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Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS)

Summary Aims There is a large population of people with type 2 diabetes mellitus (T2DM) who are Muslim and fast during Ramadan. Changes in the pattern and amount of meal and fluid intake during Ramadan, in addition to the long fasting hours, may increase the risk of hypoglycaemia, hyperglycaemia, and dehydration. The Canagliflozin in Ramadan Tolerance Observational Study (CRATOS) evaluated the tolerability of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, compared with sulphonylureas among patients with T2DM who fast during Ramadan. Methods This non‐randomised, parallel‐cohort, prospective, comparative, observational study was conducted in the Middle East during Ramadan and enrolled patients who were taking canagliflozin (n=162) or any sulphonylurea (n=159) added to metformin±dipeptidyl peptidase‐4 inhibitor. The proportion of patients who experienced hypoglycaemia events was assessed as the primary end‐point. Between‐cohort comparisons were adjusted using propensity score analysis. Results During Ramadan, fewer patients experienced symptomatic hypoglycaemia with canagliflozin vs sulphonylurea (adjusted odds ratio: 0.273 [95% CI: 0.104, 0.719]). Of hypoglycaemia events for which blood glucose was measured, two of six with canagliflozin and 27 of 37 with sulphonylurea were confirmed by blood glucose <3.9 mmol/L. More patients treated with canagliflozin experienced volume depletion events compared with sulphonylurea (adjusted odds ratio: 3.5 [95% CI: 1.3, 9.2]). Missed fasting days were few and medication adherence was high in both groups. No patients treated with canagliflozin and 9.4% treated with sulphonylurea adjusted their medication dose near the beginning of Ramadan. Both treatments were generally well tolerated, with low rates of adverse events and no serious adverse events in either group. Conclusions Overall, these findings support the use of canagliflozin for the treatment of adults with T2DM who fast during Ramadan. ClinicalTrials.gov Identifier: NCT02737657


| INTRODUCTION
Globally, approximately 116 million Muslims with type 2 diabetes mellitus (T2DM) elect to fast during the holy month of Ramadan. 1 Long periods of fasting and drastic changes in food and water intake increase the risk of hypoglycaemia, hyperglycaemia, and dehydration in these individuals. Patients with T2DM who fast during Ramadan have a 7.5-fold increased risk of severe hypoglycaemia during Ramadan compared with non-fasting months. 2 Generally, insulinindependent treatments for T2DM are associated with a lower risk of hypoglycaemia than treatments that increase insulin secretion, 3 so these treatments may be more attractive options for patients who intend to fast during Ramadan, or at other times throughout the year. Studies of newer insulin-independent treatments, such as sodium glucose co-transporter 2 (SGLT2) inhibitors, during Ramadan are limited, but have shown promising results. In a study of fasting T2DM patients treated with the SGLT2 inhibitor dapagliflozin during Ramadan, a reduced incidence of hypoglycaemia was observed with dapagliflozin compared with sulphonylureas 4 ; more patients had volume depletion-related adverse events (AEs) of postural hypotension with dapagliflozin vs sulphonylureas, but this was not statistically significant.
Canagliflozin is an SGLT2 inhibitor approved for the treatment of T2DM in adults. 5 Canagliflozin lowers plasma glucose by promoting urinary glucose excretion, which results in a mild osmotic diuresis that may be associated with a reduction in intravascular volume. [6][7][8][9] While the insulin-independent mechanism of canagliflozin leads to a low inherent risk of hypoglycaemia, the mild osmotic diuresis it causes may be associated with an increased risk of volumedepletion events, including dehydration. Across Phase 3 studies in a broad range of patients, canagliflozin provided reductions in HbA1c, body weight, and systolic blood pressure (BP) and was generally well tolerated, with a low risk of hypoglycaemia when not used in conjunction with insulin or sulphonylureas. [10][11][12][13][14][15][16][17][18][19][20][21][22] An analysis of T2DM patients living in hot climates found that canagliflozin treatment was generally well tolerated, with a low incidence of volume depletionrelated AEs. 23 The Canagliflozin in Ramadan Tolerance Observational Study (CRATOS) is the first study to evaluate the tolerability of canagliflozin in combination with metformin with or without a dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of T2DM in patients fasting during Ramadan. therapy: patients treated with canagliflozin and metformin with or without a DPP-4 inhibitor and patients treated with any sulphonylurea and metformin with or without a DPP-4 inhibitor. Eligible participants were adults between the ages of 18 and 65 years who had a confirmed diagnosis of T2DM for at least 12 months before enrolment; had been treated with canagliflozin or any sulphonylurea, each on a background therapy of metformin with or without a DPP-4 inhibitor for at least 12 weeks before enrolment; had an HbA1c measurement of ≤8.5% within 8 weeks of the beginning of Ramadan; and intended to fast during Ramadan.

