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Safety of lixisenatide plus basal insulin treatment regimen in Indian people with type 2 diabetes mellitus during Ramadan fast: A post hoc analysis of the LixiRam randomized trial

Open AccessPublished:April 14, 2020DOI:https://doi.org/10.1016/j.diabres.2020.108148

      Abstract

      Aims

      Hypoglycemia is one of the most important complications associated with Ramadan fasting in people with type 2 diabetes. LixiRam (NCT02941367) was the first randomized trial comparing safety and efficacy of lixisenatide + basal insulin (BI) vs. sulphonylurea + BI in people with type 2 diabetes who fast during Ramadan. This post hoc analysis focuses on the LixiRam study population from India.

      Methods

      Adults with type 2 diabetes insufficiently controlled with sulphonylurea + BI ± another oral anti-hyperglycemic drug were randomized 1:1 to receive lixisenatide + BI or to continue sulphonylurea + BI treatment.

      Results

      In total, 150 participants were randomized in India. One participant (1.3%) with lixisenatide + BI vs. 5 participants (6.8%) with sulphonylurea + BI experienced ≥1 documented symptomatic hypoglycemic event during the Ramadan fast (odds ratio [OR]: 0.22; 95% confidence interval [CI]: 0.02–1.93). Incidence of any hypoglycemia was numerically lower with lixisenatide + BI vs. sulphonylurea + BI during Ramadan fasting (1.3% [1/75] vs. 14.7% [11/75], respectively; OR: 0.09; 95% CI: 0.01–0.69). No new safety signals were identified.

      Conclusions

      A combination of lixisenatide prandial GLP1-RA + BI may be a suitable treatment option for people with type 2 diabetes who elect to fast during Ramadan.
      Clinical Trial Registry: clinicaltrials.gov (NCT02941367).

      Keywords

      1. Introduction

      Fasting during the holy month of Ramadan is 1 of the 5 pillars of Islam. The timings of Ramadan are based on the lunar calendar and last for 29–30 days per year, during which time the intake of food and fluids is only permitted between sunset and dawn [

      International Diabetes Federation. Diabetes and Ramadan: Practical guidelines. 2016. https://www.idf.org/component/attachments/attachments.html?id=733&task=download [Accessed 11 January 2020].

      ]. Despite being exempt from fasting, many people with type 2 diabetes who are categorized as high-risk according to the International Diabetes Federation (IDF) and Diabetes and Ramadan (DAR) International Alliance guidelines [

      International Diabetes Federation. Diabetes and Ramadan: Practical guidelines. 2016. https://www.idf.org/component/attachments/attachments.html?id=733&task=download [Accessed 11 January 2020].

      ] choose to observe the Ramadan fast. In DAR-MENA, a prospective, observational study in participants with type 2 diabetes who fast during Ramadan in the Middle East and North America, 57.3% (943/1645) of participants fasted for the full 30-day duration of the 2016 Ramadan period [
      • Hassanein M.
      • Al Awadi F.F.
      • El Hadidy K.E.S.
      • Ali S.S.
      • Echtay A.
      • Djaballah K.
      • et al.
      The characteristics and pattern of care for the type 2 diabetes mellitus population in the MENA region during Ramadan: an international prospective study (DAR-MENA T2DM).
      ]. The majority of participants reported personal decisions (80.4%) as their reason to fast, whilst other reasons cited included coping with family and the community (23.5%), improving health (9.3%) or enhancing self-discipline (8.7%) as their motivating factor [
      • Hassanein M.
      • Al Awadi F.F.
      • El Hadidy K.E.S.
      • Ali S.S.
      • Echtay A.
      • Djaballah K.
      • et al.
      The characteristics and pattern of care for the type 2 diabetes mellitus population in the MENA region during Ramadan: an international prospective study (DAR-MENA T2DM).
      ].
      People with type 2 diabetes who fast during Ramadan are at an increased risk for hypoglycemia, dehydration, thrombosis and abnormalities in blood glucose stability [

      International Diabetes Federation. Diabetes and Ramadan: Practical guidelines. 2016. https://www.idf.org/component/attachments/attachments.html?id=733&task=download [Accessed 11 January 2020].

