How tight is too tight? Glycaemic control and mortality in older people

What are the risks associated with intensification of glucose lowering in older people? And why is overtreatment for diabetes dangerous? These are the two important questions we should be asking ourselves following the results of phase II of the Freemantle Diabetes Study. The special features of diabetes in older adults, which have recently been comprehensively reviewed,demonstrate the frequently high complexity of illness and the multi-domain evaluation approach to diabetes care (Sinclair et al, 2015).
The Freemantle prospective cohort study, summarised in our Digest here, investigated the impact of baseline HbA1c (median 50 mmol/mol, 6.7%) on subsequent mortality in adults 75 years of age or older. Researchers foundthat after a median follow up of about 7 years, almost 41% of participants had died. Baseline HbA1c was significantly associated with increased mortality in all treatment groups studied: metformin alone when HbA1c was <48 mmol/mol (<6.5%; HR 2.63); sulpholylurea-based when HbA1c was 48 to 52 mmol/mol (6.5 to 6.9%; HR 2.49); and insulin-based when HbA1c was <53 mmol/mol  (<7.0%; HR 2.22). The authors conclude that older people with diabetes may be overtreated based on lowered HbA1c measures and point out the adverse nature of this. 
The evidence that tight HbA1c control, which was considered to be <53 mmol/mol (<7.0%), reduces macrovascular outcomes – the major cause of mortality in type 2 diabetes in middle-aged and older adults – is patchy (Boussageon et al, 2011)and recent clinical guidelines indicate HbA1c target levels of 53 to 59 mmol/mol (7.0 to 7.5%) to minimise hypoglycaemia and retain some microvascular benefit (Sinclair et al, 2012; American Diabetes Association, 2018). Recent US data suggest that up to about half of all older adults with diabetes may be overtreated, and this will be associated with hazardous consequences such as frequent hypoglycaemia and its related sequelae (Lipska et al, 2015). 
Quite clearly, we need more observational and clinical trial evidence to better document these shortfalls of care. Evidence is also needed to inform clinicians of the most favourable HbA1c range for older people with varying functional categories, such as well functioning, frail or cognitively impaired (Dunning et al, 2014).
A recent retrospective cohort study has also raised the issue of high and low glycaemic thresholds and their associated risks in older people with diabetes (Forbes et al 2018). Data from The Health Improvement Network (THIN) database, which contains information from nearly 600 general practices in the UK (>50,000 people aged 70 years and over with type 1 or type 2 diabetes) have demonstrated an increase in all-cause mortality with both high (>64 mmol/l, >8.0%) and low (<42 mmol/mol, <6.0%) HbA1c levels. These findings point to glycaemic stability being a goal of hyperglycaemia treatment; something clinicians rarely consider important. 
Other factors, such as the presence of frailty in those with low HbA1c levels (Abdelhafiz and Sinclair, 2015), may also influence the risk of mortality in older people with diabetes. Further studies examining mortality risk at both ends of the glycaemic spectrum are therefore necessary to gain a better understanding of influential factors.

References
Abdelhafiz AH, Sinclair AJ (2015) Low HbA1c and increased mortality risk – is frailty a confounding factor? Aging Dis 6: 262-70 
American Diabetes Association (2018) 11. Older Adults: Standards of Medical Care in Diabetes-2018. Diabetes Care 41(Suppl 1): S119-S125
Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M et al (2011) Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 343: d4169
Dunning T, Sinclair A, Colagiuri S (2014) New IDF Guideline for managing type 2 diabetes in older people. Diabetes Res Clin Pract 103: 538-40
Forbes A, Murrells T, Mulnier H, Sinclair AJ (2018) Mean HbA1c, HbA1c variability, and mortality in people with diabetes aged 70 years and older: a retrospective cohort study. Lancet Diabetes Endocrinol 6: 476-486
Lipska KJ, Ross JS, Miao Y et al (2015) Potential overtreatment of diabetes mellitus in older adults with tight glycemic control. JAMA Intern Med 175: 356-62
Sinclair A, Dunning T, Rodriguez-Mañas L (2015) Diabetes in older people: new insights and remaining challenges. Lancet Diabetes Endocrinol 3: 275-85
Sinclair A, Morley JE, Rodriguez-Manas L et al (2012) Diabetes mellitus in older people: position statement on behalf of the International Association of Gerontology and Geriatrics (IAGG), the European Diabetes Working Party for Older People (EDWPOP), and the International Task Force of Experts in Diabetes. J Am Med Dir Assoc 13: 497-502