Introduction
Relationship Between Obesity and T2D
Strategies Used for Weight-Loss in T2D
Effects of Antihyperglycemia Drugs on Body Weight
Mechanism of action | Effect on body weight (change in kg) | Disadvantages | Dosing schedule | |
---|---|---|---|---|
Associated with weight-loss | ||||
Metformin | Activate AMP-kinase ↓ hepatic glucose production | + 1.5 to − 2.9a [36] | GI side effects Vitamin B12 deficiency | Divided doses with meals |
α-glucosidase inhibitors | ||||
Acarbose miglitol | Inhibit intestinal α-glucosidase activity Slow intestinal carbohydrate digestion/absorption | GI side effects Frequent dosing schedule | Three times daily before all major meals | |
GLP-1 RAs | ||||
Short-acting: exenatide, lixisenatide Long-acting: liraglutide, exenatide extended-release, albiglutide dulaglutide, semaglutide | Activate GLP-1 receptors ↑ insulin secretion (glucose dependent) ↓ glucagon secretion (glucose dependent) Slow gastric emptying (short-acting agents) ↑ satiety (short-acting agents) | GI side effects Effect on heart rate Acute pancreatitis Injectable Black box warning for risk of thyroid c-cell tumors (albiglutide, exenatide extended-release, dulaglutide) | Exenatide: within 1 h prior to morning and evening meals Lixisenatide: once daily within 1 h before the first meal of the dayb Albiglutide, exenatide extended-release, dulaglutide: once weekly, any time of day, with or without food Semaglutide: once weekly | |
Amylin mimetics | ||||
Pramlintide | Activate amylin receptors ↓ glucagon secretion Slows gastric emptying ↑ satiety | − 2.57c [51] | GI side effects Hypoglycemia Injectable Frequent dosing schedule | Before all major meals |
SGLT2 inhibitors | ||||
Canagliflozin, dapagliflozin, empagliflozin | Inhibit SGLT2 in the proximal nephron Block glucose reabsorption in the kidney → increased glucosuria | Genitourinary infections Polyuria Volume depletion/hypotension/dizziness Boxed warning for association with lower limb amputation in patients with established CVD (canagliflozin) Risk of diabetic ketoacidosis Risk of fractures | Canagliflozin: once daily before the first meal of the day Dapagliflozin/empagliflozin: once daily, taken in the morning, with or without food | |
Weight-neutral | ||||
DDP-4 inhibitors | ||||
Sitagliptin, saxagliptin, linagliptin, alogliptin | Inhibit DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentration ↑ insulin secretion (glucose dependent) ↓ glucagon secretion (glucose dependent) | Angioedema/urticaria Acute pancreatitis ↑ heart failure hospitalizations (saxagliptin, alogliptin) | Once daily, with or without food | |
Fixed-ratio combination therapy | ||||
IDegLira, iGlarLixi | Complementary mechanisms of its components; basal insulin targets FPG, GLP-1 RA lowers PPG | Nausea Vomiting Diarrhea Hypoglycemia | Once daily | |
Associated with weight gain | ||||
Sulfonylureas | ||||
Glyburide, glipizide, glimepiride | Close KATP channels on β-cell plasma membrane ↑ insulin secretion | Hypoglycemia | Once daily with first meal of the day | |
Thiazolidinediones | ||||
Pioglitazone, rosiglitazone | Activate nuclear transcription factor PPAR-γ ↑ insulin sensitivity | Edema/heart failure Bone fractures | Various | |
Meglitinides | ||||
Repaglinide, nateglinide | Close KATP channels on β-cell plasma membrane ↑ insulin secretion | Hypoglycemia Frequent dosing schedule | Before meals (usually 3 times daily) | |
Insulins | ||||
Basal, rapid-acting, short-acting, intermediate-acting, premix | Activate insulin receptors ↑ glucose disposal ↓ hepatic glucose production Suppress ketogenesis | Hypoglycemia Injectable | Various |