Type 2 Diabetes Update 2024

TMED Blog

| 23 January 2024

Written by Dalia Miller, MSc 25' (Candidate)

On January 18th, Queen’s University Medical Grand Rounds, coordinated by the Department of Medicine, had the opportunity to listen to a lecture hosted by Dr. Robyn Houlden who discussed Type 2 Diabetes (T2D) Updates in 2024. Dr. Houlden introduced the upcoming role of weekly basal insulin injections, revealed the use of dual GIP/GLP-1 receptor agonist (RA) drugs, and concluded by introducing GLP-1 receptor combination drugs in development. Once the presentation concluded, the TMED program had the privilege of engaging in a thought-provoking conversation with Dr. Houlden.

Gold-standard T2D insulin treatment relies on the individual self-administering daily doses of insulin, which can be perceived as burdensome1. A shift to once-weekly basal insulin would effectively simplify treatment, which ultimately has been shown to improve health-related quality of life, treatment acceptance, and adherence2. Two once-weekly basal insulin competitors are being investigated: Insulin Icodec (II) and Insulin Efsitora (IE), created by Novo Nordisk and Eli Lilly respectively3,4.

II resembles human insulin, with three amino acid substitutions, has a half-life of 8 days, and reaches a steady state after 3-4 weekly injections3. IE is an insulin fusion protein that combines a single-chain variant of insulin with human IgG2 FC domain, it has a half-life of 17 days, and is slow binding to receptors4. Dr. Houlden noted that II is currently finished its phase 3 clinical trials (ONWARDS programs) and is in front of Health Canada, while comparatively, IE is just commencing its phase 3 clinical trial.

The ONWARDS3 program was conducted in insulin naïve T2D individuals and recommends starting doses of 70U/ week (II) and 10U/day (degludec). The decision whether to adjust doses were determined using the mean of 3 daily prebreakfast self-measured blood glucose (SMBG), and doses were increased by 20U (II) or 3U (degludec)5. The program showed lowered A1C levels, no weight change, and a higher rate of level 2/3 hypoglycemic events with II (Figure 1)5.

ONWARDS4 compared individuals already on insulin, basal insulin (daily) and basal-bolus insulin (with a meal)6. II dosing was determined to be seven times the dose pre-trial, with +50% bolus dose6. The program showed slightly lowered A1C levels and minimal differences in continuous glucose monitoring (CGM) with II6

In ONWARDS6, II was investigated to treat Type 1 Diabetes (T1D). Dosing is the same as ONWARDS4, however, if A1C levels are high, +100% bolus dose is administered7. There are notable limitations with using II to treat T1D, namely, increased hypoglycemia and inability to make basal insulin dose adjustments more than once a week7.

Dr. Houlden, as a distinguished educator, highlighted that while once-weekly II is appealing, there are education sessions that must take place and several questions yet to be answered. For example, patients, pharmacists, and physicians must be educated about the high-doses of weekly insulin to put it into perspective and some key unanswered questions include cost and potential side effects.

We then shifted our focus to GIP and GLP-1, learning that these incretin hormones respond to food digestion8. Dr. Houlden explained that GLP-1 receptor agonists (RA) can have effects throughout the body, improving cardiovascular outcomes (MACE), hepatic outcomes (NAFLD), and renal outcomes (both directly and indirectly).

Additionally, GLP-1 RA’s play a large role in obesity management, through its interaction with appetite sensors to reduce hunger and food cravings, and ultimately suppress appetite9. Two commonly known T2D GLP-1 RA drugs that are used for weight management include Ozempic and Rybelsus. Studies investigating the effects of GLP-1 RA’s and obesity (SELECT) revealed reductions in weight, waist circumference, A1C, Systolic BP, and CRP levels10

Dr. Houlden concluded her presentation by introducing Tirzepatide – a GIP/GLP-1 RA and Retatrutide – a GIP/GLP-1/Glucagon RA11,12. There is a significantly greater reduction in A1C levels and weight reduction in Tirzepatide, when compared to Ozempic13. While Tirzepatide is a favourable treatment choice that is available by vial and syringe, there are already shortages11. Retatrutide has been shown to suppress appetite and increase energy expenditure and phase 2 clinical trials have shown that participants are losing on average 16-17% of their body weight12.

