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 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.

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 BSL’s

◦ 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.