Drugs in t2 dm jap_2015_16

Drugs in t2 dm jap_2015_16

• 1.
  Drugs and TheirTargets in Type 2 Diabetes Mellitus Professor John A. Peters E-mail j.a.peters@dundee.ac.uk
• 2.
   Revise thepathology of type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively)  List the classes of drug currently employed to treat T2DM noting whether, or not, their action is dependent upon insulin  Understand the action of sulfonylureas upon the KATP channels of pancreatic  cells and how closure of this channel causes release of insulin  Outline the mechanism by which glinides (meglitinides) cause insulin release  Explain why GLP-1 analogues and inhibitors of DPP-4 (Gliptins) are used in the treatment of T2DM  Describe the use of metformin as a first line pharmacological intervention in T2DM  Be aware of the use of -glucosidase blockers in T2DM  Comment on the mechanism of action of thiazolidinediones in 2TDM  Describe the novel approach to 2TDM presented by inhibitors of SGLT2 Learning Objectives
• 3.
   Current therapiesfor type 2 diabetes mellitus (T2DM) act by:  Increasing secretion of insulin (e.g. sulfonylureas, incretin mimetics, glinides (aka meglitinides), DPP-4 inhibitors (gliptins) - insulin dependent action  Decreasing insulin resistance and reducing hepatic glucose output [e.g. biguanides, thiazolidinediones (glitazones)] – insulin dependent action  Slowing glucose absorption from the G.I. tract (e.g. α-glucosidase inhibitors) – insulin independent action  Enhancing glucose excretion by the kidney [sodium glucose type-2 (SGLT2) inhibitors] - insulin independent action Drugs in Type 2 Diabetes Mellitus
• 4.
  Cellular Energy Statusis Linked to Insulin Secretion in the Pancreatic -cell Elevation of blood glucose concentration Mechanisms of Disease: advances in diagnosis and treatment of hyperinsulinism in neonates Diva D De León and Charles A Stanley Nature Clinical Practice Endocrinology & Metabolism (2007) 3, 57-68 Increased diffusion of glutamate into the -cell by facilitated transport (GLUT2) Phosphorylation of glucose by glucokinase Increased ATP/ADP ratio within cell closes ATP-sensitive K+ channels causing membrane depolarization Glycolysis of glucose-6-phosphate in mitochondria yielding ATP Opening of voltage-activated Ca2+ channels increases intracellular Ca2+ that triggers insulin secretion
• 5.
  The KATP Channeland its Regulation  ATP binding to each of the Kir6.2 subunits closes the channel causing depolarization of the  cell and insulin release (when extracellular glucose is high)  ADP-Mg2+ binding to the SUR1 subunits opens the channel maintaining the resting potential of the  cell and inhibits insulin secretion (when extracellular glucose is low)  Sulfonylureas (SUs) used in T2DM bind to SUR1 and close the channel causing depolarization and insulin release independent of plasma glucose concentration  Octomeric complex of 4 potassium inward rectifier 6.2 subunits (Kir6.2) and four sulphonylurea receptor 1 subunits (SUR1)  Tetramer of Kir6.2 subunits form a potassium selective ion channel  SUR1 subunits regulate potassium channel activity K+ K+
• 6.
  Sulfonylureas  Examples aretolbutamide (first generation), glibenclamide (aka glyburide) and glipizide (second generation)  All incorporate the sulfonylurea moiety (red) with differing R and R2 substituents  Appear to act by displacing the binding of ADP-Mg2+ from the SUR1 subunit (thus closing the KATP channel and stimulating insulin release)  Relative to tolbutamide, glibenclamide and glipazide are more potent and longer acting (but probably have no significant clinical advantage)  Orally active, generally well tolerated, but may cause hypoglycaemia due to excessive insulin secretion (greater risk with long acting agents and in the elderly, or patients with reduced hepatic/renal function)  May be used in conjunction with metformin, or thiazolidinediones  Tend to cause undesirable weight gain
• 7.
  Glinides (Meglitinides)  Actsimilarly to the sulfonylureas – bind to SUR1 (at a distinct benzamido site) to close the KATP channel and trigger insulin release – examples are repaglinide and nateglinide  Have rapid onset/offset kinetics – less likely to cause hypoglycaemia than sulfonylureas  Active orally, taken before meals to reduce postprandial rise in blood glucose  Can be used in conjunction with metformin and thiazolidinediones
• 8.
  Incretin Analogues andDPP-4 Inhibitors (1) Ingestion of food stimulates release of Glucagon Like 1 (GLP-1) and Glucose Dependent Insulinotropic Peptide (GIP) from enteroendocrine cells in the small intestine (L cells in the ileum and colon and K cells in the jejunum/duodenum, respectively GLP-1 and GIP enhance (increment) insulin release from pancreatic -cells (and delay gastric emptying) GLP-1 decreases glucagon release from pancreatic α- cells Enhanced glucose uptake and utilization GLP-1 and GIP enter portal blood Decreased glucose production Decreased blood glucose
• 9.
