dr larry distiller bsc mb bch fcp(sa) frcp face specialist ... treatment options and...

Dr Larry Distiller BSc MB BCh FCP(SA) FRCP FACE Specialist Physician / Endocrinologist Centre for Diabetes and Endocrinology, Houghton Hon Visiting Professor, Cardiff University School of Medicine

Insulin resistance Beta-cell function

Blood glucose

Euglycaemia Type 2 diabetes

Adequate Inadequate

Obesity Sedentary lifestyle Aging Genetics Glucotoxicity FFA levels

Adapted from Matthaei et al. Endocrine Reviews 2000;21:585-618. Adapted from Edelman. Adv Intern Med 1998;43:449-500.

Insulin response

Bianchi C et al. Diabetes Voice 2011;56:28-31

And many more in development

What are the incretins and gliptins?

Why should we use them?

When should they be used?

Should we be using them?

Potent enhancers of glucose induced insulin secretion

Glucose-dependant insulinotropic

polypeptide, (GIP), formerly called gastric inhibitory polypeptide

Glucagon-Like Polypeptide 1 (GLP-1)

L-cell

(ileum)

K-cell

(jejunum)

Proglucagon

GLP-1 [7–37]

GLP-1 [7–36 NH2]

ProGIP

GIP [1–42]

Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169

Stomach: Helps regulate gastric

emptying

Promotes satiety and reduces appetite

Liver: Glucagon reduces

hepatic glucose output Beta cells: Enhances glucose-dependent

insulin secretion

Alpha cells: Postprandial

glucagon secretion

GLP-1: Secreted upon the

ingestion of food

Slower gastric emptying - Direct effect on gastric emptying

Feeling of satiety - Blocks satiety centre centrally

Reduction in post-prandial glucose levels - Direct effect on insulin secretion (incretin effect) - Suppression of glucagon

N = 6; Mean (SE); *P0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498

C-p

ep

tid

e (

nm

ol/

L)

Time (min)

0.0

0.5

1.0

1.5

2.0

Incretin Effect *

*

*

*

* *

*

Oral Glucose

Intravenous (IV) Glucose

Pla

sma

Glu

cose

(m

g/d

L)

200

100

0

Time (min)

60 120 180 0 60 120 180 0

The incretin effect is severely reduced or even abolished in patients with Type 2 diabetes

Secretion of GIP is near-normal in most patients

with Type 2 diabetes, but insulinotropic effect of GIP is largely ablated in type 2 diabetes, even when infused at supraphysiologic levels

The secretion of GLP-1 is significantly impaired

Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and

glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes. 2004;53(suppl 3):S190-S196.





Nauck MA, Baller B, Meier JJ. Diabetes.2004;53(suppl 3):S190-S196.

Time, min

IR In

suli

n,

mU

/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

180 60 120 0

Control Subjects (n=8)

Patients With Type 2 Diabetes (n=14)

Time, min

IR In

suli

n,

mU

/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

180 60 120 0

Oral glucose load

Intravenous (IV) glucose infusion

Incretin Effect

The incretin effect is diminished

in type 2 diabetes.

Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.

Data are mean±SEM. GIP, gastric inhibitory peptide; type 2 diabetes patients (n=8) Vilsbøll et al. Diabetologia 2002:45:1111–9

GLP-1 (but not GIP) increases both early- and late-stage insulin secretion

Mean (SE); n=10; *p<0.05; type 2 diabetes patients (n=10) Nauck et al. Diabetologia 1993;36:741–4

Placebo (PBO)

Native human GLP-1

The Problem

Native GLP-1 and GIP are broken down by DPP-4 in 1-2 minutes

The Solution ?

- GLP-1 analogues

- DPP-4 inhibitors

Exenatide (Byetta®, Eli Lilly)

Liraglutide (Victoza®, NovoNordisk) Others in the pipeline

Synthetic version of the salivary protein found in the Gila monster

More than 50 % amino acid

sequence identity with human GLP-1

▪ Binds to known human GLP-1 receptors

▪ Resistant to DPP-4 inactivation

Nielsen LL, et al. Regul Pept. 2004;117:77-88 Kolterman OG, et al. Am J Health-Syst Pharm. 2005;62:173-181

Following injection, exenatide is measurable in plasma for up to 10 hours

A slightly modified version of the GLP-1

molecule that attaches to albumin and therefore is released slowly, adopting the pharmacokinetic profile of albumin

