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Glucagon Levels During Short-Term SGLT2 Inhibition Are Largely Regulated by Glucose Changes in Patients With Type 2
Per Lundkvist1, Maria J Pereira1, Prasad G Kamble1
1Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Context:
The mechanism mediating sodium glucose cotransporter-2 (SGLT2) inhibitor-associated increase in glucagon levels is unknown.
Objective:
To assess short-term effects on glucagon, other hormones, and energy substrates after SGLT2 inhibition and whether such effects are secondary to glucose lowering. The impact of adding a dipeptidyl peptidase-4 inhibitor was addressed.
Design, Setting, And Patients:
A phase 4, single-center, randomized, three-treatment crossover, open-label study including 15 patients with type 2 diabetes treated with metformin.
Interventions:
Patients received a single-dose of dapagliflozin 10 mg accompanied by the following in randomized order: isoglycemic clamp (experiment DG); saline infusion (experiment D); or saxagliptin 5 mg plus saline infusion (experiment DS). Directly after 5-hour infusions, a 2-hour oral glucose tolerance test (OGTT) was performed.
Results:
Glucose and insulin levels were stable in experiment DG and decreased in experiment D [P for difference (Pdiff) < 0.001]. Glucagon-to-insulin ratio (Pdiff < 0.001), and levels of glucagon (Pdiff < 0.01), nonesterified fatty acids (Pdiff < 0.01), glycerol (Pdiff < 0.01), and β-OH-butyrate (Pdiff < 0.05) were lower in DG vs D. In multivariate analysis, change in glucose level was the main predictor of change in glucagon level. In DS, glucagon and active GLP-1 levels were higher than in D, but glucose and insulin levels did not differ. During OGTT, glucose levels rose less and glucagon levels fell more in DS vs D.
Conclusion:
The degree of glucose lowering markedly contributed to regulation of glucagon and insulin secretion and to lipid mobilization during short-term SGLT2 inhibition.
Insights
Sodium glucose cotransporter-2 (SGLT2) inhibitors lower glucagon by reducing glucose levels. Adding a dipeptidyl peptidase-4 inhibitor further impacts glucagon and GLP-1 levels.
Area of Science:
- Endocrinology
- Metabolism
- Pharmacology
Background:
- The mechanism behind increased glucagon levels with sodium glucose cotransporter-2 (SGLT2) inhibitors is not fully understood.
- Understanding these hormonal and metabolic effects is crucial for optimizing diabetes management.
Purpose of the Study:
- To investigate the short-term effects of SGLT2 inhibition on glucagon, other hormones, and energy substrates.
- To determine if these effects are a consequence of glucose lowering.
- To assess the impact of combining SGLT2 inhibitors with dipeptidyl peptidase-4 inhibitors.
Main Methods:
- A phase 4, randomized, crossover study involving 15 patients with type 2 diabetes on metformin.
- Single doses of dapagliflozin (SGLT2 inhibitor) or saxagliptin (DPP-4 inhibitor) were administered with or without an isoglycemic clamp.
- Oral glucose tolerance tests were conducted post-infusion.
Main Results:
- SGLT2 inhibition with an isoglycemic clamp maintained glucose levels and significantly reduced glucagon, the glucagon-to-insulin ratio, and markers of lipolysis compared to saline infusion.
- Glucose lowering was identified as the primary driver for glucagon regulation.
- Combining SGLT2 inhibition with a DPP-4 inhibitor increased glucagon and active GLP-1 levels.
Conclusions:
- Glucose lowering is the main factor regulating glucagon and insulin secretion during short-term SGLT2 inhibition.
- SGLT2 inhibition significantly impacts lipid mobilization through glucose-dependent mechanisms.
- Combination therapy with DPP-4 inhibitors introduces additional hormonal changes beyond glucose lowering.
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