin treatment. Although population studies suggest FPG concentrations increase with age,³⁷ the rate of increase appears to slow in people older than 60 years, with analysis of US National Health and Nutrition Examination Survey data suggesting an increase in the order of 0·0056 mmol/L (0·1 mg/dL) per year of age between age 60 and 70 years.³⁸ Additional studies characterising the phenotypic and genetic risk for the development of diabetes in older populations will be important to clarify any future role of targeting inflammation and to balance the risks and benefits of aspirin use.

We also report an increased risk of major bleeding, which is an important consideration for older community-dwelling individuals. The magnitude of this increased risk was commensurate with that reported by other low-dose aspirin trials, including the ASCEND trial in patients with type 2 diabetes, but higher than that reported by the ARRIVE trial in people with a low-to-moderate cardiovascular risk.^39,40 Of particular importance for future studies will be the comprehensive assessment and mitigation of bleeding risk and any other safety issues associated with use of anti-inflammatory agents.^18,19,41,42 Indeed, novel formulations of aspirin that could enhance the beneficial anti-platelet and anti-inflammatory effects but reduce gastrointestinal toxicity are currently being evaluated.^43,44

One limitation of this post-hoc analysis was the definition of diabetes, which was based on self-reporting, commencement of glucose-lowering medication, or a single FPG measurement and did not include a second confirmatory blood test within 2 weeks. In addition, HbA_1c concentrations and oral glucose tolerance testing, which were not routinely tested in all participants, could not be included in the definition. However, the repeated assessment of FPG concentrations over time, with the results being communicated directly to the general practitioners providing care to the study participants gives some assurance that cases were not missed or misclassified.

Our study also had several strengths. All ASPREE participants had no previous cardiovascular events, dementia, or independence-limiting physical disability at trial entry, and were selected as relatively healthy ambulatory community-dwelling participants. Therefore, our data do not allow conclusions as to whether aspirin prevents diabetes among other populations or older adults in high-risk racial or ethnic groups, including those likely to be most vulnerable to the risks of incident diabetes and its consequences. Nonetheless, the large sample size of older participants, the long duration of follow-up to 4·7 years with detailed annual data capture, the large number of incident diabetes cases, and high adherence to treatment (more than 70% of participants were taking ≥50% of the study pills on average in both groups during the entire follow-up) gives us confidence that the effects were robust.

Subgroup analyses might have modest power to detect differences in treatment effects, such as the differences by sex, country of residence (Australia or USA), and BMI category. The qualitative differences in point estimates observed need to be further studied to understand where the true effects lie and whether these effects are enduring with longer follow-up of the trial cohort.

In this post-hoc analysis, aspirin treatment appeared to reduce incident diabetes and slow the increase in FPG concentration but also increased major bleeding in initially healthy adults aged 65 years or older when compared with placebo. Given the increasing prevalence of diabetes around the world, the potential for anti-inflammatory agents such as aspirin to prevent or delay incident diabetes or improve glucose levels warrants further study.

Research in context.

Evidence before this study

Diabetes is a global public health problem and one of the major causes of disability and mortality in populations of adults 65 years or older. Inflammation has been implicated in the pathogenesis of diabetes, and medications with anti-inflammatory properties, such as aspirin, might be beneficial for preventing incident type 2 diabetes among older people. We searched PubMed for randomised studies published between database inception and Nov 1, 2022, that investigated the potential effect of preventive aspirin on incident diabetes in any age group. Two large randomised studies were identified: the Physicians’ Health Study, which reported that low-dose aspirin (325 mg every other day) followed by self-selected aspirin use decreased the risk of incident diabetes by 14% in healthy men (mean age 54 [SD 9] years) initially given aspirin for 5 years and then followed for up to 22 years; and the Women’s Health Study, which reported that low-dose aspirin (100 mg every other day) did not decrease the risk of incident diabetes in women older than 45 years given aspirin for 10 years. However, the Physicians’ Health Study and the Women’s Health Study were both conducted more than 20 years ago, used alternate daily dosing of aspirin, and mostly included adults aged 50–60 years.

Added value of this study

This study is the first analysis of a more contemporary randomised trial assessing the effect of low-dose aspirin in preventing type 2 diabetes in an older community-dwelling population (>70 years for participants in non-minority ethnic groups and ≥65 years for participants in minority race and ethnic groups). We found that use of 100 mg enteric-coated aspirin daily reduced the risk of incident diabetes by 15% and significantly slowed the rate of increase in fasting blood glucose among participants without diabetes between baseline and year 5. However, aspirin also increased the risk of major bleeding (primarily gastrointestinal bleeding).

Implications of all the available evidence

Our results are similar to those of the Physicians’ Health Study, which showed a 14% reduction in type 2 diabetes risk with low-dose aspirin use. Given the increasing prevalence of diabetes around the world, the potential for anti-inflammatory agents, such as aspirin, to prevent or delay incident type 2 diabetes or improve glucose levels warrants further study, including assessment of all potential safety events.

Data sharing

Requests for data access can be made via the ASPREE principal investigators, with details for applications provided at https://aspree.org/aus/for-researchers/ or https://aspree.org/usa/for-researchers/.