Efficacy

The only included trial that was designed to assess the impact of IDeg on cardiovascular outcomes was DEVOTE, and in this study, IDeg was noninferior to IGlar for a composite of MACEs in a population with T2DM and cardiovascular disease. In the SWITCH and BEGIN trials, these types of cardiovascular events were infrequent; therefore, there was no clear evidence of any difference between groups across these trials. Macrovascular disease, as opposed to microvascular, is more common in T2DM than in T1DM, while complications related to microvascular disease, such as renal failure, retinopathy, and neuropathy, are more associated with T1DM. Given that IDeg is an insulin, T1DM will be the condition where it would be expected to have the greatest impact, although since T2DM is far more common than T1DM, IDeg may also be commonly used in T2DM. There was no evidence of an impact of IDeg on development of microvascular disease, and this was not a focus of any of the included trials; therefore, the impact of IDeg on morbidity in T1DM is essentially unknown.

Although there was no evidence that IDeg or its comparators reduced the risk of microvascular complications of T1DM, there was consistent evidence that IDeg was noninferior to other basal insulins (IGlar and IDet) with respect to reducing A1C. A1C is a well-established surrogate for clinical complications of diabetes mellitus; therefore, the consistent effects of IDeg versus its basal insulin comparators in reducing A1C does enhance confidence in its clinical effects despite the lack of clinical outcomes data in T1DM. Given that A1C is an established marker of control over the disease, patient input suggests that A1C is of importance to patients. Variability in blood glucose is an additional marker of glycemic control, and there were no consistent differences noted in extent of blood glucose variability between IDeg and other basal insulins, although many trials were not designed to test superiority for this outcome. The pharmacokinetic data would suggest that IDeg is longer acting than comparators; however, there is not enough consistent evidence to suggest that this longer action translates into a meaningful clinical benefit for the patient. Due to the longer action, the clinical expert notes that an advantage of IDeg may be that it can be administered at any time of day, which may be meaningful to patients as it increases flexibility in dosing.

Quality of life was typically not assessed as a confirmatory outcome in the included studies, and significant differences between IDeg and comparators were seen infrequently and not very consistently across the included trials; therefore, one cannot conclude that IDeg improves HRQoL compared with other basal insulins or other comparators. Quality of life is an important issue to patients with diabetes mellitus; however, the lack of improvement in quality of life is perhaps not surprising given that the frequency of administration and adverse effects did not differ consistently between IDeg and its basal insulin comparators.

Harms

Hypoglycemia is a key safety issue associated with the use of insulins, particularly in T1DM, where the risk of hypoglycemia is high. The longer duration of action of IDeg may have the potential to reduce the risk of hypoglycemia by reducing the risk of variability in plasma glucose; however, the hypoglycemia results were mixed among the included trials. In DEVOTE, there was a statistically significant reduction in the risk of severe hypoglycemia events, although the effect size between groups was small (4.9% of IDeg participants experienced a severe hypoglycemia event versus 6.6% of IGlar participants). In the SWITCH studies, where occurrence of severe or blood glucose–confirmed hypoglycemia events was a primary outcome, there was a reduced risk of events occurring with IDeg versus IGlar in each of the trials, and these differences were again statistically significant; this was also the case for nocturnal hypoglycemia events. This was the case both in a population with T1DM (SWITCH-1) and T2DM (SWITCH-2), both studies featuring participants with a previous history of issues with hypoglycemic events (a severe hypoglycemic event in the past year, hypoglycemic symptom “unawareness,” and a recent hypoglycemic event within 12 weeks of randomization). Even with the statistically significant difference in event rate between groups, the difference between groups in proportion of participants experiencing a hypoglycemic event was relatively small, particularly in SWITCH-1 (77% with IDeg and 80% with IGlar). Conversely, in the BEGIN trials, there was no consistent evidence of an improvement in risk of confirmed hypoglycemic events with IDeg versus other insulins in either T1DM or T2DM. Populations in BEGIN trials were not to have had recurrent episodes of severe hypoglycemia before enrolment. The SWITCH trials were the only studies that were designed to focus on hypoglycemic events; however, there were a large number of hypoglycemic events in the BEGIN trials as well, particularly in the trials in T1DM.

