Anti diabetic Agents

Dr. dr. Budhi Setiawan, M.Kes

Diabetes Mellitus
Diabetes Mellitus
 Insulins

▪ Binds to insulin receptors in cell membranes consisting of alpha subunits on the outside
surface and cytoplasmic beta subunits having tyrosine kinase activity
▪ Liver: increased storage of glucose as glycogen, decreases the breakdown of proteins
▪ Muscle: stimulates glycogen and protein synthesis, Increased GLUT 4 insertion into cell
membranes
▪ Adipose tissue: facilitates triglyceride storage by activating plasma lipoprotein lipase,
increased glucose transport into cells via GLUT 4, reduced intracellular lipolysis
▪ Used for Type 1 and type 2 diabetes
▪ Toxicity: Hypoglycemia, weight gain, lipodystrophy (site of injection)
 Insulins

▪ The goal of subcutaneous insulin therapy is to mimic both the normal prandial insulin
secretion and the basal between-meal insulin levels as close as possible.
▪ To accomplish this goal most current regimens use at least two different insulin analogs:
▪ Long-acting or Intermediate acting insulins are used to provide basal insulin levels
▪ Rapid or Short-acting insulins are used to correct the transient (prandial)
hyperglycemia associated with meals
Insulins
Insulins
Insulins
Insulins
Insulins
Insulins
 Sulfonylureas

▪ Mechanism of Action: Close K+ channels in beta cells, stimulating insulin release from the
β cells of the pancreatic islets.
▪ In patients with functioning beta cells, reduce circulating glucose increase glycogen, fat,
and protein formation, gene regulation
▪ Used as adjuncts to diet and exercise in patients with type 2 diabetes mellitus.
▪ Used as monotherapy or in combination with other oral antidiabetic agents
▪ Precaution in patients with renal or hepatic impairment.
▪ Toxicity: Hypoglycemia, weight gain

▪ Gen 1 : Tolazamide, tolbutamide, chlorpropamide

▪ Gen 2 : Glipizide, Glyburide/Glibenclamide, Glimepiride
 Glitinides

▪ Similar to sulfonylureas - inhibits potassium efflux (blocks ATP-regulated K channels),

causing depolarization & insulin release from pancreatic β-cells
▪ Stimulates a transient release of insulin from pancreatic beta cells, when administered
with a meal, is useful for controlling postprandial hyperglycemia associated with Type 2
diabetes
▪ may be used in patients who have an allergy to sulfonylureas
▪ Toxicity: Hypoglycemia
▪ Because of their short action, glinides have a lower incidence & severity of side effects
than sulfonylureas. Glinides exert a lower incidence of hypoglycemia compared to
sulfonylureas
▪ Repaglinide, Nateglinide
Sulfonylureas and Glitinides
Sulfonylureas and Glitinides
 Biguanides

▪ Decreases the liver's production of glucose via activation of AMP-activated protein kinase
(AMPK)
▪ A first line drug in the treatment of type II diabetes
▪ Decreased endogenous glucose production
▪ Toxicity: Gastrointestinal symptoms, lactic acidosis, cannot be used if impaired
renal/hepatic function, congestive heart failure (CHF), hypoxic/acidotic states, alcoholism.
▪ Metformin
Biguanides
 Alpha-Glucosidase inhibitors

▪ Inhibit intestinal alpha-glucosidase inhibitors

▪ Reduce conversion of starch and disaccharides to monosaccharides reduce postprandial
hyperglycemia
▪ As adjunct therapy in type II diabetes mellitus
▪ Poorly absorbed. Should be taken with the first bite of breakfast, lunch, and dinner
▪ The hypoglycemic goal in diabetics typically cannot be met with these drugs alone
▪ Toxicity: Gastrointestinal symptoms, cannot use if impaired renal/hepatic function,
intestinal disorders
▪ Acarbose, Miglitol
Alpha-Glucosidase inhibitors
Alpha-Glucosidase inhibitors
 Thiazolidinediones

▪ Regulates gene expression by binding to PPAR- α (Rosiglitazone), PPAR- α and PPAR- γ

