Curalin supplement for patients with type 2 diabetes mellitus

To examine the efficacy and safety of Curalin supplement in patients with type 2 diabetes.


| INTRODUCTION
In Western countries, the estimated prevalence of type 2 diabetes is over 10% of the adult population. 1 Patients with uncontrolled diabetes on antidiabetic drugs or who have significant side-effects might be able to improve their glycaemic indices by supplementing with complementary and alternative medicine (CAM) therapy. 2,3 Curalin, a combination of natural herbal plants with hypoglycemic traits that are used in traditional medicine, achieves a synergistic effect through several mechanisms of action (details in supplement). [4][5][6][7][8][9][10][11][12][13][14][15] This pilot, double-blind placebo, randomized control trial was designed to evaluate the efficacy of Curalin versus placebo as an addon therapy among 36 adults with uncontrolled, type 2 diabetes.
Safety and treatment satisfaction were also evaluated.

| Study design
The study was powered at 80% to detect any statistical difference between groups under the assumptions of a mean difference in HbA1c of 0.8% between groups, with a standard deviation of 0.75%.
Eligible patients received two capsules of either Curalin or placebo thrice daily for 30 days ( Figure S1). Patients were asked to take 7 glucose measurements once-a-week on the same day using a Freestyle glucometer that was supplied to them. Information on concomitant medications was collected by study site personnel from medical record reviews and patient interviews. Visits and their timing are summarised in Table S1.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

| Ethics information
The study was registered at clinicalTrials.gov (Number NCT0543 9473). Ethical approval was obtained from the Edith Wolfson Medical Center Ethics Committee (0160-20-WOMC). Patients provided written informed consent to participate.

| Outcomes
The primary efficacy endpoint was change in HbA1c after 1 month of Curalin treatment. The secondary endpoint was defined as the number of patients with significant improvement in HbA1c (>0.5% and >1%) and in the mean of the 7 blood glucose measurements taken on the same day, once-a-week. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was used as an exploratory endpoint. In addition to adverse events (Aes) and serious adverse events (SAEs), safety variables included fasting blood count, biochemical tests, and vital signs.

| Blinding and randomisation
Within 1-2 weeks after screening, the participants were randomized 1:1 into the supplement and placebo groups, using stratification based on HbA1c levels at screening (7.5%-9% and >9%-11%), according to a computer-generated randomisation scheme. Of the 36 patients in the study, 24 with HbA1c ≤ 9% and 12 with HbA1c > 9% were equally allocated between treatment arms.

| Statistical methods
Continuous baseline variables are presented as mean, standard deviation (SD), median, interquartile range (IQR), and range. Dichotomous variables are presented as count and proportion. Treatment arms were compared using both the t-test and Wilcoxon rank sum test for continuous variables and the Wald test or Fisher's exact score for dichotomous variables, each as appropriate. For the primary outcome of change in HbA1c, comparisons between treatment arms for the overall study sample as well as for a subgroup of predefined HbA1c levels at baseline were calculated and evaluated using a t-test. Linear regression was built to analyse the association between the decrease in HbA1c and the treatment group adjusted for baseline HbA1c. In addition, improvement in HbA1c was defined based on the thresholds of decrease in HbA1c during the study of at least 0.5% or at least 1%. A comparison between treatment arms was tested on the basis of Fisher's exact score. The changes in clinical measurements between treatment arms were compared using a t-test. Treatment satisfaction was calculated based on the DTSQ questionnaire responses at the beginning and end of the study. The total and individual scores at baseline and their change during the study are presented as mean, SD, median, interquartile range, and range. Changes in scores between treatment arms were compared using the Wilcoxon rank sum test.
Means and 95% confidence intervals (CI) of the 7 daily blood glucose measurements are presented and compared using t-test.
Statistical significance was set at a p-value<0.05. All analyses were performed using R software v3.4.1.

| RESULTS
From 3 August 2021 to 1 May 2022, 51 patients with type 2 diabetes were enroled in the study ( Figure S1). Among them, 36 eligible patients were randomized. Each treatment arm consisted of 18 patients. One patient randomized to the placebo group reported an AE and discontinued the study on day 10 due to abdominal pain. A total of 35 patients completed the study per protocol.

