oral hypoglycaemic agents

see also:

• insulin
• metformin
• hypoglycaemia
• diabetes mellitus

• although for many years sulfonylureas were the first drugs to be used in new cases of type 2 diabetes (NIDDM), in the 1990s it was discovered that obese patients might benefit more from metformin.
• SGLT2 inhibitors have revolutionized the treatment of patients with T2DM with established or at risk for atherosclerotic cardiovascular disease (ASCVD) and patients with diabetic kidney disease

• see also sulphonylurea oral hypoglycaemics
• act by increasing insulin secretion from pancreatic beta cells by binding an ATPase K+ channel ⇒ reduced K efflux ⇒ depolarisation ⇒ opens voltage gated Ca gates ⇒ rise in intracellular calcium ⇒ increased fusion of insulin granulae with the cell membrane ⇒ increased secretion of (pro)insulin.
• potentially teratogenic and cannot be used in pregnancy or in patients who may become pregnant.
• can induce weight gain, mainly as a result their effect to increase insulin levels and thus utilization of glucose and other metabolic fuels
• may cause hypoglycaemia
• have varying half lives thus some can be taken once a day while others need to be taken bd or tds
• 1st generation:
  • chlorpropamide
  • tolbutamide (bd or tds dosing)
• 2nd generation:
  • have increased potency by weight
  • glipizide
  • gliclizide
  • glibenclamide - now the most popular sulfonylurea agent. May cause cholestasis.
  • gliquidone
  • glyclopyramide
  • glimepiride (once daily dosing)

• bind to same ATPaseK channel as sulphonylureas but at a different binding site
• repaglinide (Prandin)
• nateglinide (Starlix)

• mimic the action of the incretin glucagon-like peptide-1 (GLP-1)
• appears to enhance growth of pancreatic beta cells
• inhibits the production of glucagon, the hormone that increases glycogenolysis and gluconeogenesis
• reduces food intake by lowering appetite and slowing down digestion in the stomach
• lower risk of hypoglycaemia
• also used in Mx of obesity
• may cause many GIT symptoms plus gastroparesis, ileus, bowel obstruction, pancreatitis
• contraindicated in people with a personal or family history of medullary thyroid carcinoma or with multiple endocrine neoplasia type 2 due to risk of GLP-1-mediated thyroid C-cell hyperplasia
• GLP-1 peptide analogs
  • as these are peptides, need to be given by s/c injection
  • exenatide (2005)
  • liraglutide (2010)
  • semaglutide (2012) (Ozempic)

• DPP-4 inhibitors increase incretin levels ⇒ reduce glucagon ⇒ increased insulin secretion & decreases gastric emptying
• sitagliptin - was approved by the FDA in 2006
• vildagliptin (EU approved 2008)
• saxagliptin (FDA approved in 2009, marketed as Onglyza)
• linagliptin (FDA approved in 2011, marketed as Tradjenta)
  • usual dose 1-10mg once daily
• alogliptin (approved 2013, marketed as Nesina)
  • usual dose 25mg once daily as adjunct to either metformin or a sulphonylurea

• see metformin

• agonists of the peroxisome proliferator-activated receptor γ (PPARγ)
• may cause fluid retention and cardiac failure
• troglitazone
• rivoglitazone
• rosiglitazone
• pioglitazone (Actos)
  • NB. The TGA has advised that pioglitazone (Actos) should not be used in patients with bladder cancer or a history of bladder cancer as there appears to be a 1.4x risk in use for more than 1 year.¹⁾

• act upon the two or more peroxisome proliferator-activated receptor isoforms
• aleglitazar
• muraglitazar
• tesaglitazar

• at normal concentrations of plasma glucose, the kidneys reabsorb almost all filtered glucose (~180g/day) with less than 1% excreted in urine.
• glycosuria occurs when plasma glucose concentrations exceed the glucose reabsorbing capacity of the proximal tubules. This plasma glucose threshold is ~ 11mmol/L.
• sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa of the small intestine (SGLT1) and the proximal tubule of the nephron (SGLT2 in PCT and SGLT1 in PST).
• 90% of reabsorption of glucose in the renal proximal tubules is via SGLT2 active transport while the remaining 10% is via SGLT1 active transport

• see gliflozins / SGLT2 inhibitors

• work by preventing the digestion of carbohydrates
• acarbose (Precose)
• miglitol (Glyset)
• voglibose

• amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin.
• There appears to be at least three distinct receptor complexes that bind with high affinity to amylin. All three complexes contain the calcitonin receptor at the core, plus one of three receptor activity-modifying proteins, RAMP1, RAMP2, or RAMP3
• pramlintide (brand name Symlin)