Welcome to PracticeUpdate! We hope you are enjoying access to a selection of our top-read and most recent articles. Please register today for a free account and gain full access to all of our expert-selected content.
Already Have An Account? Log in Now
Once-Weekly Insulin Icodec Compared With Daily Basal Insulin Analogues in Type 2 Diabetes
abstract
This abstract is available on the publisher's site.
Access this abstract nowAIM
To perform a participant-level post hoc meta-analysis of Phase 3a trials in type 2 diabetes (T2D) to characterize the hypoglycaemia safety and glycaemic efficacy of once-weekly insulin icodec (icodec).
MATERIALS AND METHODS
All ONWARDS 1-5 randomized participants were pooled as overall T2D, insulin-naive, an insulin-experienced subgroups, and by once-daily trial comparator (degludec or glargine U100). The main outcomes included incidence and rates of clinically significant and severe hypoglycaemia. Additional endpoints included change in glycated haemoglobin (HbA1c) from baseline and HbA1c target achievement without clinically significant or severe hypoglycaemia.
RESULTS
The meta-analysis comprised 3765 participants (1882 icodec vs. 1883 comparators). In the overall T2D pool, clinically significant hypoglycaemia incidence was similar in the icodec group versus the comparator group (17.9% vs. 16.2%, odds ratio [OR] 1.14, 95% confidence interval [CI] 0.94, 1.38); however, rates were low but significantly higher in the icodec group (1.15 vs. 1.00 episodes/participant-year of exposure, estimated rate ratio 1.51 [95% CI 1.24, 1.85]). Fewer severe hypoglycaemic episodes occurred with icodec than with comparators (8 vs. 18). A greater reduction in HbA1c occurred with icodec versus comparators, irrespective of subgroup (estimated treatment difference range [-0.10 to -0.29%]; all p < 0.05). Across subgroups, except for the insulin-experienced subgroup, the odds of achieving HbA1c <53 mmol/mol (7.0%) without clinically significant or severe hypoglycaemia were greater with icodec than with comparators (OR range 1.30-1.55; all p < 0.05).
CONCLUSIONS
Icodec was associated with a similar incidence but higher rates of clinically significant hypoglycaemia (equating to one additional hypoglycaemic episode every 6 years) and fewer severe hypoglycaemic episodes versus comparators. Our findings also confirmed the greater efficacy of icodec that was demonstrated in the ONWARDS trial programme.
Additional Info
Disclosure statements are available on the authors' profiles:
Once-weekly insulin icodec compared with daily basal insulin analogues in type 2 diabetes: Participant-level meta-analysis of the ONWARDS 1-5 trials
Diabetes Obes Metab 2024 Jul 01;[EPub Ahead of Print], HS Bajaj, B Ásbjörnsdóttir, TJ Bari, K Begtrup, T Vilsbøll, J RosenstockFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Adherence and persistence has been low in individuals with type 2 diabetes on insulin, resulting in poorer than accepted outcomes outside of clinical trials.1,2 Once-weekly insulin injections have been developed as an appealing alternative to daily basal insulin injections, especially with the rise in popularity of once-weekly incretin therapies. Giving one or two injections once a week could theoretically reduce burden and simplify the treatment regimen. This is, however, only true for people with type 2 diabetes. People with type 1 diabetes are ideally treated with an automated insulin delivery system and, if on injections, must give both basal as well as more frequent prandial insulin. Once-weekly insulin icodec was submitted to the FDA for use in people with type 1 diabetes and has so far failed to be approved due to concerns about hypoglycemia. However, this patient-level meta-analysis of the ONWARDS 1–5 trials by Bajaj and colleagues highlights the utility of once-weekly icodec in people with type 2 diabetes.3
ONWARDS 1–5 were randomized, controlled, multicenter, phase IIIa trials in people with type 2 diabetes lasting for 26 to 52 weeks (some with an extension phase). In the ONWARDS 1, 3, and 5 trials, the participants were basal-insulin naïve and in ONWARDS 2, individuals had been previously treated with basal insulin alone or on basal-bolus therapy (ONWARDS 4). Comparator insulins were once-daily glargine and degludec.
