Abstract
Background
Glucagon-like peptide-1 receptor agonists (GLP-1RA) and Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) are effective antidiabetic therapies in patients with type 2 diabetes mellitus (T2DM). However, real-world evidence regarding the combined effectiveness and safety of these agents in this population remains limited. This study aimed to evaluate the effectiveness and safety of GLP-1RA/SGLT2-i therapy (GLP-1RAs and/or SGLT2-i) in patients with T2DM, in comparison with standard treatment approaches.
Methods
This retrospective cohort study reviewed medical records of patients with T2DM attending the diabetes clinic at the University Hospital of Sharjah. Patients on anti-diabetic medications for at least 6 months were included, while those with irregular follow-up, a T2DM diagnosis within the past year, or non-diabetic obesity were excluded. Data were collected at baseline, 3, 6, 12, and 18 months and compared the effectiveness (HbA1c, blood pressure, weight) and safety (gastrointestinal and genitourinary symptoms) of GLP-1RA/SGLT2-i therapy (GLP-1 RA and/or SGLT2-I) with standard treatment.
Results
A total of 199 patients were included in the analysis, of whom 50% were female, with a median age of 61 years (interquartile range [IQR] = 19). Patients receiving the GLP-1RA/SGLT2-i therapy demonstrated a statistically significant reduction in body weight (p = 0.002), whereas no significant weight change was observed in the standard treatment group over the 18-month follow-up period.
Glycaemic outcomes showed greater improvement in the GLP-1RA/SGLT2-i therapy (median change:−2% VS -1%; p=0.001) in 18 months. Both groups demonstrated modest improvements in blood pressure, with no clear superiority observed between the treatment arms.
Regarding safety, hypoglycaemia was the most commonly reported adverse event in the standard treatment group (5.5%, n=11). Within the GLP-1RA/SGLT2-i therapy group, GLP-1 RA were associated with gastrointestinal side effects in 0.5% of patients, leading to treatment discontinuation, while SGLT2 inhibitors were associated with genitourinary symptoms in 2.5% of patients.
Conclusion
GLP-1RA/SGLT2-i therapy with SGLT2-i and/or GLP-1RA showed clinically significant weight loss and HbA1c, with a low percentage of patients experiencing side effects that led to discontinuation and improvement in blood pressure.
Keywords: type 2 diabetes mellitus, glucagon-like peptide-1 agonists, sodium-glucose co-transporter 2 inhibitors, HbA1c, blood pressure
Plain Language Summary
This study looked at how GLP-1RA/SGLT2-i therapy medications, GLP-1 receptor agonists and SGLT2 inhibitors, work in real-life patients with type 2 diabetes in the UAE. We found that these medications were more effective in lowering blood sugar levels and body weight compared to standard treatments. However, their effect on blood pressure was not significantly different from that of standard treatment. Side effects were generally mild but may have been underreported. These findings help clinicians understand how these medications perform outside clinical trials.
Introduction
Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent noncommunicable diseases. 1 It is estimated that, by the year 2030, there will be more than 643 million individuals worldwide living with diabetes. 2 The prevalence of diabetes contributes to a large number of deaths worldwide. In 2021, diabetes was responsible for 6.7 million deaths around the globe. 3 The United Arab Emirates (UAE), in comparison to other countries, has a high prevalence of T2DM, with an estimated prevalence of 16%. 4
For decades, in the absence of contraindications, metformin has been the first-line treatment for T2DM patients. Metformin is generally well tolerated, inexpensive, does not cause hypoglycemia, and has moderate weight loss effects. 5 On the other hand, sulfonylureas and insulin may have unfavorable side effects on patients, such as hypoglycemia and weight gain. Clinical care has evolved in the past few decades to encompass not only managing hyperglycemia per se but also protecting against both macrovascular and microvascular complications. Glucagon-like peptide-1 Receptor Analogue (GLP-1RA) and Sodium-Glucose Co-Transporter 2 inhibitor (SGLT2-i) belong to a new class of antihyperglycemic medications and have been investigated during the last decade by several clinical trials for their efficacy and potential benefits in controlling and preventing complications associated with T2DM. Both GLP-1RA and SGLT2-i provide wide-ranging benefits in diabetes management. Glucagon-like peptide 1 (GLP-1) is an incretin mimetics hormone encoded in the proglucagon gene.6,7 It is produced mainly in enteroendocrine L cells of the small intestine when blood glucose level rises after food intake. GLP-1 has a half-life of ∼2 minutes and is degraded by the enzyme Dipeptidyl peptidase-4 (DPP4). 8 Therefore, a synthetic glucagon-like peptide receptor analogue that resists the DPP-4 and thus has a longer half-life, has been clinically integrated. Various actions are triggered in the body by GLP-1. For instance, it increases satiety in the brain and decreases gastric emptying in the stomach which explains weight loss. In addition, there has been research showing that because GLP-1 has anti-atherosclerotic action, it improves endothelial dysfunction by lowering oxidative stress and inflammatory indicators. This may explain the beneficial effects of GLP1-RA in the improvement of blood pressure. 