Observational Study of Once-Daily Insulin Detemir in People with Type 2 Diabetes Aged 75 Years or Older

The difficulties in managing type 2 diabetes mellitus (T2DM) in the elderly are myriad. Factors to consider in relation to advancing age that influence treatment decisions include co-morbidity, polypharmacy, visual and cognitive impairment, severity of vascular complications, psychosocial limitations, renal insufficiency, an increased risk of falling, and a limited life expectancy [1, 2]. These considerations are in addition to the regular management principles of diabetes—those with the overall aim of achieving good glycaemic control [3].

Diabetes mellitus is a common metabolic problem affecting an estimated 336 million people worldwide [4]. Of people aged ≥25 years, the 2008 prevalence was thought to be approximately 10 % [5]. This rate is increasing. Improvements in cardiovascular risk factors and the management of diabetic complications have contributed to the increasing longevity of people living with diabetes, which in turn has led to the increase in prevalence. In 2011, an estimated 25.8 million people of all ages in the USA had diabetes. In people aged over 65 years, 26.9 % had diabetes, representing 10.9 million people and over 40 % of the total number of people with diabetes in the USA [6]. Globally, the current largest cohort living with diabetes is the 40–59-years age group, but by 2030, the 60–79-years age group is expected to supersede them, with 196 million people affected [7]. Most patients with diabetes over 65 years of age are presently between the ages of 65 and 75 years; however, there will continue to be a shift in demography over the coming decades, so that the majority of the elderly population with diabetes will be ≥75 years of age [8].

The annual global costs of the disease burden of diabetes mellitus are thought to have been in the range of US$465 billion in 2011. By 2030, this cost is predicted to rise to US$595 billion [9]. The average per-person healthcare expenditure of people with diabetes in the USA is 2.3 times that of those without the disease, [10] with three-quarters of global healthcare spending on diabetes involving people aged 50–70 years [9]. Furthermore, elderly patients have a higher rate of diabetes-related hospitalizations compared with younger patients with diabetes. The former are responsible for 65.1 % of all diabetes-related healthcare costs compared with 34.8 % for patients <65 years of age in the USA [11].

In managing people with T2DM, as glycaemic targets are approached, the risk of hypoglycaemia increases. The risk of hypoglycaemia is even higher in the elderly because of age-related complications, including co-morbidity, renal impairment, drug–drug interactions, irregular meal patterns, and poor self-monitoring of blood glucose [1, 12]. The risk of serious morbidity as a result of hypoglycaemia is higher in this elderly cohort [1], and may include cardiac ischaemia [13] and an increased risk of falling [14‐16]. In addition, as a result of longer duration of diabetes, older people with diabetes may be at increased risk of developing hypoglycaemic unawareness [17].

In absolute terms, although severe hypoglycaemia remains a rare event, the rate increases rapidly amongst certain groups. These include very elderly persons with co-morbid conditions, those who are unaware of hypoglycaemic symptoms, and those on insulin therapy [18]. It has been shown that hypoglycaemia in the elderly with T2DM is common [19], but actual rates may be higher than reported [20]. Currently, there is also a paucity of data on the pharmacological treatment of T2DM in the elderly [21].

The purpose of this sub-analysis is to evaluate the response to once-daily insulin detemir in patients aged 75 years or above, compared with those aged below 75 years, using data from SOLVE (Study of Once Daily LeVEmir), which included a large number of older people. The primary objective of the overall SOLVE study was to assess the incidence of serious adverse drug reactions (SADRs), including severe hypoglycaemic events, during 24 weeks in patients initiating once-daily treatment with insulin detemir in real-life clinical practice.

SOLVE was a multinational, open-label observational study of patients with T2DM treated with one or more oral antidiabetic drugs (OADs) initiating insulin detemir treatment. The study involved 3,219 investigators and 2,817 project sites from ten countries: Canada, China, Germany, Israel, Italy, Poland, Portugal, Spain, Turkey and the UK.