The overall pooled population was 3765 individuals, with approximately half randomized to insulin icodec. The primary focus of the meta-analysis was the difference in the occurrence of hypoglycemia. The authors assessed the hypoglycemia incidence (percentage of participants) and rates (number of episodes/person-year of exposure [PYE]). The investigators broke down the data in terms of the various levels of hypoglycemia, particularly in terms of clinically significant (level 2), which was defined as a fingerstick glucose reading of less than 54 mg/dL. Across the overall pool, the incidence of clinically significant hypoglycemia was not different between icodec versus once-daily comparators. However, the rates of clinically significant hypoglycemia were statistically significantly higher with icodec versus the comparators (1.15 vs 1.000 episodes/PYE; P = .0002). Rates of severe (level 3) hypoglycemia were low and numerically fewer with icodec.
The reduction in HbA1c level was small but statistically significantly greater with icodec than with once-daily basal comparators (0.20%-points [95% CI, −0.30 to −0.11]; P < .0001) at planned end of treatment. Additionally, the number reaching an HbA1c target of <7% was statistically significantly greater with icodec than with once-daily basal comparators in the overall type 2 diabetes pool (OR, 1.45 [95% CI, 1.25–1.57]; P < .0001).
As a clinician, these small changes in HbA1c and hypoglycemia rates seem relatively unimportant if this insulin improves adherence and persistence. Where I work, in an under-resourced area, use of insulin is erratic and only rarely reduces HbA1c levels to target levels both in people with type 1 and type 2 diabetes. If used differently than in a clinical trial, for instance, with a goal of reducing episodes of diabetic ketoacidosis in a population where rates are high, a meaningful benefit might be found. This could mean targeting a mean glucose level of 180 mg/dL and lowering HbA1c levels from 12%–14% down to 8%–9%, which is high but still much better than the under-insulinization sometimes seen with more frequently administered insulin. Similarly, in our large population of people with type 2 diabetes who need basal insulin, if the target was HbA1c less than 8% instead of less than 7%, as it was in the ONWARDS trials, perhaps the differences in rates of hypoglycemia would not occur while glycemic outcomes would be improved.
Icodec has now been approved for use in multiple countries around the world, including Canada, Australia, the European Union, Switzerland and Japan. This will allow for some understanding of the patient characteristics as to whom clinicians start on a once-weekly insulin as well as what the outcomes are. Once-weekly insulin is but one potential option in our toolbox for treating people with diabetes; but, if used wisely, it might be able to help some of our patients, which could improve outcomes in ways that more frequently dosed insulin cannot.
References
Icodec is a new long-acting basal insulin. As icodec's long duration of action allows for once-weekly injection and possibly better adherence, and its stable action profile may reduce the risk of hypoglycemia, it might yield better glucose control or lower risk of hypoglycemia than once-daily insulins. A series of well-designed studies (ONWARDS 1–6) has tested this hypothesis in several settings. ONWARDS 6 in type 1 diabetes showed equivalent glucose control with a weekly injection of icodec versus daily injections of insulin degludec, but disappointingly, the rate of clinically significant or severe hypoglycemia was higher with icodec. Studies of type 2 diabetes (ONWARDS 2–5) have reported some evidence of better glucose control but inconclusive findings regarding risk of hypoglycemia. Recently, pooling patient-level data from 3765 participants in studies on type 2 diabetes allowed for a more powerful analysis of the safety and efficacy of icodec versus insulin glargine or insulin degludec. The meta-analysis included participants using a range of insulin regimens — no prior insulin, prior use of basal insulin, prior use of basal, and bolus insulins. It included comparisons with glargine and degludec separately and examined various categories of hypoglycemia. The results did much to clarify the questions posed, but the findings were still mixed. About 0.2% greater reduction of HbA1c was confirmed with icodec, but effects of icodec on hypoglycemia were less encouraging. Icodec caused clinically significant or severe hypoglycemia in the same proportions of individuals as the once-daily insulins, but there were more such events overall (that is, more people using icodec had multiple episodes). Additionally, icodec caused a modest but consistent and statistically greater weight gain than glargine and degludec. The excess mean gain with icodec in studies enrolling participants using different insulin regimens ranged from 0.67 kg to 1.16 kg. Overall, these analyses suggest a modest improvement in glucose control with icodec, but no advantage in avoiding hypoglycemia or controlling weight. Further, the entry criteria for the studies did not allow for study of the most vulnerable people with type 2 diabetes; therefore, the present findings may not be generalizable to a representative population, including more frail individuals. A subgroup or a titration regimen that could benefit from this promising new insulin may yet be identified, but a population or a clinical approach for which insulin icodec is predictably better than other basal insulins was not revealed by the present analysis.