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Original paper: Efficacy and safety analysis of insulin degludec/insulin aspart compared with biphasic insulin aspart 30: A phase 3, multicentre, international, open-label, randomised, treat-to-target trial in patients with type 2 diabetes fasting during Ramadan
Internal Medicine Department, Head Division of Endocrinology, Rafic Hariri University Hospital, Bir Hassan, Jinah, POB: 5244, 2833-7401, Beirut, Lebanon
IDegAsp had similar glycaemic efficacy to BIAsp 30 before, during and after Ramadan.
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During Ramadan, IDegAsp achieved significantly lower pre-iftar SMPG vs BIAsp 30.
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IDegAsp caused significantly less overall and nocturnal hypoglycaemia vs BIAsp 30.
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During Ramadan, IDegAsp had significantly less daytime hypoglycaemia vs BIAsp 30.
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IDegAsp and BIAsp 30 are suitable for patients on insulin who choose to fast.
Abstract
Aims
To compare the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) and biphasic insulin aspart 30 (BIAsp 30) before, during and after Ramadan in patients with type 2 diabetes mellitus (T2DM) who fasted during Ramadan.
Methods
In this multinational, randomised, treat-to-target trial, patients with T2DM who intended to fast and were on basal, pre- or self-mixed insulin ± oral antidiabetic drugs for ≥90 days were randomised (1:1) to IDegAsp twice daily (BID) or BIAsp 30 BID. Treatment period included pre-Ramadan treatment initiation (with insulin titration for 8–20 weeks), Ramadan (4 weeks) and post-Ramadan (4 weeks). Insulin doses were reduced by 30–50% for the pre-dawn meal (suhur) on the first day of Ramadan, and readjusted to the pre-Ramadan levels at the end of Ramadan. Hypoglycaemia was analysed as overall (severe or plasma glucose <3.1 mmol/L [56 mg/dL]), nocturnal (00:01–05:59) or severe (requiring assistance of another person).
Results
During the treatment period, IDegAsp (n = 131) had significantly lower overall and nocturnal hypoglycaemia rates with similar glycaemic efficacy, versus BIAsp 30 (n = 132). During Ramadan, despite achieving significantly lower pre-iftar (meal at sunset) self-measured plasma glucose (estimated treatment difference: −0.54 mmol/L [−1.02; −0.07]95% CI, p = .0247; post hoc) with similar overall glycaemic efficacy, IDegAsp showed significantly lower overall and nocturnal hypoglycaemia rates versus BIAsp 30.
Conclusions
IDegAsp is a suitable therapeutic agent for patients who need insulin for sustained glucose control before, during and after Ramadan fasting, with a significantly lower risk of hypoglycaemia, versus BIAsp 30, an existing premixed insulin analogue.
]. Ramadan is the ninth month of the Islamic calendar, and fasting (total abstinence from food or drink) from dawn to sunset during Ramadan month constitutes one of the five pillars (religious obligations) of Islam. Depending on the exact time of the year in which Ramadan takes place, and the geographic location, each period of fasting may last up to 20 h [
]. In the Middle East and Asia, regions which are home to large Muslim populations, high-carbohydrate foods, including rice and bread, are popular daily meals [
]. The daily Ramadan fast starts after the pre-dawn meal – suhur, which is normally a small meal, and is concluded with a meal at sunset (iftar), which often includes a large amount of high-carbohydrate foods [
]. In addition, at the end of Ramadan, there is a 3-day festival – Eid ul-Fitr, during which, overindulgence in food consumption is common even among patients with diabetes [
Fasting during Ramadan is associated with an increased risk of dehydration and hypoglycaemia. The consumption of high-carbohydrate meals during Ramadan puts patients with diabetes at high risk of post-prandial hyperglycaemia, diabetic ketoacidosis and thrombosis. The International Diabetes Federation-Diabetes and Ramadan (IDF-DAR) Practical Guidelines categorise people with diabetes into three risk groups – very high risk, high risk and moderate/low risk [
]. Patients with very high or high risk include those with type 2 diabetes mellitus (T2DM) treated with premixed insulin or multiple daily insulin injections. These patients are advised by the medical and religious authorities not to fast during Ramadan [
]. Nevertheless, according to the EPIDIAR and CREED studies, a large proportion of patients with type 1 diabetes mellitus (T1DM) and T2DM, irrespective of knowing their risk of diabetic complications, choose to fast during Ramadan [
]. Therefore, medical guidance for these patients needs to be emphasised, especially when they are treated with insulin.
