The dipeptidyl peptidase-4 inhibitor alogliptin in combination with pioglitazone improves glycemic control, lipid profiles, and increases pancreatic insulin content in ob/ob mice.
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.
Moritoh
Yusuke
Y
Pharmacology Research Laboratories I, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
Takeuchi
Koji
K
Asakawa
Tomoko
T
Kataoka
Osamu
O
Odaka
Hiroyuki
H
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004338:Drug Combinations; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006728:Hormones / Q000097:blood; D006946:Hyperinsulinism / Q000097:blood / Q000188:drug therapy; D007328:Insulin / Q000378:metabolism*; D008055:Lipids / Q000097:blood*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D000077205:Pioglitazone; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D006728:Hormones; D007328:Insulin; D008055:Lipids; D010880:Piperidines; D045162:Thiazolidinediones; D014498:Uracil; C520853:alogliptin; D000077205:Pioglitazone