      ,
      • Hassanein M.
      • Al Awadi F.F.
      • El Hadidy K.E.S.
      • Ali S.S.
      • Echtay A.
      • Djaballah K.
      • et al.
      The characteristics and pattern of care for the type 2 diabetes mellitus population in the MENA region during Ramadan: an international prospective study (DAR-MENA T2DM).
      ,
      • Salti I.
      • Benard E.
      • Detournay B.
      • Bianchi-Biscay M.
      • Le Brigand C.
      • Voinet C.
      • et al.
      A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries: results of the epidemiology of diabetes and Ramadan 1422/2001 (EPIDIAR) study.
      ,
      • Beshyah S.A.
      • Hassanein M.
      • Ahmedani M.Y.
      • Shaikh S.
      • Ba-Essa E.M.
      • Megallaa M.H.
      • et al.
      Diabetic hypoglycaemia during Ramadan fasting: A trans-national observational real-world study.
      ,
      • Lessan N.
      • Hannoun Z.
      • Hasan H.
      • Barakat M.T.
      Glucose excursions and glycaemic control during Ramadan fasting in diabetic patients: insights from continuous glucose monitoring (CGM).
      ,
      • Alghadyan A.A.
      Retinal vein occlusion in Saudi Arabia: possible role of dehydration.
      ]. Severe hypoglycemia is one of the most important risks that needs to be considered when fasting by anyone with type 2 diabetes who uses glucose-lowering therapies such as basal insulin (BI) and sulphonylureas (SU), and is an important consideration for the treating physician when managing an individual who elects to fast during Ramadan [
      • Hassanein M.
      • Al Awadi F.F.
      • El Hadidy K.E.S.
      • Ali S.S.
      • Echtay A.
      • Djaballah K.
      • et al.
      The characteristics and pattern of care for the type 2 diabetes mellitus population in the MENA region during Ramadan: an international prospective study (DAR-MENA T2DM).
      ,
      • Salti I.
      • Benard E.
      • Detournay B.
      • Bianchi-Biscay M.
      • Le Brigand C.
      • Voinet C.
      • et al.
      A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries: results of the epidemiology of diabetes and Ramadan 1422/2001 (EPIDIAR) study.
      ,
      • Al-Arouj M.
      • Assaad-Khalil S.
      • Buse J.
      • Fahdil I.
      • Fahmy M.
      • Hafez S.
      • et al.
      Recommendations for management of diabetes during Ramadan: update 2010.
      ]. However, the majority of people with type 2 diabetes can safely fast during Ramadan as long as they seek appropriate advice from healthcare professionals, and adhere to medical advice regarding their diet and medication schedule during fasting [

      International Diabetes Federation. Diabetes and Ramadan: Practical guidelines. 2016. https://www.idf.org/component/attachments/attachments.html?id=733&task=download [Accessed 11 January 2020].

      ,
      • Hassanein M.
      • Al Awadi F.F.
      • El Hadidy K.E.S.
      • Ali S.S.
      • Echtay A.
      • Djaballah K.
      • et al.
      The characteristics and pattern of care for the type 2 diabetes mellitus population in the MENA region during Ramadan: an international prospective study (DAR-MENA T2DM).
      ,
      • Benaji B.
      • Mounib N.
      • Roky R.
      • Aadil N.
      • Houti I.E.
      • Moussamih S.
      • et al.
      Diabetes and Ramadan: review of the literature.
      ,
      • Hassanein M.
      • Al-Arouj M.
      • Hamdy O.
      • Bebakar W.M.W.
      • Jabbar A.
      • Al-Madani A.
      • et al.
      Diabetes and Ramadan: Practical guidelines.
      ].
      The use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has been suggested for type 2 diabetes management during Ramadan in recent guidelines due to their favorable efficacy and safety profiles [

      International Diabetes Federation. Diabetes and Ramadan: Practical guidelines. 2016. https://www.idf.org/component/attachments/attachments.html?id=733&task=download [Accessed 11 January 2020].

