Do new high-concentration insulins paradoxically bring improved safety in older people with diabetes?

Age-attenuated beta-cell function and increased insulin resistance underlie the increase in prevalence of type 2 diabetes with age, and in many cases such individuals will require insulin therapy (with or without oral agents) in due course, mainly to improve glucose regulation. We now have 11 classes of glucose-modulating drugs to manage diabetes, in addition to insulin regimens.

In older patients, insulin therapy carries with it the excess complexity of dosing, timing, meal alignment, and the burden of hypoglycaemia and its consequences, such as emergency room visits and hospital admissions (Sinclair and Bellary, 2016; Zaccardi et al, 2016). Physiological changes leading to impaired awareness of falling glucose levels, the increased risk of cognitive dysfunction in ageing adults with diabetes, and associated comorbidities and frailty exacerbate the likelihood of hypoglycaemia and, together, create an urgent need for safer insulin schemes (Sinclair et al, 2015). Longer-acting insulin analogues, which are designed to mimic physiological basal insulin secretion, with an associated lower hypoglycaemia risk, are now widely used in routine clinical practice, but their efficacy and safety in older people need to be confirmed.

The multinational SENIOR study, summarised in our Digest here, was the first to evaluate over 6 months the efficacy and safety of two preparations of a basal insulin analogue (insulin glargine 100 units/mL and 300 units/mL) in older people (>65 years) with type 2 diabetes. It was also designed to have approximately 20% of the cohort aged 75 years and over, which enabled statistical comparisons of glycaemic control and hypoglycaemia in this age group. The 1014 participants were either already receiving a basal insulin or were insulin-naïve. Once-daily administration was employed, with adjustments in insulin dosage every 3–4 days, with the objective to meet a plasma glucose range of 5.0–7.2 mmol/L, which is the range currently recommended by the American Diabetes Association (2017) for healthy older adults. The primary outcome was change in HbA1c from baseline to week 26 of the trial. The main secondary outcomes were the percentages of participants with one or more confirmed “hypos” (blood glucose ≤3.9 mmol/L) or severe hypoglycaemia, occurring at any time, day or night.

The study demonstrated comparable glucose control in each group, with a trend for lower incidence and rates of symptomatic hypoglycaemia with glargine 300 units/mL versus 100 units/mL. Remarkably, a lower hypoglycaemia risk was observed with the higher concentration of glargine in those participants aged 75 years and over. The relatively low reported hypo event rates may have limited the power to show statistically significant differences between the groups.

The results of the SENIOR study confirm those of previous basal insulin studies (the EDITION series) and a recent post hoc analysis of the EDITION 2 and 3 studies (Yki-Järvinen et al, 2014; Bolli et al, 2015; Munshi et al, 2018). In this latter analysis, changes in weight and insulin dose from baseline were significantly smaller with increasing age. Overall, these studies provide evidence that a high-concentration basal insulin (glargine 300 units/mL) can also be considered an effective and relatively safe treatment in this potentially vulnerable population of older people with diabetes.

Other key papers
Care home residents with diabetes also stand out as a highly vulnerable group, with a high risk of hypoglycaemia leading to avoidable hospital admissions, and they represent one of the most difficult challenges to health professionals and care staff in optimising diabetes and medical care. A recent detailed review, summarised here, examined the literature relating to care-home diabetes over the last 25 years and produced new priority recommendations to enhance care. The review concluded that a Call to Action is required, as diabetes care remains fragmented, suboptimal and in need of investment in these settings. If action is not taken, residents with diabetes in care homes will continue to have their needs unfulfilled.

Older vulnerable people with diabetes are often frail, which, in a display of reverse causality, leads to an increase in hypoglycaemia risk (Abdelhafiz et al, 2015). Although international guidance on frailty management in diabetes is now available (Sinclair et al, 2017), there has been little consensus on how to detect frailty and how to implement a care pathway within primary care. Recently, a national collaborative stakeholder initiative in the UK has published a framework for modern-day management and assessment of frailty within primary care and secondary care. This is summarised in our Digest here. The intended impact of this work is to reduce complications and improve quality of life, but a wider impact to influence the Quality and Outcomes Framework in primary care can only be hoped for!

References
Abdelhafiz AH, Rodríguez-Mañas L, Morley JE, Sinclair AJ (2015) Hypoglycemia in older people – a less well recognized risk factor for frailty. Aging Dis 6: 156–67
American Diabetes Association (2017) Standards of Medical Care in Diabetes – 2017. Diabetes Care 40(Suppl 1): 1–135
Bolli GB, Riddle MC, Bergenstal RM et al; EDITION 3 study investigators (2015) New insulin glargine 300 U/mL compared with glargine 100 U/mL in insulin-naïve people with type 2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab 17: 386–94
Munshi MN, Gill J, Chao J et al (2018) Insulin glargine 300 U/mL is associated with less weight gain while maintaining glycemic control and low risk of hypoglycemia compared with insulin glargine 100 U/mL in an aging population with type 2 diabetes. Endocr Pract 24: 143–9
Sinclair AJ, Bellary S (2016) Preventing hypoglycaemia: an elusive quest. Lancet Diabetes Endocrinol 4: 635–6
Sinclair A, Dunning T, Rodriguez-Mañas L (2015) Diabetes in older people: new insights and remaining challenges. Lancet Diabetes Endocrinol 3: 275–85
Sinclair AJ, Abdelhafiz A, Dunning T et al (2017) An international position statement on the management of frailty in diabetes mellitus: summary of recommendations 2017. J Frailty Aging 7: 10–20
Yki-Järvinen H, Bergenstal R, Ziemen M et al (2014) New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care 37: 3235–43
Zaccardi F, Davies MJ, Dhalwani NN et al (2016) Trends in hospital admissions for hypoglycaemia in England: a retrospective, observational study. Lancet Diabetes Endocrinol 4: 677–85