Treatment considerations for elderly patients with diabetes
Preventing hypoglycaemia and minimizing glycaemic variability are important targets in diabetes management, particularly among older patients. In an interview with MIMS Doctor, Dr Paul Lee, Specialist in Endocrinology, Diabetes and Metabolism in Hong Kong, discussed the global burden of diabetes, focusing on challenges in the management of elderly patients, specifically in relation to poor glycaemic control and cognitive dysfunction, and the benefits of using long-acting basal insulin such as insulin degludec (IDeg) injections (Tresiba®, Novo Nordisk) in achieving glycaemic targets and improving patient outcomes.
The growing global burden of diabetes
According to the International Diabetes Federation (IDF), the predicted number of people with diabetes worldwide will reach 700 million by 2045, which represents a 51 percent increase from the 2019 estimate of 463 million. Globally, over 135 million people aged >65 years are estimated to have diabetes, and the figure is expected to double by 2045 to 276.2 million. [IDF Diabetes Atlas, 9th Edition, 2019] Based on the 2006–2014 Hong Kong census data, more than 50 percent of patients with diabetes are 60 years of age or older. [Diabet Med 2017;34:902-908]
“Thus, driven by ageing, the disease burden is also expected to increase in the elderly population,” continued Lee.
Challenges in elderly patients with diabetes
“Older patients with diabetes have a longer duration of disease than their younger counterparts and are thus likely to have microvascular and macrovascular comorbidities,” Lee noted. [Diabetes in America, 3rd Edition]
“While recent epidemiological data from the US showed that mortality rates of diabetes-related vascular disease have improved, other diabetic, nonvascular, noncancer complications, such as Alzheimer’s disease [AD], are becoming important contributors to death among patients with diabetes,” said Lee. [Lancet 2018;391:2430-2440]
Diabetes and dementia
“People with diabetes have a higher risk of dementia. With more patients living longer, dementia has become an important comorbidity to consider and manage in many older patients,” stressed Lee. [Diabetologia 2005;48:2460-2469; Biol Psychiatry 2010;67:505-512]
A systematic review reported that measures of glycaemia, specifically, high HbA1c concentration, hypoglycaemic events and glucose variability, are associated with worse cognitive function in people with type 2 diabetes mellitus (T2DM) without underlying dementia. [Lancet Diabetes Endocrinol 2015;3:75-89]
“Evidence also shows that insulin resistance could facilitate the formation of both amyloid plaques and tau oligomers, leading some experts to suggest AD is ‘type 3 diabetes’,” said Lee. [Front Neurosci 2018;12:383]
“Indeed, diabetes has been shown to be an independent risk factor for dementia, specifically AD,” noted Lee. [Biol Psychiatry 2010;67:505-512]
Bidirectional relationship between cognition and diabetes
“The brain depends almost entirely on glucose as its main fuel, making hypoglycaemia a great threat to cognitive function,” explained Lee. “Recurrent severe hypoglycaemia may cause permanent cognitive impairment or promote cognitive decline and accelerate the onset of dementia in middle-aged and elderly people with diabetes.” [Nat Rev Endocrinol 2014;10:711-722]
The bidirectional relationship between severe hypoglycaemia and dementia was demonstrated in a prospective population-based study involving 783 older adults with diabetes (mean age, 74.0 years). During the 12-year follow-up period, 7.8 percent of patients reported experiencing a hypoglycaemic event and 18.9 percent developed dementia. Those who experienced a severe hypoglycaemic event had a 2-fold increased risk of developing dementia vs those who did not have a hypoglycaemic event (34.4 percent vs 17.6 percent; multivariate-adjusted hazard ratio [HR], 2.1; 95 percent confidence interval [CI], 1.0 to 4.4; p<0.001). At the same time, older adults with diabetes who developed dementia also had an increased risk of experiencing subsequent hypoglycaemic events vs those who did not develop dementia (14.2 percent vs 6.3 percent; multivariate-adjusted HR, 3.1; 95 percent CI, 1.5 to 6.6; p<0.001). [JAMA Intern Med 2013;173:1300-1306]
The relationship between glycaemic control, in particular long-term glycaemic variability, and dementia in patients with diabetes was further demonstrated in a population-based retrospective cohort study in Taiwan enrolling 63,084 patients with T2DM between 2002 and 2004. After examining visit-to-visit variations in fasting plasma glucose (FPG) and HbA1c represented by the coefficient of variation (CV), both FPG CV and HbA1c CV were independently associated with AD (HR, 1.27; 95 percent CI, 1.06 to 1.52 for the third tertile in FPG CV; HR, 1.32; 95 percent CI, 1.11 to 1.58 for the third tertile in HbA1c CV, respectively). (Figure 1) [Diabetes Care 2017;40:1210-1217]
Preventing hypoglycaemia and glycaemic variability in older patients with diabetes
As hypoglycaemia is a frequent adverse effect associated with T2DM treatments, such as insulin and sulphonylureas, strategies are needed to optimize glycaemic control in older patients while considering treatment convenience. [J Clin Endocrinol Metab 2019;104:1520-1574; Nat Rev Endocrinol 2014;10:711-722]
IDeg is an ultra-long-acting, once-daily basal insulin with a more predictable day-to-day glucose-lowering effect vs insulin glargine (IGlar). In a randomized, single-centre, parallel-group, double-blind trial, the day-to-day variability of IDeg was four times lower than that of IGlar U100 in patients with type 1 diabetes. [Diabetes Obes Metab 2012;14:859-864]
“IDeg also demonstrated a low risk of severe and nocturnal severe hypoglycaemia in the DEVOTE trial, which was a treat-to-target, randomized, double-blind study that primarily aimed to evaluate the cardiovascular safety of IDeg vs IGlar U100 in patients with T2DM,” said Lee. [N Engl J Med 2017;377:723-732]
Results showed that among patients with T2DM at high risk of cardiovascular events, IDeg was noninferior to IGlar U100 with respect to the incidence of major cardiovascular events (HR, 0.91; 95 percent CI, 0.78 to 1.06; p<0.001 for noninferiority). “Importantly, patients treated with IDeg reported significantly lower rates of severe hypoglycaemia and nocturnal severe hypoglycaemia vs those who received IGlar U100.” (Figure 2) [N Engl J Med 2017;377:723-732]
Lower rates of hypoglycaemia associated with IDeg vs IGlar U100 were also demonstrated in the randomized, double-blind, treat-to-target crossover SWITCH 2 trial. Results of this 32-week study showed a reduced rate of overall symptomatic hypoglycaemia with IDeg vs IGlar U100. [JAMA 2017;318:45-56]
“In addition, IDeg offers flexible dosing, which may help improve adherence to basal insulin therapy by allowing injection time adjustment according to individual needs. IDeg may thus be a more convenient option for older patients, especially those who depend on caregivers,” noted Lee.
Improved glycaemic control and prevention of hypoglycaemia are important treatment targets for older patients with diabetes. Cognitive impairment is another key factor that should be taken into account when tailoring diabetes management for elderly patients.