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Effective glycaemic control with co-formulation of basal and rapid-acting insulin

Dr. Man-Wo Tsang
Specialist in Endocrinology and Metabolism
Hong Kong
07 Oct 2020

Effective management of type 2 diabetes mellitus (T2DM) requires patients’ compliance with therapy. In patients who need treatment with basal and prandial insulin, compliance may be limited by the treatment burden and perceived risk of hypoglycaemia. A co-formulation of basal insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp) (ie, IDegAsp; Ryzodeg®, Novo Nordisk) has the advantages of a simple regimen with a low risk of hypoglycaemia. At an interview with MIMS Doctor, Dr Man-Wo Tsang, Specialist in Endocrinology and Metabolism in Hong Kong, discussed study findings supporting its use in T2DM management.

Unmet needs with insulin regimens

“In T2DM patients with secondary failure to oral antidiabetic drugs [OADs], early initiation of basal insulin therapy is recommended,” said Tsang. [J Endocrinol Invest 2008;31:371-379]

However, the use of basal insulin is limited by the gradual decline in â-cell function and reduction in insulin secretion in T2DM. Treatment with basal-plus or basal-bolus insulin regimens (basal insulin QD plus bolus insulin 1–≥3 times daily) or premixed insulin is thus required to provide postprandial glucose control in patients who do not achieve HbA1c target with basal insulin therapy. [Diabetologia 2012;55:1577-1596]

In a survey on insulin adherence behaviours and barriers that included 1,530 insulin-treated patients (T2DM, 88.2 percent), a considerable proportion reported difficulties in taking insulin at daily prescribed times (27.6 percent), difficulties with the number of daily injections (23.1 percent), and difficulties in adjusting insulin doses (16.8 percent). A majority (81.4 percent) of patients felt that insulin therapy should be flexible and should fit into their lives, and 54.4 percent expressed difficulties in living a normal life while managing diabetes. Furthermore, 72 percent of 1,250 primary care physicians surveyed reported that aggressive treatment for T2DM was limited by concerns about hypoglycaemia. [Diabet Med 2012;29:682-689]

“Patients’ fear of hypoglycaemic episodes has an impact on treatment adherence,” said Tsang. A survey (n=335; T2DM, 39.7 percent) showed that 57.5 percent and 43 percent of insulin-treated patients reduced their mean total daily insulin dose following a severe and nonsevere episode of hypoglycaemia, respectively. [Can J Diabetes 2005;29:186-192]

IDegAsp: Soluble co-formulation of basal & rapid-acting insulin

In the IDegAsp co-formulation, IDeg and IAsp exist as separate entities of soluble dihexamers and hexamers, respectively, in a 70:30 ratio at neutral pH. [Ther Adv Chronic Dis 2015;6:375-388] Following subcutaneous injection, IDeg dihexmers self-associate to form multihexamers, with IDeg monomers subsequently slowly released to provide stable basal insulin coverage. IAsp hexamers, on the other hand, undergo rapid dissociation into IAsp monomers to provide short-acting insulin coverage. [Pharm Res 2015;32:2250-2258]

Insulin glargine (IGlar) U100 tends to form micro-precipitates at neutral pH (7.4), whereas IAsp remains soluble at pH 7.4 in solution. Insulin detemir (IDet) tends to form mixed hexamers when mixed with IAsp in solution, resulting in unstable pharmacodynamic action of IAsp. Therefore, both IGlar U100 and IDet are not available in combination formulations. [Pharm Res 2012;29:2104-2114; Ther Adv Chronic Dis 2015;6:375-388; Diabetes Care 2012; 35: 690-692]

IDegAsp co-formulation provides insulin replacement that closely mimics endogenous insulin secretion, addressing limitations of traditional premixed insulin formulations that include variation in glycaemic control, presence of a ‘shoulder effect’ (ie, interference of the protaminated fraction with the soluble fraction, leading to an undesired and prolonged glucose-lowering effect, causing an overlap with the peak action of the protaminated fraction following a meal), as well as incomplete 24-hour coverage and the need of re-suspension due to protamination. [Ther Adv Chronic Dis 2015;6:375-388; Clin Pharmacokinet 2017;56:339-354]

Efficacy and safety

In a 38-week trial, 532 insulin-treated T2DM patients (with or without OAD treatment) with HbA1c of 7–10 percent were randomized (1:1) to receive IDegAsp QD or IGlar U100 QD plus IAsp QD. Intensification to IDegAsp BID (at weeks 26 and 32) or with additional IAsp injections at week 26 (maximum IAsp BID) or week 32 (maximum IAsp TDS) was allowed. [Diabetes Res Clin Pract 2019;147:157-165]

IDegAsp QD/BID was administered with the largest meal(s) each day at the discretion of each patient, whereas IGlar was dosed according to label. Intensification from IDegAsp QD to BID was performed by splitting the total daily dose into two doses, with dosage dependent on the size of each meal. Patients self-titrated insulin regimens to self-measured blood glucose (SMBG) targets of 4–5 mmol/L for IDegAsp and IGlar U100, and 4–6 mmol/L for IAsp.

