The global diabetes mellitus (DM) epidemic poses significant health challenges in Asia and the rest of the world. At a symposium, Professor Lawrence Leiter of the University of Toronto, Canada, discussed the critical role of early insulinization to reduce long-term complications. He also shared how long-acting insulin analogue injections, such as insulin degludec (IDeg) and its combination with insulin aspart (IDegAsp), which provide longer time in target glucose range with lower hypoglycaemic risks, may help patients achieve long-term treatment goals.
Early glucose control to minimize CV complications
In Hong Kong, the age-standardized event rates of DM-related complications, including coronary heart disease, heart failure, stroke, and hospitalization for hyperglycaemic crisis, declined in both men and women from 2001 to 2016. However, according to Swedish data, DM patients continue to face about double the risk of cardiovascular disease (CVD) hospitalization compared with those without DM. [J Diabetes Investig 2024;15:402-409; N Engl J Med 2017;376:1407-1418]
To mitigate CVD risk, the American Diabetes Association guideline encourages early glucose lowering to achieve near-normal HbA1c targets. “Tight glucose control [ie, HbA1c <7 percent] early in the course of type 2 DM [T2DM] can reduce long-term CVD risk,” explained Leiter. [Diabetes Care 2024;47(Suppl 1):S111-S125]
At the time of diagnosis, patients with T2DM have typically lost 50 percent of β-cell function and show elevated postprandial glucose levels. As T2DM progresses, much of the β-cell response is lost over the next 10 years, often leading to a need for additional insulin. Without early intensive intervention, long-standing hyperglycaemia could create a ‘bad glycaemic legacy’ that drives the risk for complications. A 1-year delay in treatment intensification in T2DM patients with HbA1c ≥7 percent was significantly (p<0.01) associated with an increased risk of MI by 67 percent, stroke by 51 percent, heart failure by 64 percent, and CVD events by 62 percent compared with patients with HbA1c <7 percent, as observed in a UK retrospective study (n=105,477). [Review Postgrad Med 2020;132:676- 686; Diabetologia 2009;52:1219-1226; Cardiovasc Diabetol 2015;14:100]
“Immediate intensive treatment for newly diagnosed patients may be necessary to avoid irremediable long-term risks for diabetic complications and mortality. Much data have shown that early achievement of HbA1c targets can reduce the risk of complications,” said Leiter. [Cardiovasc Diabetol 2015;14:100; Diabetes Care 2019;42:416-426; Diabet Med 2016;33:1575-1581]
Advantages of longer-acting basal insulin analogues
Glycaemic variability may heighten the risk of hypoglycaemia – a major barrier to achieving good glycaemic control and a complication associated with medical, psychological and social consequences. Fear of future hypoglycaemic episodes often causes overeating and other behavioural changes in patients. Misunderstanding the precipitant for hypoglycaemia leads some patients to inappropriately reduce their insulin dose following a hypoglycaemic event, thus compromising glycaemic control, while the hypoglycaemic event may in fact have stemmed from a missed meal or other factors. [Lancet Diabetes Endocrinol 2019;7:221-230; Nat Rev Endocrinol 2014;10:711-722; Diabetes Care 2011;34:S132-S137; Health Qual Life Outcomes 2008;6:73; Can J Diabetes 2005;29:186-192]
“An ideal basal insulin should have high potency, a flat time-action profile, low variability, and a long half-life of over 24 hours to ensure effective glycaemic control, simplicity of use, low risk of hypoglycaemia, and increased time in range [TIR],” said Leiter.