Insulin treatment carries an increased risk of hypoglycaemia in patients fasting during Ramadan, compared with those who are not fasting, hence the inclusion of these patients in the IDF-DAR Practical Guidelines high-risk category [
] – therefore the use of insulin analogues during Ramadan fasting is recommended.
Because of these risks associated with insulin treatment during Ramadan fasting, only a small number of trials have been performed on patients fasting during Ramadan. Eight trials (three randomised, five observational) in patients with T2DM [
The Ramadan study G. Effect of a new insulin treatment regimen on glycaemic control and quality of life of Muslim patients with type 2 diabetes mellitus during Ramadan fast – an open label, controlled, multicentre, cluster randomised study.
A multicenter, prospective, non-interventional evaluation of efficacy and safety of using biphasic insulin aspart as monotherapy, or in combination with oral hypoglycemic agent, in the treatment of type 2 diabetic patients before, during, & after Ramadan.
] have been conducted to assess various insulin regimens during Ramadan. However, conclusions from these trials are limited by the lack of statistically significant results. Thus, data from large randomised controlled trials in this area are still lacking [
], and there is a need for more evidence-based guidance on the use of insulin, in conjunction with dietary advice, as part of diabetes management during Ramadan.
Diabetes treatments that target post-prandial hyperglycaemia, such as premixed insulins, are widely used in the Middle East and Asia [
Management and control of patients with type 2 diabetes mellitus in Lebanon: results from the International Diabetes Management Practices Study (IDMPS).
], because of their simplicity of use. Biphasic insulin aspart 30 (BIAsp 30; NovoMix®30) is a mixture of 30% soluble (rapid-acting) and 70% protaminated (intermediate-acting) IAsp, which is indicated for the treatment of diabetes as monotherapy or in combination with oral antidiabetic drugs (OADs) [
]. Insulin degludec/insulin aspart (IDegAsp; Ryzodeg® 70/30) is a novel, soluble co-formulation of 70% insulin degludec (IDeg) and 30% insulin aspart (IAsp) in a single injection. By adding IAsp to IDeg, the benefits of the flat pharmacokinetic profile and long duration of action of IDeg and the rapid onset of IAsp are combined, leading to the biphasic basal/prandial profile observed with IDegAsp, without the undesirable shoulder effect observed as a result of the interaction between the soluble and protaminated molecules in premixed combinations [
Comparison of insulin degludec/insulin aspart and biphasic insulin aspart 30 in uncontrolled, insulin-treated type 2 diabetes: a phase 3a, randomized, treat-to-target trial.
]. During Ramadan, treatment with IDegAsp twice daily (BID) is expected to cover the basal insulin requirements (through the ultra-long acting IDeg component) and provide prandial insulin coverage (through IAsp) for the meals following iftar and before suhur. IDegAsp has been extensively investigated in a large clinical trial programme (BOOST), which included trials comparing IDegAsp and BIAsp 30 in insulin-naïve and previously treated patients with T2DM [
Comparison of insulin degludec/insulin aspart and biphasic insulin aspart 30 in uncontrolled, insulin-treated type 2 diabetes: a phase 3a, randomized, treat-to-target trial.
Insulin degludec/insulin aspart versus biphasic insulin aspart 30 in Asian patients with type 2 diabetes inadequately controlled on basal or pre-/self-mixed insulin: a 26-week, randomised, treat-to-target trial.
]. In these studies, IDegAsp was non-inferior in HbA1c efficacy, with significantly lower rates of overall and nocturnal hypoglycaemia, compared with BIAsp 30 [
Comparison of insulin degludec/insulin aspart and biphasic insulin aspart 30 in uncontrolled, insulin-treated type 2 diabetes: a phase 3a, randomized, treat-to-target trial.
Insulin degludec/insulin aspart versus biphasic insulin aspart 30 in Asian patients with type 2 diabetes inadequately controlled on basal or pre-/self-mixed insulin: a 26-week, randomised, treat-to-target trial.