The plasma half-life for this compound is

12 hours. It therefore provides exposure for over 24 hours following a single subcutaneous injection

Vildagliptin (Galvus® ,Novartis) Saxagliptin (Onglyza®, AstraZenica) Sitagliptin (Javunia® , Merck)

Linagliptin (Tradjenta®, BI / Eli Lilly)

Alogliptin

Release of active incretins GLP-1 and GIP Blood glucose in

fasting and postprandial states

Ingestion of food

Glucagon (GLP-1)

Hepatic glucose

production

GI tract

DPP-4 enzyme

Inactive GLP-1

X DPP-4

inhibitor

Insulin (GLP-1 & GIP)

Glucose- dependent

Glucose dependent

Pancreas

Inactive GIP

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

Beta cells

Alpha cells

Glucose uptake by

peripheral tissue

GLP-1 Analogues DPP4-Inhibitors

• Supra-physiological levels of GLP-1 • Approaches physiological levels of GLP-1

*GLP-1 levels for liraglutide calculated as 1.5% free liraglutide

Degn et al. Diabetes 2004;53:1187–94; Mari et al. J Clin Endocrinol Metab 2005;90:4888–94

GLP-1 Analogues DPP4-Inhibitors

• Supra-physiological levels of GLP-1 • Approaches physiological levels of GLP-1

• Significant and sustained weight loss • Weight neutral

• Injected therapy • Oral therapy

• Potential GIT Side-effects • Minimal GIT side-effects

• Low rates of hypoglycaemia • Low rates of hypoglycaemia

• Improved CV risk factors • Limited data on CV risk factors

insulin secretion glucagon release food intake, slow gastric emptying

insulin secretion glucagon release

Exenatide (twice daily)

Liraglutide (once daily)

Change from baseline to 30 weeks

HbA1c (%) Body weight (kg)

Existing oral therapy

Exenatide

5 µg bid

Exenatide 10µg bid

Exenatide 5 µg bid

Exenatide 10 µg bid

Sulphonylurea1 0.46§ 0.86§ 0.9 1.6*

Metformin2 0.40‡ 0.78‡ 1.6§ 2.8§

Metformin + sulphonylurea3

0.60¶ 0.80¶ 1.6† 1.6†

*p<0.05; †p0.01; ‡p<0.002; §p<0.001; ¶p<0.0001;

all versus placebo

1. Buse J, et al.2004 2. DeFronzo R, et al.2005 3. Kendall D, et al. 2005.

-1.5

-1.0

-0.5

0.0

104-Week Completers at Week 30 104-Week Completers at Week 104

104-wk Completers; N = 195; Mean (SE); Weight is a secondary endpoint Data on file, Amylin Pharmaceuticals, Inc.

A

1C (

%)

W

eig

ht

(kg

) -6

-5

-4

-3

-2

-1

0 Mean baseline A1C: 8.2% Mean baseline weight: 101 kg

Significant *vs. comparator; #Change in HbA1c from baseline for overall population (LEAD-4,-5) add-on to diet and exercise failure (LEAD-3); or add-on to previous OAD monotherapy (LEAD-2,-1)

Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009; 32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5)

• Weight and blood pressure did not differ between add-on and switch concept

*Change calculated by ANCOVA analysis

Nauck et al. Diabetes 2009;58(Suppl. 1):A122 (abstract 459-P)

Liraglutide 1.8 mg/day

Liraglutide 1.2 mg/day

Glimepiride 8 mg/day

• Waist circumference was reduced from baseline by 3.0 cm with liraglutide 1.8 mg

• Waist circumference increased by 0.4 cm with glimepiride (p<0.0001)

***p<0.0001 for change from baseline

Garber et al. Lancet 2009;373(9662):473–81 (LEAD-3)

• Both liraglutide and exenatide were combined with met and/or SU

Buse et al. Lancet 2009;374:39–47 (LEAD-6)

Mean (2SE)


GLP-1 receptors are expressed in multiple organs including: Pancreas

Peripheral tissue

Central nervous system

Heart

Kidney

Lung

Gastrointestinal tract

GLP-1 appears to have a range of neurotrophic

neuroprotective and cardioprotective effects

GLP-1 receptors have been localized t0: ▪ Cardiomyocytes

▪ Endocardium

▪ Microvascular endothelium

▪ Coronary artery smooth muscle cells;

GLP-1

Heart (myocardium) • Protects against Ischaemia /

reperfusion injury • Improves myocardial function

Vascular System • Improves Endothelial function • Vasorelaxation

The Kidney • Increased diuresis and Na+ excretion Adapted from:

Chilton R et al. The American Journal of Medicine 2011;124, S35–S53

Promote Weight loss

Lower Triglyceride and raise HDL

Lower Blood pressure (?)