9 There are several forms of GLP-1 RA medications available including Exenatide (Byetta, Bydureon), Liraglutides (Victoza,), Dulaglutide (Trulicity), and Semaglutide (Ozempic), Lyxumia (Lixisenatide), Rybelsus (Semaglutide). Moreover, patients receiving GLP-1 RA usually experience diarrhea, nausea, and vomiting after the start of the treatment. GLP-1 RA is most associated with nausea, with up to 50% of patients experiencing it. 3 Although these side effects gradually decrease in frequency by time, 10 more than 4% of GLP-1 RA discontinuations are due to these gastrointestinal (GI) symptoms. Consequently, it is vital to acknowledge these symptoms as a real concern. 11 Additionally, other side effects such as rash, erythema, or itching might be experienced at the injection site. 12
The main function of SGLT2-i is that it inhibits renal glucose absorption in the renal tubules, resulting in glucose excretion in the urine, which leads to a reduction in blood glucose levels and body weight. 13 This in turn leads to HbA1c reduction and weight loss. However, on the other hand, SGLT2-i increases patients’ susceptibility to urinary tract infections (UTI) and genitourinary (GU) problems. 14 The clinical efficacy of GLP-1RA and SGLT2-i has urged physicians to rely completely on them as a first medication option after metformin for most patients with T2DM. Both these drug classes lower glucose concentrations (through distinct mechanisms) without increasing the risk of hypoglycaemia, reduce body weight and albuminuria and prevent cardiovascular events, but they have opposing effects on glucagon secretion which is augmented by SGLT-2 inhibitors but suppressed by GLP-1 receptor agonists. 15
A meta-analysis incorporating data up to 2021 reported that GLP-1RA/SGLT2-i therapy demonstrated greater efficacy in controlling both fasting and postprandial hyperglycaemia, as well as in reducing low-density lipoprotein cholesterol (LDL-C) levels. However, adverse events leading to treatment discontinuation such as hypoglycaemia, vomiting, and diarrhea were more frequently observed with combination regimens. In contrast, a more recent meta-analysis including studies published up to 2023 indicated that these metabolic benefits associated with combination therapy are unlikely to surpass those achieved with GLP-1 receptor agonist monotherapy.
However, real-world evidence from this region remains limited, underscoring the need for context-specific studies to evaluate the effectiveness of these therapies. It is essential that clinicians and patients are supported by robust evidence regarding the safety and efficacy of these agents.
Accordingly, the primary aim of this study is to evaluate the effectiveness of GLP-1RA/SGLT2-i therapy (GLP-1 RA and/or SGLT2-i) in reducing HbA1c, blood pressure, and body weight in patients with T2DM, compared with standard treatment care. The secondary aim of this study is to identify the side effects of GLP-1 RA, in relation to GI symptoms, and of SGLT2-i in relation to GU symptoms as reported by patients with T2DM.
Methods
Study Design
This study is a retrospective observational cohort study conducted using real-world data from medical records. It aimed to study the safety and effectiveness of GLP-1RA/SGLT2-i therapy (GLP-1RA and/or SGLT2-i) under real-world conditions. The study utilized a retrospective cohort research design where retrospective analysis of patients’ records was conducted to collect different demographic and biochemical data. The study aimed to compare patients with T2DM who received GLP-1RA/SGLT2-i therapy (GLP-1 RA and/or SGLT2-i) with standard treatments for T2DM during the past two years.
Study Location
The study was conducted at the endocrine and diabetes outpatient clinic at the University Hospital Sharjah (UHS). The UHS is a private, national, co-educational university situated in University City, Sharjah, in the United Arab Emirates.
Sample Size Calculation
In this study, no sampling method calculation was applied as all medical records of patients registered in the diabetes clinics at UHS were reviewed and only patients who met the study’s eligibility criteria (inclusion and exclusion) were selected. Up to 10,000 patients visited the endocrine and diabetes clinic between 2020 and 2024, 3,435 files were reviewed and only 199 patients’ records met the eligibility criteria (Figure 1). A patient was considered eligible to be included in this study if they were aged ≥18 years, were on treatment for more than 6 months and had a regular follow up. Non-diabetic obese patients and those using GLP-1 RA for obesity management were excluded, as well as patients with irregular follow-up and newly diagnosed T2DM within one year.
Figure 1.
Selection criteria for the studied population.
Ethical Consideration
Since this study relied on reviewing medical records only and did not require contacting patients, patients’ consent was not obtained. Instead, a waiver of consent was sought from the UHS research ethics committee before accessing the patients’ medical records (Approval reference number is HERC-110-25092022). To maintain the confidentiality of the patients’ data, medical records were anonymized and coded prior to data collection.
