Download - Endocrinology DM Therapeutics
But which one?
Agent Cost/PB
S Efficacy
Side Effects
Weight Gain
Hypo’s
BMD OUTCOM
ES
Metformin Cheap ++ GIT NIL Few None Decr.
mortality
DPP-4 inhib’s
PBS + Few NIL Few ? ?
GLP1 analogues
Expensive ++ Few NIL Few ? ?
TZD’s PBS + +++ +++ ++ Loss ?
Sulfonyl-ureas
PBS ++ Few ++ +++ None Decr.
Morbidity
Insulin PBS ++ Few ++ +++ None ?
Bariatric Surgery
Expensive +++ +++ NIL + ?
Decr. Morbidity & 30% decr. Mortality
Lifestyle ∆ Cheap ++ Nil NIL NIL Improv
ed Decr.
Mortality Sept. 09 2 E. C. Hendrich, FRACP
Mechanisms of Action of Major Oral Monotherapies Do Not Target 3 Core Defects in Type 2 Diabetes
Oral Monotherapies
SUs
Meglitinides
TZDs
Metformin
α-Glucosidase
Inhibitors
DPP-4
Inhibitors
Improves insulin secretion
Improves insulin resistance
Lowers hepatic glucose production
SUs=sulfonylureas; TZD=thiazolidinediones; DPP-4=dipeptidyl peptidase 4. Inzucchi SE. JAMA 2002;287:360–372; Gallwitz B. Minerva Endocrinol. 2006;31:133–147.
Key D
efe
cts
Dr. E.C.Hendrich 4
Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403
Cumulative Incidence of Diabetes According to Study Group
Physiology-Enteroinsular axis Incretins: ―GI hormones that stimulate insulin
release after enteral nutrition‖ Creutzfeld, 1979
GLP-1: Glucagon-Like Peptide - 1 GIP = Glucose-dependent Insulinotropic
Polypeptide Ghrelin – receptors in pancreatic islets, inhibits
insulin secretion. Levels are up pre-meals & reduced post-prandially. Inversely related to body weight. Acts on hypothalamus to regulate appetite.
Neural signalling: Protein YY – Increases satiety & delays gastric emptying via neuropeptide Y signalling in CNS & PNS.
Sept. 09 5 E. C. Hendrich, FRACP
Incretin Hormones Regulate Insulin and Glucagon Levels
Adapted from Kieffer T. Endocrine Reviews. 1999;20:876–913. Drucker DJ. Diabetes Care. 2003;26:2929–2940. Nauck MA et al. Diabetologia. 1993;36:741–744. Adapted with permission from Creutzfeldt W. Diabetologia. 1979;16:75–85. Copyright © 1979 Springer-Verlag.
Pancreas Gut
Nutrient signals ● Glucose
Hormonal signals
• GLP-1 • GIP
Glucagon (GLP-1)
Insulin (GLP-1,GIP)
Neural signals
cells cells
Sept. 09 6 E. C. Hendrich, FRACP
Increased ghrelin – decr. appetite Increased PYY – Incr. satiety, delay G-emptying.
Role of Incretins in Glucose Homeostasis
Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
Ingestion of food
β cells α cells
Release of gut
hormones —
incretins*
Pancreas
Glucose-dependent Insulin from β cells
(GLP-1 and GIP)
Glucose uptake
by muscles
Glucose dependent
Glucagon from α cells
(GLP-1)
GI tract
Active GLP-1 & GIP
DPP-4 enzym
e
Inactive GIP
Inactive GLP-1
*Incretins are also released throughout the day at basal levels.
Glucose production
by liver
Blood glucose in fasting and postprandial
states
Sept. 09
7 E. C. Hendrich, FRACP
GLP-1
Sept. 09 8 E. C. Hendrich, FRACP
Glucose dependent insulin secretion
Inhibits glucagon secretion
Delays gastric emptying
Blunts post prandial hyperglycaemia
Enhances satiety – Decreased food intake
Increases glycogenesis in hepatocytes & sk. mm
Increases lipogenesis – in adipocytes
Inactivated by DPP-4: T1/2 =2 mins
GLP-1
GIP
Sept. 09 9 E. C. Hendrich, FRACP
GIP
Enhances late phase of gluc- regulated insulin release
Less potent than GLP-1
Increases Lipoprotein Lipase activity
No effect on gastric emptying, but reduces gastric acid secretion
No effect on satiety.