The study duration was 24 weeks, and data were collected on each patient during three routinely scheduled clinic visits (baseline, interim and final) approximately 12 weeks apart. Data were collected during the period 4 February 2008 (first patient’s first visit) to 28 March 2011 (last patient’s last visit).

The full analysis set comprised 17,374 patients, of whom 13,767 (79 %; effectiveness analysis set) had a measurement of FPG, HbA_1c, weight or hypoglycaemia at baseline and final visit. Of all the patients included in the full analysis set, 2,398 (13.8 %) were aged ≥75 years. The proportion of patients aged ≥75 years varied between the ten countries, ranging from 5 % in China and Turkey, to more than 18 % in some participating Western European countries (Table 1).

Table 1 shows the pre-insulin characteristics of the population by age ≥75 and <75 years. There were a higher proportion of female patients in the subgroup aged ≥75 years (55.4 % vs. 45.7 %), and a higher proportion of the older age group was White than of ‘other’ ethnicity (87.5 % vs. 72.0 %). Unsurprisingly, the older cohort also had a longer mean (± SD) duration of diabetes (14 ± 9 vs. 9 ± 6 years) and OAD treatment (12 ± 8 vs. 8 ± 6 years). The older age group also had a lower average (± SD) weight (75.6 ± 14.8 vs. 81.7 ± 17.8 kg) and BMI (28.5 ± 4.8 vs. 29.3 ± 5.4 kg/m²) than the younger cohort.

Pre-insulin OAD treatments differed between the two age cohorts, with a lower proportion of patients aged ≥75 years prescribed more than two OADs compared with those aged <75 years (10.8 % vs. 16.9 %). Patients aged ≥75 years were more likely to be prescribed sulphonylurea (65.0 %) and glinides (18.3 %) than the younger group (58.6 % and 15.7 %, respectively), but the proportion of older patients prescribed metformin, thiazolidinedione, and α-glucosidase inhibitors was lower (Table 1).

Pre-insulin average HbA_1c and FPG measurements were similar in both age groups.

This subgroup analysis comparing patients with T2DM aged ≥75 years to those aged <75 years showed similar improvements in glycaemic control without an increased risk of severe hypoglycaemia or minor nocturnal hypoglycaemia in both age groups. The presented analyses highlight differences in OAD prescribing before and during the initiation of insulin. Also apparent is a lack of confidence among healthcare professionals in prescribing insulin to older age patients, although the time taken to train patients and the satisfaction of insulin achieving target HbA_1c reported by healthcare professionals in this observational study was similar irrespective of patient age.

Historically, previous studies have found similarly low rates of prevalence of severe hypoglycaemia. In the USA, the Veterans Affairs Cooperative Study (VA CSDM) compared ‘standard’ (one injection per day) against intensive ‘stepped’ insulin regimens amongst veterans with a mean age of 60 years and found a rate of severe hypoglycaemia of 2 episodes per 100 patient-years, with no difference between treatment groups [23]. Higher incidence rates were found in the UK Prospective Diabetes Study (UKPDS). In patients undergoing ‘intensive’ management of T2DM, severe hypoglycaemic episode rates per year were higher in insulin-treated groups (1.8 %) than in those treated with glibenclamide (1.4 %), chlorpropamide (1.0 %) or ‘conventional’ treatment (0.7 %). These findings should be interpreted in the context of an average HbA_1c amongst the intensive group of 7.0 %, and the fact that the UKPDS was not focused on an elderly cohort [24]. A retrospective observational population-based study from Tennessee looked at the incidence of serious hypoglycaemia amongst Medicaid T2DM patients aged ≥65 years. The reported incidences were 1.23 and 2.76 episodes per 100 patient-years amongst the sulphonylurea- and insulin-treated groups, respectively [25].