This international, multicentre, open-label, randomised, treat-to-target trial aimed to compare the efficacy and safety of IDegAsp with BIAsp 30 before, during and after Ramadan in patients with T2DM who fasted during Ramadan in Algeria, India, Lebanon, Malaysia and South Africa. These countries represent diverse geographical locations covering Africa, Middle East and Asia, with patients fasting for periods of between 12 and 16 h daily during Ramadan.
2. Materials and methods
2.1 Trial design
This phase 3, open-label, randomised, treat-to-target clinical trial was conducted before, during and after Ramadan in patients with T2DM (Fig. 1), across 27 sites in Algeria, India, Lebanon, Malaysia and South Africa from 4 January 2016 to 5 September 2016, with Ramadan taking place between 6 June 2016 and 5 July 2016.
The total trial duration was between 22 and 34 weeks and patients exposure to trial drugs was between 16 and 28 weeks (Fig. 1). After a 2-week screening period, treatment initiation with IDegAsp BID ± OADs or BIAsp BID ± OADs for a period of between 8 and 20 weeks was instituted, depending on how long before Ramadan patients were randomised (minimum 8-week treatment initiation period to ensure adequate time to titrate the trial products effectively before the start of Ramadan). On the first day of Ramadan, the insulin doses were reduced by 30–50% at suhur, based on an algorithm described in detail below. At the end of the 4-week Ramadan period, the doses were readjusted to the pre-Ramadan levels and the patients were observed for another 4 weeks (post-Ramadan period) to evaluate the durability of the glycaemic control during the post-Ramadan feast (Eid ul-Fitr celebration).
The study was conducted according to the Declaration of Helsinki and its amendments [
]. Prior to trial initiation, the protocol, written informed consent and patient information sheet were reviewed and approved according to local regulations by appropriate health authorities, and by an independent ethics committee/institutional review boards.
2.2 Study population
This trial included adult patients (≥18 years in India, Lebanon, Malaysia and South Africa, ≥19 years in Algeria) with T2DM, treated with any basal, pre- or self-mixed insulin ± OADs for ≥90 days (OADs included metformin, sulphonylureas, glinides, dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, sodium-glucose co-transporter-2 inhibitors), with HbA1c levels between 7.0 and 10.0% [53–86 mmol/mol] and body mass index (BMI) ≤45.0 kg/m2. Patients had expressed their intention to fast during Ramadan – irrespective of medical advice, and their willingness to undergo blood tests during Ramadan. The main exclusion criteria were hypersensitivity to trial products and high probability of an unsuccessful fasting from a medical perspective. The inclusion and exclusion criteria selected for this trial allowed for inclusion of a broad spectrum of patients, which was to ensure the relevance of the trial results to the diverse population of patients with T2DM, who fast during Ramadan.
2.3 Interventions
Patients were randomised using an interactive response system with an allocation ratio of 1:1 to IDegAsp (100 units/mL solution, FlexTouch® 3-mL pre-filled pen, Novo Nordisk A/S, Denmark) ± OADs or BIAsp 30 (100 units/mL suspension, FlexPen®, 3-mL pre-filled pen, Novo Nordisk A/S) ± OADs, both administered BID via subcutaneous injection prior to the two main meals. Differences in the insulin pens and the physical properties of the insulins (IDegAsp: clear solution [
A structured titration algorithm (Table 1) was established to optimise glycaemic control throughout the treatment period and to ensure the safety of patients. The starting dose of IDegAsp or BIAsp 30 was converted (unit to unit) from the patient’s previous insulin dose, with no minimum or maximum dose, as per the product labels. To reduce the risk of hypoglycaemia during Ramadan fasting, the following insulin dose modification (Table S1), based on the IDF-DAR Practical Guidelines, was recommended at the beginning of Ramadan [
]: option 1: the recent breakfast/lunch dose should be reduced by 30–50% and taken at suhur; the iftar dose is left unchanged, i.e. the same dose as at the latest evening meal; option 2: the recent evening dose should be reduced by 30–50% and taken at suhur; the recent breakfast/lunch dose should be taken with iftar. At the end of Ramadan, the following dose adjustment was recommended: the breakfast/lunch dose should be changed to the breakfast/lunch dose taken prior to Ramadan, and the evening meal dose should be changed to the evening meal dose prior to Ramadan.
