Clinical effectiveness of Liraglutide 3.0 mg and impact of weight loss in improving obesity‐related comorbid conditions in King Fahad Medical City, Kingdom of Saudi Arabia: A real‐world experience

Obesity has emerged as one of the most challenging worldwide problems and, if left untreated, can lead to major illnesses and consequences that can impair patients' health The study's objective was to evaluate the effectiveness of Liraglutide 3.0 mg in inducing weight loss and to assess the improvement of obesity‐related comorbid conditions among people living with obesity (PwO) in the Kingdom of Saudi Arabia (KSA). A retrospective cohort review of PwO with or without diabetes and taking Liraglutide 3.0 mg in combination with diet and exercise for weight management was performed and evaluated at King Fahad Medical City, Riyadh, KSA. We collected patient data from electronic medical records for different parameters. The side effects were not recorded. A cohort of 399 patients who used Liraglutide 3.0 mg for 6 months was included in the study. At baseline, the mean age of the cohort was 46.4 (±12.1) years, mean BMI was 40.4 (±7.7) kg/m2 and most patients (74.4%) were women. Their mean average weight loss was 6.5 (±9.5) kg; p < .001. In the entire cohort, 52.6% of subjects had lost ≥5% of their bodyweight, 27.8% of subjects had lost ≥10%, and 11.3% of subjects had lost ≥15% of their bodyweight. There was a significant reduction in HbA1c by 0.5% (p < .0001) at 6 months of the treatment. Liraglutide 3.0 mg treatment did not affect systolic blood pressure and alanine transferase. Liraglutide 3.0 mg resulted in clinically significant weight loss with better glycaemic control, confirming the drug's effectiveness in the real‐world evidence setting.

kg/m2 is classified as pre-obesity and BMI >=30 kg/m2 is classified as obesity. 1 Due to its drastically rising global prevalence, about 3-fold from 1975 to 2016, it has become a critical public health issue. 2 If the trend continues to upsurge, it is estimated that by 2025, about onethird of the world's adult population will have pre-obesity, and more than 1 billion adults will be living with obesity (PwO). 1 This obesity pandemic carries a large negative economic impacty due to its high healthcare cost. 3 Obesity is a chronic, progressive, relapsing disease associated with a wide range ofobesity-related complications (ORCs) such as cardiovascular disease (CVD), gastrointestinal disorders, type 2 diabetes (T2DM), joint and muscular disorders (e.g. gout and osteoarthritis), respiratory problems, cancer, chronic kidney disease, end-stage renal disease, obstructive sleep apnoea, hepatobiliary disease among other reported physical and mental complications ultimately negatively impacting life expectancy of those individuals living with obesity. 4,5 Obesity is also associated with an increased risk of non-alcoholic fatty liver disease 6 and impaired health-related quality of life. 7 It has also has also emerged as a novel risk factor for hospitalization and death due to  Obesity and pre-obesity are a growing problem globally, with high rates in both developed and developing countries. 4 The Kingdom of Saudi Arabia (KSA) is one of the nations with the highest preobesity and obesity rates among both men and women affecting all different age groups. Family history, diet patterns, eating habits, genetic factors, and lack of physical activity were reported as the leading factors responsible for the high prevalence of obesity in KSA. 9 Previous studies evaluating the prevalence of obesity in KSA reported that CVDs, type 2 diabetes, cancer, hypertension, hyperlipidaemia, obstructive sleep apnoea, and osteoarthritis are among the most significant consequences of obesity in the country. 9,10 These obesity related complications were also reported in the recent nationwide crosssectional survey conducted over phone interviews in June 2020. 11 Regarding its economic burden, a recent study published in the British Medical Journal of Global Health has reported that obesity costs KSA $19 billion annually, and this figure could rise steeply by 2060 if the problem remains unaddressed. 12 The Saudi Vision 2030, an economic and transformative initiative by the govenment of the Kingdom of Saudi Arabia, has emphasized its focus on obesity through its quality-of-life programme aimed at reducing obesity rates by implementing different initiatives including increasing physical activity and lowering the consumption of carbonated beverages among other initiatives targeting the disease. 13 Treatments of obesity, include lifestyle interventions, with a focus on a healthy diet, increasing physical activity, addressing sleep disturbances and circadian rhythm distruption, stress reduction in addition to pharmacotherapy and metabolic surgery. 5 Several clinical trials recurrently demonstrated that glucagon-like peptide-1 receptor analougues (GLP-1RA) are effective treatments for obesity. 14 Liraglutide 3.0 mg is a GLP-1 receptor agonist, marketed as Saxenda ® and developed as an anti-obesity agent. Several phase III clinical trials using a 3.0 mg daily dose of Liraglutide have shown encouraging results. [15][16][17][18][19][20] As a result, Liraglutide 3.0 mg daily has become one of the Food and Drug Authority and Saudi Food and Drug Authority (SFDA)-approved drugs for chronic weight management in subjects with a BMI ≥ 30 kg/m 2 (obesity) or ≥27 kg/m 2 to <30 kg/m 2 (pre-obesity) in the presence of at least one weight-related complication and adjuvant to a healthy diet and increased physical activity. 21 One of the randomized controlled trials (RCTs) studies investigating the efficacy and safety of Liraglutide versus placebo for weight management revealed that significant weight loss was observed over 56 weeks upon the daily use of subcutaneous Liraglutide 3.0 mg among patients with pre-obesity, obesity, and T2DM. 19 Another RCT of Liraglutide 3.0 mg in obesity management; involving 3731 patients with BMI ≥ 27, treated or untreated dyslipidaemia or hypertension, and without T2DM, also reported that Liraglutide 3.0 mg, as an adjunct to a healthy diet and exercise, was associated with reduced bodyweight and improved metabolic outcomes. 18 Real-world evidence (RWE) studies are essential to gather knowledge that can complement and expand the information obtained in RCTs. The evidence provided by the data from the RWE study can inform the payers, clinicians, and patients about the performance of the intervention outside the narrow research setting boundaries, long-term safety and effectiveness of a drug in a large population, its economic performance and comparative effectiveness with other treatments. 22 The recent RWE study investigated the real-world clinical effectiveness of Liraglutide 3.0 mg, combined with diet and exercise, in Canada. 23 Another RWE study assessing the effectiveness of Liraglutide 3.0 mg and patient persistence in treatment in a real-world setting was carried out as a retrospective, observational study by extracting the data from de-identified electronic medical records (EMRs) from an obesity management clinic in Switzerland. 24 Such a RWE study investigating the effectiveness of Liraglutide 3.0 mg in a real-world setting in KSA was not conducted. Therefore, in this study, we aimed to assess the real-world effectiveness of Liraglutide 3.0 mg in KSA through a retrospective database study using an EMR from the obesity center at King Fahad Medical City, Riyadh, KSA. We evaluated the effectiveness of Liraglutide 3.0 mg in inducing weight loss and assessed the improvement of obesity-related complications within the local population of PwO in KSA.
The primary objective of the present study was to evaluate the effectiveness of Liraglutide 3.0 mg in inducing weight loss, and the secondary objective was to assess the improvement of obesity-related complications.