Improve endothelial dysfunction

Reduce CRP and other inflammatory markers

Increase myocardial insulin sensitivity

Increase myocardial glucose uptake

Koska J et al Diabetes Care 2010;33:1028-1030 Courreges JP et al Diabetes Medicine 2008;25:1129-1134 Nikolaidis LA st al. Circulation 2004;110:955-961 Bhashyam S. Et al Circ Heart Fail 2010;3:512-521

In Addition: Reduced monocyte adhesion to endothelial cells promoted

by inhibition of the inflammatory response to macrophages

Development of atherosclerotic lesions was suppressed in mice

GLP-1 was found to enhance coronary blood flow after induced ischaemia in rats

In one study, exenatide treated animals were shown to have as much as

40 % reduction in MI size when compared with controls

Chilton R et al. The American Journal of Medicine 2011;124, S35–S53

No effect of Exenatide 10 µg on QT interval

No relevant increases in the QTc interval using liraglutide once daily

No prolongation of the QT interval using exenatide once weekly

Chatterjee DJ et al. J Clin Pharmacol 2009;49:1353-59 Amylin Pharmaceuticals. Data on file.

LifeLink Study 39,000 patients treated with exenatide were compared with [approximately] 390,000 patients treated with all other interventional strategies

Significant decrease in cardiovascular events with Exenatide (hazard ratio, 0.81; [95 % confidence interval, 0.68-0.95; P=0.01]), indicating a 16 % decrease in cardiovascular events

Best JH et al. Diabetes Care 2011;34:90-95

Vilsboll T et al. BMJ 2012;344:d7771doi: Published Jan 2012

Exenatide Liraglutide

Administration s.c. Twice daily s.c. Once daily

Mean Reduction in HbA1c ~o.8-1.1 % ~1.1-1.5 %

Mean reduction in FPG ~0.6 mmol/l ~1.7 mmol/l

Mean reduction in body weight 2.87 kg 3.24 kg

Persistence of nausea (after 26 weeks) 10 % 5 %

Liraglutide appears the better option on all fronts, but this may change with once-weekly exenatide which seems better than daily liraglutide

Adapted from: Buse et al. Lancet 2009;374:39–47 (LEAD-6)

Vildagliptin (Galvus® ,Novartis) Saxagliptin (Onglyza®, AstraZenica) Sitagliptin (Javunia® , Merck)

Linagliptin (Tradjenta®, BI / Eli Lilly)

Alogliptin

–0.8

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Ch

an

ge in

A1C

, %

Mean Baseline: 8.0 % P<0.001*

†

‡

A1C

(95 % CI: –1.0, –0.6)

* Compared with placebo. † Least squares means adjusted for prior antihyperglycaemic therapy status & baseline value. ‡ Difference from placebo.

n=229

Mean Baseline: 170 mg/dL

P <0.001*

–17

-25

-20

-15

-10

-5

0

Ch

an

ge

in

FP

G, m

g/d

L

†

‡

FPG

(95 % CI: –24, –10)

n=234

Mean Baseline: 257 mg/dL

P<0.001*

–47

-60

-50

-40

-30

-20

-10

0

Ch

an

ge i

n 2

-hr

PP

G,

mg

/dL

†

‡

2-hr PPG

(95 % CI: –59, –34)

n=201

C. F. Deacon CF. Diabetes, Obesity and Metabolism 2010;13:7-18

Triangle, sitagliptin (100 mg qd) Circle, vildagliptin (50 mg bid or 100 mg qd) Square, saxagliptin (5 mg qd); Diamond, alogliptin (25 mg qd) Star, linagliptin (5 mg qd)

http://onlinelibrary.wiley.com/doi/10.1111/j.1463-1326.2010.01306.x/full

Sitagliptin administration at a single dose of 100 mg in patients with CAD:

Preserved LV function

Enhanced LV response to stress

Improved global and regional LV performance compared

with placebo

Read PA. Circ Cardiovasc Imaging 2010; 3: 195–201

No definitive evidence for this as yet.