| Demographics and preprocedural baseline characteristics
There were no significant differences in baseline characteristics between the Curalin and placebo groups, indicating overall balanced randomisation (P > 0.05) ( Table 1).

| HbA1c change
The primary efficacy endpoint was the mean decrease in HbA1c after   Table 2). The results of this analysis are based on the intention to treat 36 patients with imputation for the patient who discontinued the study due to an AE. The secondary endpoint demonstrated a significant decrease in HbA1c of >0.5% in 72% of patients treated with Curalin versus 35% of patients treated with placebo (P < 0.05). Among patients who received Curalin, 44.4% experienced a >1% decrease in HbA1c, compared to 11.8% of patients in the placebo group (P = 0.06, Figure 1).

| Glucose measurements
The mean glucose levels for all patients in both treatment arms during the 30-day trial are presented in Figure 2. There was a T A B L E 1 Patient demographics and clinical characteristics at baseline.   Note: Change in HbA1c is presented as mean, SD, median, interquartile range, and range. A comparison between treatment arms was performed using a t-test. Linear regression analysed the association between a decrease in HbA1c and treatment group, adjusted for baseline HbA1c.

| Anti-diabetes drugs
Differences in drug use between treatment arms were not significant (Table S2).

| Clinical measurements
Overall, the differences between treatment arms in clinical and laboratory measurements before and at the end of the study were not significant ( Table 1, Table S3).

| Treatment satisfaction questionnaire
The DTSQ was used to measure patients' treatment satisfaction at baseline and at the end of the study. DTSQ scores at baseline were not significantly different between treatment arms (Table S4A). At the end of the study, the Curalin group had significantly higher scores for improvement in treatment satisfaction (Q1) (P = 0.01), recommendation of treatment (Q7) (P = 0.038), continuing treatment (Q8) (P = 0.008), and perceived hyper-and hypoglycemia levels (Q2 and Q3) (P = 0.002 and P = 0.005, respectively) (Table S4B). 16

| Adverse events
Patients experiencing AEs reported them as mild. No deaths or SAEs occurred during the study (Table S5).

| DISCUSSION
This study evaluated the effect of Curalin as an add-on therapy for patients with type 2 diabetes mellitus. The results showed that participants in the Curalin arm experienced a significant reduction in HbA1c levels after 1 month of therapy. The study also demonstrated 2-fold and 4-fold decreases in HbA1c of >0.5% and >1% in patients treated with Curalin versus placebo. The effect was on fasting, pre-, and post-prandial blood glucose levels.
This effect was observed in 35/36 patients with long-term diabetes who had previously received anti-diabetes drugs but failed to attain the desired HbA1c target values.
In a meta-analysis of different food supplements for weight loss, subjects who took nutritional supplements were found to have reduced appetite, increased energy expenditure, and a 2 kg decrease in body weight. 17 In the current study, the short exposure to Curalin supplement failed to result in reduced body weight. Longer studies using Curalin supplement may show a reduction in body weight as a benefit in addition to significant decreases in haemoglobin HbA1c.
Based on the DTSQ, patients in the Curalin treatment arm perceived overall higher satisfaction than placebo-treated patients.
Curalin, which was added to the patients' treatment regimen that included hypoglycemic drugs, was shown to be well-tolerated.
The use of CAM for the treatment of type 2 diabetes mellitus has been previously researched; however, inter-study comparisons are challenging. Most studies that demonstrated the superiority of CAM over placebo included mostly naïve patients or patients taking one anti-diabetes drug. 18 The efficacy and minimal side-effects of Curalin therapy reported here support the need for larger and longer studies to approve the findings of this pilot study.

| Limitations
The study included a relatively small sample and was too short in duration to demonstrate the effect of the supplement on HbA1c over a long exposure. The participants were not on dietary control; consequently, we cannot draw conclusions based on their dietary behaviour. The effect of the supplement is more difficult to evaluate compared to pharmacological drugs due to possible differences in efficacy between batches. -5 of 6 editing the manuscript. All authors take responsibility for the accuracy of the manuscript. Julio Wainstein is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis and for the work as a whole.

ACKNOWLEDGEMENTS
This study was fully funded by CuraLife. CuraLife did not influence the conduct of the study.

CONFLICTS OF INTEREST STATEMENT
Itamar Raz is a paid consultant for CuraLife. The rest of the authors have no conflicts of interest to declare.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
Not Applicable.