| Study overview
We conducted the retrospective database study using a database of with bodyweight measurements at baseline (90 days before index) and during follow-up (until 180 ± 30 days) were included. The primary analysis assessed the change in the weight from baseline to 6 months; secondary analyses assessed proportional weight change, categorical weight change and change in BMI, HbA1c, blood pressure, lipid profile and ALT levels.

| Study design and study type
This was a non-interventional, retrospective cohort study based on anonymous patient EMR data in Saudi Arabia. Patients were asked to start initiation on Liraglutide 3.0 mg with dose escalation on a weekly interval, starting with 0.6, 1.

| Endpoints
The primary endpoint was to assess the change from baseline to end of the study in bodyweight for individuals who initiated treatment with Liraglutide 3.0 mg. The secondary endpoints were to evaluate the percentage of individuals who succeeded with 5%, 10% or 15% categories and to evaluate change in systolic blood pressure (SBP), diastolic blood pressure (SBP; mmHg), HbA1c, total cholesterol (mg/dL), alanine aminotransferase (ALT; IU/L) from baseline (index date) to end of study follow-up (180 ± 30 days).

| Statistical analysis
Demographic and clinical characteristics of study patients were reported as mean (SD) or median (25th and 75th percentiles) for normally and non-normally distributed continuous variables, respectively. Data normality was tested using the Shapiro-Wilk test.
Additionally, categorical variables will be reported as counts (percentages). Mann-Whitney U and Kruskal-Wallis tests were used to examine the difference in weight loss and blood pressure with

| Study population and baseline characteristics
The cohort of 399 patients who met all selection criteria was included in the study. All 399 participants stayed on the therapy for 6 months.

| Change in HbA1c/glycaemic control
The glycated haemoglobin level was significantly reduced in treating Liraglutide 3.0 mg. The mean change in the level of HbA1c was found to be À0.5 (95% CI: À0.6 to À0.4; p < .0001) at 6 months of treatment compared to baseline. The subgroup analysis by diabetes category revealed that the mean HbA1c changes at 6 months of treatment in people with diabetes were À0.7 (±1.3) and À0.9 (±1.2) (Figures 4, S2 and Table S3).

| Change in SBP and DBP
There were no statistically significant changes in SBP. The mean change in SBP was found to be À1. Note: Data are presented as mean (SD) unless stated otherwise. Abbreviations: ALT, alanine aminotransferase; BMI, body mass index; DBP, Diastolic blood pressure; n, number of patients; SBP, systolic blood pressure; SD, standard deviation.

F I G U R E 2
The proportion of patients with ≥5%, ≥10% and ≥15% weight loss.
F I G U R E 3 Change in mean BMI from baseline. BMI, body mass index.
F I G U R E 1 Change in mean weight loss from baseline.

| Change in ALT level
The as compared to baseline ( Figure S4).

| DISCUSSION
Obesity is a chronic, progressive, and relapsing disease; it is crucial to provide patients with obesity multifaceted support. 25 Anti-obesity medications are valuable tools for treatment of obesity. 26  was a non-significant reduction in SBP and a slight significant increase in DBP by 2.4 mmHg in the entire cohort at 6 months of treatment with Liraglutide 3.0 mg. Our findings follow previous studies reporting a slight increase in DBP by 2 mmHg in a retrospective cohort study in Saudi outpatients 33 and a non-significant increase in DBP in patients studied in Canada. 23 However, we found a non-significant decrease in the TC and ALT levels with 2, 4 and 6 months of Liraglutide 3.0 mg treatments in the selected PwO.
This study is a one-armed observational, non-interventional, retrospective cohort study to analyse anonymous patients' EMR data in