During the post-round discussion, Dr. Houlden and TMED students extended the conversation, emphasising insurance coverage and ongoing alternate of T2D drugs. It is imperative to acknowledge that more than 50% of the population is projected to be obese, so insurance should consider covering GLP-1 in the future to avoid inability to access treatment. Additionally, misuse of T2D treatments, specifically for weight loss, are contributing to shortages, and stressing the gap in education on the root causes of poor health that should be further explored.

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References

1. Giugliano D, Scappaticcio L, Longo M, et al. Simplification of complex insulin therapy: a story of dogma and therapeutic resignation. Diabetes Research and Clinical Practice. 2021;178:108958-108958. doi:https://doi.org/10.1016/j.diabres.2021.108958

2. Bajaj HS, Bergenstal RM, Christoffersen A, et al. Switching to Once-Weekly Insulin Icodec Versus Once-Daily Insulin Glargine U100 in Type 2 Diabetes Inadequately Controlled on Daily Basal Insulin: A Phase 2 Randomized Controlled Trial. Diabetes Care. 2021;44(7):1586-1594. doi:https://doi.org/10.2337/dc20-2877

3. Bajaj HS, Goldenberg RM. Insulin Icodec Weekly: A Basal Insulin Analogue for Type 2 Diabetes. 2023;19(1):4-4. doi:https://doi.org/10.17925/ee.2023.19.1.4

4. Heise T, Chien JY, Beals JM, et al. Pharmacokinetic and pharmacodynamic properties of the novel basal insulin Fc (insulin efsitora alfa), an insulin fusion protein in development for once‐weekly dosing for the treatment of patients with diabetes. Diabetes Obesity and Metabolism. 2023;25(4):1080-1090. doi:https://doi.org/10.1111/dom.14956

5. Ildiko Lingvay, Marisse Asong, Desouza C, et al. Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes. American Medical Association. Published online June 24, 2023. doi:https://doi.org/10.1001/jama.2023.11313

6. Mathieu C, Björg Ásbjörnsdóttir, Bajaj HS, et al. Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial. The Lancet. Published online May 1, 2023. doi:https://doi.org/10.1016/s0140-6736(23)00520-2

7. Russell‐Jones D, Tetsuya Babazono, Cailleteau R, et al. Once-weekly insulin icodec versus once-daily insulin degludec as part of a basal-bolus regimen in individuals with type 1 diabetes (ONWARDS 6): a phase 3a, randomised, open-label, treat-to-target trial. The Lancet. 2023;402(10413):1636-1647. doi:https://doi.org/10.1016/s0140-6736(23)02179-7

8. Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: Similarities and differences. Journal of Diabetes Investigation. 2010;1(1-2):8-23. doi:https://doi.org/10.1111/j.2040-1124.2010.00022.x

9. Shah M, Vella A. Effects of GLP-1 on appetite and weight. Reviews in endocrine & metabolic disorders. 2014;15(3):181-187. doi:https://doi.org/10.1007/s11154-014-9289-5

10. A. Michael Lincoff, Kirstine Brown‐Frandsen, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. The New England Journal of Medicine. Published online November 11, 2023. doi:https://doi.org/10.1056/nejmoa2307563

11. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine. 2022;387(3). doi:https://doi.org/10.1056/nejmoa2206038

12. Jastreboff AM, Kaplan LM, Frias JP, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. The New England Journal Of Medicine. Published online June 26, 2023. doi:https://doi.org/10.1056/nejmoa2301972

13. Heise T, DeVries JH, Urva S, et al. Tirzepatide Reduces Appetite, Energy Intake, and Fat Mass in People With Type 2 Diabetes. Diabetes Care. Published online March 1, 2023. doi:https://doi.org/10.2337/dc22-1710

Type 2 Diabetes Update 2024

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Type 2 Diabetes Update 2024

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