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An observational study published in BMJ Open Diabetes Research and Care looks at use of oral diabetes medications and dementia risk in US veterans aged ≥60 years with type 2 diabetes.
Prof David Strain , Associate Professor in Cardiometabolic health in Older Adults, said:
“This is a really interesting paper on two counts. First the association of lower risk of dementia with the use of the thiazolidinediones (glitazones), however also an association of increased risk of dementia in those using sulfonylureas, which are still very commonly prescribed drugs in people living with type two diabetes, in part because of their efficacy at lowering glucose, but in no small part because of their low acquisition cost.
“The link between insulin resistance and dementia is well established, although there are multiple different mechanisms at play, and there are conflicting data. The glitazones work directly on insulin resistance in both the brain and the blood vessels. They have already been demonstrated to reduce the risk of stroke in those with and without diabetes in the IRIS trial. Within that trial, however, the known side effects of the glitazones were highlighted, namely, weight gain, increased fracture risk and fluid retention that exacerbates heart failure. This established side effect profile, which has a greater impact in older adults, has failed to see their general utilisation in stroke or other disease prevention. This database analysis would fail to capture the risk and impact of these side effects, due to the selection process in prescribing these drugs by the family physicians. Until we have clarity as to the risk:benefit ratio when choosing a drug it is difficult to make recommendations as to choosing these agents
“The other, very concerning, result reported here is the 11% increase in risk of dementia in people living with type 2 diabetes treated with sulfonylureas. These were the first class of tablets available for the management of type 2 diabetes and are still widely used within the NHS due to their low acquisition costs. The key side effect of these drugs is the risk of hypoglycaemia – a low blood sugar that limits brain and bodily function. These hypo events have been linked to the risk of dementia in several other studies, so this is not a surprise, however as a class they continue to be widely utilised. New initiations of these drugs have declined dramatically over the last 5 years from 27% down to ~9%, however many of our more mature population, those at greatest risk from dementia, continue on this class of drug as a legacy of their longevity with diabetes. In order to reduce this risk, an active switch programme is likely to be required to move people from sulfonylureas to alternatives, however this will take time in an already overstretched healthcare system trying to build back after the pandemic.
“Anyone worried about the type of medication they are on should not stop taking it but speak to their doctor.”
Dr Elizabeth Robertson, Director of Research at Diabetes UK, said:
“Living with type 2 diabetes increases a person’s risk of dementia and finding ways to reduce that risk will help more people live well and longer with diabetes.
“This study explores links between different type 2 diabetes medications, prescribed to manage high blood sugar levels, and the onset of dementia. While positive associations were discovered between certain type 2 medication use, particularly thiazolidinediones, and reduced risk of dementia, the study design means that we can’t say with any certainty that the medications were responsible for this lowered risk or whether this association would be seen in other population groups.
“Further research that helps us understand this would be welcome, as it could help people living with type 2 and their healthcare teams make informed decisions about their best treatment options for managing high blood sugars and reducing the risk of devasting long-term complications.”
Dr James Connell, Head of Translational Science at Alzheimer’s Research UK, said:
“Nearly one million people in the UK have dementia, and we need to explore all possible treatment approaches to tackle the diseases that cause it. Repurposing an existing drug used for another health condition would be a cheaper and quicker way to bring about a new dementia treatment.
“While this observational study found that that those with type 2 diabetes taking thiazolidinedione had a lower dementia risk than those on the most common medication for type-2 diabetes, it only shows an association between taking the drug and dementia risk and not a causal relationship. Double-blind and placebo-controlled clinical trials are needed to see whether the drug could help lower dementia risk in people with and without diabetes. Anyone with any questions about what treatments they are receiving should speak to their doctor.
“Diabetes is a risk factor for dementia and there is a lot of interest in the links between the two conditions. Our brains don’t operate in isolation from the rest of our bodies, and we know that there are many things people can do to promote physical health.
“As well as tackling diabetes and maintaining a healthy blood pressure, the best current evidence suggests that not smoking, drinking within the recommended guidelines, staying mentally and physically active, eating a balanced diet, and keeping cholesterol levels in check can all help to keep our brains healthy as we age.”
Dr Ivan Koychev, Senior Clinical Researcher at the University of Oxford, said:
“This is a large, well-conducted real-world data study that highlights the importance of checking whether already prescribed medications may be useful for preventing dementia. That glitazones show promise is in line with existing literature linking other type 2 diabetes drugs (GLP-1 receptor agonists and Sodium/glucose cotransporter 2 inhibitors) with reduced risk for dementia. The main limitations of this study is that following the initial 2-year period the authors were interested in, the participants may have been prescribed one of the other type 2 diabetes drugs (GLP-1RA or SGLT-2) that have been found to reduce dementia risk thus potentially making the direct glitazone effect more difficult to discern. It is also important to note that people with type 2 diabetes do run a higher risk of both dementia and cognitive deficits and that these medications are only prescribed in these patients so all this data is from this patient group rather than the general population. The advantage of testing formally such ‘repurposed’ drugs for dementia is that we already have good grasp of their safety thus cutting years off the process of treatment discovery.”
‘Use of oral diabetes medications and the risk of incident dementia in US veterans aged ≥60 years with type 2 diabetes’ Xin Tang et al. was published in BMJ Open Diabetes Research and Care at 23:30 UK time on Tuesday 11 October.
DOI:10.1136/bmjdrc-2022-002894
Declared interests
Prof David Strain has received speaker honoraria, unrestricted educational grants and research funding from many of the major companies in the diabetes disease area including Takeda, the manufacturer of Pioglitazones.
He was responsible for the consensus statement that informed the NICE guidance and the GP contract targets for the management of diabetes in frail older population.
Dr James Connell: “No conflicts to declare.”
Dr Ivan Koychev: “I do have a relevant COI – I am the Chief Investigator on a trial testing if a diabetes compound (GLP-1RA called semaglutide) may be useful in reducing the risk for dementia in ageing adults. The trial is sponsored by Oxford but funded by Novo Nordisk.”
For all other experts, no reply to our request for DOIs was received.