Data Collection Procedure
Using the hospital’s database system, data were collected from the UHS list of patients visiting the endocrine and diabetes clinic. A total of 3,435 patients’ records were reviewed between January 2020 and February 2023. We then categorized study participants into two groups, GLP-1RA/SGLT2-i therapy vs standard treatment. The “ GLP-1RA/SGLT2-i therapy ” group included patients who were taking at least one of the two medications, GLP-1 RA and/or SGLT2-i, irrespective of taking any other medication. Patients in the “Standard treatment’ group were those who were taking any of the antidiabetic medications including metformin, sulfonylurea, thiazolidinedione (TZD), insulin, and DPP4-I but not GLP-1 RA or SGLT2-i. Several clinical and demographic characteristics were collected from the patients’ records, including their age, gender, weight, BMI, blood pressure, creatinine, lipid profile, HbA1c, urine analysis results and other reported side effects. To monitor changes and evaluate the effectiveness of the treatment, clinical parameters data were collected at five different time points: at baseline, before starting the treatment, followed by subsequent assessments at 3, 6, 12 and 18 months.
Data Analysis
The data were analysed using SPSS 28.0 after cleaning and coding. Descriptive statistics were used for univariate analyses, including measures of data summarization (frequency and relative frequency), central tendency (mean, median, and mode), and variability (standard deviation and interquartile range), as appropriate to the data type. Normality of scale data was first tested visually using the histogram and Q-Q plots and then statistically using the Kolmogorov-Smirnov test and Shapiro-Wilk test and appropriate tests were used. Bivariate analysis was performed to study associations between categorical variables. Inferential statistics tests, including Chi-square, t-test, ANOVA and Pearson correlation were conducted as appropriate to the type of analysis and variables involved. For example, to study the reduction in HbA1c levels at a single point in time as compared to the baseline value, we used either the paired samples t-test when the paired difference showed a normal distribution or the Wilcoxon test when differences showed skewed distribution. Furthermore, Mann-Whitney U test was used to compare medians of HbA1c reduction between the two treatment groups. Two-way repeated measures ANOVA were performed to measure the change in means between different time points within the same group of patients and between the two treatment groups (standard and GLP-1RA/SGLT2-i therapy). This analysis was done to determine whether time had a significant effect in changing the clinical outcomes and to determine whether any change in the clinical outcome was the result of the interaction between the two studied factors, which are time and type of treatment. The level of significance was set at 5% and therefore, a p-value below 0.05 was considered statistically significant.
Results
Baseline Characteristics
Out of the 3,435 patient records reviewed, 199 met the study eligibility criteria and were included in the analysis. The baseline demographic, clinical, and biochemical characteristics of the study participants are summarized in Table 1. Briefly, the cohort had a median age of 61 years and included a nearly equal distribution of males and females. Most participants were overweight or obese, and a considerable proportion had comorbid conditions, including hyperlipidemia and hypertension. At baseline, glycemic control was generally suboptimal, with a median HbA1c of 8.6% (IQR = 3.4); only 15% of participants had HbA1c levels below 7%, whereas 37.5% and 45.6% had HbA1c levels of 7–9% and >9%, respectively.
Table 1.
Baseline Demographic and Clinical Characteristics of Study Participants (N=199)
| | Total | Type of treatment | p-value | ||||
|---|---|---|---|---|---|---|---|
| Standard | GLP-1RA/SGLT2-i | ||||||
| N | % | N | % | N | % | ||
| Gender | |||||||
| Male | 99 | 49.7 | 79 | 84.0 | 15 | 16.0 | 0.635 |
| Female | 100 | 50.3 | 79 | 81.4 | 18 | 18.6 | |
Values are presented as N(%), Median/IQR or Mean/SD. Statistical significance was set at p < 0.05.
*Median and IQR were reported for data with skewed distribution.
**Mean and SD were reported for data with normal distribution.
Abbreviation: BMI: Body mass index, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, TG: Triglycerides, LDL: Low density lipoprotein, HDL: High density lipoproteins, IQR: Interquartile range, N: Numbers, SD: Standard deviations.
Types of Antidiabetic Medications Used in the Studied Population
The medications that were most used at baseline were Metformin (54%, n=109), DPP4-I (30.5%, n= 50), insulin (17%, n=35), SGLT2-i (14%, n=28), GLP-1 RA (3.5%, n=7), and TZD (0.5%, n=1) (Table 2, Figure 2). SGLT2-i became the second most prescribed medication at the 3-, 6-, 12- and 18-months visits after Metformin. A comparison of the proportion of standard vs. GLP-1RA/SGLT2-i therapy treatments used at baseline, 3, 6, 12, and 18 months later is shown in Figure 3. According to the baseline data, 79% (n=158) of the patients were receiving standard treatment, while 31% (n=33) were receiving GLP-1RA/SGLT2-i therapy treatment. In the following 3, 6, 12, and 18 months, 78% (n=156) received the GLP-1RA/SGLT2-i therapy, while 21% (n=43) received the standard treatment (Figure 3).
