Conference Coverage

Long-term cholinesterase inhibition may slow cognitive decline – and more


Key clinical point: Evidence from an uncontrolled, observational registry suggests that long-term use of cholinesterase inhibitors slows the cognitive decline of Alzheimer’s disease.

Major finding: Patients taking the drugs lost almost 1 point less on the Mini Mental State Exam each year than did those who didn’t take them.

Data source: The 3-year observational study comprised almost 29,000 patients in the Swedish Dementia Registry.

Disclosures: Dr. Eriksdotter had no financial disclosures.

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Compelling results, but are they valid?

The cholinesterase inhibitors are widely used for patients with Alzheimer’s disease, and to some extent other forms of cognitive impairment (rightly or wrongly). Their observed symptomatic benefits are modest and families frequently question whether the drugs are having any beneficial effect. So the idea that they may have long-term benefits is an extremely encouraging thought.

Dr. Richard J. Caselli is a professor of neurology at the Mayo Clinic in Scottsdale, Ariz. He also is associate director and clinical core director of Mayo’s Alzheimer’s Disease Center.
Dr. Richard J. Caselli
In that context, the findings in this large observational study of slowed dementia progression and reduced risk of heart attack, stroke, and death are certainly compelling, but are they valid? Because the randomized, controlled donepezil and vitamin E study from Ronald C. Petersen, MD, PhD, and colleagues showed no protective effect of donepezil (or vitamin E) (N Engl J Med. 2005;352:2379-88), one has to wonder about the differences between those treated and those not treated in this uncontrolled, observational study based on the Swedish Dementia Registry, and whether those differences explain the findings more than the cholinesterase inhibitor. For example, as the authors note, the treated patients were younger and less impaired at entry. Those receiving drugs likely had someone caring for them who could administer and supervise not only that drug but any drug as well as their general state of health. Also, 70% of those treated had a diagnosis of Alzheimer’s disease, so 30% had something else, the details of which we do not have at the moment. Did the authors look for similar effects of memantine given such concerns would be shared by that different class of drug? The authors stated that higher doses conferred greater benefits. Did that apply to the 23-mg dose of donepezil which has been associated with greater adverse side effects including even syncope? In diabetics, insulin was associated with a higher mortality, which probably reflects the greater need for more intensive diabetic therapy, and so that need more likely explains the higher death rate because we know from history that insulin saves lives.

We do not have all the information that may be available at this time, and all or many of these issues undoubtedly occurred to the investigators who may have controlled for them, or been able to at least partially control for them, so that for now, I want to believe and am hoping the investigators are able to justify that belief with further data.

Richard J. Caselli, MD, is professor of neurology and medical director for service at the Mayo Clinic, Scottsdale, Ariz., and is associate director and clinical core director of the Arizona Alzheimer’s Disease Center. He has no relevant disclosures.



– Long-term use of cholinesterase inhibitors appears to confer a number of benefits, including protection from heart attack, stroke, diabetes-related mortality, and – according to a large new observational study – an annual 30% slowing of the cognitive decline associated with Alzheimer’s disease.

Long-term follow-up of thousands of patients in the Swedish Dementia Registry (SveDem) finds consistent, dose-dependent benefits associated with the drugs, Maria Eriksdotter, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Most recently, her 3-year analysis of 29,000 patients showed that each year, those taking the drugs lost almost a point less on the Mini Mental State Exam (MMSE) than did nontreated patients.

Dr. Maria Eriksdotter of the Karolinska Institute in Stockholm.
Dr. Maria Eriksdotter
The findings should prompt clinicians to rethink the benefit of these medications, which are often seen as marginally effective, temporary stopgaps in the dementia process, said Dr. Eriksdotter, registrar of SveDem and head of the department of neurobiology, care sciences, and society at the Karolinska Institute, Stockholm.

“These drugs do reduce mortality and cardiovascular events, and improve cognitive decline,” she said in an interview. “It can be a difficult discussion to have with families, because yes, the patient is still declining, although more slowly. But combined with these other benefits that we are showing, I would say there is no reason not to get patients on a cholinesterase inhibitor as soon as possible. You want to get those benefits online as early as possible.”