      ,
      • Hassanein M.
      • Al-Arouj M.
      • Hamdy O.
      • Bebakar W.M.W.
      • Jabbar A.
      • Al-Madani A.
      • et al.
      Diabetes and Ramadan: Practical guidelines.
      ,
      • Pathan M.F.
      • Sahay R.K.
      • Zargar A.H.
      • Raza S.A.
      • Khan A.K.
      • Siddiqui N.I.
      • et al.
      South Asian Consensus Guideline: Use of GLP-1 analogue therapy in diabetes during Ramadan.
      ,
      • Pathan F.
      • Latif Z.A.
      • Sahay R.K.
      • Zargar A.H.
      • Raza S.A.
      • Khan A.
      • et al.
      South Asian consensus guideline: Use of GLP-1 receptor agonists during Ramadan: Update 2016 Revised Guidelines on the use of GLP-1A in Ramadan.
      ]. Lixisenatide is a once-daily prandial GLP-1 RA that effectively improves glycemic control through its immediate and sustained effects of lowering both post-prandial and fasting glucose concentrations in people with type 2 diabetes, with a relatively low risk for hypoglycemia [

      Sanofi. Lyxumia summary of product characteristics. 2013. https://www.ema.europa.eu/en/documents/product-information/lyxumia-epar-product-information_en.pdf [Accessed 13 November 2019].

      ]. In the recently published LixiRam study (NCT02941367) [
      • Hassanein M.M.
      • Sahay R.
      • Hafidh K.
      • Djaballah K.
      • Li H.
      • Azar S.
      • et al.
      Safety of lixisenatide versus sulfonylurea added to basal insulin treatment in people with type 2 diabetes mellitus who elect to fast during Ramadan (LixiRam): An international, randomized, open-label trial.
      ], lixisenatide as an add-on therapy to BI was shown to be beneficial for the treatment of type 2 diabetes both before and during Ramadan fasting. Rates of any hypoglycemic event were lower with lixisenatide + BI vs. the comparator group, SU + BI.
      This post hoc analysis aims to compare the safety and efficacy of lixisenatide + BI with SU + BI in participants with type 2 diabetes who elect to fast during Ramadan, in the Indian population of the LixiRam study. It is important to assess safety and efficacy in the Indian population as Indian Muslims constitute the third largest global population of Muslims. The participants in the LixiRam study from India represent a more homogenous population compared with the overall study population, with similar fasting hours and practices such as fasting, dietary and celebration habits. The results may be extrapolated to other Indian populations outside of India where Ramadan fasting practices remain the same.

      2. Materials and methods

      2.1 Trial design

      The full methodology of the LixiRam trial has been previously published [
      • Hassanein M.M.
      • Sahay R.
      • Hafidh K.
      • Djaballah K.
      • Li H.
      • Azar S.
      • et al.
      Safety of lixisenatide versus sulfonylurea added to basal insulin treatment in people with type 2 diabetes mellitus who elect to fast during Ramadan (LixiRam): An international, randomized, open-label trial.
      ]. Briefly, LixiRam was a phase IV, randomized, multicenter, open-label, 12–22-week, 2-arm parallel-group clinical trial conducted around the 2017 Ramadan holy month, which occurred between May 27 and June 24–25, 2017. The study was conducted in 5 countries (India, Israel, Kuwait, Lebanon and Turkey).
      Participants with type 2 diabetes diagnosed for ≥1 year at the time of screening (visit 1) insufficiently controlled (glycated hemoglobin [HbA1c] ≥58 to ≤86 mmol/mol; ≥7.5 to ≤10%) with SU (≤50% maximum allowed dose) and BI, with or without additional oral anti-hyperglycemic drugs, and who intended to fast during the 2017 Ramadan period were enrolled. After screening, participants were randomized 1:1 to receive BI, ± existing metformin, plus either open-label lixisenatide or open-label SU in a pre-Ramadan treatment period lasting from 8 to 12 weeks, followed by the 29–30 days of Ramadan, and a 0–4-week period post-Ramadan. All other oral anti-hyperglycemic drugs were stopped at randomization.
      For the lixisenatide + BI group, lixisenatide was to be administered once daily, within 1 h before a meal, starting at a dose of 10 μg, increasing to 20 μg after 2 weeks. During the Ramadan fast, lixisenatide was administered within 1 h prior to iftar (meal after sunset). If the 20 μg lixisenatide dose was not tolerated, the guidance from the summary of product characteristics was to be followed [

      Sanofi. Lyxumia summary of product characteristics. 2013. https://www.ema.europa.eu/en/documents/product-information/lyxumia-epar-product-information_en.pdf [Accessed 13 November 2019].

