Developments in the Treatment of T2DM Dr John Clark.

Developments in the Treatment of T2DM

Dr John Clark

Diabetes Prevalence

0

1 million

2 million

3 million

1995 2000 2013

Type 1Type 2

Audit of West Suffolk Hospital In-Patients

One day (23/9/12)

440 in-patients, in total, in WSH that day

75 known to have Diabetes

17% of in-patients are Diabetic (1 in 6)

Glycaemic ControlGlycaemic Control Drugs to use Drugs to use (prior to 2010)(prior to 2010)

Drug of choiceDrug of choice MetforminMetformin

Next StageNext Stage MetforminMetformin + + SulphonylureaSulphonylurea oror MetforminMetformin + + PioglitazonePioglitazone

Next StageNext Stage Metformin Metformin + + Pioglitazone + SUPioglitazone + SU

Final StageFinal Stage MetforminMetformin + + basal insulinbasal insulin

New DevelopmentsNew Developments

The incretin effect and GLP-1 The incretin effect and GLP-1

Treatments Treatments A) DPP-4 InhibitorsA) DPP-4 Inhibitors

Treatments Treatments B) GLP-1 Agonists B) GLP-1 Agonists

Oral glucose load (50 g) iv. glucose infusion

Pla

sma g

luco

se (

mm

ol/L)

–10 –5 60 120 180

10

Time (min)

5

0

15

Plasma glucose

The Incretin Effect

• Insulin response is greater following oral glucose than i.v. glucose, despite similar plasma glucose concentration

Insulin response

Insu

lin (

mU

/L)

80

60

40

20

–10 –5 60 120 1800

Time (min)

Incretineffect

Healthy volunteers (n=8); i.v.: intravenousNauck et al. Diabetologia 1986;29:46–52

Date of preparation: August 2009UK/LR/0809/0384

The Incretin Effect is Reduced in Subjects with Type 2 Diabetes

Nauck MA, et al. Diabetologia 1986;29:46–52. *P ≤.05 compared with respective value after oral load.

Time (min)

Intravenous GlucoseOral Glucose

0

20

40

60

80

Ins

uli

n (

mU

/L)

0 30 60 90 120 150 180

** *

** **

Control subjects

0

20

40

60

80

0 30 60 90 120 150 180

Time (min)

**

*

Subjects with type 2 diabetes

Ins

uli

n (

mU

/L)

The Incretin Effect accounts for ~ 60% of total Insulin release following a meal

Studies of the entero-insular axis following pancreas transplantation in man: neural or

hormonal control?Clark JDA, Wheatley T, Brons IG, Bloom SR, Calne RY.

Department of Medicine and Surgery, Addenbrooke's Hospital, Cambridge, UK.

Diabetic Medicine. 1989 Dec,6, 813-7.

To study the role of hormonal and neural factors in the control of the entero-insular axis, the responses to oral and intravenous glucose were investigated in 5 patients who had received a combined kidney and paratopic pancreas transplant

As the incretin effect was preserved, despite

a denervated pancreas, hormonal rather than neural factors may be more important in mediating increased insulin secretion after oral carbohydrate. The normal GIP response is compatible with its proposed role as an insulinotropic hormone.

Incretin EffectIncretin Effect

Larger insulin response toLarger insulin response to ora oral rather than IV l rather than IV glucose. Why?glucose. Why?

Oral glucose stimulates release of Oral glucose stimulates release of GLP-1GLP-1 from from

small intestinesmall intestine

GLP-1 GLP-1 augments insulin releaseaugments insulin release from B cells of from B cells of

pancreaspancreas

What is glucagon-like peptide-1 (GLP-1)?

Lys

His Ala Thr Thr SerPheGlu Gly Asp

Val

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

• A 31 amino acid peptide

• Cleaved from proglucagon in L-cells in the GI tract

• Secreted in response to meal ingestion

GI: gastrointestinalDrucker & Nauck. Lancet 2006;368:1696–705


GLP-1: Effects in HumansGLP-1: Effects in Humans

Promotes satiety and reduces appetite

-cells:Enhances glucose-

dependent insulin secretion

GLP-1: Glucagon-like peptide 1Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.