At baseline, HbA1c and fasting plasma glucose (FPG) were 8.2 percent and 9.0 mmol/L for the IDegAsp group, vs 8.1 percent and 8.8 mmol/L for the IGlar U100 plus IAsp group.

A similar reduction in mean HbA1c was observed between patients on IDegAsp and those on IGlar QD plus IAsp QD during treatment initiation (weeks 0–26), confirming noninferiority of IDegAsp for the primary endpoint (-1.1 percent vs -1.1 percent; estimated treatment difference [ETD], 0.07 percent; 95 percent confidence interval [CI], -0.06 to 0.21). (Figure 1) HbA1c levels in both groups continued to decrease during weeks 26–38.


A comparable decrease in FPG was observed throughout the entire treatment period (weeks 0–38) with IDegAsp vs IGlar U100 plus IAsp (-2.7 mmol/L vs -2.3 mmol/L; ETD, -0.24; 95 percent CI, -0.60 to 0.13).

However, IDegAsp QD was associated with a significantly lower mean total insulin dose at weeks 0–26 vs IGlar U100 QD plus IAsp QD (70.9 U vs 79.4 U; odds ratio [OR], 0.88; 95 percent CI, 0.81 to 0.95). A significant difference in mean total insulin dose with IDegAsp vs IGlar U100 plus IAsp was maintained through 38 weeks (83.4 U vs 89.3 U; OR, 0.91; 95 percent CI, 0.83 to 0.99), with the difference being attributed to basal insulin dose (58.4 U vs 65.3 U).

In addition, rates of symptomatic blood glucose-confirmed nocturnal hypoglycaemia (<3.1 mmol/L at 00:01–05:59) per patient were significantly lower with IDegAsp vs IGlar U100 plus IAsp during weeks 0–26 (estimated rate ratio [RR], 0.55; 95 percent CI, 0.34 to 0.90) and throughout 38 weeks (estimated RR, 0.61; 95 percent CI, 0.40 to 0.93).

Efficacy and safety in Asians

In the 26-week BOOST trial, 296 insulin-naïve Japanese patients with T2DM were randomized (1:1) to receive IDegAsp QD or IGlar U100 QD. IDegAsp QD demonstrated a significant reduction in mean HbA1c from baseline vs IGlar U100 QD (7.0 percent vs 7.3 percent; ETD, -0.28 percent; 95 percent Cl, -0.46 to -0.10; p<0.01), without a significant increase in rate of nocturnal hypoglycaemia (estimated RR, 0.75; 95 percent CI, 0.34 to 1.64). [Diabetes Obes Metab 2013;15:826-832]

Clinical implications

“IDegAsp is recommended as an effective treatment option for glycaemic control for patients who require insulin treatment with a predictable action profile and coverage for postprandial surge, without an increased risk of hypoglycaemia or weight gain compared with a basal insulin–only regimen. These include young patients who need tight glycaemic control to prevent or delay T2DM complications, and elderly patients who need a well-tolerated treatment with a low risk of hypoglyacemia,” suggested Tsang.

Compared with basal-plus and basal-bolus insulin regimens, IDegAsp offers a simpler option for stepwise treatment intensification in a single device, with a reduced number of daily injections (1–2 injections vs 3–5 injections).

“Importantly, IDegAsp provides flexibility in injection timing to meet the needs of patients’ daily meal intake. It can be injected at any time of the day with the main meal [as long as injections are given at least 3–5 hours apart], making it particularly convenient for patients with irregular mealtimes and those who work in shifts.” [Ryzodeg Hong Kong Prescribing Information, January 2015]

“With these considerations, IDegAsp would be more convenient for GPs to handle than basal-bolus insulin regimens, with patients’ compliance ensured,” he explained.


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Elvira Manzano, 07 Oct 2020
Exendin-4 imaging targeting GLP-1* receptor (GLP-1R) ably detects residual, dysfunctional pancreatic beta cells in individuals with long-standing type 1 diabetes (T1D), according to a study presented at EASD 2020. This breakthrough brings research closer to the possibility of restoring insulin-producing cells depleted in T1D.