DM Therapeutics

Elke Hendrich
2015

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
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

Mechanisms of Action of Major Oral Monotherapies Do Not

Target 3 Core Defects in Type 2 Diabetes
SUs=sulfonylureas; TZD=thiazolidinediones; DPP-4=dipeptidyl peptidase 4.
Inzucchi SE. JAMA 2002;287:360372; Gallwitz B. Minerva Endocrinol. 2006;31:133147.

Cumulative Incidence of Diabetes According to

Study Group

Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403

Dr. E.C.Hendrich

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

Incretin Hormones Regulate Insulin and Glucagon Levels

Increased ghrelin decr. appetite
Increased PYY Incr. satiety, delay Gemptying.

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

Role of Incretins in Glucose Homeostasis

Ingestion of food

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

*Incretins are also released throughout the day at basal levels.

Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876913; Ahrn B. Curr Diab Rep. 2003;2:365372;
Drucker DJ. Diabetes Care. 2003;26:29292940; Holst JJ. Diabetes Metab
Res09Rev. 2002;18:430441.
Sept.
E. C. Hendrich,
FRACP

GLP-1

GLP-1

Inactivated by DPP-4: T1/2 =2 mins

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
Sept. 09 E. C. Hendrich, FRACP
Increases lipogenesis
in adipocytes

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

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
Sept. 09 E. C. Hendrich, FRACP
No effect on body weight

Demonstrated Effects of the Incretin Hormones

GLP-1 and GIP

GLP-1

GIP

Is released from L cells in

ileum and colon

Is released from K cells in

duodenum

Stimulates insulin response

from
cells in a glucose-dependent
manner

Stimulates insulin response

from
cells in a glucosedependent manner

Inhibits gastric emptying

Has minimal effects on

gastric emptying

Reduces food intake and

body weight

Has no significant effects on

satiety or body weight

Inhibits glucagon secretion

from cells in a glucosedependent manner

Does not appear to inhibit

glucagon secretion from
cells

Effect on -cell turnover in

preclinical models

Effect on -cell turnover in

preclinical models

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

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

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

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
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

Dose adjustment for renal impairment:

Mod renal impt: Cr. Clear. 30 to 50 ml/min: half dose: 50
mg/d.
Severe Renal impt: Creat Clear. < 30 ml/min: Quarter: 25
mg/day
Diab, Obesity & Metabolism: 2008,
10(7), 545-55

E. C. Hendrich, FRACP

Exanatide: GLP-1 mimetic:

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

Sept. 09

E. C. Hendrich, FRACP

14

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 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.

Amylin analogues: Pramlintide

PPAR gamma inhibitors

Other

Suggestions

Type II DM
Start with Metformin or Incretin
Add sulfonylurea or SGLT2
Add insulin
Taylor insulin to pts BSLs
Need co-operation

Insulin secretory response

Tailor the Treatment

Diabetes Care

Suggestions: -Define targets

TII DM
Failure to reach goal HbA1c on max. oral
agents:
Try once daily glargine: push to FBG of 5.5
mmol/L

Failure to reach HbA1c with incr. basal insulin

Try bd mixed insulin tds mixed insulin also
effective

Mix & Match according to pt. preference.