| Study design and patient population
Patients who were treated with insulin or any T2DM therapy other than canagliflozin, any sulphonylurea, or metformin with or without a DPP-4 inhibitor; changed their T2DM therapy within 12 weeks of enrolment; were being treated with loop diuretics; had a history of severe hypoglycaemia events (for which the patient required assistance from another person or that resulted in seizure or loss of consciousness) or severe volume depletion events within the 6 months prior to enrolment; had a history of diabetic ketoacidosis; had heart failure (New York Heart Association class 3-4); had advanced cardiovascular disease; or had an estimated glomerular filtration rate (eGFR) <60 mL/ min/1.73 m 2 were excluded from the study.
Patients in the study were required to keep a patient diary during Ramadan, where they recorded days when fast was broken; daily use of canagliflozin or sulphonylurea, metformin, and a DPP-4 inhibitor, if applicable; reasons for any missed medication doses; hypoglycaemia and volume depletion events; and self-monitored blood glucose measurements.

What's known
There are approximately 116 million Muslims with T2DM who fast each year during the month of Ramadan. During this time, food and water intake patterns are drastically altered, which can affect T2DM treatment; therefore, the safety and tolerability of T2DM medications in fasting patients must be established. Treatment with the SGLT2 inhibitor dapagliflozin was reported to result in lower rates of hypoglycaemia when compared to sulphonylurea during Ramadan fasting.

What's new
This study is the first to evaluate the SGLT2 inhibitor canagliflozin in patients with T2DM fasting an average of 15 hours daily during Ramadan; it shows that patients have a lower risk of hypoglycaemia with canagliflozin compared with sulphonylureas. Canagliflozin was generally well tolerated, with low rates of adverse events and higher rates of medication and fasting adherence, but was associated with an increased risk of volume depletion events.

| Study end-points
The prespecified primary end-point of this study was the proportion of patients with ≥1 hypoglycaemia episode during Ramadan.
Hypoglycaemia episodes included symptomatic episodes (ie, symptoms of dizziness, visual blurring, palpitations, nausea, sweating, confusion, tremor, or intense hunger with or without biochemical confirmation), biochemically confirmed episodes (ie, self-monitored blood glucose measurement of <3.9 mmol/L with or without symptoms), and severe episodes (ie, episodes for which the patient required assistance from another person or that resulted in seizure or loss of consciousness). Hypoglycaemia events for which blood glucose measurements were ≥3.9 mmol/L or no blood test was done were considered not confirmed. The 3.9 mmol/L threshold used to define hypoglycaemia was based on the American Diabetes Association (ADA) and Endocrine Society consensus report definition. 24 In addition, hypoglycaemia events with blood glucose <3.0 mmol/L were reported in accordance with an ADA and European Association for the Study of Diabetes joint position statement, which defines these events as serious and clinically meaningful. 25 Other parameters of interest included the proportion of patients with ≥1 volume depletion event (ie, symptoms of hypotension, orthostatic hypotension, postural dizziness, dehydration, syncope, or presyncope) during Ramadan, number of days that fasting was broken, and treatment adherence, based on the percentage of prescribed doses of canagliflozin or sulphonylurea taken by patients.
In addition to patient-reported episodes, physician-reported episodes of hypoglycaemia and volume depletion events were reported as AEs. The incidence of other AEs of interest potentially related to SGLT2 inhibition (including urinary tract infections, genital mycotic infections, and osmotic diuresis-related AEs) and metformin (gastrointestinal AEs) were also assessed. In addition, HbA1c, BP, body weight, and eGFR were measured at the pre-and post-Ramadan visits.

| Statistical analysis
Because of the exploratory nature of this observational study, sample size was based on the width of the 95% confidence interval (CI) of the observed proportion of patients with ≥1 episode of hypoglycaemia during the Ramadan period in the canagliflozin cohort. For an observed sample proportion of 0.15, the two-sided Wilson 95% CI is 0.081 to 0.261 for a sample size of 60. To ensure that comparisons could be adjusted between the treatment cohorts for a non-overlap in propensity score (PS), which was estimated to be 50%, the sample size was increased to 120 per cohort and subsequently increased to 150 to account for an expected rate of 20% unevaluable patients.
Analyses were conducted using the tolerability analysis set, which consists of all eligible patients who received ≥1 dose of canagliflozin or any sulphonylurea during the observation period, who fasted for at least 1 day, and for whom postbaseline tolerability data are available.
For patients in the tolerability analysis set who switch to treatment with another T2DM therapy during the Ramadan period, only the observation period until the switch was included in the primary endpoint. For patients in the tolerability analysis set who stopped their fast entirely during Ramadan, only the observation period until the stop was included in the primary end-point.
As this is an observational study, no direct statistical comparisons of the events of interest could be made between cohorts. Instead, the PS method was used to account for the probability that a patient in the treatment analysis subset received a treatment based on observed confounders. The following observed confounders were evaluated: baseline age, baseline body mass index (BMI), diabetes duration, treatment duration, baseline HbA1c, baseline eGFR, use of a DPP-4 inhibitor, sex, current smoker status, presence of complicating diagnosis, home country, antihypertensive use, and diuretic use. The PS analysis was done in four steps. In step 1, the balance between treatment cohorts was investigated for each of the potential confounding factors by calculating the univariate odds ratio (OR) and 95% CI using logistic regression. In step 2, the predictive power was investigated separately for each potential confounder by means of a logistic regression analysis with the event (Y/N) as a dependent variable and the confounder as the predictor, and corrected for treatment group. In step 3, the confounders were selected and the PS model was created, which produced the PS, which represents the probability of being treated with canagliflozin. Finally, the adjusted treatment effect (OR and associated 95% Wilson CI) was estimated by a logistic regression analysis, with hypoglycaemia as the dependent and treatment as the independent variable of interest, while adjusting for the PS. The unadjusted and PSadjusted ORs and 95% Wilson CIs are presented for hypoglycaemia and volume depletion events.