Table 2.
Percentage of all Antidiabetic Medications Used at 0, 3, 6, 12 and 18 Months
| Treatment | Baseline | 3 months | 6 months | 12 months | 18 months |
|---|---|---|---|---|---|
| Metformin | 54% | 83.4% | 82.9% | 82.9% | 82.9% |
| TZD | 0.5% | 4% | 4% | 4% | 4% |
| SU | 27% | 16.1% | 16% | 16.1% | 16% |
| DPP4-I | 30.5% | 53.3% | 53% | 54% | 53.3% |
| Insulin | 17.5% | 27% | 28.1% | 27% | 27.5% |
| SGLT2-i | 14% | 68% | 68% | 69.3% | 69% |
| GLP-1RA | 3.5% | 24.1% | 25.1% | 25.6% | 25.6% |
Values are presented as numbers (%) for categorical variables.
Abbreviations: TZD: Thiazolidinediones, SU: Sulfonylureas, DDP4-I: Dipeptidyl peptidase 4 inhibitors.
Figure 2.
Percentage of antidiabetic medications of GLP-1RA/SGLT2 inhibitor therapy and standard drug groups at baseline, 3-, 6-, 12-, and 18- months treatment duration.
Figure 3.
A comparison of the percentage of patients who were on standard versus new treatments at baseline then at 3, 6, 12, and 18 months.
Effects of the Standard and GLP-1RA/SGLT2-I Therapy on HbA1c
Within the standard treatment group, the median values of HbA1c at baseline, 3, 6, 12, and 18 months were 7.7% (IQR=3.9), 6.6% (IQR=1.6), 6.5% (IQR=0.8), 6.6% (IQR=0.9), 6.8% (IQR=0.8), respectively. The median change in HbA1c from baseline value was -0.8 % (IQR= 1.8, p = 0.002) at 3 months, -1% (IQR= 4.2, p < 0.001) at 6 months, -0.8% (IQR= 3.7 p = 0.002) at 12 months, and -1% (IQR= 3.4 p < 0.001) at 18 months. On the other hand, within the “GLP-1RA/SGLT2-i therapy treatment” group, the median values of HbA1c were 8.9% (IQR=3.5), 7% (IQR=1.4), 6.9% (IQR=1.3), 6.9% (IQR=1.8), 6.9% (IQR=1.8), at baseline, 3, 6, 12 and 18 months, respectively. The median reduction in HbA1c at 3, 6, 12, and 18 months, as compared to baseline values, was -1.5% (IQR=2.2, p < 0.001) at 3 months, -1.7% (IQR=2.4, p < 0.001) at 6 months, -1.9% (IQR = 2.4, p < 0.001) at 12 months, and -2% (IQR = 2.8, p < 0.001) at 18 months.
The median reductions in HbA1c from baseline values were compared between the standard and GLP-1RA/SGLT2-i therapy treatment groups for different times (3, 6, 12 and 18 months). The analysis revealed that reductions at all time points (3 months, 6 months, 12 months and 18 months) were significantly different between the two treatment groups (Figure 4).
Figure 4.
Comparison of the decreased levels in HbA1c levels between baseline and 3, 6, 12, and 18 months by type of treatment (standard treatment vs. new treatment). * (P<0.05).
A Two-way repeated measures ANOVA were conducted to study the effect of interaction between time and treatment on the change in HbA1c levels from baseline to 3, 6, 12, and 18 months. There was a significant effect of the time factor within each group (F= 24.7, p < 0.001). However, there was no interactive effect between time and treatment (F=1.2, p = 0.310) (Table 2, Figure 5A). Furthermore, between-subjects effects of the treatment were statistically insignificant (F=2.8, p = 0.091). Multiple pairwise comparisons of mean difference in HbA1c revealed that HbA1c values at baseline, were significantly different from values at 3, 6, 12 and 18 months, whereas differences between HbA1c values from 6 months onwards were statistically insignificant (Figure 5A).
Figure 5.
Changes of the clinical outcome between the two treatment groups by time. (A) Changes in HbA1c by time in standard treatment group vs. new treatment group. (B) Changes in weight by time in both groups. (C) Changes in SBP by time in both treatment groups. (D) Changes in DBP by time in both treatment groups.