Table 1Titration algorithm for both IDegAsp and BIAsp 30 arms.
Parameter
Titration algorithm
PG titration target
4.0–5.0 mmol/L before and after Ramadan; 5.0–7.0 mmol/L during Ramadan
Titration frequency
Twice weekly
Dose adjustment
+2/−2 units if not on target based on the lowest pre-suhur or pre-iftar SMPG readings during Ramadan and the lowest fasting or pre-main evening meal SMPG readings before and after Ramadan
To compare the efficacy and safety of IDegAsp with BIAsp 30 before, during and after Ramadan in patients with T2DM who participated in Ramadan fasting, various efficacy and safety endpoints were investigated. The efficacy endpoints were change in HbA1c and fructosamine levels from baseline to the end of Ramadan (12–24 weeks) and from baseline to the end of post Ramadan (16–28 weeks), HbA1c responders (<7% [53.0 mmol/mol]) and 8-point SMPG profile at the end of Ramadan and post Ramadan. The safety endpoints included numbers of overall symptomatic, nocturnal symptomatic and severe (post hoc) hypoglycaemic episodes from baseline to end of Ramadan, and 4 weeks post-Ramadan. Insulin doses and adverse events during the trial were also analysed.
Overall symptomatic hypoglycaemia was defined as severe or blood glucose (BG)-confirmed (confirmed as plasma glucose [PG] <3.1 mmol/L [56 mg/dL]) episodes accompanied by typical symptoms of hypoglycaemia. Nocturnal symptomatic hypoglycaemia was defined as severe or BG-confirmed (PG < 3.1 mmol/L [56 mg/dL]) symptomatic episodes occurring between 00:01 and 05:59, both inclusive. Severe hypoglycaemia was defined as those episodes requiring assistance of another person. Daytime symptomatic hypoglycaemia was defined as severe or BG-confirmed (PG < 3.1 mmol/L [56 mg/dL]) symptomatic episodes occurring from 2 h post-suhur to pre-iftar (post hoc).
2.5 Statistical analysis
Analysis of all endpoints was based on the full analysis set (FAS; all randomised patients) following the intention-to-treat (ITT) principle. All efficacy endpoints were summarised for the FAS, and safety endpoints were summarised for the safety analysis set (SAS; patients receiving at least one dose of investigational product or comparator). Number of patients needed to evaluate the primary objective (to compare the efficacy of IDegAsp BID and BIAsp 30 BID in controlling glycaemia from baseline to the end of Ramadan) was 250, assuming that the standard deviation in HbA1c levels at end of Ramadan was 1.3.
Change from baseline to end of Ramadan and 4 weeks post-Ramadan in HbA1c, fructosamine and SMPG levels were analysed using a mixed model for repeated measurements (MMRM) with an unstructured covariance matrix. The model included treatment, sex, region, previous OAD treatment, pre-Ramadan trial exposure and visit as factors, and age and the baseline value of the endpoint as covariates. Interactions between visit and all other factors and covariates were included in the model. A post hoc analysis was conducted to investigate change from baseline to end of Ramadan in the mean pre-iftar SMPG values between IDegAsp BID and BIAsp 30 BID using the same model.
The analysis of the HbA1c responders was based on a logistic regression model with treatment, region, pre-Ramadan trial exposure, antidiabetic treatment and sex as factors, and age and HbA1c at baseline as covariates. Missing values were imputed from the MMRM model of HbA1c.
The rate of hypoglycaemic episodes was analysed using a negative binomial model with a log-link function and the logarithm of the time period, in which a hypoglycaemic episode is considered treatment emergent as offset. The model included treatment, region and sex as fixed factors and age as covariate. Additionally, a post hoc analysis was performed to investigate the rate of daytime and overall symptomatic hypoglycaemic episodes between the IDegAsp BID and BIAsp 30 BID arms during the 4-week Ramadan period using the same model.