      ].
      For the SU + BI arm, SU was started at the same dosing regimen used previously and could be adjusted based on glycemic control and hypoglycemia risk at the investigator’s discretion. During Ramadan fast, SU was to be administered at iftar, if taken once daily, and at suhur (predawn meal) and iftar, if taken twice daily. In participants with well-controlled blood glucose levels, the SU dose could have been reduced at iftar for once daily SU and could have been reduced at suhur for twice daily SU. Second-generation SUs were to be used in preference and older SUs were to be avoided due to higher risk of hypoglycemia, in line with the IDF-DAR guidelines [

      International Diabetes Federation. Diabetes and Ramadan: Practical guidelines. 2016. https://www.idf.org/component/attachments/attachments.html?id=733&task=download [Accessed 11 January 2020].

      ].
      Participants continued the BI taken prior to screening. For the lixisenatide + BI group, the BI dose could be reduced by 20% based on the participant’s HbA1c and was to be kept stable for the first 4 weeks and then adjusted weekly according to glucose values. For the SU + BI group, BI was to be adjusted weekly according to fasting glucose values during the pre-Ramadan period. In both groups, the BI dose was to be adjusted weekly according to fasting glucose and could be adjusted at any time for hypoglycemia. During Ramadan fasting, switching from twice daily to once daily BI administration (at randomization) by reducing total insulin dose was recommended for both treatment groups.
      The study protocol was designed and monitored in accordance with Good Clinical Practice and the Declaration of Helsinki, and all applicable amendments, and complied with the laws and regulations, as well as any applicable guidelines, of the countries where the study was conducted. All participants provided written informed consent.

      2.2 Post hoc analysis and endpoints

      The primary endpoint was the percentage of participants with ≥1 documented symptomatic hypoglycemia event (plasma glucose ≤3.9 mmol/L; ≤70 mg/dL) during the Ramadan fast.
      Secondary safety endpoints included the percentage of participants with any hypoglycemia event from baseline (visit 2, i.e. randomization) to pre-Ramadan fasting, during Ramadan fasting, and during the whole treatment period. ‘Any hypoglycemia’ consisted of severe hypoglycemia, documented symptomatic hypoglycemia (≤3.9 mmol/L and <3.0 mmol/L; ≤70 mg/dL and <54 mg/dL), relative hypoglycemia (>3.9 mmol/L; >70 mg/dL), asymptomatic hypoglycemia (≤3.9 mmol/L and <3.0 mmol/L; ≤70 mg/dL and <54 mg/dL) and probable symptomatic hypoglycemia. The whole treatment period included pre-Ramadan, Ramadan and post-Ramadan, and was defined as from first day of study drug administration to last day of study drug administration + 3 days. The pre-Ramadan period was defined as the period between baseline (visit 2) to the pre-Ramadan visit (<4 weeks prior to Ramadan). The Ramadan fast was defined as the period from the start to end of Ramadan holy month.
      Secondary efficacy endpoints included mean change in HbA1c, body weight and treatment dose (BI, lixisenatide and SU) from baseline (visit 2) to the pre-Ramadan visit (visit 4) and post-Ramadan visit (visit 6).
      Other endpoints included the number of participants using the maximum treatment dose; the type of SU used; the number of days fasted; hypoglycemia events for Ramadan fasting over a 24-h period; and the distribution of the number of hypoglycemic events by participant.
      Treatment-emergent adverse events (TEAEs) were reported for the pre-Ramadan period, Ramadan on-treatment period, and whole treatment period. The Ramadan on-treatment period was defined as being from the pre-Ramadan visit (visit 4) to the post-Ramadan visit (visit 6) or the last day of study drug administration + 3 days, whichever came first.
      Treatment adherence was reported; this was defined as the actual number of days with at least 1 administration of the study drug compared with the planned number of days with the administration during the treatment period up to discontinuation.

