A meta-analysis of 7 trials, including those previously mentioned, was conducted to evaluate the combination of GLP-1 RA and SGLT2i.8 The combination significantly reduced HbA1c levels by 0.61% and 0.85% compared with GLP-1 RA or SGLT2i, respectively. Our trial showed greater HbA1c level reduction of 1% with combination therapy compared with either agent separately. This may have been due in part to a higher baseline HbA1c level in our real-world veteran population. The meta-analysis found the combination decreased body weight 2.6 kg and 1.5 kg compared with GLP-1 RA or SGLT2i, respectively.8 This only reached significance with comparison vs GLP-1 RA alone. Our study demonstrated impressive weight loss of up to about 5 kg after 26 and 52 weeks of combination therapy. This is equivalent to about 5% weight loss from baseline, which is clinically significant.9 Liraglutide and semaglutide are the GLP-1 RAs associated with the greatest weight loss, which may contribute to greater weight loss efficacy seen in the present trial.1
In our trial SBP fell lower compared with the meta-analysis. Combination therapy significantly reduced SBP by 4.1 mm Hg and 2.7 mm Hg compared with GLP-1 RA or SGLT2i, respectively, in the meta-analysis.8 We observed a significant 9 to 12 mm Hg reduction in SBP after 26 to 52 weeks of combination therapy compared with baseline. This reduction occurred despite relatively controlled SBP at baseline (135 mm Hg). Each reduction of 10 mm Hg in SBP significantly reduces the risk of MACE, stroke, and heart failure, making our results clinically significant.10 Neither the meta-analysis nor present study found a significant difference in DBP or eGFR with combination therapy.
AEs were similar in this trial compared with the meta-analysis. Combination treatment with GLP-1 RA and SGLT2i did not increase the incidence of severe hypoglycemia in either study.8 Hypoglycemia was the most common AE in this study, but frequency was similar with combination and separate therapy. Both medication classes are associated with low or no risk of hypoglycemia on their own.1 Baseline medications likely contributed to episodes of hypoglycemia seen in this study: About 80% of patients were prescribed basal insulin, 15% were prescribed a sulfonylurea, and 13% were prescribed prandial insulin. There is limited overlap between the known AEs of GLP-1 RA and SGLT2i, making combination therapy a safe option for use in patients with T2DM.
Our study confirms greater reduction in HbA1c levels, weight, and SBP in veterans taking GLP-1 RA and SGLT2i medications in combination compared with separate use in a real-world setting in a veteran population. The magnitude of change seen in this population appears greater compared with previous studies.
Limitations
There were several limitations to our study. Given the retrospective nature, many patients included in the study did not have bloodwork drawn during the specified time frames. Because of this, many patients were excluded and missing data on renal outcomes limited the power to detect differences. Data regarding AEs were limited to what was recorded in the EHR, which may underrepresent the AEs that patients experienced. Finally, our study size was small, consisting primarily of a White and male population, which may limit generalizability.
Further research is needed to validate these findings in this population and should include a larger study population. The impact of combining GLP-1 RA with SGLT2i on cardiorenal outcomes is an important area of ongoing research.
ConclusionS
The combined use of GLP-1 RA and SGLT2i resulted in significant improvement in HbA1c levels, weight, and SBP compared with separate use in this real-world study of a VA population with T2DM. The combination was well tolerated overall. Awareness of these results can facilitate optimal care and outcomes in the VA population.
Acknowledgments
Serena Kelley, PharmD, and Michael Brenner, PharmD, assisted with study design and initial data collection. Julie Strominger, MS, provided statistical support.