The findings also strongly argue for cholinesterase inhibition to stay part of the standard treatment picture, even after disease-modifying medications do come on board.

“One could say you gain 30% of the decline back, and that 30% is something we could start from when we eventually begin talking about these therapies,” Dr. Eriksdotter said.

SveDem, launched in 2007, is a national project to improve the quality of diagnostics, treatment, and care of Swedish patients with dementia disorders. Patients newly diagnosed with a dementia disorder are registered and followed up yearly. Currently, it contains information on close to 70,000 patients.

The cognition study comprised almost 29,000 of those (CTAD abstract OC15). Dr. Eriksdotter and her colleagues categorized them as using or not using cholinesterase inhibitors (ChEI), and then examined the 3-year curves of cognitive decline, adjusting for age, sex, and a propensity score of whether or not they got a ChEI at baseline. The primary endpoint was MMSE decline by 3 years

At baseline, patients were a median of 80 years old. Alzheimer’s dementia was the most common diagnosis (63%), and 63% were taking a ChEI. Prescribing increased during each year of follow-up; by year 3, 91% were taking a ChEI. The median baseline MMSE was 22; this declined over time, to a median of 18. Patients taking the drugs were significantly younger than those not taking them (79 vs. 83 years), and less cognitively impaired (MMSE of 22 vs. 20). Most patients taking them had a diagnosis of Alzheimer’s dementia (70%), while others had a mix of vascular, frontotemporal, and Parkinson’s disease dementia.

Patients in both groups declined cognitively over the 3-year period, but the curves of decline were significantly different. The median MMSE decline regardless of treatment was 2.89 points. But in the fully adjusted model, those taking the drugs declined by about 0.85-point less each year than did those not taking them. This translated into an annual 30% reduction in cognitive decline, compared with untreated patients, Dr. Eriksdotter said.

She briefly discussed additional SveDem data supporting the drugs’ benefits in cardiovascular disorders and diabetes.

In 2013, she and her colleagues examined the link between ChEIs and heart attack in more than 7,000 SveDem registrants over a period of up to 5 years (Eur Heart J. 2013 Sep;34[33]:2585-91). After adjustment for confounding factors, the team found that ChEIs conferred a 34% risk reduction for a composite endpoint of myocardial infarction or death, compared with nonusers. The differences in the individual endpoints were also significant: a 36% lower risk of heart attack and 38% lower risk of death. She also found a dose-dependent response, with patients taking the highest recommended doses having the lowest risk of heart attack (hazard ratio, 0.35) and death (HR, 0.54).

Data from a similar study on stroke risk have been submitted for publication, Dr. Eriksdotter noted. This observational study comprised 22,300 patients followed for up to 5 years. Those who had ever taken a ChEI had a 33% decreased risk of ischemic stroke and 38% decreased risk of all-cause mortality. While the benefit was seen with the use of donepezil, rivastigmine, and galantamine, it was most pronounced with galantamine (30% decreased stroke risk, 32% decreased mortality risk). The study further determined that only patients taking high-dose ChEIs experienced the significant stroke benefit (HR, 0.59). The decreased risk of death was significant for all doses, but showed a dose-dependent benefit (low: HR, 0.85; medium: HR, 0.73; high: HR, 0.57).

Finally, Dr. Eriksdotter discussed a study in preparation comprising about 7,000 Alzheimer’s disease patients who also had diabetes. Of these, about 1,600 were taking a ChEI. In a fully adjusted model, the drugs were associated with a 16% decreased risk of death – exactly the same mortality benefit conferred by metformin. As an interesting side note, insulin use in this population was associated with a significant 15% increase in the risk of death, after full adjustment for confounding factors. None of the other antidiabetes medications (thiazolidinediones, dipeptidyl peptidase-4 inhibitors, or any newer drugs) showed any significant mortality benefit.

The protective mechanisms at work in these studies aren’t fully elucidated, Dr. Eriksdotter said. “But we do know that cholinesterase inhibitors exert an anti-inflammatory effect, and inflammation is definitely part of the cardiovascular disease and diabetes pictures. They also tend to slow heart rate, which has been found to have survival benefit in animal models.”

She had no financial disclosures.

On Twitter @Alz_Gal

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