3. Results
3.1 Trial patients
Of the 468 patients screened, 263 were randomised to either IDegAsp (n = 131) or BIAsp 30 (n = 132). Fifteen patients withdrew from the trial, which resulted in 248 completers (121 completers in the IDegAsp arm and 127 completers in the BIAsp 30 arm, Fig. S1). Demographics and baseline characteristics were similar between the two treatment arms, apart from a difference in the percentage of male/female participants (Table 2). The number of patients who did not stop fasting even for a day was 86 (71%) in the IDegAsp arm and 80 (65%) in the BIAsp 30 arm, respectively.
Table 2Baseline characteristics.
Characteristic
IDegAsp BID
BIAsp 30 BID
Full analysis set
131
132
Female/male, %
51.1/48.9
60.6/39.4
Race: Asian/Other/White, %
58.8/6.1/35.1
59.8/6.1/34.1
Age, years
54.9 (±9.8)
55.3 (±9.2)
Weight, kg [lb]
81.1 (±15.9) [178.8 (±35.0)]
77.3 (±13.2) [170.4 (±29.2)]
BMI, kg/m2
30.2 (±4.7)
29.8 (±4.7)
Duration of diabetes, years
12.1 (±6.8)
12.3 (±7.4)
HbA1c, % [mmol/mol]
8.5 (±0.9) [69.1 (±9.4)]
8.5 (±0.9) [69.2 (±9.6)]
FPG, mmol/L [mg/dL]
9.9 (±10.4) [177.9 (±187.5)]
10.6 (±16.3) [191.8 (±294.3)]
OAD treatment at screening, n (%)
No OAD OAD Pre-mix/self-mix Basal Bolus
9 (6.9) 122 (93.1) 80 (61.1) 48 (36.6) 3 (2.3)
9 (6.8) 123 (93.2) 78 (59.1) 50 (37.9) 4 (3.0)
Data are from full analysis set; values are mean (±SD) unless otherwise stated.
BIAsp 30, biphasic insulin aspart 30; BID, twice daily; BMI, body mass index; FPG, fasting plasma glucose; IDegAsp, insulin degludec/insulin aspart; OAD, oral antidiabetic drug; SD, standard deviation.
Glycaemic control was maintained in both treatment arms over the whole treatment period, despite the reduction in insulin doses during Ramadan (Fig. S2). The mean HbA1c values fell from 8.5% at baseline to 7.4% at end of Ramadan and to 7.5% at the end of 4 weeks post-Ramadan in both treatment arms, with almost all of the reduction occurring during the pre-Ramadan period. There was no significant difference between IDegAsp and BIAsp 30 arms in terms of HbA1c reduction from baseline to end of Ramadan (estimated treatment difference [ETD]: 0.02%; [−0.20; 0.24]95% CI, p = .8426), or end of 4 weeks post-Ramadan (ETD: 0.03%; [−0.20; 0.26]95% CI, p = .8121). Similarly, there was no significant difference between IDegAsp and BIAsp 30 arms in terms of the change of fructosamine levels from baseline to end of Ramadan (p = .9382) or end of 4 weeks post-Ramadan (p = .8893; Fig. S3).
There was no significant difference between the treatment arms in the HbA1c responder endpoint, with an estimated odds ratio (OR) of 0.91 [0.52; 1.60]95% CI, p = .7433 at the end of Ramadan, and OR: 0.87 [0.49; 1.55]95% CI, p = .6460 at the end of post-Ramadan. By the end of the post-Ramadan period, 40 patients with an average HbA1c of 8.3% at baseline with a longer titration period before Ramadan (16–20 weeks) achieved an average HbA1c of 7.1% (1.2% reduction from baseline), whereas 208 patients with a titration period of 8–15 weeks pre-Ramadan achieved an average HbA1c levels of 7.6% (0.9% reduction from baseline; Fig. S4).
The 8-point SMPG profiles were similar for both treatment arms at baseline (Fig. S5). There was no significant difference between treatment arms in the change from baseline to the end of Ramadan in mean 8-point SMPG profile (ETD: −0.30 mmol/L [−0.67; 0.08]95%CI, p = .1237), and to the end of post Ramadan (ETD: −0.12 mmol/L [−0.53; 0.30]95%CI, p = .5800). During the 4-week Ramadan period, the mean pre-iftar SMPG values were significantly lower in the IDegAsp arm compared with the BIAsp 30 arm (ETD: −0.54 mmol/L; [−1.02; −0.07]95% CI, p = .0247).
