The combination of two agents with different but complementary mechanisms of action is a logical approach for treating patients with
type 2 diabetes. Thus, we evaluated chronic combination
therapy with
alogliptin, a highly selective dipeptidyl peptidase-4 inhibitor that enhances the action of
incretins, and
pioglitazone, a
thiazolidinedione that improves peripheral and hepatic
insulin sensitivity. Studies were designed to investigate the chronic metabolic and pancreatic effects of
alogliptin (0.03%) plus
pioglitazone (0.003%) combination treatment in obese ob/ob mice. After 4-5 weeks of treatment,
alogliptin significantly increased plasma active
glucagon-like peptide-1 levels up to 4.1-fold and decreased plasma
glucagon up to 25%, whereas
pioglitazone significantly increased plasma
adiponectin up to 1.3-fold. Combination treatment exhibited a complementary effect, increasing plasma
insulin levels by 3.2-fold (
alogliptin alone, 1.6-fold;
pioglitazone alone, 1.5-fold) and decreasing
glycosylated hemoglobin by 2.3% (
alogliptin alone, 1.0%;
pioglitazone alone, 1.5%), and non-fasting and fasting plasma
glucose by 37% and 62% (
alogliptin alone, 17% and 24%;
pioglitazone alone, 30% and 45%), respectively. Combination treatment also decreased plasma
triglycerides by 67% and non-
esterified fatty acids by 25% (
alogliptin alone, 24% and 11%;
pioglitazone alone, 54% and 8%). Moreover, combination treatment increased pancreatic
insulin content by 2.2-fold (
alogliptin alone, 1.3-fold;
pioglitazone alone, 1.6-fold), with no significant changes in
body weight. These results indicate that combination treatment with
alogliptin and
pioglitazone improved
glycemic control,
lipid profiles and increased pancreatic
insulin content in ob/ob mice by preventing
incretin inactivation and improving
insulin resistance. These results provide a strong argument for using
alogliptin in combination with
pioglitazone.