Stomach: Helps regulate

gastric emptying

GLP-1 secreted upon the ingestion of food

Native GLP-1 is rapidly degraded by DPP-4 (Di-Peptidyl Peptidase-4)

Human ileum, GLP-1-producingL-cells

Capillaries,DPP-4

Double immunohistochemical staining for DPP-4 (red) and GLP-1 (green) in the human ileum

Hansen et al. Endocrinology 1999;140:5356–63


The family of incretin-based The family of incretin-based therapiestherapies

Human GLP-1 analogues, liraglutide

Exendin-basedtherapies,

exenatide + lixisenatide

GLP-1 receptor agonists

DPP-4 inhibitors, sitagliptin vildagliptin saxagliptinlinagliptin

Incretin-basedtherapies


DPP-4 Inhibitors (Gliptins)DPP-4 Inhibitors (Gliptins)

OralOral

Weight neutralWeight neutral

Minimal hypoglycaemiaMinimal hypoglycaemia

NICE – must lower HbA1c by 0.5% within 6/12NICE – must lower HbA1c by 0.5% within 6/12

Mr K S age 65

Type 2 Diabetes for 10 years

Gradual increase in OHA dosage

June 2010 HbA1c 7.8%

Metformin 500mg bd + glipizide 10mg bd

Mr K S

June 2010 - Add in Sitagliptin 100 mg od

October 2010 - HbA1c 7.4%

Glipizide reduced to 2.5 mg am, 5 mg pm.

Do Exenatide/Liraglutide/Lixisenatide Do Exenatide/Liraglutide/Lixisenatide Work?Work?

Exenatide vs. Insulin Glargine Exenatide vs. Insulin Glargine

Reductions in HbAReductions in HbA1c1c

-1.1% -1.1%

-1.5

-1.0

-0.5

0.0

% C

ha

ng

e i

n H

bA

1c

HbA1c <7% HbA1c <6.5%

46% 48%

32%

25%

0

10

20

30

40

50

60

% P

ati

en

ts A

ch

iev

ing

H

bA

1c t

arg

ets

Exenatide

Insulin glargine

ITT population; Mean ± SE shown.Heine RJ et al. Ann Intern Med. 2005;143:559-569.

(n=275)

(n=260)

Exenatide vs. Insulin GlargineExenatide vs. Insulin GlargineChange in Body WeightChange in Body Weight

Exenatide (n = 275) Insulin glargine (n = 260)

Time (weeks)

Ch

an

ge

in

bo

dy

we

igh

t (k

g)

0 2 4 8 12 18 26

-3

-2

-1

0

1

2

**

**

**

+1.8 kg

-2.3 kg

4.1 kg

HbAHbA1c1c and weight loss: and weight loss: from LEAD trials 1–6from LEAD trials 1–6

% patients

Weig

ht

loss

Weig

ht

gain

HbA1c decrease HbA1c increase

LEAD-2. ITT, LOCF. n=232

Glimepiride 4 mg

51%

32%

HbAHbA1c1c and weight change: and weight change: sulphonylurea sulphonylurea

HbA1c decrease

Weig

ht

loss

Weig

ht

gain

HbA1c increase

5%

12%

Data on file Composite Endpoint,Novo Nordisk


Pioglitazone

10%15%

49% 26%

HbAHbA1c1c and weight change: and weight change: thiazolidinedionethiazolidinedione

ITT, intention-to-treat; LOCF, last observation carried forward

HbA1c decrease

Data on file, Composite Endpoint, Novo Nordisk

HbA1c increase

Weig

ht

loss

Weig

ht

gain


Glargine 24 IU

63% 10%

2%25%

HbAHbA1c1c and weight change and weight change: : glargineglargine

HbA1c decrease

Weig

ht

loss

Weig

ht

gain

HbA1c increase

Data on file Composite Endpoint, Novo Nordisk


Exenatide 10 μg BD

5%14%

9%72%

HbAHbA1c1c and weight change and weight change: : exenatideexenatide

HbA1c decrease

Weig

ht

loss

Weig

ht

gain

HbA1c increase



Liraglutide 1.2 mg

72% 13%

4%10%

HbAHbA1c1c and weight change: and weight change: liraglutide liraglutide 1.2 mg1.2 mg