Effects of Standard and GLP-1RA/SGLT2-I Therapy Treatment on Weight
Within the standard treatment group, the median values of weight at baseline, 3, 6, 12 and 18 months were 74 kg (IQR=30), 78 kg (IQR=23), 80 kg (IQR=23), 79 kg (IQR=24), and 77kg (IQR=22), respectively. Over the timeframe of the study, no weight loss was observed in the standard treatment group; however, median weight changes of +0.5kg (IQR=3.3), +1.5kg (IQR=5), +1kg (IQR=7), and +2kg (IQR=5), were observed, indicating weight gains that were not statistically significant. On the other hand, within the “ GLP-1RA/SGLT2-i therapy treatment” group, the median values of weight were 84 kg (IQR=20) at baseline, then 82 kg (IQR=20) at 3 months, 82 kg (IQR=20) at 6 months, 82 kg (IQR=20) at 12 months, and 82 kg (IQR=20) at 18 months. Weight loss was noted with the GLP-1RA/SGLT2-i therapy treatment, with significant weight changes of -1.7 kg (IQR=3, p < 0.001), -2 kg (IQR=5, p < 0.001), -2 kg (IQR=7, p < 0.001), and -3 kg (IQR=6, p < 0.001) at 3, 6, 12 and 18 months, respectively, as compared to baseline weight values (Figure 6).
Figure 6.
The change in weight from baseline in two groups of patients: Patients on (standard treatment vs. patients on new treatment). (* p<0.05).
The median reductions from baseline values in weight were compared between the standard and GLP-1RA/SGLT2-i therapy treatment groups for different times (3, 6, 12 and 18 months). The analysis revealed that reductions at 3 months, 6months, 12 months and 18 months were significantly different between the two treatment groups (Figure 6).
Two-way repeated measures ANOVA was conducted to study the interaction effect of time and treatment on the change in weight levels from baseline to 3, 6, 12 and 18 months. There was no significant effect of the time factor within each group (F=0.518, p-value = 0.72). However, there was interactive effect between time and treatment (F=5.5, p-value < 0.001) (Table 3). In other words, there is a combined effect of time and treatment on the dependent variable (weight). In this case, there is no main effect for time but there is an interactive effect between time and treatment in general. Therefore, the treatment had a significant effect on the dependent variable weight (F=9.6, p-value = 0.002). Multiple pairwise comparisons of mean differences in weight revealed that weight values at baseline, were insignificantly different from values at 3, 6, 12 and 18 months (Figures 5 and 6). Table 4 compares the median reductions of the clinical outcomes (HbA1c and weight) at baseline then after 3, 6, 12, and 18 months.
Table 3.
Two Way Repeated-Measures ANOVA Showing the Effect of Time, Treatment and Interaction Between Time and Treatment on Clinical Outcomes (HbA1c, Weight, BP)
| Clinical outcome | Time | Standard treatment (mean) | GLP-1RA/SGLT2-i therapy (mean) | Two-way repeated measures ANOVA | ||
|---|---|---|---|---|---|---|
| Time | Treatment | Time*Treatment | ||||
| F (p-value) | F(p-value) | F (p-value) | ||||
| HbA1c (%) | Baseline | 8.6 | 9.2 | 24.7 (<0.001) | 2.8 (0.091) | 1.2 (0.310) |
| 3 months | 7.2 | 7.5 | ||||
| 6 months | 6.7 | 7.1 | ||||
| 12 months | 6.6 | 7.1 | ||||
| 18 months | 6.8 | 7 | ||||
| Weight (Kg) | Baseline | 75 | 87 | 0.518 (0.722) | 9.6 (0.002) | 0.892 (<0.0005) |
| 3 months | 76 | 86 | ||||
| 6 months | 76 | 85 | ||||
| 12 months | 77 | 85 | ||||
| 18 months | 77 | 85 | ||||
| Systolic BP (mmHg) | Baseline | 128 | 130 | 4.3 (0.002) | 1.3 (0.24) | 2 (0.099) |
| 3 months | 120 | 127 | ||||
| 6 months | 120 | 126 | ||||
| 12 months | 123 | 127 | ||||
| 18 months | 126 | 124 | ||||
| Diastolic BP (mmHg | Baseline | 78 | 78 | 1.17 (0.35) | 1.6 (0.196) | 0.32 (0.85) |
| 3 months | 75 | 78 | ||||
| 6 months | 76 | 77 | ||||
| 12 months | 76 | 79 | ||||
| 18 months | 75 | 77 | ||||
Data are presented as mean values. F values and corresponding p values are reported for main and interaction effects. Statistical significance was set at p < 0.05.
Table 4.
Comparing Median Changes in Clinical Outcomes at 3, 6, 12, and 18 Months From Baseline Values, Between New Treatment and Standard Treatment Groups
| Clinical outcome | HbA1c (%) | |||
|---|---|---|---|---|
| Standard treatment | GLP-1RA/SGLT2-i therapy | Mann-Whitney | p-Value | |
| Median | Median | |||
| 0-3 months | -0.8% | -1.5% | 2477 | 0.001 |
| 0-6 months | -1% | -1.7% | 2572 | 0.001 |
| 0-12 months | -0.8% | -1.9% | 2507 | 0.001 |
| 0-18 months | -1% | -2% | 2371 | 0.001 |
Data are presented as median values. Between-group comparisons were performed using the Mann–Whitney U test. A negative value indicates a reduction from baseline. Statistical significance was defined as p < 0.05.
