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Elke Hendrich
2015
Cost/PB
S
Efficacy
Side
Effects
Weight
Gain
Hypo
s
BMD
OUTCOM
ES
Metformin
Cheap
++
GIT
NIL
Few
None
Decr.
mortality
DPP-4
inhibs
PBS
Few
NIL
Few
GLP1
analogues
Expensive
++
Few
NIL
Few
TZDs
PBS
+++
+++
++
Loss
Sulfonylureas
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
E. C. Hendrich, FRACP
Oral Monotherapies
Key Defects
Improves insulin
secretion
SUs
Meglitinides
TZDs
-Glucosidase
Metformin
Inhibitors
DPP-4
Inhibitors
Improves insulin
resistance
Lowers hepatic
glucose production
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
E. C. Hendrich, FRACP
Hormonal
signals
GLP-1
GIP
Glucagon
(GLP-1)
cells
Neural
signals
cells
Gut
Pancreas
Nutrient signals
Insulin
(GLP1,GIP)
Glucose
Adapted from Kieffer T. Endocrine Reviews. 1999;20:876913. Drucker DJ. Diabetes Care. 2003;26:29292940. Nauck MA
et al. Diabetologia. 1993;36:741744. Adapted with permission from Creutzfeldt W. Diabetologia. 1979;16:7585.
Copyright 1979
Springer-Verlag.
E. C. Hendrich,
FRACP
Sept. 09
GI tract
Pancreas
Release of
gut
hormones
incretins*
Active
GLP-1 & GIP
DPP-4
enzym
e
Inactive Inactive
GLP-1
GIP
Glucose-dependent
Insulin from cells
(GLP-1 and GIP)
Glucose
uptake
by muscles
Blood glucose in
fasting and
postprandial
states
cells
cells
Glucose
dependent
Glucagon from
cells
(GLP-1)
Glucose
production
by liver
GLP-1
GLP-1
GIP
Inactivated by DPP-4: T1/2 =5-7 mins
GIP
Acquired defect in DM vs 1
feature
GIP defect reversible with
restoration of BSLs
GLP1 & GIP potentiate each
others actions
GLP-1
GIP
Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587606; Drucker DJ. Diabetes Care.
2003;26:29292940. Farilla L et al. Endocrinology. 2003;144:51495158.
E. C. Hendrich, FRACP
10
DPP-4
Widely expressed
E. C. Hendrich, FRACP
11
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,N
Sept. 09 E. C. Hendrich, FRACP
12
Safety
HbA1c
Hypos
Deaths
Sitagliptin:
-06.% vs
Placebo: -0.2%
Sitagliptin:
Sitagliptin:
4.6%
5/65
Glipizide 23.1%
Glipizide 1/26
vs
vs
Adverse Events: Not significantly different, Deaths not deemed drug related
E. C. Hendrich, FRACP
Sept. 09
E. C. Hendrich, FRACP
14
SGLT-2 inhibitors
Pros:
Lowers HbA1
Independent of insulin
Weight loss effect
Lowers BP
Cons
Sulfonylureas
Bind ATP sensitive K channels on
pancreatic 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 SUs
Cyt P450 metabolism
Good in renal impt. 7 in the elderly.
Other
Suggestions
Type II DM
Start with Metformin or Incretin
Add sulfonylurea or SGLT2
Add insulin
Taylor insulin to pts BSLs
Need co-operation
Diabetes Care
TII DM
Failure to reach goal HbA1c on max. oral
agents:
Try once daily glargine: push to FBG of 5.5
mmol/L