Findings from three indirect treatment comparisons (see Appendix 6) suggest that there is no statistically significant difference in rate of confirmed hypoglycemia between IDeg and IGlar in T1DM. In T2DM, results differed between the indirect treatment comparison, as a published report found a reduced risk of nocturnal hypoglycemia but an increased risk of symptomatic hypoglycemia with IDeg versus IGlar, both statistically significant. Conversely, in the manufacturer-submitted analysis, there was a reduction in nocturnal hypoglycemia with IDeg versus both IGlar and NPH which was statistically significant; however, the analysis of overall hypoglycemia could not be interpreted because the authors stated that both the fixed-effects and random-effects models showed poor fit with high residual deviance values. Findings from a patient-level meta-analysis (see Appendix 7) suggested that IDeg had a lower rate of hypoglycemia than IGlar, although none of the analyses focused on symptomatic events only. In agreement with the findings of the CADTH Common Drug Review clinical review, the network meta-analysis also found no statistically significant differences between groups for change from baseline in A1C.

Potential Place in Therapy^[2]

While insulin remains the most effective treatment available to lower blood glucose (and the only treatment for T1DM), the margin between too much and too little insulin is narrow. Patients and their caregivers walk a fine line between hypoglycemia and hyperglycemia to achieve modern targets for good glycemic control. Based on the experience of the clinical expert consulted for this review, patients are frequently frustrated by day-to-day variations in blood glucose that arise after apparently managing their glucose the same way (within-patient variability). Some of these problems arise because of variability in the duration, peak action, and time-action profile of currently available insulins, especially basal insulins. An insulin that has less within-patient variability could theoretically provide a substantial advantage to patients. Greater certainty about the response to insulin by reducing the fear of hypoglycemia could lead to improved glycemic control and improved quality of life by reducing hypoglycemia and weight gain.

IDeg is a new basal insulin that forms soluble multihexamers on subcutaneous injection, resulting in a depot from which monomers are slowly and continuously absorbed into the circulation. This mechanism leads to the reported ultra-long pharmacokinetic and pharmacodynamic profiles and reduced variability in insulin action compared with IGlar.² Trials in a large clinical development program show noninferiority of IDeg to IGlar for the primary outcome of glycemic control for both T1DM and T2DM both in multiple-dose injection therapy and basal plus oral regimens (BEGIN trials) and for cardiovascular outcomes in T2DM.³ Results for the key secondary outcomes of glucose variability, hypoglycemia, and quality of life are less convincing. While there is a trend to superiority in the reduction of nocturnal hypoglycemic events for people in clinical trials for T1DM, in only one trial does this approach statistical superiority (P = −0.011).⁴ In T2DM, while again there is a trend to an improved efficacy, there is no consistent statistically significant result. There were no quality-of-life differences. Exclusion criteria for most trials included recent severe or recurrent hypoglycemia, which does not allow evaluation of the role of IDeg in this potential group of patients.

The SWITCH trials included groups of patients said to be at high risk of hypoglycemia (recent severe or non-severe hypoglycemia, hypoglycemia symptom unawareness, moderate chronic renal failure, or long disease duration or long-time insulin use) but the data provided do not include sufficient information to identify which of these very different groups might benefit. Although the results show a significantly lower rate of overall, nocturnal, and severe hypoglycemia versus IGlar in both T1DM and T2DM patients, this finding is specific to the trial definitions of these events, and it is not clear how it would translate to clinical practice. Of concern, nocturnal hypoglycemia is defined to a six-hour time period from midnight, and results from a longer sleep period (10 p.m. to 8 a.m.) are not given.

One potential advantage is that the BEGIN Flex T1DM and T2DM studies showed that IDeg can be administered at any time of day, with injection timing varied, without compromising glycemic control or safety.⁵ This may improve basal insulin adherence by allowing injection-time adjustment according to individual needs; however, there is no evidence to assess this potential advantage.

In summary, IDeg appears to achieve similar safety and efficacy outcomes as IGlar in patients with T1DM and T2DM; however, there is no convincing evidence that it is superior in preventing hypoglycemic events. It may be of advantage for those who find difficulty taking basal insulin at a regular time.