Effects of Standard and GLP-1RA/SGLT2-I Therapy Treatment on Blood Pressure
In terms of blood pressure and within the standard treatment group, the median values of SBP/DBP at baseline, 3, 6, 12 and 18 months were 126/80, 120/76, 119/77, 120/77, and 120/77 respectively. At 3, 6, 12, and 18 months, the percentage of patients experiencing improved blood pressure with standard treatment was 30 %, 29 %, 28 %, and 22 %, respectively. Improvements of BP values from baseline was compared between the standard and GLP-1RA/SGLT2-i therapy treatment groups for the different times (3, 6, 12 and 18 months). The analysis revealed that improvements at 3 months, 6 months, 12 months and 18 months were not significant between the two treatment groups (Figure 7).
Figure 7.
Percentage of improvement in BP from baseline to 3, 6, 12, and 18 months between standard treatment and new treatment (p values were 0.2, 0.3, 0.3, 0.9) respectively
Within the GLP-1RA/SGLT2-i therapy treatment group, the median values of SBP/DBP were 128/79, 126/79, 125/79, 125/81 and 125/78 at baseline, 3, 6, 12 and 18 months, respectively. At 3, 6, 12 and 18 months after starting the GLP-1RA/SGLT2-i therapy treatment 21%, 20%, 14%, and 22.3% of patients had improved blood pressure, respectively (p-values were 0.2, 0.3, 0.9) (Figure 7). Yet, the differences in the rates of improvement in BP, at each time point, between the two treatment groups were not statistically significant.
Findings from the Two-way repeat measures ANOVA for the SBP had revealed that there was significant effect of time within group (F=4.3, p = 0.002). However, there was no interaction effects between time and treatment group (F=2.0, p = 0.09). For the DBP, neither time (F=1.17, p = 0.35) nor treatment group had any effects (F=0.32, p = 0.85) on the change of the DBP values. Furthermore, no interaction effect was noted between time and treatment factors (Table 3, Figure 5C and D).
Safety and Tolerability of Both Treatment Groups
In terms of side effects, hypoglycemia was the most common side effect reported by patients in the standard treatment group, occurring in 5.5% (n=11) of patients (Table 5). Among patients in the standard treatment group, 1% (n=2) were unable to tolerate metformin, resulting in abdominal pain and bloating. UTI and genital itching were reported by 2.5% (n=3) of patients taking SGLT2-I, and one patient experienced hearing loss while taking empagliflozin. Patients who were on GLP-1 RA experienced GI symptoms (0.5%, n=1), reported as nausea and vomiting while a single patient (0.5%) reported severe diarrhea.
Table 5.
Reported Side Effects Associated With the Standard and New Treatment
| Side effects | Treatment types | |
|---|---|---|
| Standard treatment | GLP-1RA/SGLT2-i therapy | |
| Hypoglycemia | 5.5%(n=11) | - |
| Abdominal Pain | 1%(n=2) | - |
| Nausea & Vomiting | - | 0.5%(n=1)* |
| Diarrhea | - | 0.5%(n=1)* |
| Genitourinary | - | 2.5%(n=3)* * |
| Hearing Loss | - | 0.5%(n=1)* * |
Data are presented as percentage (number of patients).
*Side effects associated with GLP-1 RA.
**Side effects associated with SGLT2-i.
Discussion
To our knowledge, this study is one of the few real-world studies that were conducted in the UAE and aimed at evaluating the effectiveness of GLP-1RA/SGLT2-i therapy (GLP1-RA and SGLT2-i) compared to other standard treatments in lowering HbA1c, blood pressure, and weight in patients with T2DM. The study also aimed to identify the side effects of these medications among patients with T2DM.
The study findings demonstrated that the GLP-1RA/SGLT2-i therapy (SGLT2-I and GLP-1 RA) significantly reduced HbA1c from baseline at 3, 6, 12 and 18 months in comparison with the standard treatment. This finding is consistent with that reported by Carretero et al who found statistically significant reduction in HbA1c in patients with T2DM treated with SGLT2-I and GLP-1 RA). 16
In this study, we further investigated the effectiveness of SGLT2-I and GLP-1 RA in reducing weight in T2DM patients. The study findings have shown that there was significant weight loss at 3, 6, 12, and 18 months in patients treated with SGLT2-I and GLP-1 RA. Similarly, Brown et al and Deol et al reported in their retrospective cohort studies that their cohorts lost weight between -3.1 kg and 3.01 kg, respectively when GLP-1 RA and SGLT2-I were combined.17,18
In this study, lack of superiority in patients receiving dual treatment (SGLT2-I &/or GLP-1 RA) to standard treatment was found although both groups of patients showed some improvement in blood pressure. Similarly, Deol et al, within their cohort study, showed no significant improvement in BP for patients on dual therapy. 17
However, baseline differences between the treatment groups, particularly in HbA1c and body weight, may have influenced the observed outcomes and limited direct comparability. In addition, important confounding factors such as duration of diabetes, baseline antidiabetic therapy, medication dosage, renal function, and lifestyle factors (including diet and physical activity) were not adjusted for in the analysis, which may have affected treatment response.