      2.3 Statistical analysis

      Post hoc analyses for the hypoglycemia and efficacy endpoints were mostly based on the intention-to-treat population, defined as all randomized participants treated at least once with the study treatment and grouped according to randomization assignment. However, the primary endpoint (percentage of participants with ≥1 documented symptomatic hypoglycemia during Ramadan fast) used the intention-to-treat visit 4 population, defined as participants included in the intention-to-treat population who were on study treatment and assessed at the pre-Ramadan visit 4. Analysis of TEAEs was performed in the safety population and included all randomized participants who received study treatment at least once.
      The percentage of participants with ≥1 documented symptomatic hypoglycemia event and any hypoglycemia event were analyzed using a logistic regression model to estimate odds ratio (OR) and 95% confidence interval (CI). Differences in proportion (95% CI) are also presented. Changes in HbA1c, body weight and BI dose were analyzed using a mixed model for repeated measures and assessed with least squares (LS) mean change. The estimated difference between treatment groups and 2-sided 95% CIs were calculated for HbA1c. TEAE data were analyzed by descriptive statistics.

      3. Results

      3.1 Population demographics and characteristics

      Of the 184 participants randomized in the LixiRam trial [
      • Hassanein M.M.
      • Sahay R.
      • Hafidh K.
      • Djaballah K.
      • Li H.
      • Azar S.
      • et al.
      Safety of lixisenatide versus sulfonylurea added to basal insulin treatment in people with type 2 diabetes mellitus who elect to fast during Ramadan (LixiRam): An international, randomized, open-label trial.
      ], 150 were recruited at investigational sites in India and received either lixisenatide + BI (n = 75) or SU + BI (n = 75). Baseline characteristics were comparable between treatment groups (Table 1).
      Table 1Baseline demographics and disease characteristics.
      Lixisenatide + BI (n = 75)SU + BI (n = 75)
      Age, mean ± SD, years50.7 ± 9.352.8 ± 10.7
      Age, n (%)
       <65 years68 (90.7)64 (85.3)
       ≥65 years7 (9.3)11 (14.7)
      Gender, female, n (%)45 (60.0)41 (54.7)
      Weight, mean ± SD, kg73.4 ± 13.873.4 ± 10.1
      BMI, mean ± SD, kg/m229.0 ± 5.128.6 ± 4.0
      Duration of diabetes, mean ± SD, years5.9 ± 3.65.9 ± 4.0
      HbA1c, mean ± SD, mmol/mol (%)70 ± 8 (8.6 ± 0.7)69 ± 8 (8.5 ± 0.7)
      HbA1c, n (%)
       <58 mmol/mol (<7.5%)0 (0)0 (0)
       58–64 mmol/mol (7.5–8.0%)16 (21.3)27 (36.0)
       64–86 mmol/mol (8.0–10.0%)59 (78.7)48 (64.0)
       ≥86 mmol/mol (≥10.0%)0 (0)0 (0)
      Fasting plasma glucose, mean, ± SD, mmol/L (mg/dL)9.5 ± 3.1 (171.5 ± 55.1)9.2 ± 3.5 (166.1 ± 63.7)
      Pre-breakfast SMPG, mean, ± SD, mmol/L (mg/dL)9.3 ± 2.7 (167.6 ± 49.3)8.2 ± 2.1 (148.3 ± 37.0)
      Previous non-insulin anti-hyperglycemic treatments, n (%)
       13 (4.0)6 (8.0)
       267 (89.3)66 (88.0)
       >25 (6.7)3 (4.0)
      Biguanides (metformin), n (%)71 (94.7)68 (90.7)
      SU, n (%) / mg ± SD
       Glibenclamide4 (5.3)/7.8 ± 2.6
       Gliclazide0 (0.0)
       Glimepiride65 (86.7)/3.6 ± 0.9
       Glipizide3 (4.0)/8.3 ± 2.9
       Glimepiride + metformin3 (4.0)/4.0 ± 0.0
      Previous insulin therapy duration, mean ± SD, years1.1 ± 0.41.2 ± 0.8
      BI dose, mean ± SD, U23.1 ± 16.722.3 ± 18.4
      BI therapy, n (%)
       Intermediate-acting12 (16.0)12 (16.0)
       Long-acting63 (84.0)62 (82.7)
       Combined with rapid insulin0 (0)1 (1.3)
      Intention-to-treat population.
      BI, basal insulin; BMI, body mass index; HbA1c, glycated hemoglobin; SD, standard deviation; SMPG, self-measured plasma glucose; SU, sulphonylurea.

      3.2 Number of fasted days

      The median (Q1:Q3) number of days fasted during Ramadan was 29.0 (28.0:29.0) for both the lixisenatide + BI and SU + BI groups.