Awaiting outcome of TECOS, SAVOR and other trials.

While the effects on glucagon, gastric emptying and satiety may well persist, the major effect of these drugs is still on insulin secretion

Therefore, the better the residual insulin secretory capacity (the more β-cell reserve), the better the expected response

None of these drugs are registered for first-line or monotherapy

But that is probably where they will prove to be most beneficial

Makes therapeutic sense: Basal insulin to target FPG; incretin to target PPG.

Sitagliptin has registration for use with insulin.

Exenatide has FDA approval for use with basal

insulin.

Liraglutide has been shown to be effective when combined with basal insulin.

DPP-4 is found on endothelial and epithelial cells

throughout the vascular bed, and in the kidneys, intestines, exocrine pancreas, gastrointestinal tract,

biliary tract, thymus, lymph nodes, uterus, placenta, prostate, myocardium, and brain, as well as the adrenal, sweat, salivary, and mammary glands.

In addition, DPP-4 is also expressed on circulating T-lymphocytes and is found in soluble form in seminal and cerebrospinal fluid and plasma.

DPP-4 inhibition has not, as yet, been associated with any human disease.

96 DPP-4 inhibitors have shown a very positive safety and

tolerability profile in clinical studies involving thousands of patients with type 2 diabetes

DPP-4 inhibitor treatment has been associated with slightly elevated risks of nasopharyngitis, bronchitis, urinary tract infection and headaches

The debate rages!

Case reports have raised concerns about an increased risk of acute pancreatitis in patients treated with GLP-1 agonists

But Type 2 diabetes itself is said to be associated with a 3-fold increased risk of developing pancreatitis

So - is the incidence of pancreatitis higher with GLP-1

analogues or is it just a case of “awareness”?

A review of 10,000 patients on 19 clinical trials in patients on sitagliptin showed no increased risk of pancreatitis

In all animal studies, there is no evidence that DPP4-I cause pancreatitis

Engel SS et al. In J Clin Pract 2010;64:984-990 C. F. Deacon CF. Diabetes, Obesity and Metabolism 2010;13:7-18

http://onlinelibrary.wiley.com/doi/10.1111/j.1463-1326.2010.01306.x/full

German data base identified 11 cases of pancreatic cancer in association with exenatide

No such “signal” with DPP4-I

Exenatide promotes pancreatic ductal hyperplasia

However, the time between tumour induction, tumour growth and clinical diagnosis is > 10 years

Exenatide exposure was 2-33 months ▪ ? does exenatide promote tumour progression rather than initiation

Liraglutide induces thyroid C-cell focal hyperplasia and C-cell tumours in a dose-related manner in rats, which may lead to medullary thyroid cancer

In a 104-week exenatide carcinogenicity study in rats, an increased incidence of benign thyroid C-cell adenomas was seen

(Rats develop spontaneous C-cell lesions at a high frequency, while C-cell neoplasia is extremely

rare in humans)

This has not been seen in any of the clinical studies performed to

date

Knudsen LB. Endocrinology 2010; 151: 1473–1486 Parks M. N Engl J Med 2010; 362: 774–777

Elashoff M et al Gastroenterology 2011;141:150-156

We don’t know!

There are those who remain opposed to these drugs on basis of uncertainty

There are those who believe in these drugs implicitly

And many in-between! The jury is still out

“ History has taught us that enthusiasm for new classes of drugs, heavily promoted by the

pharmaceutical companies that market them, can obscure the caution that should be exercised when long-term consequences are

unknown”

Peter Butler. Diabetes Care 2010

We are constantly being pressurised by industry to prescribe newer and more expensive drugs

For most of us, there are intangible rewards for doing this

Don’t trust me, I’m a doctor…

“As to the honour and conscience of doctors, they have as much as any other class of men, no more and no less

And what other men dare pretend to be impartial where they have a strong pecuniary interest on one side?”

George Bernard Shaw, 1911

“Prediction is very difficult, especially about the future”

Niels Bohr

Thank you for your

attention

dr larry distiller bsc mb bch fcp(sa) frcp face specialist ... treatment options and...

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