Insulin is a well-established treatment for both type 1 and type 2 diabetes and has been in use now for nearly a century. During this time, the source, structure, purity and delivery of insulin has changed significantly. What has not changed, however, is the ability of insulin to control blood glucose, improve quality of life, avoid complications and save lives. The ability of insulin to prevent micro- and micro-vascular complications has been demonstrated in two landmark trials, namely the Diabetes Control and Complication Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) [1, 2].

While the above-mentioned benefits of insulin are not disputed, the occurrence of side effects, such as weight gain and hypoglycaemia, did lead to concerns about the cardiovascular safety of this drug [3,4,5]. One large study reported that intensive and rapid glycaemic control measures using insulin as one of many interventional components increased the risk of cardiovascular events and all-cause mortality [3]. The authors, however, did comment that the study was not designed to identify the particular component causing increased events. A meta-analysis also showed that fasting hyperinsulinemia is significantly associated with cardiovascular mortality in non-diabetic adults [6]. However, this hyperinsulinemia may be due to insulin resistance, which itself is linked to cardiovascular dysfunction.

Certain insulin analogues were also thought to be linked to increased cancer risk because of their growth-promoting properties [7,8,9,10,11,12]. Unfounded concerns about the “pushing “of insulin by manufacturers added fuel to fire [13]. These uncertainties led to a debate on whether insulin use to achieve euglycemia in type 2 diabetes follows the dictum ‘primum succurrere’ (first hasten to help) without respecting the philosophy of ‘primum non nocere’ (first do not harm). However, these issues, raised by non-specialists in the field, have effectively been put to rest with the ORIGIN and DEVOTE trials.

The ORIGIN trial (Outcome Reduction with an Initial Glargine Intervention) showed insulin glargine to have cardiovascular safety when administered to participants with newly diagnosed type 2 diabetes or prediabetes [14]. The authors of the ORIGIN trial highlighted the large difference in insulin use between the insulin glargine and control group, as well as the glycaemic equipoise achieved between them. Hence, the cardiovascular safety demonstrated in the intervention (glargine) group related more to glargine or insulin per se than to good glycaemic control.

The DEVOTE trial Trial (Comparing Cardiovascular Safety of Insulin Degludec vs. Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events) studied 7637 participants with type 2 diabetes and a high cardiovascular risk profile who were being treated with one or more oral or injectable anti-diabetic agent, with a glycated haemoglobin A1c (HbA1c) of >7.0%. Participants with a HbA1c of <7.0% were included in the trial if their current basal insulin requirement was >20 U/day. All participants were randomized in a double-blinded manner, in a 1:1 ratio, to either an insulin degludec + standard of care arm or an insulin glargine + standard of care arm. They were seen weekly for 2 weeks, monthly for 6 months and quarterly for the rest of the trial [15]. This trial design differed from ORIGIN with respect to inclusion criteria, trial structure and choice of comparator arm and frequency of follow-up (Table 1). It must be noted that ORIGIN had a placebo arm, while DEVOTE used an active comparator arm.

Table 1 Parameters of the ORIGIN and DEVOTE trials
Full size table

The DEVOTE trial included participants with a longer duration of diabetes and a higher cardiovascular risk profile. The inclusion criteria were reflective of a real world diabetes outdoor clinic which included participants of a similar background who could be initiated on (or switched to) a basal insulin analogue. The primary endpoint of the study, i.e. the MACE composite outcome of first occurrence of cardiovascular death, non-fatal stroke and myocardial infarction, showed a hazard ratio of 0.91 in favour of degludec relative to insulin glargine U100, but this difference was not statistically significant [16]. Thus, degludec demonstrated cardiovascular safety, relative to glargine, allaying concerns about its use in type 2 diabetes patients at risk of cardiovascular disease.

The secondary endpoint, i.e. hypoglycaemia, occurred in fewer participants on degludec than in those on glargine. While 27% fewer participants in the degludec arm experienced an episode of severe hypoglycaemia, there was a 40% reduction in the number of total episodes of adjudicated severe hypoglycaemia and a 54% relative reduction in the rate of nocturnal severe hypoglycaemia, with all these difference achieving statistical significance. These results are concordant with those reported in the BEGIN and BOOST clinical trial programmes of insulin degludec and degludec aspart [17, 18].

Hypoglycaemia per se is a risk factor for cardiovascular mortality and is known to impair quality of life [19, 20]. Hence, avoidance of hypoglycaemia is one of the aims of safe and effective diabetes care and is included in the glycaemic pentad [21].

While detailed data of the DEVOTE trial will be reported at a later time, the top-line results are encouraging. The trial provides evidence that one can use insulin degludec to achieve better glycaemic control without fear of hypoglycaemia and without fear of cardiovascular adverse effects. This will encourage the timely use of insulin in persons with type 2 diabetes, including those with cardiovascular risk factors. In the debate between two contrasting philosophies of action, ‘Primum succurrere’, and ‘Primum non nocere’, degludec proves its DEVOTion to diabetes care: Auxiliendo, Primum non nocere.