No effect on glucagon secretion
No effect on body weight
Inactivated by DPP-4: T1/2 =5-7 mins
Acquired defect in DM vs 1° feature GIP defect – reversible with restoration of BSL’s GLP1 & GIP potentiate each other’s actions
Demonstrated Effects of the Incretin Hormones GLP-1 and GIP
◦ Is released from L cells in ileum and colon
◦ Stimulates insulin response from β cells in a glucose-dependent manner
◦ Inhibits gastric emptying
◦ Reduces food intake and body weight
◦ Inhibits glucagon secretion from α cells in a glucose-dependent manner
◦ Effect on β-cell turnover in preclinical models
◦ Is released from K cells in duodenum
◦ Stimulates insulin response from β cells in a glucose-dependent manner
◦ Has minimal effects on gastric emptying
◦ Has no significant effects on satiety or body weight
◦ Does not appear to inhibit glucagon secretion from α cells
◦ Effect on β-cell turnover in preclinical models
GLP-1 GIP
Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606; Drucker DJ. Diabetes Care. 2003;26:2929–2940. Farilla L et al. Endocrinology. 2003;144:5149–5158.
10 E. C. Hendrich, FRACP
Sept. 09 11 E. C. Hendrich, FRACP
DPP-4 Widely expressed
Soluble & membrane bound forms
Reduces receptor affinity of GLP1 1000 fold and GIP 4fold
Eliminates insulinotropic effects
Bypassing DPP-4 – develop selective inhibitors of the enzyme – sitagliptin
Or develop analogues / mimetics resistant to DPP-4 action - exenatide.
Sept. 09 E. C. Hendrich, FRACP 12
Sitagliptin - Januvia
Large scale studies with DPP-4 inhibitors – remarkably benign safety profile Infrequent hypoglycaemia Absence of weight gain Adverse events rate – similar to placebo Consistent efficacy in reducing HbA1c levels, greatest
reductions in those with highest baseline HbA1c.
DPP4 inhibitors & the Management of Type 2 Diabetes mellitus: Current Opinion in Endocrinology, Diabetes & Obesity. Vol14,No2,2007
Safety
Sitagliptin & Renal Impairment: TII DM + Impaired renal function: Sitagliptin vs Placebo or Glipizide
Creat clear: ≥30 to ≤50 ml/min, < 30 ml/min, incl. pts on dialysis
54 wk randomised, dble blind, parallel group study: n=65Rx, 26 PBO
∆ HbA1c Sitagliptin: -06.% vs Placebo: -0.2%
Hypo’s Sitagliptin: 4.6% vs Glipizide 23.1%
Deaths Sitagliptin: 5/65 vs Glipizide 1/26
Adverse Events: Not significantly different, Deaths not deemed drug related
Dose adjustment for renal impairment:
Mod renal imp’t: Cr. Clear. ≥30 to ≤50 ml/min: half dose: 50 mg/d.
Severe Renal imp’t: Creat Clear. < 30 ml/min: Quarter: 25 mg/day
E. C. Hendrich, FRACP
Diab, Obesity & Metabolism: 2008, 10(7), 545-55
Exanatide: GLP-1 mimetic:
Sept. 09 E. C. Hendrich, FRACP 14
Exenatide (Byetta) injected s/c twice daily
50% structural homology with GLP-1
Replicates all of the known actions of GLP1
Once weekly formulation – soon (LAR)
Side effects
nausea – no diff. w. LAR
pancreatitis
Contraindicated in renal impairment
SGLT-2 inhibitors ◦ Lower the glucosuric effect in the renal tubules
◦ Pros: Lowers HbA1
Independent of insulin
Weight loss effect
Lowers BP
◦ Cons Genitourinary infections/side effects esp: mycotic vaginal & penile infections
Sulfonylureas
Bind ATP sensitive K channels on pancreatic ß cells – channel closes, cell depolarises, calcium enters cell & insulin is released.
This ATP channel has a SUR1 regulatory subunit – which binds the SU.
Meglitinides – (Repaglinide) ◦ Also acts on the SUR and closes the ATP – K channel- but lacks the sulfonylurea moiety.
◦ Inactivated in 1 hour post prandially
◦ Weight gain
◦ Hypoglycaemia: but less than SU’s
◦ Cyt P450 metabolism
◦ Good in renal impt. 7 in the elderly.
Suggestions
Type II DM ◦ Start with Metformin or Incretin
◦ Add sulfonylurea or SGLT2
◦ Add insulin
◦ Taylor insulin to pts BSL’s
◦ Need co-operation