Weight neutrality with the DPP-4 inhibitor, vildagliptin: mechanistic basis and clinical experience.
Various factors may confound how diabetes medications affect a patient's weight. Agents that induce hypoglycemia may promote weight gain through "defensive eating". Conversely, patients whose hyperglycemia exceeds the renal glucose threshold may overeat to compensate for calories lost in urine and so gain weight when drug therapy ablates glycosuria. Some drugs, such as thiazolidinediones, may promote weight gain via increased lipid storage. Glucagon-like peptide-1 receptor agonists increase satiety, delay gastric emptying, and generally produce weight loss. Dipeptidyl peptidase (DPP)-4 inhibitors are generally weight-neutral, although modest weight loss has been observed with the DPP-4 inhibitor, vildagliptin, in patients with relatively low baseline glycemia. The weight neutrality of vildagliptin likely results in part from its intrinsically low risk for hypoglycemia. Recent studies point to additional potential mechanisms. One study found that drug-naïve patients randomized to vildagliptin exhibited significantly lower chylomicron lipid and apolipoprotein levels than placebo patients, suggesting that vildagliptin may inhibit intestinal fat extraction. Another trial found that patients randomized to vildagliptin versus placebo experienced paradoxical postprandial increases in markers of fatty acid mobilization and oxidation, in conjunction with increased sympathetic stimulation. Elaboration of these and other pathways could further clarify the origins of the favorable weight profile of vildagriptin.
Foley
James E
JE
Clinical Research and Development, Novartis Pharmaceutical Corporation, East Hanover, NJ 07936, USA. james.foley@novartis.com
Jordan
Jens
J
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007333:Insulin Resistance; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D000077597:Vildagliptin; D015430:Weight Gain / Q000187:drug effects
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D005947:Glucose; D000218:Adamantane