| Patients
Of the 379 patients enrolled in the study, 321 were included in the tolerability analysis (reasons for exclusion are shown in Figure 1). A total of 162 patients received canagliflozin and 159 received sulphonylurea; their baseline characteristics are shown in Table 1 inhibitor at or just after the beginning of Ramadan.

| Hypoglycaemia events
Six patients treated with canagliflozin (3.7%) reported ≥1 symptomatic hypoglycaemia episode compared to 21 patients treated with sulphonylurea (13.2%) during Ramadan (Figure 2A). The proportion of patients who experienced a hypoglycaemia event was related to treatment arms after adjustment for observed cofounders by means of the PS method.
After adjustment for factors determined to be confounders (baseline age, baseline BMI, diabetes duration, treatment duration, baseline

| Treatment adherence
Adherence to study treatments was high in both groups; 98.8%  (reported as a volume depletion event) and one dose was missed because the patient forgot to take their medication. In the sulphonylurea group, four doses were missed to prevent hypoglycaemia, one dose was missed as a precaution, and one dose was missed because the patient forgot to take their medication. Adherence to metformin was also high in both study groups; 100.0% (162/162) of patients in the canagliflozin group and 98.7% (157/159) of patients in the sulphonylurea group reported no missed doses of metformin. In the sulphonylurea group, one dose was missed because the patient forgot to take their medication, and the reason one dose was missed was listed as "other."

| Fasting adherence
The number of missed fasting days was low in both study groups; 82.1%

| Adverse events
Canagliflozin and sulphonylurea were generally well tolerated, with similar rates of AEs in both groups; no patients in either group experienced any serious AEs or AEs leading to discontinuation of study medication (

| HbA1c, body weight, BP and eGFR
Patients treated with canagliflozin and sulphonylurea had an average (standard deviation) of 87 (26) and 92 (26) days, respectively, between pre-and post-Ramadan measurements. During this time, there were small reductions in HbA1c and body weight observed in both treatment groups, with numerically greater reductions in patients treated with canagliflozin (Table 5). Small changes were observed in systolic BP, diastolic BP and eGFR between pre-and post-Ramadan measurements; small reductions from baseline in patients treated with canagliflozin and small increases from baseline in patients treated with sulphonylurea were observed.

| DISCUSSION
Overall, the findings from this study showed that canagliflozin was generally well tolerated for the treatment of patients with T2DM fasting during Ramadan. Over the month of Ramadan, patients treated with canagliflozin had a lower risk of experiencing a hypoglycaemia episode compared to patients treated with sulphonylurea. Patients treated with canagliflozin also had a low number of missed fasting days and did not have to change canagliflozin dose for Ramadan.
The reduced risk of hypoglycaemia observed with canagliflozin is consistent with the results from a previous study that examined the safety and tolerability of the SGLT2 inhibitor dapagliflozin in patients with T2DM fasting during Ramadan. 4 The consistency of these results suggests that the insulin-independent mechanism of action of SGLT2 inhibitors may be associated with a lower risk of hypoglycaemia compared to insulin secretagogues, like sulphonylureas.
Because the mechanism of SGLT2 inhibitors causes mild osmotic diuresis, volume depletion events may be a concern for patients who are fasting for many hours each day and are at increased risk for de-  systolic blood pressure. 26 In this study, patients treated with canagliflozin were at a higher risk of experiencing volume depletion events (mostly dehydration) compared to patients treated with sulphonylurea.
In addition, patients in the canagliflozin group experienced a greater number of volume depletion-related and osmotic diuresis-related was performed to balance potential confounding factors in the patient population, bias due to demographic factors that were not considered cannot be ruled out.
Overall, canagliflozin was associated with a reduced risk of hypoglycaemia compared with sulphonylurea, an increased risk of volume depletion events that did not lead to breaking of the fast or discontinuation of treatment, and a low rate of AEs in patients with T2DM fasting for Ramadan. Therefore, the findings from this study support the use of canagliflozin for the treatment of these patients.

ACKNOWLEDGEMENTS
This study was supported by Janssen Pharmaceutica NV. The sponsor was involved in the study design, data collection, data analysis,  and drafted, reviewed and approved the manuscript.