Dr Ray O’Connor continues his look at the latest clinical papers on therapeutics, with an emphasis on prescribing for the elderly
Prescribing in elderly
A rapid demographic transition toward an older population is occurring throughout the world. Increasing life span is a major contributor to this shift, with the percentage of older adults who survive into their 80s and 90s greatly increasing.
However, healthy life lifespan has not increased to the same extent; older adults still face major consequences from cardiovascular disease, as well as dementia. Today we consider four papers looking at drugs that are commonly prescribed in the older age groups for these two conditions.
Dr Ray O’Connor
1. Statins in elderly
It is well-established that statins reduce the risk of myocardial infarction and ischemic stroke in adults at high risk, including those with diabetes or established cardiovascular disease. However, the effects of initiating and maintaining treatment with statins in older patients remain uncertain and are intensely debated. Two recent papers consider this issue.
The first trial1 was a double-blind, randomized, placebo-controlled trial at general medical practices across Australia. Community-dwelling adults at least 70 years of age with no history of cardiovascular disease, diabetes, or dementia were randomly assigned in a 1:1 ratio to receive atorvastatin at a dose of 40 mg once daily or identical placebo. The two primary end points were a composite of death from cardiovascular causes, nonfatal myocardial infarction or stroke, or coronary revascularization (to assess effects on major cardiovascular events) and a composite of death from any cause, dementia, or persistent physical disability (to assess effects on disability-free survival). Analyses were performed according to a hierarchical testing plan.
A total of 9,971 participants were enrolled: 4,984 were assigned to receive atorvastatin and 4,987 to receive placebo. The mean age of the participants was 74.7 years, and 51.9 per cent were women. After a median of 5.9 years, a primary cardiovascular event had occurred in 297 participants (10.9 events per 1,000 person-years) in the atorvastatin group and in 412 participants (15.5 events per 1000 person-years) in the placebo group (hazard ratio, 0.70; 95 per cent confidence interval [CI], 0.61 to 0.82; P<0.001).
Death from any cause, dementia, or persistent physical disability occurred in 637 participants (21.6 events per 1,000 person-years) in the atorvastatin group and in 676 participants (23.0 events per 1,000 person-years) in the placebo group (hazard ratio, 0.94; 95 per cent CI, 0.84 to 1.05; P = 0.25). Serious adverse events occurred in 131 participants (2.7 per cent) in the atorvastatin group and in 129 (2.7 per cent) in the placebo group, with musculoskeletal, hepatobiliary, and diabetes-related adverse events occurring more commonly in the atorvastatin group.
The authors concluded that treatment with atorvastatin led to a lower risk of major cardiovascular events than placebo at a median of 5.9 years but did not result in longer disability-free survival among community-dwelling older adults without clinical cardiovascular disease.
What about those elderly who are already on statins? What are the effects of stopping the drug?
This was the subject of a study from France. The authors aimed to assess the non-inferiority of statin cessation in terms of all-cause mortality under real-life conditions in individuals aged 75 years or older who were prescribed statins for the primary prevention of Atherosclerotic Cardiovascular Disease (ASCVD).
The study2 was a multicentre, open-label, parallel-group, phase 3 randomised controlled trial in 297 primary care offices. Individuals who were aged 75 years or older, were prescribed any statin for at least one year for the primary prevention of ASCVD, had no history of ASCVD, and could provide informed consent were randomly assigned (in an unbalanced 5:4 ratio) to continue or stop their statin treatment and were followed up for 36 months.
Participants were excluded if they had a progressive disease with a life expectancy of three months or less, were diagnosed with dementia, had known homozygous or double heterozygous familial hypercholesterolaemia, or were unable to provide informed consent. Randomisation was computer-generated and implemented via a central electronic system; masking was not done. The primary endpoint was all-cause mortality at three years, analysed in participants according to the primary estimand (participants who met all key eligibility criteria and were randomly assigned to statin discontinuation or continuation less than 90 days after inclusion).
