The combination of an SGLT2i plus a GLP-1 RA, canagliflozin plus liraglutide, results in surprising effects on endogenous glucose production and HBA1c.
In an ongoing effort to optimize type 2 diabetes (T2D) treatment, researchers and clinicians have hypothesized that combination therapy of different classes of hyperglycemic medications would produce additive or synergistic HBA1c-lowering effects. One such combination is a sodium-glucose cotransporter 2 inhibitor (SGLT2i) with a glucagon-like peptide-1 receptor antagonist (GLP-1 RA). SGLT2is exert their antihyperglycemic effects by inhibiting glucose reabsorption in the kidney and promoting excretion of glucose in the urine. Countering their antihyperglycemic mechanism mentioned above, SGLT2is also, through an unknown mechanism, increase endogenous glucose production (EGP) and cause a decrease in insulin production and an increase in glucagon production. The rise in EGP by SGLT2is replaces up to 50% of the plasma glucose lost through the SGLT2is other mechanisms to lower blood glucose, thus negating its effect. In contrast to SGLT2is, GLP-1 RAs exert their antihyperglycemic effect by increasing insulin production, decreasing glucagon production, and enhancing insulin glucose sensitivity. The hypothesis in the study by Ali et al. is that a GLP-1 RA’s antihyperglycemic mechanism will counter the hyperglycemic effects of the SGLT2i, resulting in an HBA1c-lowering additive impact.
To determine the long-term effects of SGLT2i plus GLP-1 RA combination on EGP and HBA1c versus either drug alone, researchers at the University of Texas conducted a 16-week trial of 45 T2D patients. Patients were randomized to receive either liraglutide 1.2 mg/day (LIRA), canagliflozin 100 mg/day (CANA), or canagliflozin 100 mg plus liraglutide 1.2 mg (CANA/LIRA). Patients were either treatment naïve (n=6) or on a stable dose of metformin +/- a sulfonylurea (n=39) and were well matched based on HBA1c, age, weight, sex, and duration of diabetes. Basal EGP was measured at the start of the research before and after medication infusion and again at 16 weeks. Researchers collected patient HBA1c, body weight, and hormone (glucagon and insulin) concentrations in addition to EGP.
After the study, CANA/LIRA produced the greatest effect on HBA1c, reducing it by a mean of 1.67% +/- 0.29% (p=0.0001). Reduction of HBA1c by CANA/LIRA was significantly greater than CANA monotherapy (p=0.05), which reduced the HBA1c 0.89% +/- 0.24% (p=0.004); however, statistical significance was not achieved when comparing CANA/LIRA to LIRA monotherapy, which reduced the HBA1c by 1.44% +/- 0.39% (p=0.004). As expected, LIRA was associated with a decrease in EGP (2.36 +/- 0.08 to 2.17 +/- 0.11 mg/kg/min, p=0.02) while CANA was associated with an increase (2.29 +/- 0.07 to 2.50+/- 0.15 mg/kg/min, p=0.05) and a 21% increase in plasma glucagon concentrations. Against the researchers’ hypothesis that the CANA/LIRA combination would prohibit any increase in EGP, CANA/LIRA instead increased EGP at 16 weeks by 16% (2.40 +/- 0.14 2.78 +/- 0.16 mg/kg/min, p <0.01). Interestingly, the plasma glucagon and insulin remained unchanged in the CANA/LIRA group indicating that the intended mechanism to counter the SGLT2i EGP increase was successful. Still, it did not correlate with the clinical success of an additive effect in HBA1c. In contrast to CANA/LIRAs effect on HBA1c, its effect on body weight was additive with a mean decrease of 6.0 +/- 0.8 kg (p<0.0001), which was significantly different in comparison to both CANA (-3.5 +/- 0.5 kg, p<0.0001) and LIRA (-1.9 +/- 0.8 kg, p=0.03).
By combining diabetes drug classes, this research sheds light on the mechanisms, specifically EGP, that these drugs exert on the body. Previous work by these researchers and others had previously shown that a combination of an SGLT2i and a GLP-1 RA does not produce an additive HBA1c-lowering effect, but newly presented in this research is the effect on EGP. From a scientific research perspective, two things are made clear by this research. First, despite a proposed competing mechanism, GLP-1 RAs failed to curb an increase in EGP caused by SGLT2is. Second, despite the lack of an increase in plasma glucagon and insulin, the CANA/LIRA group still increased EGP, demonstrating that EGP is controlled by a mechanism other than glucagon and insulin. The mechanism remains unclear, but the researchers postulate an increase in renal, rather than hepatic, gluconeogenesis may be the culprit in SGLT2i-induced EGP increase. From a clinical perspective, the evidence supporting the combination of an SGLT2i to a GLP-1 RA in T2D patients for the sole purpose of lowering their HBA1c is weak. However, as shown in this research, if the patient were to have a compelling need for weight reduction not achieved through non-pharmacological measures, combining an SGLT2i to a GLP-1 RA may be a viable option.
- The HBA1c-lowering effect of a combination of canagliflozin, an SGLT2i, plus liraglutide, a GLP-1 RA, was not significantly different from that of liraglutide monotherapy.
- GLP-1 RAs produce an increase in basal endogenous glucose production, which negates up to 50% of the plasma glucose lost by the SGLT2is effect on glucose reabsorption in the kidney.
- Despite the lack of effectiveness in the SGLT2i/GLP-1 RA combination in HBA1c-lowering, there was a significant difference in weight loss compared to either drug alone, presenting a potential clinical role for the combination.
Ali, Ali Muhammed, et al. “Combination Therapy With Canagliflozin Plus Liraglutide Exerts Additive Effect on Weight Loss, but Not on HbA1c, in Patients With Type 2 Diabetes.“ Diabetes care vol. 43,6 (2020): 1234-1241. doi:10.2337/dc18-2460
David Clarke, PharmD Candidate, University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences