Adherence to antihyperglycemic treatment: a work in progress

Type 2 diabetes mellitus (T2DM) is a major public health problem. The prevalence of T2DM is increasing worldwide, driven by the aging of the population and the pandemic of obesity [1]. The microvascular complications of T2DM represent the leading cause of end-stage renal disease, blindness, and nontraumatic amputation in high-income countries [1]. In addition, T2DM is also a major risk factor for cardiovascular disease (CVD) and patients with T2DM appear to have comparable all-cause mortality with patients with established CVD [1]. On the other hand, tight glycemic control reduces the risk of development and progression of diabetic nephropathy, retinopathy and neuropathy [2]. Accumulating data also suggest that antihyperglycemic treatment might also reduce cardiovascular morbidity and mortality in patients with T2DM [3]. Despite these beneficial effects of glycemic control, several studies showed that adherence to antihyperglycemic treatment is suboptimal in patients with T2DM. Nonadherence to oral antidiabetic agents, defined as a medication possession ratio <0.8, ranges between 13% and 31% [4,5]. Interestingly, adherence rates to oral agents appear to be lowest with metformin, the first-line agent for management of T2DM [4]. However, other studies did not identify differences in adherence to metformin, sulfonylureas, and pioglitazone [6]. Importantly, adherence to fixed-dose combinations of oral antidiabetic treatments is better than adherence to free drug combinations [7]. Not surprisingly, nonadherence to treatment is consistently associated with poorer glycemic control; HbA1c levels are higher by 0.4–0.7% in nonadherent compared with adherent patients [4]. Younger age, female sex, lower education, lower income, and higher out-of-pocket costs are independently associated with lower adherence to antihyperglycemic treatment [5]. Lower daily total pill burden and nonendocrinology specialist prescribers versus primary care also predict suboptimal adherence [5]. Patients with a recent diagnosis of T2DM and those who belong to ethnic minorities are also less adherent to treatment [5,8]. Regarding adherence to insulin treatment, more than one third of patients report omission of insulin on a mean of 3 days per month [9]. Male gender, younger age, increased cost, and more frequent hypoglycemic episodes are associated with suboptimal adherence to insulin treatment [9]. Previous studies reported that adherence is better in patients using premixed insulin and basal insulin compared with those using a basal bolus regimen [10]. In the present issue of Expert Opinion on Pharmacotherapy, the results of the first study that compared adherence to human insulin with analogue insulin are reported [11]. It is well established that analogue insulins are similarly effective in glucose-lowering compared with human insulins and are also associated with lower risks of hypoglycemia [12]. However, adherence was similarly low in human and analogue insulin in the present study (70.5 and 68.1%, respectively) [11]. In agreement with previous reports, lower levels of education and younger age predicted suboptimal adherence to insulin treatment [11]. Given that analogue insulins are more expensive than human insulins, it is possible that this reduced risk of hypoglycemia counteracts the negative effects of the increased cost on adherence [11]. However, neither cost nor frequency of hyperglycemia was evaluated in the present study [11]. Overall, the present and previous studies highlight a pressing need to improve adherence to antihyperglycemic treatment. Several interventions appear to be useful tools for achieving this target, including education, monitoring, participatory decision-making, and sending reminders [13,14]. However, no single intervention has been consistently shown to improve adherence and to improve glycemic control, suggesting that multiple interventions and individualized approaches might be needed [13]. It is important to bear in mind that even though nonadherence to medication is associated with lower pharmacy and outpatient costs in patients with T2DM, it considerably increases in-hospital costs resulting in a significant net increase in total health-care costs [15]. Therefore, concerted efforts from health-care professionals are needed to improve adherence to antihyperglycemic agents, which will translate into reduced rates of both microvascular and macrovascular complications in patients with T2DM.