3.3 Insulin dose
The lowest SMPG value for dose adjustment was similar for both treatment arms before breakfast (during Ramadan, suhur) and before the main evening meal (during Ramadan, iftar) throughout the whole treatment period (Fig. S6). For both treatment arms, the mean total daily doses gradually rose during the titration period, and, as per the protocol, decreased at the start of Ramadan (30–50% reduction of the latest pre-Ramadan breakfast/lunch or evening dose), and increased to the pre-Ramadan level immediately after Ramadan (Fig. 2). Based on the IDF-DAR recommendation, a less demanding PG titration target was used during Ramadan, compared with those used during pre-Ramadan (5.0–7.0 mmol/L [90–126 mg/dL]). At the end of Ramadan, the titration target reverted to pre-Ramadan levels. The insulin dose (U/kg) ratio (IDegAsp versus BIAsp 30) after 4-weeks post-Ramadan was 0.99.
Fig. 2a. Total daily actual insulin dose, b. insulin dose at breakfast/lunch (suhur) and, c. insulin dose at dinner (iftar) from baseline to end of post-Ramadan. Data are from safety analysis set. BIAsp 30, biphasic insulin aspart 30; BID, twice daily; IDegAsp, insulin degludec/insulin aspart; U, units.
The rate of overall hypoglycaemia throughout the treatment period was statistically significantly lower in the IDegAsp arm compared with in the BIAsp 30 arm, estimated rate ratio (ERR) 0.26 [0.16; 0.44]95%CI, p < .0001, therefore a 74% reduction in the rate of overall hypoglycaemia (Fig. 3, Table S2). During the same period, the rate of nocturnal hypoglycaemia was also statistically significantly lower in the IDegAsp arm compared with the BIAsp 30 arm (ERR 0.17 [0.08; 0.38]95%CI, p < .0001), translated into an 83% reduction in the rate of nocturnal hypoglycaemia in patients receiving IDegAsp. The rate of severe hypoglycaemia was 44% lower, in the IDegAsp arm compared with in the BIAsp 30 arm (ERR 0.56 [0.07; 4.36]95%CI, p = .5801; Fig. 3, Table S2).
Fig. 3Hypoglycaemia rate ratios of the IDegAsp arm compared with the BIAsp 30 arm during the 16- to 28-week treatment period and 4-week Ramadan period. Data are from full analysis set. Overall symptomatic hypoglycaemia: severe or BG-confirmed (<3.1 mmol/L [56 mg/dL]) episodes accompanied by typical symptoms of hypoglycaemia; Nocturnal symptomatic hypoglycaemia: severe or BG-confirmed (<3.1 mmol/L [56 mg/dL]) symptomatic episodes occurring between 00:01 and 05:59, both inclusive; Severe hypoglycaemia: episodes requiring third-party assistance, and confirmed by a blinded adjudication committee; Daytime symptomatic hypoglycaemia: severe or BG-confirmed (<3.1 mmol/L [56 mg/dL]) symptomatic episodes occurring from 2 h post-suhur to pre-iftar (post hoc). BG, blood glucose; BIAsp 30, biphasic insulin aspart 30; CI, confidence interval; ERR, estimated rate ratio; IDegAsp, insulin degludec/insulin aspart. Republished with permission of Springer-Verlag from Efficacy and safety of insulin degludec/insulin aspart vs biphasic insulin aspart 30: an international randomised trial in adults with type 2 diabetes fasting during Ramadan, Hassanein M et al., 60, abst 159, 2017; permission conveyed through Copyright Clearance Center, Inc.
During the Ramadan period, a statistically significantly lower rate of overall hypoglycaemia (62% reduction) was observed in the IDegAsp arm compared with the BIAsp 30 arm (ERR 0.38 [0.19; 0.77]95%CI, p = .0070; Fig. 3, Table S2). During the same period, patients in the IDegAsp arm had a statistically significantly lower rate of nocturnal hypoglycaemia (ERR 0.26; [0.08; 0.88]95% CI, p = .0304) and daytime hypoglycaemia (ERR 0.44; [0.21; 0.94]95%CI, p = .0327) compared with those in the BIAsp 30 arm (Fig. 3, Table S2), achieving 74 and 56% reductions in rates of nocturnal and daytime hypoglycaemia, respectively.
