INTRODUCTION
Sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1RA) are novel and effective treatment options for patients with type 2 diabetes mellitus (T2DM) [
1]. Both drugs showed cardiovascular benefits and are strongly recommended for T2DM patients with cardiovascular disease (CVD) or at high risk of CVD [
2,
3]. SGLT2i inhibits renal glucose reabsorption in the proximal tubule, producing glycosuria and ameliorating glucotoxicity [
2,
3]. GLP-1RA decreases plasma glucose levels by enhancing glucose-stimulated insulin secretion and inhibiting glucagon secretion [
2,
3]. In clinical trials, the combination of SGLT2i and GLP-1RA was significantly better than either drug alone in glycemic control and weight loss, while having an acceptable safety profile [
4-
6]. Furthermore, a few retrospective studies reported the effectiveness of this combination [
7-
9]. The beneficial effects of SGLT2i and GLP-1RA are likely complementary and potentially additive, making them a compelling duet for treating patients with T2DM. However, real-world data regarding this combination therapy in Asian population is lacking. Thus, we investigated the efficacy and safety of GLP-1RA and SGLT2i combination therapy in Korean patients with T2DM in real-world practice.
METHODS
Study population
We retrospectively reviewed the medical records of 104 T2DM patients at Asan Medical Center (AMC), Korea, who applied the combination of SGLT2i (dapagliflozin or empagliflozin) and GLP-1RA (dulaglutide) for at least 1 year between January 2016 and September 2020. The exclusion process is provided in
Supplementary Fig. 1. This study was conducted following the guidelines in the Declaration of Helsinki and was approved by the Institutional Review Board of AMC (2020-1814). Informed consent was waived by the board.
Clinical and laboratory measurements
The baseline data included age, sex, body weight, height, body mass index (BMI), blood pressure (BP), duration of diabetes, use of other medications, and presence of diabetic complications. Laboratory measurements including glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (LDL-C), liver enzymes, and renal parameters, and adverse events were collected. These data were collected 6 months (±4 weeks) and 1 year (±4 weeks) after initiating the combination therapy.
Dulaglutide was started at 0.75 mg and was escalated to 1.5 mg after 2 to 4 weeks, unless the patients experienced adverse events, reached the glycemic target with 0.75-mg dulaglutide, or desired not to increase the dose.
Outcomes
The study’s primary outcome was the efficacy of the combination therapy in glycemic control in 1 year. The secondary outcomes were changes in other laboratory parameters, such as FPG, body weight, BP, lipid parameters, liver enzymes, renal measures, and insulin dose.
Statistical analysis
Continuous variables were expressed as the mean±standard deviation and categorical variables as percentages. Paired t-test assessed changes in HbA1c, FPG, and body weight from baseline after 6 months and 1 year. Univariate and multivariate linear regression analyses assessed the parameters affecting the glycemic response. Subgroup analyses compared the reduction of HbA1c according to age, BMI, duration of diabetes, combination sequence, baseline HbA1c, and previous insulin use. All statistical analyses were done using SPSS software version 23.0 for Windows (IBM Co., Armonk, NY, USA).
DISCUSSION
In this real-world data analysis, the combination treatment of SGLT2i and GLP-1RA was effective and safe in patients with T2DM. HbA1c and weight were significantly reduced after 1 year. Additionally, SBP and lipid profile were improved. The baseline HbA1c was associated with the glucose-lowering effect of the combination therapy.
SGLT2i and GLP-1RA emerged as game changers in treating T2DM, as they not only showed efficacy in glycemic control and weight loss but also proved cardiovascular and renal benefits [
1]. Hemodynamic changes induced by SGLT2i and anti-atherogenic effects of GLP-1RA are probable mechanisms of cardiovascular benefits [
10,
11]. Combining the two drugs targeting different pathophysiologic mechanisms of T2DM has been expected to have a synergistic effect [
1].
Previous clinical trials showed the effectiveness of the SGLT2i and GLP-1RA combination. In the DURATION-8 trial, patients started the combination of once-weekly exenatide and dapagliflozin, which was significantly better than either drug alone in decreasing HbA1c, weight, and SBP [
4]. Additionally, in AWARD-10 and SUSTAIN-9 trials, dulaglutide and semaglutide were superior to placebo when added to SGLT2i in lowering blood glucose and weight [
5,
6]. The addition of SGLT2 inhibitors to GLP-1RA was also effective and tolerable in clinical trials conducted in Japan [
12,
13].
Accordingly, a meta-analysis showed that the addition of GLP-1RA to SGLT2i was superior in HbA1c reduction, body weight loss, and lowering of SBP, TC, and LDL-C to SGLT2i alone [
14]. Furthermore, a systematic review also showed that the combination reduced HbA1c, body weight, and SBP significantly more than either drug alone [
15].
Retrospective studies showed similar results regarding combination therapy. For example, in the study of 79 patients, the combination therapy for 3 to 6 months significantly reduced HbA1c and body weight by 1.05% and 3.07 kg, respectively [
8]. Likewise, adding dapagliflozin to GLP-1RA in 109 for a median of 10.9 months resulted in a 0.69% reduction in HbA1c and 2.4 kg reduction in weight [
7]. Another Spanish study showed that the combination therapy reduced HbA1c by 1.1% and weight by 3.5 kg weight loss in 212 patients for 16.4±6.5 months [
9]. Accordingly, our study showed significant improvement in HbA1c, weight, SBP, and cholesterol levels.
The incidence of adverse events was similar to previous real-world studies [
7,
9]. However, no genital infection events were recorded, and most of the events were gastrointestinal and injection site problems associated with dulaglutide. The exclusion of fourteen patients who discontinued the combination therapy due to adverse events during the selection process could be the reason for this finding.
The limitations of this study are as follows. First, this study was conducted without a comparison arm. Second, concurrent use of other anti-diabetic, anti-hypertensive, and lipid-lowering agents might have affected the results. Third, because adverse events were only retrospectively reviewed from medical records, missed events might be present. Lastly, only Korean patients from one institution were included in the analysis.
Despite such limitations, to our knowledge, this is the first to analyze the effectiveness of the SGLT2i and GLP-1RA combination in Asian patients in real-world practice. Also, all study patients continued the combination therapy for more than 1 year, longer than most previous studies, providing evidence for long-term efficacy and safety.
In conclusion, SGLT2i and GLP-1RA combination is effective and tolerable in T2DM patients in real-world practice.