In the GLP-1RA/SGLT2-i therapy treatment group, the most common side effects were genital itching and urinary tract infections due to glucosuria associated with SGLT2-i. For instance, Mathieu et al reported a cumulative incidence of GU infection of less than 6.0% which almost synchronized this study. 19 In this study, hearing loss was reported by one patient taking empagliflozin, yet it was unclear whether hearing loss was attributed to the empagliflozin or to diabetes disease. However, the patient reported that when he stopped taking the empagliflozin, he regained his hearing ability. This incident of hearing loss is supported by a large cohort study which concluded that diabetic patients were found to have higher rates of hearing loss than non-diabetic patients (9.2% vs. 1.8%). 20 On the other hand, there are no reports of hearing loss or tinnitus associated with any of the FDA-approved diabetes medications currently available. 21 In our study, due to GI symptoms associated with GLP-1 RA, only one patient reported severe diarrhea and another reported nausea and vomiting, leading to the discontinuation of these medications. In general, both groups of medications were well tolerated in this cohorts.
GLP-1 RA and SGLT2-I have shown a noticeable change in the flow of the diabetes management guidelines. When GLP-1 RA and SGLT2-I were combined, HbA1c, weight, and blood pressure were reduced. 22 Findings of clinical trials have been supported by Real-World Studies (RWS) that have shown similar results reporting minimal side effects of these medications. Cultured human cardiomyocytes exposed to high glucose showed increased expression of SGLT2 protein compared to cells exposed to normal glucose. The presence of SGLT2 in cardiomyocytes supports the hypothesis of SGLT2i-mediated impact on metabolic pathways within cardiomyocytes. 23
SGLT2-I therapy may reduce about 65% the risk to have major adverse cardiovascular events at 1 year of follow-up, via ameliorative effects on glucose homeostasis, and by the reduction of systemic inflammatory burden, and local effects on the atherosclerotic plaque inflammation, lipids’ deposit, and fibrous cap thickness in multi vessel non-obstructive coronary stenosis patients with T2DM. 24 Metformin therapy might ameliorate cardiovascular outcomes by reducing inflammatory parameters, SGLT2, leptin levels and finally improving Sirtuin 6 levels in acute myocardial infarction -pre-diabetes patients treated with coronary artery bypass grafting. 25 GLP-1 RA drugs in addition to conventional hypoglycemic therapy may significantly reduce systemic inflammation and circulating Brain natriuretic peptide levels in cardiac resynchronization therapy with a defibrillator patients with diabetes, leading to a significant improvement of left ventricular ejection fraction and of the 6 min walking test, and to a reduction of the arrhythmic burden. 26
In addition to their established cardiometabolic benefits, emerging evidence suggests that GLP-1 receptor agonists and SGLT2 inhibitors may influence molecular pathways involved in aging and metabolic regulation. Sirtuin 1 (SIRT1), an anti-aging regulatory gene, plays a critical role in insulin sensitivity, inflammation control, and cellular stress resistance, and is increasingly recognized in the pathophysiology of type 2 diabetes mellitus. Previous studies have demonstrated that activation of SIRT1 is associated with improved glucose homeostasis, reduced oxidative stress, and attenuation of cellular senescence and apoptosis.27-29
Although long-term clinical data (3–5 years) directly evaluating the effects of GLP-1 receptor agonists and SGLT2 inhibitors on SIRT1 remain limited, these therapies may indirectly enhance SIRT1 activity through their anti-inflammatory and metabolic effects. Improvements in oxidative stress, mitochondrial function, and systemic inflammation may contribute to modulation of anti-aging pathways. Further longitudinal studies are warranted to clarify the sustained impact of these agents on SIRT1 and related biomarkers.