3.5 Adverse events
A total of 471 adverse events (AEs) occurred during the trial in 170 patients (65%). There were 271 AEs occurring in 88 (67.7%) patients in the IDegAsp arm and 200 events occurring in 82 (62.1%) patients in the BIAsp 30 arm (Table S3). There were nine serious AEs in five patients in the IDegAsp arm and nine serious AEs in three patients in the BIAsp 30 arm. One treatment emergent death in the IDegAsp arm was reported, but the cause of death was undetermined and deemed not related to the treatment, adjudicated by the external review committee. No new safety issues were identified.
4. Discussion
This is the largest randomised controlled trial to compare the efficacy and safety of two insulin analogues in patients with T2DM who have a high risk of developing hypoglycaemia and hyperglycaemia, in the period before, during and after Ramadan fasting.
As would be expected in a treat-to-target trial, both treatments had similar overall effects on glycaemic control. The changes in HbA1c observed during this study are consistent with the findings of two previous phase 3a trials in insulin-treated patients with T2DM (BOOST: INTENSIFY PREMIX [
Comparison of insulin degludec/insulin aspart and biphasic insulin aspart 30 in uncontrolled, insulin-treated type 2 diabetes: a phase 3a, randomized, treat-to-target trial.
Insulin degludec/insulin aspart versus biphasic insulin aspart 30 in Asian patients with type 2 diabetes inadequately controlled on basal or pre-/self-mixed insulin: a 26-week, randomised, treat-to-target trial.
]) comparing IDegAsp BID with BIAsp 30 BID. The data indicate that glycaemic control was maintained in both treatment arms across the whole study period and during the 4-week Ramadan fasting, despite the reduction in the insulin dose at the start of Ramadan. During Eid ul-Fitr, a 3-day festival celebrated at the end of Ramadan, patients are at high risk of developing hyperglycaemia and acute diabetic complications that are associated with the overindulgence in food consumption [
]. In this study, the glycaemic control was maintained after Ramadan by adjusting the insulin doses and titration target to the pre-Ramadan levels. These findings suggest IDegAsp BID may be an effective treatment regimen for glycaemic control in patients who intend to fast during Ramadan.
In this trial, patients with a titration duration of between 16 and 20 weeks achieved greater HbA1c reductions (reaching and maintaining the ADA HbA1c target during and after Ramadan), than those with a titration duration of between 8 and 15 weeks. This reinforces the importance of avoiding treatment inertia and optimising treatment regimen, as well as educating patients who have expressed a desire to fast on the potential risks of fasting, and the benefits of beginning preparation well in advance of Ramadan.
The insulin dose was reduced at the beginning of Ramadan, and reverted to the pre-Ramadan dose at the end of Ramadan, in accordance with the IDF-DAR Practical Guidelines [
]. This trial is the first where this recommended dose adjustment has been studied in a controlled manner. The structured dose adjustment and SMPG-guided titration in the trial design provides patients with a simple dose titration algorithm, which fits with current treatment guidelines [
]. The results of this trial support the use of the dose adjustment and titration algorithm from both the efficacy and safety perspectives.
In this study, hypoglycaemic episodes with PG less than 3.1 mmol/L (56 mg/dL) were recorded. This is in line with the recent recommendation made by the International Hypoglycaemia Study Group whereby hypoglycaemic episodes with PG less than 3.0 mmol/L (54 mg/dL), should be considered clinically significant and included in reports involving clinical trials of diabetes treatments [
International hypoglycaemia study group. Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care; 2016.
]. In addition to the reduction in rates of hypoglycaemia in this study, the proportion of patients experiencing hypoglycaemia was also reduced with IDegAsp use compared to BIAsp. The significantly lower rates of overall and nocturnal symptomatic hypoglycaemia in the IDegAsp BID arm compared with the BIAsp 30 arm during the whole study period and the 4-week Ramadan period were comparable to the findings from the meta-analysis of BOOST: INTENSIFY PREMIX and ALL [
Lower rates of hypoglycemia during maintenance treatment with insulin degludec/insulin aspart versus biphasic insulin aspart 30: a combined analysis of two phase 3a studies in type 2 diabetes.