  Incretin Analogues  Incretinanalogues (i.e. extenatide) mimic the action of GLP-1 but are longer lasting  Extenatide is a synthetic version of extendin-4, peptide found in the saliva of the Gila monster  Increases insulin secretion, suppresses glucagon secretion, slows gastric emptying, decreases appetite  Causes modest weight loss, reduces hepatic fat accumulation  Administered subcutaneously (s.c.) twice daily  May cause nausea, hypoglycaemia, far more rarely pancreatitis  Binds to GPCR GLP-1 receptors that increase intracellular cAMP concentration  Liraglutide is a longer acting agent, suitable for once daily s.c. administration
• 10.
  DPP-4 Inhibitors (Gliptins) Actions of GLP-1 and GIP are very rapidly terminated (within minutes) by the enzyme dipeptidyl peptidase-4 (DPP-4)  Gliptins competitively inhibit DPP-4, prolonging the actions of GLP-1 and GIP  Sitagliptin, orally active administered once daily, is generally well tolerated – no hypoglycaemia (when used as monotherapy), weight neutral  Usually used in combination with thiazolidinediones, or metformin, but can be employed as monotherapy  Other agents in the class include saxigliptin and vildagliptin
• 11.
  -Glucosidase Inhibitors (Acarbose) Dietary carbohydrate require digestion to monosaccharides in order to be absorbed in the small intestine  -Glucosidase is a brush border enzyme that breaks down starch and disaccharides to absorbable glucose  Inhibitors of -glucosidase (i.e. acarbose) delay absorption of glucose thus reducing postprandial increase in blood glucose  Used in 2TDM patients inadequately controlled by life style measures or other drugs  Adverse effects occur in the G.I. tract – flatulence, loose stools, diarrhoea, abdominal pain, bloating – undigested carbohydrate is welcomed by colonic bacteria!  Pose no risk of hypoglycaemia
• 12.
  Biguanides  The onlytherapeutic agent in this class is metformin (originally found in French lilac) Metformin (biguanide moiety ringed) French lilac  Metformin • First line agent in the treatment of T2DM in obese patients (with normal hepatic and renal function) • Reduces hepatic gluoconeogenesis [by stimulating AMP-activated protein kinase (AMPK)] • Increases glucose uptake and utilization by skeletal muscle (increases insulin signalling) • Reduces carbohydrate absorption • Increases fatty acid oxidation
• 13.
  Metformin – ClinicalAspects • Prevents hyperglycaemia but does not cause hypoglycaemia Desirable • Causes weight loss (unlike insulin and agents that promote insulin release) • Suitable for oral administration • May be combined with other agents (e.g. insulin, thiazolidinediones, sulfonylureas) • Rarely lactic acidosis (avoid routine use in patients with hepatic, or renal, disease) Adverse • Gastrointestinal upsets (diarrhoea, nausea, anorexia)
• 14.
  Thiazolidinediones (TZDs, Glitazones) Enhance the action of insulin at target tissues, but do not directly affect insulin secretion – reduce the amount of insulin required to maintain a given blood level of glucose  Act as exogenous agonists of the nuclear receptor peroxyisome profilerator-activated receptor- (PPAR) which associates with retinoid receptor X (RXR) - PPAR is largely confined to adipocytes  Activated PPAR-RXR complex acts as a transcription factor that binds to DNA to promote the expression of genes encoding several proteins involved in insulin signalling, among others  Lipoprotein lipase  Fatty acid transport protein  GLUT4  Desirable effects  Promote fatty acid uptake and storage in adipocytes, rather than skeletal muscle and liver  Reduced hepatic glucose output
• 15.
   Adverse effects Weight gain – differentiation of adipocytes contributes along with…  Fluid retention – TZDs promote Na+ reabsorption by the kidney  Several members of the class (e.g. ciglitazone, troglitazone) cause serious hepatotoxicity – only pioglitazone (which does not cause liver dysfunction is now used  Increased incidence of bone fractures Thiazolidinediones (TZDs, Glitazones)  Pioglitazone may be used in combination with either metformin, or SUs, to achieve adequate control of blood glucose
• 16.
  Sodium-Glucose Cotransporter-2 (SGLT2)Inhibitors  Represent a novel approach to treatment of T2DM that is not dependent upon insulin  Act to selectively block the reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron to deliberately cause glucosuria  Cause decrease in blood glucose with little risk of hypoglycaemia  Calorific loss (i.e. glucose voided) and water accompanying glucose (i.e. osmotic diuresis) contributes to weight loss  Currently licensed agent is dapagliflozin