“Compared with first-generation insulin, longer-acting basal insulin analogues demonstrate less within-day glycaemic variability, lower day-to-day variability, lower risk of hypoglycaemia, and more flexibility, which certainly improves patients’ quality of life,” he commented. [Diabetes Obes Metab 2012;14:859-864; J Diabetes Sci Technol 2018;12:356-363; Diabetes Obes Metab 2017;19:1032-1039; JAMA 2017;318:33-44; JAMA 2017;318:45-56]
Although both insulin detemir and insulin glargine (IGlar) U100 have longer half-lives than neutral protamine hagedorn (NPH) insulin, their half-lives do not exceed 12 hours. In contrast, IGlar U300 has a half-life of 19 hours, while IDeg has a half-life of approximately 25 hours due to a different method of protraction involving formation of soluble multi-hexamers in the bloodstream. [J Pharm Technol 2016;32:260-268; Tresiba Hong Kong Prescribing Information, 2022]
With an extended half-life and flat time-action profile, IDeg consistently demonstrated a lower incidence of hypoglycemia vs IGlar in randomized clinical trials and real-world studies in type 1 DM (T1DM) and T2DM patients. [Diabetes Obes Metab 2013;15:175-184; JAMA 2017;318:45-56; N Engl J Med 2017; 377:723-732; Diabetes Obes Metab 2018;20:689-697; J Clin Endocrinol Metab 2019;104:5977-5990]
TIR: New metric in DM management
TIR, referring to time spent within target glucose range, has emerged as a crucial metric in evaluating glycaemic control and long-term outcomes. It offers valuable insights that enhance assessment of current glycaemic management, complementing traditional HbA1c levels. [Diabetes Care 2017; 40:1631-1640]
A post hoc analysis of the DEVOTE study (n=5,644) showed that T2DM patients with a derived TIR >70 percent had a significantly lower estimated rate of first major adverse cardiovascular event vs those with derived TIR ≤70 percent (hazard ratio [HR], 0.73; 95 percent confidence interval [CI], 0.59–0.90; p<0.01) or derived TIR ≤50 percent (HR, 0.69; 95 percent CI, 0.52–0.91; p<0.01). (Figure 1) [Bergenstal RM, et al, ADA 2020, poster 21-LB]
In the same analysis, derived TIR was found to be significantly associated with time to first severe hypoglycaemic episode (p<0.0001) and microvascular event (p=0.019), with lower risks for patients with TIR >70 percent and TIR >50–≤70 percent vs those with TIR ≤50 percent. [Bergenstal RM, et al, ADA 2020, poster 21-LB]
IDeg vs IGlar in TIR
In the 41-week, randomized, crossover, open-label, multicentre, active-controlled SWITCH PRO trial, IDeg 100 U/mL demonstrated superiority to IGlar 100 U/mL in terms of TIR (3.9–10 mmol/L) in adults with T2DM (mean, 72.1 vs 70.7 percent; estimated treatment difference [ETD], 1.43 percent; 95 percent CI, 0.12–2.74; p=0.03). [Diabetes Obes Metab 2021;23:2572-2581]
An analysis of exploratory endpoints of SWITCH PRO showed that nocturnal time below range (TBR) was significantly lower with IDeg vs IGlar U100 for hypoglycaemia level 1 (3.0–3.8 mmol/L) (ETD, -0.59 percent; 95 percent CI, -0.89 to -0.29), level 2 (<3 mmol/L) (ETD, -0.29 percent; 95 percent CI, -0.54 to -0.04), and combined levels 1+2 (ETD, -0.88 percent; 95 percent CI, -1.34 to -0.42). [Diabetes Obes Metab 2021;23:2572-2581]
IDeg: A suitable option for most DM patients
With flexible administration timing, IDeg can be a suitable option for DM patients with difficulties injecting insulin at the same time each day. “This is a major advantage and not just for shift workers and people who travel a lot for work. If the patient, for example, wishes to sleep in one morning and take his/her insulin a few hours later in the morning, there is no loss of glycaemic control,” emphasized Leiter. [Expert Rev Endocrinol Metab 2012;7:9-14]
IDeg could also be an appropriate choice in the management of gestational DM. In the EXPECT study, IDeg was compared with insulin detemir (previously approved for use during pregnancy) in pregnant women with T1DM. The study found IDeg to be noninferior to insulin detemir in HbA1c control before delivery (p<0.0001), as well as demonstrating comparable pregnancy outcomes and safety profiles for both women with T1DM and their foetuses. [Lancet Diabetes Endocrinol 2023;11:86-95]
IDegAsp: Co-formulation with distinct basal and prandial effects
IDegAsp has distinct basal and prandial glucose-lowering properties. The insulin aspart (IAsp) component is rapidly absorbed into the bloodstream, providing quick glucose control. Meanwhile, the IDeg component delivers stable, long-lasting basal insulin coverage due to its flatter and more consistent pharmacodynamic profile, with a half-life of over 24 hours. [Diabetes Ther 2014;5:255-265]
The 26-week randomized BOOST CHINA trial evaluated the efficacy and safety of IDegAsp BID vs biphasic IAsp (BIAsp) 30 BID in 543 Chinese adults with T2DM. Results confirmed noninferiority of IDegAsp vs BIAsp for change in HbA1c from baseline to week 26 (ETD, -0.08 percent; 95 percent CI, -0.20 to 0.05; p<0.0001). Additionally, IDegAsp significantly lowered estimated rates of nocturnal-confirmed hypoglycaemic episodes by 47 percent (p=0.0056) and total confirmed hypoglycaemic episodes by 43 percent (p=0.0001) vs BIAsp 30. (Figure 2) [Diabetes Obes Metab 2019;21:1652-1660]
“Multiple studies comparing IDegAsp vs BIAsp showed similar glycaemic control, lower insulin doses, and less hypoglycaemia with IDegAsp,” said Leiter. [Diabetes Care 2014;37:2084-2090; J Diabetes 2016;8:720-728; Diabetes Res Clin Pract 2015;107:139-147; Diabetes Obes Metab 2019;21:1652-1660]
Summary
Hypoglycaemia remains a barrier to optimal glycaemic control. Longer-acting basal insulin analogues, such as IDeg and IDegAsp, which have longer half-life, less variability, and lower risk of hypoglycaemia, offer a flexible option to help DM patients achieve glycaemic targets.