Missing data were handled using multiple imputation. The non-inferiority margin was five per cent for the absolute between-group difference in mortality. Between June 15, 2016, and Jan 7, 2020, 1,180 participants were randomly assigned, and 1,160 participants were included in the analysis of the primary estimand. Some 639 participants were randomly assigned to the statin continuation group, and 521 participants were assigned to the statin discontinuation group.
The median age was 80 years, and 775 (66⋅8 per cent) of 1160 participants were women; 342 (29⋅5 per cent) of 1,160 participants had diabetes, and 896 (77⋅2 per cent) of them had hypertension. At 36 months, 48 (7⋅9 per cent) of 604 participants in the statin continuation group and 35 (7⋅2 per cent) of 484 participants in the statin discontinuation group had died.
The absolute difference in all-cause mortality between groups was −0⋅68 per cent (95 per cent CI −3⋅95 to 2⋅60). Statin discontinuation was noninferior to continuation for three-year all-cause mortality as the upper bound of the between group difference 95 per cent CI did not exceed the prespecified non-inferiority margin. Adverse events occurred in 461 (73⋅1 per cent) of 631 participants in the continuation group, and in 390 (74⋅0 per cent) of 527 in the discontinuation group. Non-cardiovascular adverse events occurred in 456 (72⋅3 per cent) of 631 participants in the continuation group and 383 (72⋅7 per cent) of 527 in the discontinuation group.
The authors concluded that in persons aged 75 years or older receiving statins for primary prevention and with no previous history of ASCVD, discontinuation of statins was non-inferior to continuation in terms of all-cause mortality over three years. These findings support individualised decision-making regarding statin discontinuation in older adults.
The clear message seems to be that cessation of statins in older adults is a safe consideration.
2. Dementia
Antipsychotic use in people living with dementia has been linked to serious adverse outcomes. Guidelines recommend limiting antipsychotic treatment to short-term use (<12 weeks), followed by tapering and cessation.
However, antipsychotic treatment in routine practice often exceeds the recommended duration. The effect of discontinuing antipsychotics on reducing adverse outcomes in practice remains unclear. The authors of this study3 aimed to use linked primary and secondary care data in England to investigate whether tapering or abrupt discontinuation of antipsychotics, versus continuation, affected the risk of stroke, death, fracture, delirium, and pneumonia in people living with dementia.
Using UK primary care data from the Clinical Practice Research Datalink, linked with hospital and mortality data from Jan 1, 1998, to March 31, 2021, the authors emulated two sets of target trials, one after 12 weeks of antipsychotic treatment and another after 24 weeks of antipsychotic treatment, to compare continuing treatment versus tapering treatment and continuing treatment versus abrupt discontinuation of treatment. Patients aged 65 years and older at incident dementia diagnosis with antipsychotic treatment duration of at least 12 weeks were included.
Study outcomes were incidence of fracture, stroke, hospitalisation for delirium, hospitalisation for pneumonia, and all-cause mortality within 24 months. A negative control outcome of skin conditions was included to measure potential unmeasured confounding. A clone-censor-weight approach was used with a six-month grace period allowed for discontinuing antipsychotics.
Some 134,549 eligible patients had a new antipsychotic treatment after dementia diagnosis, of whom 24,822 (18⋅4 per cent) had a treatment period of at least 12 weeks and 16,795 (12⋅5 per cent) had a treatment period of at least 24 weeks and met the eligibility criteria. The mean age was 83⋅57 in the 12-week trial and 83⋅65 in the 24-week trial; 16,725 (67⋅4 per cent) of 24,822 patients were female and 8,097 were male in the 12-week trial and 11,523 (68⋅6 per cent) of 16,795 patients were female and 5,272 were male in the 24-week trial.
Compared with continuation after 12 weeks of treatment, estimated risks of delirium and fracture under the tapering strategy corresponded to 24-month absolute risk differences (ARDs) of −2⋅46 per cent (95 per cent CI −4⋅10 to −1⋅27) and −2⋅80 per cent (−4⋅14 to −1⋅29), respectively. Estimated risks for stroke, pneumonia, and all-cause mortality were similar between strategies.