There appears to be some variation in reported rates of minor hypoglycaemia. While basal insulin analogues have been previously shown to lower the risk of hypoglycaemia with respect to human insulin preparations and more intensive regimens including rapid-acting insulin [26, 27], there remains a paucity of clinical trial data concerning the ≥75-years age group [21], and definitions of hypoglycaemia also vary [28]. In this sub-analysis, there was an increase in the number of minor hypoglycaemic episodes throughout the study period from 1.1 to 2.0 and 1.7 to 1.8 episodes per patient-year in both the ≥75- and <75-years age groups, respectively. The incidence of all hypoglycaemic episodes amongst insulin-treated diabetic veterans in the VA CSDM study was 1.5 per patient-year with once-daily standard injections versus 16.5 per patient-year amongst the intensive group [23]. Recall reliability of minor hypoglycaemia amongst patients with insulin-dependent T2DM is unknown [28], but in people with type 1 diabetes, it has been found to be poor after 1 week [29, 30]. Thus, there may be gross under-reporting of hypoglycaemia. In one study of elderly patients with HbA_1c levels of 8 % or greater, continuous glucose monitoring over 3 days found that 93 % of hypoglycaemic episodes were not recognized by symptoms or four-times-daily blood glucose monitoring [20].

Evidence on the safety of tighter glycaemic control remains mixed. One study comparing intensive versus standard treatment of people with T2DM with high HbA_1c levels found a statistically significant increase in the rate of all-cause mortality in the intensive therapy group, with no differences according to age in a subgroup analysis of patients aged <65 versus ≥65 years [31]. A similar study found no difference in cardiovascular mortality amongst veterans with poorly controlled T2DM given intensive or standard treatment [32]. Both studies conveyed some modest benefit in regard to microvascular complications associated with the disease [31, 32].

A move toward more individualized HbA_1c targets in the elderly—specifically, more lenient targets in the frail elderly or those with limited life expectancy—has been mooted [33, 34], as treatment is placed in a risk–benefit context between good glycaemic control and the risk of hypoglycaemia [2, 20, 35, 36]. Current American Diabetes Association guidelines seem to reinforce this notion of loosening targets in the face of increasing risk, seen especially in the elderly [37]. Conversely, in those patients with few co-morbidities and lengthy life expectancy, tighter glycaemic control may be a viable option as long as significant hypoglycaemia does not occur [37]. However, one study implementing such higher HbA_1c targets (8 % or less as proposed by the American Geriatrics Society) in a poorly controlled population resulted in fewer overall hyperglycaemic episodes, but more hypoglycaemic episodes requiring emergency room attendance during the early implementation phase [38]. Clearly, such relaxed targets are no panacea for preventing hypoglycaemic episodes, and raising HbA_1c targets alone may not be enough to prevent hypoglycaemia in the elderly [20]. Conversely, there is some evidence to suggest that in elderly patients with tight glycaemic control (HbA_1c ≤6 %), reducing or withdrawing diabetic medications is safe and may decrease the risk of hypoglycaemia [19].

Nevertheless, there is still a need for appropriate management of T2DM in the elderly that considers the heterogeneous needs of the patient and targets all aspects of their care, including hypertension, hyperglycaemia, hyperlipidaemia, mood problems, and other geriatric syndromes [2, 21, 34]. Many patients with T2DM will eventually require insulin therapy to reach glycaemic goals because of contraindications to OADs or progressive worsening of pancreatic β-cell function [2, 21]. Further, renal dysfunction associated with advancing age can often herald the inability to use oral agents. There is some evidence of a tendency amongst clinicians to continue prescribing OADs in the elderly, especially sulphonylurea, despite contraindications (for example, renal impairment). This practice is thought to substantially adversely impact the risk of severe hypoglycaemia in this population, and alternative therapies minimizing the risk of hypoglycaemia have been called for [39].

The treatment of T2DM in the elderly is complex, and involves consideration of multiple factors that may not be present in a younger population. The situation is further complicated by a general lack of clinical trial data pertaining specifically to the elderly population. This sub-analysis of the SOLVE study data shows that treatment with insulin detemir in patients aged ≥75 years was effective at improving HbA_1c, and safe in terms of the risk of hypoglycaemia. Long-acting basal insulin analogues are a useful treatment option in elderly patients with T2DM, where polypharmacy or medication adverse effects associated with OADs may become a barrier to achieving appropriate glycaemic control.