]. Whilst there was a numerically lower rate of severe hypoglycaemia in the IDegAsp BID arm during the whole study period, this difference was not statistically significant as a result of the low number of cases in both treatment arms. With significantly lower pre-iftar SMPG and a lower rate of daytime hypoglycaemia, IDegAsp BID, compared with BIAsp 30 BID, may potentially be a better treatment option in those patients with a high risk of developing hyperglycaemia and hypoglycaemia who choose to fast during Ramadan.
Patients with longer duration of preparation (titration) prior to Ramadan achieved better glycaemic control during Ramadan fasting. The results of this trial might also be extrapolated to Muslim patients with T2DM who perform intermittent fasting outside of Ramadan, as well as patients with T2DM, independent of their faith, who choose to fast.
Results from this clinical trial in patients with T2DM who fasted during Ramadan provide guidance for the management of patients who are at high risk of hypoglycaemia, hyperglycaemia and other diabetes-related complications during fasting. As demonstrated by the results of this trial, at least 4-month preparation prior to Ramadan fasting may be beneficial. A structured titration – PG target of between 4.0 and 5.0 mmol/L before and after Ramadan, and between 5.0 and 7.0 mmol/L during Ramadan – is recommended, allowing patients to adapt to the lifestyle changes before, during and after Ramadan. On the first day of Ramadan, the recent breakfast/lunch or evening dose is recommended to be reduced by 30–50% and taken at suhur, with the dose at iftar being left unchanged. These doses are recommended to be reverted to the pre-Ramadan dose at the end of Ramadan.
This trial has some limitations. Firstly, the open-label design may result in treatment bias, as the two treatment arms could not be blinded, because IDegAsp is a clear solution [
]. Secondly, whilst the populations involved ensure a range of daily fasting periods, this trial did not include a patient population with a fasting period greater than 20 h per day.
In conclusion, compared with BIAsp 30 BID, IDegAsp BID had similar glycaemic control, which was maintained before, during and after Ramadan, despite the dose reductions at the beginning of Ramadan. IDegAsp BID was associated with significantly lower rates of overall and nocturnal symptomatic hypoglycaemia during the 28-week treatment period and the 4-week Ramadan period. Despite significantly lower pre-iftar SMPG values, IDegAsp was associated with a significantly lower rate of daytime hypoglycaemia compared with BIAsp 30. The results of this trial indicate the viability of IDegAsp BID as a therapeutic modality for patients on insulin who choose to fast during Ramadan.
Acknowledgments
Medical writing and submission support were provided by Jin Heppell and Germanicus Hansa-Wilkinson of Watermeadow Medical, an Ashfield company, part of UDG Healthcare plc, funded by Novo Nordisk. We thank Edmond Gabriel Fita (Novo Nordisk) for his review and input to the manuscript.
Funding
This trial (ClinicalTrials.gov number: NCT02648217) and the secondary analysis were funded by Novo Nordisk A/S.
Declaration of interest
MH has received honoraria for presentation from Novo Nordisk, Eli Lilly, Sanofi, Novartis and MSD. ASE has been a speaker for Novo Nordisk, Sanofi, AstraZeneca, MSD, Lilly, Boehringer, Merck, and Novartis; and a Principal Investigator in clinical trials for Novo Nordisk, MSD, Sanofi, Boehringer, Astra Zeneca, Merck and Novartis. RM has served as an advisory group member/scientific board member for Novo Nordisk. MO has received honoraria as an advisory board member and speakers’ bureau member for Novo Nordisk. SSS has no conflict of interest. ME and KK are employees of Novo Nordisk and NAK has received honoraria and research funding as an advisory group member and study investigator for Novo Nordisk.
Contributor statements
All authors had full access to all of the study data and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors had final responsibility for the decision to submit for publication. Individual contributions were as follows:
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Study concept and design: MH, ME, KK.
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Acquisition, analysis, or interpretation of data: MH, ME, KK.
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Writing and review of manuscript: MH, ASE, RM, MO, SSS, ME, KK, NZK.
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