      3.3 Hypoglycemia events

      3.3.1 Participants with at least one documented symptomatic hypoglycemia event

      For the primary endpoint, the percentage of participants experiencing ≥1 documented symptomatic hypoglycemia event (plasma glucose ≤3.9 mmol/L; ≤70 mg/dL) during the Ramadan fast was 1.3% (1/75) with lixisenatide + BI and 6.8% (5/74) for SU + BI (OR: 0.22; 95% CI: 0.02–1.93; Fig. 1).
      Figure thumbnail gr1
      Fig. 1Number and percentage of participants who experienced ≥1 hypoglycemic event with comparisons between groups shown as ORs and proportion differences. These post hoc analyses were exploratory and hypothesis-generating only. Intention-to-treat visit 4 population, defined as participants included in the intention-to-treat population who were assessed at the pre-Ramadan visit (visit 4). During Ramadan fast is defined as from the start to the end dates for Ramadan. §Intention-to-treat population, defined as all randomized participants treated at least once with the study treatment assessed according to treatment group to which they were randomized. Whole treatment period is defined as from the first study drug administration to the last study drug administration + 3 days. BI, basal insulin; CI, confidence interval; Lixi, lixisenatide; NE, not estimable due to questionable validity of the model fit; OR, odds ratio; SU, sulphonylurea.

      3.3.2 Any hypoglycemia event

      The percentage of participants with any hypoglycemia event was numerically lower with lixisenatide + BI (1/75 [1.3%]) compared with SU + BI during the whole treatment period (15/75 [20.0%]; OR 0.06; 95% CI: 0.01–0.46; Fig. 1).
      The number of participants with any hypoglycemic event by time of day during Ramadan fast is shown in Fig. 2. No hypoglycemic events occurred in the lixisenatide + BI group during fasting hours (04:00–19:59), whereas 9 participants (out of 75; 12.0%) experienced a hypoglycemic event in the SU + BI group during the same timeframe. One hypoglycemic event occurred in the lixisenatide + BI group (1/75; 1.3%) and 6 participants (8%) experienced a hypoglycemic event in the SU + BI group occurred between 20:00–03:59.
      Figure thumbnail gr2
      Fig. 2Number of participants with any hypoglycemia event by time of day during the Ramadan fast. Intention-to-treat population. The shaded area highlights the approximate daily fasting period (04:00–19:59) during Ramadan. BI, basal insulin; SU, sulphonylurea.
      Severe hypoglycemia was rare; only one participant (out of 75; 1.3%) reported a severe hypoglycemic event in the SU + BI group during the Ramadan fast.

      3.4 Treatment dose

      The LS mean BI dose increased slightly in both the lixisenatide + BI and SU + BI groups from baseline to post-Ramadan but the change was lower in the lixisenatide + BI group vs. the SU + BI group; mean change from baseline ± standard error (SE) was 2.50 ± 0.74 U and 3.61 ± 0.75 U, respectively. There was no change or only a very small (≤1.3 mg) mean increase in SU dose according to type of SU from baseline to post-Ramadan (Supplementary Table 1). No participants received the maximum dose of any SU during the study. Participants were > 99% adherent to study treatment in both treatment groups.

      3.5 Secondary efficacy endpoints

      3.5.1 HbA1c

      HbA1c decreased from baseline to post-Ramadan with lixisenatide + BI (70 ± 8 mmol/mol; 8.6 ± 0.7% at baseline; LS mean change from baseline ± SE, –5 ± 1 mmol/mol; –0.5 ± 0.1%) and SU + BI (69 ± 8 mmol/mol; 8.5 ± 0.7% at baseline; –5 ± 1 mmol/mol; –0.5 ± 0.1%) and reductions were similar between the 2 groups (LS mean difference ± SE, 0 ± 2 mmol/mol; 0.0 ± 0.2%).

      3.5.2 Body weight

      Body weight from baseline to post-Ramadan decreased with lixisenatide + BI (LS mean change from baseline ± SE, –1.8 ± 0.3 kg) and SU + BI (–1.4 ± 0.3 kg; LS mean difference between groups ± SE, 0.4 ± 0.4 kg).

