Effects of GLP-1RA and SGLT2i, Alone or in Combination, on Mouse Models of Type 2 Diabetes Representing Different Disease Stages

Abstract

Glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-dependent glucose transporter 2 inhibitor (SGLT2i), in addition to lowering glucose, have pleiotropic effects on the heart, kidneys, and liver. These drugs have thus come into widespread use for treating type 2 diabetes (T2DM). However, mechanistic comparisons and effects of combining these drugs have not been adequately studied. Employing diet-induced obese (DIO) mice and db/db mice as models of the early and advanced stages of T2DM, we evaluated effects of single or combined use of liraglutide (a GLP-1RA) and ipragliflozin (a SGLT2i). Treatments with liraglutide and/or ipragliflozin for 28 days improved glycemic control and reduced hepatic lipid accumulation similarly in DIO mice. In contrast, in db/db mice, despite similar favorable effects on fatty liver, liraglutide exerted no beneficial effects on glycemic control. Improved glycemic control in db/db mice treated with ipragliflozin was accompanied by increased pancreatic β-cell area and insulin content, both of which tended to rise further when ipragliflozin was combined with liraglutide. Our data suggest that liraglutide is more efficient at an earlier stage and ipragliflozin can be effective in both stages. In addition, their combined use is a potential option for treating advanced stage diabetes with fatty liver disease.

Glucagon-Like Peptide-1 Protects Against Atrial Fibrillation and Atrial Remodeling in Type 2 Diabetic Mice

“…This is consistent with previous studies showing that liraglutide partially improves glucose tolerance in db/db mice. 31 , 32 Thus, it is possible that a partial reduction in the level of hyperglycemia could contribute to the improvements in atrial electrophysiology elicited by GLP-1R agonists via indirect effects. It is important to note, however, that the relationship between AF prevalence and glycemic control in patients with diabetes remains unresolved with some studies suggesting worsening AF with poor glycemic control and others finding no relationship.…”

Therapy Combining Glucagon-Like Peptide-1 Receptor Agonist with Sodium-Glucose Cotransporter 2 Inhibitor Suppresses Atherosclerosis in Diabetic ApoE-Deficient Mice

“…However, a few studies directly analyzing differences between these drugs and possible mutual interactions or the mechanisms governing the effects of combining the two drug classes for inhibition of atherosclerosis. In our previous study, combination therapy of a diabetic mouse model with liraglutide and ipragliflozin, an SGLT2 inhibitor, ameliorated fatty liver while enhancing pancreatic insulin production and secretion [25].…”

“…Mice in the combo group were treated with both liraglutide and ipragliflozin, as described above. The controls, as well as the untreated and IPRA groups, were also given daily intraperitoneal saline administrations, as in our prior study [25].…”

Animal studies of sodium-glucose co-transporter 2 inhibitors in nonalcoholic fatty liver disease

“…Regarding ipragliflozin, its combination with pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, resulted in a bigger decrease in steatosis, inflammation and fibrosis compared to control and monotherapy with ipragliflozin in diabetic mice with NASH [ 65 ]. When ipragliflozin was combined with liraglutide, a glucagon-like peptide-1 receptor agonist, in 2 mouse models, the combination reduced NAS compared to controls ( Table 2 ), but did not provide extra histological benefits compared to monotherapy with either ipragliflozin or pioglitazone [ 77 ]. The combination of ipragliflozin with metformin reduced hepatic steatosis, inflammation and fibrosis compared to a control group and metformin monotherapy in diabetic mice with NASH [ 78 ].…”