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Endogenous Glucose Production After Treatment with Canagliflozin and Liraglutide

Sep 8, 2018

Pancreatic hormones, glucagon and insulin said partially responsible for unintended increase in glucose.

One of the benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors is their ability to lower blood glucose levels. However, one concern with this drug class is the rise in endogenous glucose production (EGP) after several weeks of use. So, what exactly is causing this response? In part, SGLT2 inhibitor use can unintentionally result in increased glucose reabsorption by SGLT1. However, the major reason for this effect likely stems from the rise in plasma glucagon and decline in plasma insulin after SGLT2 inhibitor administration. EGP is regulated in a couple of ways, hormonally by insulin and glucagon as well as reduced plasma glucose concentration.


Study investigators wanted to analyze the hormonal changes and predicted that co-administration of a glucagon-like peptide 1 (GLP-1) agonist (liraglutide, LIRA) with an SGLT2 inhibitor (canagliflozin, CANA) would prevent the increase in EGP. Included in this study were 36 participants diagnosed with type 2 diabetes. Subjects were randomized (1:1:1) into one of three groups, they included: 1) 100 mg dose of CANA, 2) 1.2 mg subcutaneous injection of LIRA, and 3) combination of CANA/LIRA. Patients included in the study were either drug naive (n = 6) or taking metformin ± sulfonylurea (n = 30). Additionally, EGP was measured prior to medication (pretreatment) and after medication (treatment), therefore each participant served as their own control. EGP measurements were obtained on separate days during a period of 7-14 days. Subjects were continued on the medications for four months after study completion.

The primary outcome of the study was to assess the change in EGP from baseline after the administration of medication compared to the change in EGP from baseline without medication administration. Additionally, urinary glucose excretion (UGE), fasting plasma glucose (FPG), EGP, tissue glucose disposal, plasma insulin concentration, plasma glucagon concentration, and plasma C-peptide were assessed. The results for changes in EGP, plasma insulin, and glucagon can be found in Table 1: Results.

Table 1: Results
Change in… Treatment Findings
EGP CANA Significant 50% reduction in EGP compared to baseline (p < 0.05)
LIRA No significant change in EGP
CANA/LIRA Similar reduction in EGP compared to baseline

(p < 0.05)

CANA vs LIRA and CANA/LIRA vs LIRA Similar reductions found with CANA and CANA/LIRA compared with the reductions noted after LIRA administration (p < 0.01)


CANA Significant reductions compared to baseline (p <0.01)
LIRA Small non-significant reduction from baseline
CANA/LIRA No significant reductions noted
CANA vs. LIRA and


Reduction in insulin following CANA was significantly greater than LIRA (p < 0.001) and CANA/LIRA

(p< 0.05)

Plasma Glucagon CANA Significant increase in glucagon concentration greater than baseline

(p < 0.001)

LIRA Slight reduction in glucagon concentration from baseline (p < 0.05)
CANA/LIRA Slight reduction in glucagon concentration from baseline (p < 0.05)
CANA vs LIRA and


The between group differences were significant (p < 0.001)

Some of the findings are similar to previous studies. Following administration of a single dose of CANA, a decline in EGP and plasma insulin were noted along with a rise in plasma glucagon. A distinct observation noted in this study was that LIRA was unable to attenuate the effects of CANA, specifically blocking the rise in glucagon and preventing the reduction in insulin.

Additionally, while reductions in EGP were noted for both CANA/LIRA and CANA alone, the combination was found to decrease plasma glucose more dramatically. Possible causes could be attributed to the mechanism of action of the combination, but investigators speculated this was due to the greater urinary glucose excretion and higher initial plasma glucose concentrations noted in the CANA/LIRA group compared to CANA or LIRA monotherapy. Summation of the results shows that the changes in EGP are affected by more than just insulin and glucagon. Yong et al. surmised that the response to SGLT2 inhibitors goes beyond pancreatic hormonal control and is possibly mediated by neuro-hormonal mediators.

Practice Pearls:

  • Administration of SGLT2 inhibitors, while beneficial, can be associated with unintended endogenous glucose production both acutely and four weeks after initiation.
  • Pancreatic hormones, glucagon and insulin are partially responsible for this phenomenon, but investigators suspect that neuro-hormonal mediators can also play a role.


Martinez, R., Al-Jobori, H., Ali, A., Adams, J., Abdul-Ghani, M., Triplitt, C., DeFronzo, R., and Cersosimo, E. Endogenous Glucose Production and Hormonal Changes in Response to Canagliflozin and Liraglutide Combination Therapy. Diabetes. 67 (2018): 1182-1189. https://doi.org/10.2337/db17-1278.

Kaytie A. Weierstahl, Pharm.D. Candidate, LECOM School of Pharmacy