      3.6 Treatment-emergent adverse events

      During the whole treatment period, the percentage of participants with any TEAE was 42.7% (32/75 participants) with lixisenatide + BI and 18.7% (14/75) with SU + BI. The incidence of any TEAE was 32.0% (24/75) with lixisenatide + BI and 5.3% (4/75) with SU + BI during the pre-Ramadan period. The difference in TEAE incidence between the groups observed during the pre-Ramadan period was largely attributed by the incidence of gastrointestinal (GI) TEAEs during the pre-Ramadan period with lixisenatide + BI compared with SU + BI (24.0% [18/75] vs. 0.0%, respectively); during the Ramadan fast period the number of participants with any TEAE was similar with lixisenatide + BI and SU + BI (14.7% [11/75] vs. 13.3% [10/75], respectively). The incidence of GI TEAEs was 4.0% [3/75] with lixisenatide + BI and 1.3% [1/75] with SU + BI during the Ramadan fast period. No deaths were reported.

      4. Discussion

      This post hoc analysis in the Indian population of the LixiRam trial showed that lixisenatide + BI combination therapy was associated with a numerically lower incidence of documented symptomatic hypoglycemic events than SU + BI during Ramadan fast (1.3% vs. 6.8%, respectively; OR 0.22; 95% CI: 0.02–1.93), and a lower incidence of any hypoglycemia than SU + BI during the whole treatment period (1.3% vs. 20.0%, respectively; OR: 0.06; 95% CI: 0.01–0.46), pre-Ramadan fast (0.0% vs. 9.3%, respectively; OR and 95% CI not estimable) and during the Ramadan fast (1.3% vs. 14.7%, respectively; OR: 0.09; 95% CI: 0.01–0.69). In contrast to the SU + BI group, treatment with lixisenatide + BI caused no hypoglycemic episodes during fasting hours, and there were no reported cases of severe hypoglycemia in the lixisenatide + BI group.
      In addition to a lower incidence of hypoglycemic events (documented symptomatic and any), treatment with lixisenatide + BI in the present study reduced HbA1c (by 5 mmol/mol [0.5%] from baseline to the post-Ramadan period) with a reduction in body weight (of 1.8 kg from baseline to post-Ramadan), and there were very few GI events (4.0% of participants) during the Ramadan fasting period.
      There are very few reports of studies that assess the use of a GLP-1 RA during Ramadan fast [
      • Brady E.M.
      • Davies M.J.
      • Gray L.J.
      • Saeed M.A.
      • Smith D.
      • Hanif W.
      • et al.
      A randomized controlled trial comparing the GLP-1 receptor agonist liraglutide to a sulphonylurea as add on to metformin in patients with established type 2 diabetes during Ramadan: the Treat 4 Ramadan Trial.
      ,
      • Azar S.T.
      • Echtay A.
      • Wan Bebakar W.M.
      • Al Araj S.
      • Berrah A.
      • Omar M.
      • et al.
      Efficacy and safety of liraglutide compared to sulphonylurea during Ramadan in patients with type 2 diabetes (LIRA-Ramadan): a randomized trial.
      ] and apart from the LixiRam study [
      • Hassanein M.M.
      • Sahay R.
      • Hafidh K.
      • Djaballah K.
      • Li H.
      • Azar S.
      • et al.
      Safety of lixisenatide versus sulfonylurea added to basal insulin treatment in people with type 2 diabetes mellitus who elect to fast during Ramadan (LixiRam): An international, randomized, open-label trial.
      ], there are currently no other studies that asses the use of GLP-1 RA combined with BI as an intensified treatment regimen during Ramadan fast. Despite this, recent South Asian consensus guidelines recommend the use of GLP-1 RAs as the preferred class of drugs to use before and during Ramadan due to their numerous advantages in terms of efficacy, safety, convenience, versatility and pleiotropic benefits [
      • Pathan F.
      • Latif Z.A.
      • Sahay R.K.
      • Zargar A.H.
      • Raza S.A.
      • Khan A.
      • et al.
      South Asian consensus guideline: Use of GLP-1 receptor agonists during Ramadan: Update 2016 Revised Guidelines on the use of GLP-1A in Ramadan.
      ]. The South Asian guidelines note that GLP-1 RA treatment must begin at least 6 weeks, though preferably 3 months, prior to Ramadan to ensure steady state concentrations are achieved and any potential GI side effects are addressed before Ramadan fast begins [
      • Pathan F.
      • Latif Z.A.
      • Sahay R.K.
      • Zargar A.H.
      • Raza S.A.
      • Khan A.
      • et al.
      South Asian consensus guideline: Use of GLP-1 receptor agonists during Ramadan: Update 2016 Revised Guidelines on the use of GLP-1A in Ramadan.
      ]. Other recent guidelines also advocate the use of GLP-1 RAs as an add-on treatment to pre-existing antidiabetic agents, so long as they are appropriately dose-titrated at least 6 weeks before Ramadan [