No difference in risk was observed for the negative control outcome. Similar results were found after 24 weeks of treatment and in sensitivity analyses. The authors concluded that, irrespective of method, antipsychotic discontinuation decreased the risk of delirium and fracture. Antipsychotics can be discontinued safely when treatment duration has exceeded guideline recommendations without increasing the risk of death, stroke, or pneumonia in those living with dementia.
Evidence, including animal, clinical, and real-world studies in individuals with type 2 diabetes and/or obesity, suggests reduced risk of dementia and Alzheimer’s disease after GLP-1 receptor agonist exposure. The evoke and evoke+ trials aimed to investigate the efficacy and safety of oral semaglutide in individuals with early Alzheimer’s disease. Evoke and evoke+ were multicentre, randomised, double-blind, placebo-controlled phase 3 trials conducted across 566 sites in 40 countries.
The trials4 assessed the efficacy and safety of oral semaglutide up to 14 mg once daily in participants with amyloid-confirmed Alzheimer’s disease, aged 55–85 years, with mild cognitive impairment or mild dementia due to Alzheimer’s disease. In evoke+, participants with significant small vessel pathology were included. Participants were randomly assigned (1:1) to once-daily semaglutide 14 mg (flexible dose) or placebo for up to 156 weeks.
The primary endpoint was change in Clinical Dementia Rating—Sum of Boxes (CDR-SB) score from baseline to week 104, assessed in all randomised participants. Safety was assessed in all randomised participants and reported for those receiving at least one dose of study drug. Both trials have been discontinued due to negative clinical outcome.
Between May 18, 2021, and Sept 8, 2023, 9,981 participants were screened, of whom 3,808 were randomly assigned; 1,855 in evoke (semaglutide, n=928; placebo, n=927) and 1,953 in evoke+ (semaglutide, n=976; placebo, n=977). Mean age was 72·2 years, and mean CDR-SB score was 3·7 at baseline. In evoke+, 54 (2·8 per cent) participants had small vessel pathology. In evoke and evoke+, mean changes in CDR-SB score from baseline to week 104 were 2·3 (SE 0·1) and 2·2 (0·1) with semaglutide, compared with 2·3 (0·1) and 2·1 (0·1) with placebo (estimated difference −0·08 [95 per cent CI −0·35 to 0·20], p=0·57 in evoke and 0·10 [−0·17 to 0·38], p=0·46 in evoke+).
Treatment-emergent adverse events were reported in 1,729 (91·2 per cent) of 1,896 participants receiving semaglutide versus 1613 (84·8 per cent) of 1902 receiving placebo. There were five fatalities considered treatment-related by the investigators (one in the semaglutide group and four in the placebo group). The authors concluded that oral semaglutide was not efficacious in slowing clinical progression in participants with early Alzheimer’s disease. Safety and tolerability of semaglutide in early Alzheimer’s disease is consistent with studies in other indications. 
References:
Zoungas S et al. Atorvastatin, Cardiovascular Events, and Disability-free Survival in Older Adults. N Engl J Med 2026. Published on August 29, 2026, at NEJM.org. doi:10.1056/NEJMoa2607314
Bonnet F et al. Discontinuation of statins for primary prevention of atherosclerotic cardiovascular disease in adults aged 75 years or older (SAGA/SITE): a multicentre, open-label, pragmatic, non-inferiority randomised trial. Lancet Healthy Longev 2026; 7: 100884. Published Online August 11, 2026.
Hopkinson OK et al. Abrupt discontinuation and tapering of antipsychotics in older adults with dementia: a target trial emulation study. Lancet Healthy Longev 2026; 7: 100852. Published Online June 16, 2026. https://doi.org/10.1016/j.lanhl.2026.100852
Cummings J et al. Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer’s disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials. Lancet 2026 Volume 407, Issue 10544 p2167-2179. Published Online March 19, 2026. https://doi.org/10.1016/S0140-6736(26)00459-9