Moreover, glucagon-like peptide-1 receptor agonists (GLP1-RA) have demonstrated significant benefits in patients with high cardiovascular risk, excess body weight or obesity and heart failure, in particular heart failure with reduced ejection fraction. 30 The combination of SGLT-2i and GLP-1RA is associated with a reduced incidence of cardiovascular events in patients with T2DM and acute myocardial infarction compared with either drug used alone, with a significant effect also on peri-infarcted myocardial rescue in patients without a second event. 31 The critical insights into the cardiorenal protective effects of SGLT2i, GLP-1RAs, and DPP-4i and underscores the importance of these medications in mitigating the progression of cardiovascular and renal complications, and their broader clinical implications beyond glycemic management. 32
GLP-1 RA and SGLT2I were widely used at the University Hospital of Sharjah due to their effectiveness on improving different clinical outcomes. This study aimed to evaluate the effectiveness of GLP-1RA/SGLT2-i therapy in lowering HbA1c, weight and BP in T2DM compared with the standard treatment. This study findings were like those reported by other real-world studies showing that patients receiving the GLP-1RA/SGLT2-i therapy treatment experienced significant reduction in their weight and HbA1c. Real-world clinical experience might uncover additional factors that can improve prescribing information for this useful class of drugs in the future.
Limitations of the Study
Despite the strengths of this study, which may be a source of credibility and accuracy, the study also possesses some limitations. These include the fact that it is an single-center-based study, as data were collected from a single private hospital. This might limit the generalizability of the study findings to the whole population at large. Another limitation is that variation between drugs’ doses was not taken into consideration. Medication doses can affect both the effectiveness of medications and patient compliance. Similarly, in this study, there was no consideration of ethnic background, co-morbidities, diet, or exercise which are considered as important confounding factors that should have been controlled for, as they could be associated with our clinical outcomes. Additionally, since this is a retrospective observational cohort study, it has a small sample size that limits the ability to examine factors associated with side effects. Another important limitation of this study is the presence of baseline differences between the treatment groups, particularly in HbA1c and body weight, which may have influenced the observed outcomes.
Furthermore, grouping GLP-1 receptor agonists and SGLT2 inhibitors into a single treatment category may introduce heterogeneity due to their distinct mechanisms of action and different clinical effects. Future studies should analyze these drug classes separately to provide more precise estimates of their individual effectiveness and safety profiles.
The incidence of adverse effects reported in this study may be underestimated, as data were obtained retrospectively from medical records rather than through systematic and prospective monitoring. Therefore, safety outcomes should be interpreted with caution.
Additionally, the retrospective observational design and relatively small sample size limit the statistical power and generalizability of the findings. As such, the study provides descriptive real-world evidence but is not sufficient to establish causal relationships or definitive comparative effectiveness.
In spite of these limitations, the study showed encouraging results for the benefits of the treatment of both GLP-1 RA and SGLT2-I. This study may be considered by clinicians as an exciting and motivational data source affecting their daily clinical practices.
Recommendations and Future Directions
Prospective multi-center cohort studies are recommended to be conducted in the UAE with a large number of patients in order to produce significant and valuable outcomes. Furthermore, there are other risk and confounding factors that should be considered in future studies, and these include age, co-morbidities, glucose variability, diet, exercise, doses of medications, severity and duration of diabetes. To enhance physicians’ knowledge, more real-world studies, which reflect patients’ experiences, are needed ultimately leading to better guidelines and management plans. The use of real-world studies allows researchers to generate hypotheses requiring further investigations and to address research questions that are impractical to answer using RCTs.
Conclusion
In this real-world retrospective cohort study, GLP-1 receptor agonists and SGLT2 inhibitors were associated with significant improvements in HbA1c and body weight compared to standard treatment, while no significant differences were observed in blood pressure outcomes. These therapies were generally well tolerated; however, safety outcomes should be interpreted cautiously due to the retrospective design. Further large-scale prospective studies are required to confirm these findings and to better understand long-term outcomes.
Acknowledgements
This study was supported by the University of Sharjah Centre for Diabetes. The authors wish to thank the Endocrinology and Diabetes Department at UHS for supporting this study.
Footnotes
Author Contribution: Salah Abusnana: Conceptualization, methodology, validation, data curation, writing-review and editing, visualization, supervision. Bashair Mohammed Mussa: Conceptualization, methodology, validation, data curation, writing-review and editing, visualization, supervision. Nada Maher Mahmoud: Methodology, validation, formal analysis, investigation, data curation, writing and editing original draft preparation, visualization. Amal Hussein: Data Analysis, data curation, revalidation. All authors are approved the final manuscript for submission.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
ORCID iDs
Nada Maher Mahmoud https://orcid.org/0009-0004-3139-5639
Amal Hussein https://orcid.org/0000-0002-0708-8119
Bashair M. Mussa https://orcid.org/0000-0002-1554-6319
Salah Abusnana https://orcid.org/0000-0001-6546-8622
Ethical Considerations
Ethical clearance was obtained from the UHS research ethics committee, approval letter reference number HERC-110-25092022, Dated 25-09-2022.
Data Availability Statement
Data available from the corresponding author upon reasonable request.*
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data available from the corresponding author upon reasonable request.*