      International Diabetes Federation. Diabetes and Ramadan: Practical guidelines. 2016. https://www.idf.org/component/attachments/attachments.html?id=733&task=download [Accessed 11 January 2020].

      ,
      • Hassanein M.
      • Al-Arouj M.
      • Hamdy O.
      • Bebakar W.M.W.
      • Jabbar A.
      • Al-Madani A.
      • et al.
      Diabetes and Ramadan: Practical guidelines.
      ].
      Limitations include that the LixiRam trial was not designed as a treat-to-target study. Investigators were only advised to adjust the dose of BI and SU in response to glucose values (or reduce in case of hypoglycemia); however, only minimal dose increases were observed during the study. Also, the present results are derived from a post hoc analysis, and therefore should be considered hypothesis-generating. The gathering of real-world evidence would help to support findings from LixiRam and this post hoc analysis.
      Combination therapy with lixisenatide + BI during Ramadan fast provided efficacious glycemic control in this Indian type 2 diabetes population, without additional hypoglycemia risks. Over a median of 29.0 fasted days, the incidences of symptomatic hypoglycemia and any hypoglycemia were numerically lower for lixisenatide + BI compared with SU + BI during Ramadan fast, and TEAE incidence was similar between the 2 treatment groups during this timeframe; incidence of GI events with lixisenatide + BI was very low during the fasting period. Lixisenatide + BI is a viable treatment option in this high-risk population who elect to fast during Ramadan.

      5. Contributions statement

      MH developed the study concept and design. All authors contributed to the data analysis or interpretation of the results and critically revised, provided final approvals of, and are accountable for, the accuracy and integrity of the manuscript.

      Declaration of Competing Interest

      RS is an advisory board member for Boehringer Ingelheim, Dr Reddys Laboratories, Eli Lilly and Sanofi; and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Sanofi. KH is an advisory board member for AstraZeneca, Boehringer Ingelheim, Janssen, Novo Nordisk and Sanofi; research grant from Sanofi; and speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD and Novo Nordisk. KD and MC are both employees of Sanofi. SA is a researcher and advisor for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck & Co, MSD, Novo Nordisk and Sanofi. NS is an advisory board member for Boehringer Ingelheim, MSD, Novo Nordisk and Sanofi; consultant for and grant recipient from MSD, Novo Nordisk and Sanofi; research investigator for AstraZeneca, MSD, Novo Nordisk and Sanofi; speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Sanofi; and stock owner of Novo Nordisk. WH declares consultancy fees, research grants and travel grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, MSD, Novartis, Novo Nordisk and Sanofi. MH is an advisory board member for Sanofi, Boehringer Ingelheim and Novo Nordisk; and speaker for Boehringer Ingelheim, Eli Lilly, Janssen, LifeScan, MSD, Novo Nordisk and Sanofi.

      Acknowledgements

      The authors would like to thank the participants, their families and all investigators involved in this study. The authors would also like to thank Virginia Rafael, Biostatistician, of Linical (CRO company). Medical writing support was provided by Amber Lynch, PhD, and Rob Campbell, PhD, of Prime, Knutsford, Cheshire, UK, and funded by Sanofi according to Good Publication Practice guidelines (https://annals.org/aim/fullarticle/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3). Coordination of the development of this manuscript and assistance with the revision was provided by Helena Andersson, PhD, at Sanofi. Sanofi was involved in the study design and collection, analysis and interpretation of data, as well as data checking of information provided in the manuscript. However, ultimate responsibility for the opinions, conclusions and data interpretation lies with the authors.

      Funding

      This study was funded by Sanofi.

      Data statement

      Qualified researchers may request access to participant level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan and dataset specifications. Participant level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi’s data sharing criteria, eligible studies and process for requesting access can be found at: https://www.clinicalstudydatarequest.com

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