(Pioglitazone)
▪ Reduces insulin resistance
▪ Glitazones are ligands of the peroxisome peroliferator-activated receptor gamma (PPAR-γ)
part of the steroid and thyroid superfamily of nuclear receptors
▪ Toxicity: Fluid retention, edema, anemia, weight gain, macular edema, bone fractures in
women, cannot use if CHF, hepatic disease
Thiazolidinediones
 Incretin-based drugs

▪ Exenatide: analog of GLP-1 RA (Glucagon peptide 1 receptor antagonist)

▪ Reduces post-meal glucose excursions: increases glucose - mediated insulin release, lowers
glucagon levels, slows gastric emptying, decreases appetite (↘ BW)
▪ Safety profile dispute: proliferative effect on pancreas
▪ Other examples: Liraglutide, Lixisenatide, Albiglutide, Dulaglutide, Semaglutide
▪ Toxicity:
▪ Nausea, headache, vomiting, anorexia, mild weight loss, pancreatitis (Exenatide)
 Inhibitors of dipeptidyl peptidase 4

▪ Increase incretin levels (Glucagon-like peptide-1-GLP-1 and Gastric inhibitory polypeptide-

GIP)
▪ Inhibit glucagon release, which in turn increases insulin secretion, decreases gastric
emptying, and decreases blood glucose levels
▪ No favorable effect on mortality andcardiovascular events or stroke
▪ Examples: Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin
▪ Toxicity:
▪ Rhinitis, upper respiratory infections, rare allergic reactions (Sitagliptin)
Incretin-based drugs
Incretin-based drugs & DPP-IV Inhibitors
 Amylin analog

▪ Amylin is a small peptide hormone that is normally co-released with insulin into the
bloodstream by β-cells, in response to meals
▪ Binds to amylin receptors
▪ Affect the rate of postprandial glucose appearance through a variety of mechanisms
▪ Reduces post-meal glucose excursions: Lowers glucagons levels, slows gastric emptying,
decreases appetite
▪ In patients with Type 1 or Type 2 diabetes β-cells are either absent or dysfunctional,
resulting in decreased secretion of both insulin and amylin in response to food
▪ Amylin is approved for “adjunct” therapy in combination with insulin
▪ Toxicity: Nausea, anorexia, hypoglycemia, headache
▪ Pramlintide
Amylin analog
 SGLT2 inhibitor
▪ Inhibits the Na-glucose co-transporter 2 (SGLT-2) in the kidney to reduce glucose
reabsorption, resulting in increased urinary glucose excretion, and lower plasma glucose
▪ currently mainly used as adjunct therapy in patients not meeting their glycemic goal with
other agents
▪ While rapid weight loss may be beneficial in some patients, the loss of glucose can also
result in dehydration and tiredness
▪ Low incidence of hypoglycemia - when used as monotherapy or with metformin
▪ Decrease in blood pressure (in patients with hypertension); due to its effects as an osmotic
diuretic with associated volume loss
▪ Toxicity: osmotic diuresis, genital and urinary tract infections
▪ Canagliflozin, dapagliflozin
SGLT2 inhibitor
Summary of antidiabetic agents
Summary of antidiabetic agents
 Vitamin D, Calcium, and Phosphate

▪ Vitamin D is a prohormone that serves as precursor to a number of biologically active

metabolites
▪ The regulation of vitamin D metabolism is complex, involving calcium, phosphate, and a
variety of hormones, the most important of which is PTH
▪ Calcium and phosphate, the major mineral constituents of bone, are also two of the most
important minerals for general cellular function
▪ Three hormones serve as the principal regulators of calcium and phosphate homeostasis:
parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and the steroid vitamin D
Vitamin D, Calcium, and Phosphate
Vitamin D, Calcium, and Phosphate
Vitamin D, Calcium, and Phosphate
 Vitamin D, Calcium, and Phosphate

RANKL: Receptor activator of nuclear factor kappa-Β ligand

Calcitriol : 1,25(OH)2 D MCSF: Macrophage Colony-Stimulating Factor
Calcifediol: 25(OH) D OPG : Osteoprotegerin
Vitamin D, Calcium, and Phosphate
THANK YOU