NPC Archive Item: Severe hypoglycaemia may increase the risk of dementia in elderly patients with type 2 diabetes

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22nd April 2009

A study has found that episodes of severe hypoglycaemia requiring hospital treatment were associated with an increased risk of dementia. This cohort study involved elderly patients with type 2 diabetes who had no documented prior diagnoses of dementia, cognitive impairment or memory complaints.

This study adds to the existing evidence suggesting that intensive control of blood glucose should only be considered cautiously in older people with type 2 diabetes. Health professionals and people with type 2 diabetes should prioritise lifestyle interventions (losing weight, healthy diet, stopping smoking if relevant), blood pressure control as well as taking a statin, aspirin if cardiovascular disease (CVD) is present, and metformin. We should continue to follow NICE guidance and agree individual targets for blood glucose.

What is the background to this?
Three important studies (ACCORD, ADVANCE and VADT) have already provided evidence that tighter glycaemic control (to <7% glycated haemoglobin) in older adults with type 2 diabetes does not provide substantial benefits relating to CVD. There is some evidence that this approach may in fact increase the risk of adverse outcomes. These studies and their implications have been discussed in several previous NPC blogs:

What does this study claim?
This cohort study aimed to find out whether hypoglycaemia episodes severe enough to require hospitalisation or a visit to the emergency department were associated with an increased risk of dementia. It included 16,667 people with type 2 diabetes of a mean age of 65 years and who were members of a health care delivery organisation in Northern California, USA. Hypoglycaemic events from 1980 to 2002 were collected and reviewed using hospital discharge and emergency department diagnoses. Cohort members with no prior diagnoses of dementia, mild cognitive impairment or general memory complaints on January 1st 2003 were followed up for a dementia diagnosis until January 15th 2007.

The study concluded that severe hypoglycaemia was associated with an increased risk of dementia, especially in patients with a history of multiple episodes. The absolute increase in the risk of dementia was 2.39% (95% confidence interval [CI] 1.72 to 3.01) per year of follow-up for patients with a history of severe hypoglycaemia, compared with patients with no history of this. The risk of dementia was, on average, twice as likely in patients with three or more episodes of severe hypoglycaemia (adjusted hazard ratio [HR] 1.94, 95% CI 1.42 to 2.64), compared with those with no history of hypoglycaemia.

How does this relate to other studies?
The results of this study differ from those of the DCCT randomised controlled trial (RCT), which showed no association between acute hypoglycaemia and an accelerated rate of cognitive decline in patients with type 1 diabetes and a mean age of 27 years, who were followed up over 18 years. The authors of this new study point out that this is the first study to focus on patients with type 2 diabetes and suggest that younger patients may be less vulnerable to the risks of dementia.

So what?
This study is an observational study and, as such, can only demonstrate an association between severe hypoglycaemia and a subsequent diagnosis of dementia, not that the first causes the second. However, the authors do acknowledge this limitation and have performed analyses to try and reduce the possibility that preclinical dementia was increasing the likelihood of hypoglycaemic episodes. They also point out that more robust data from RCTs on hypoglycaemic events and cognitive function measures will be available in a few years.

Until those results are available, this study provides yet another reason for caution when considering intensive glucose control in elderly people with type 2 diabetes. In contrast to observational studies and much current clinical practice, RCTs attempting to show that intensive drug strategies to control blood glucose to low target levels produces a reduction in important clinical outcomes have produced disappointing results. Indeed, in ACCORD, intensive therapy was associated with an increased risk of death.

The NICE clinical guideline on diabetes provides advice on setting a target for HbA1c. It cautions against the use of highly intensive management strategies to achieve levels of less than 6.5%, and recognises the importance of involving the patient in the setting of their own target level, which may be above that of the aspirational 6.5%. The guidance also includes recommendations for structured education programmes, dietary and lifestyle advice, and, where necessary, interventions to reduce blood pressure, manage blood lipids, reduce the risk of thrombosis (aspirin) and kidney disease (ACE inhibitors). Note, the subsequent POPADAD trial casts doubt on the value of aspirin for primary prevention of CV events in people with type 2 diabetes.

More information on the management of type 2 diabetes can be found on the type 2 diabetes section of NPC.

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Study details
Whitmer RA, Karter AJ, Yaffe K, et al. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 2009;301:1565–72

Design: This was a longitudinal cohort study to determine whether hypoglycaemic episodes severe enough to require hospitalisation are associated with an increased risk of dementia in a population of older patients with type 2 diabetes.

Patients: The study included 16,667 patients (mean 65 years) with type 2 diabetes who were members of the Kaiser Permanente Northern California Diabetes Registry between 1980 and 2007.

Outcomes: All hospitalisation and emergency department diagnoses of hypoglycaemia were identified retrospectively from January 1st 1980 to December 31st 2002. Cohort members with no prior diagnoses of dementia, mild cognitive impairment or general memory complaints were followed up from January 1st 2003 to January 15th 2007 for incident diagnoses of dementia using inpatient and outpatient databases. Patients having no hypoglycaemia served as the reference group.

Results: 1,465 patients (8.8%) had at least one episode of severe hypoglycaemia from 1980 to 2002. Of these, 68.5% had 1 episode, 18% had 2 episodes, and 13.5% had 3 or more episodes. 1,822 patients (11%) had a diagnosis of dementia during a mean follow-up of 3.8 years and median of 4.8 years. 250 patients (16.95%) had both dementia and at least one episode of hypoglycaemia.

The excess attributable risk of dementia for patients with 1 or more severe hypoglycaemic episodes compared with those with no episodes was 2.39% per year (95% CI, 1.72 to 3.01), compared with those with no episodes.

Compared with patients with no hypoglycaemia, patients with single or multiple episodes had a graded increase in risk when hazard ratios were adjusted for age, body mass index, race/ethnicity, education, sex, and diabetes duration, diabetes-related comorbidites, HbA1c level, diabetes treatment and years of insulin use.

  • One episode: HR 1.26 (95% CI, 1.10 to1.49)
  • One or more episodes: HR 1.44 (95% CI 1.25 to 1.66)
  • Two episodes: HR 1.80 (95% CI, 1.37 to 2.36)
  • Three or more episodes: HR 1.94 (95% CI, 1.42 to 2.64).

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