HbA1c decrease

Weig

ht

loss

Weig

ht

gain

HbA1c increase

Data on file Composite Endpoint,Novo Nordisk

Comparison : shifting the paradigmComparison : shifting the paradigm

Pioglitazone

Glimepiride 4 mg

Exenatide 10 μg BID

Lixisenatide 20ug od

Glargine 24 IU

25%

72%

72%

72%

Liraglutide 1.2 mg

32%

15%

HbA1c decrease HbA1c increase

Weig

ht

gain

Weig

ht

loss


Diabetes Clinic Diabetes Clinic (1/9/10)(1/9/10)

Weight HbA1c ExenatideWeight HbA1c Exenatide NJ 120 – 92kg 8.5 – 6.1 1yearNJ 120 – 92kg 8.5 – 6.1 1year

JH 117 – 96kg 7.8 – 6.0 6 monthsJH 117 – 96kg 7.8 – 6.0 6 months

NT 123 – 112kg 9.2 – 7.3 6 monthsNT 123 – 112kg 9.2 – 7.3 6 months

NICE Guidance NICE Guidance 20102010

(must satisfy all criteria)(must satisfy all criteria)

HbA1c > 7.5%HbA1c > 7.5% Already on OHAsAlready on OHAs Weight related health problemsWeight related health problems BMI > 35BMI > 35

By 6 months must achieve both targets By 6 months must achieve both targets weight loss of 3% weight loss of 3% drop in HbA1c of 1%drop in HbA1c of 1%

312 patients initiated on Exenatide since May 2008

207 patients completed 6 months treatment by December 2010

WSH Audit 2011

WSH Outcome Data: Passed v Failed @ 6 months

Passed @ 6/12(184)

HbA1c Weight (Kg) BMI

Baseline 9.6SD 1.5(7.4 to 14.0)

119.8SD 20.9(75.2 to 185.6)

41.5SD 7.2(26.0 to 84.8)

Change at 6/12

-1.6SD 1.6(-7.1 to +3.5)

-6.8SD 5.4(-25.6 to +5.6)

-2.4SD 1.9(-9.3 to +1.9)

P value P < 00001 P < 0.0001 P < 0.0001

Failed @ 6/12(23)

HbA1c Weight (Kg) BMI

Baseline 9.3(6.2 to 12.9)SD 1.6

126.4(80.2 to 183.7)SD 25.1

43.2(33.8 to 59.1)SD 7.9

Change at 6/12

-0.3(-5.4 to +3.3)SD 1.6

-6.2(-16.7 to +1.3)SD 5.1

-2.1(-5.0 to +0.4)SD 1.7

P value P = 0.35 P < 0.0001 P = 0.0014

P value (pass v non-pass)

P = 0.0004 P = 0.57 P = 0.50

WSH Data: Exenatide success @ 6/12Insulin v Non-Insulin Group

Total on Insulin (86)

HbA1c Weight (Kg)

BMI P value

Baseline 9.5SD 1.3(8.2 to 10.8)

118.7SD 17.9(100.8 to 136.6)

41.7 SD 6.2(35.5 to 37.9)

Change at 6/12

-1.6 SD 1.4(-3.0 to -0.2)

-7.3 (6.2%)SD 5.2(-12.5 to -2.1)

-2.6 SD 1.9(-4.5 to -0.7)

P <0.0001

Non-insulin (98)

HbA1c Weight (Kg)

BMI P value

Baseline 9.7SD 1.6(8.1 to 11.3)

120.8SD 23.2(97.6 to 144.0)

41.3SD 8.0(33.3 to 49.3)

Change at 6/12

-1.6 SD 1.7

(-3.3 to 0.1)

-6.5 (5.4%)SD 5.5(-12.0 to -1.0)

-2.2SD 1.9(-4.1 to -0.3)

p < 0.0001

P value P = 0.83 P = 0.32 P = 0.23

New Drug - DapagliflozinNew Drug - Dapagliflozin

Blocks reabsorption of glucose in Blocks reabsorption of glucose in kidneyskidneys

Increased urinary glucose lossIncreased urinary glucose loss Oral medication 5-10mg once dailyOral medication 5-10mg once daily

DapagliflozinDapagliflozinBenefitsBenefits

HbA1c drops by 0.5-1.0%HbA1c drops by 0.5-1.0% Weight loss of 2-3 kg over 6 monthsWeight loss of 2-3 kg over 6 months Low risk of hypos (not reliant on Low risk of hypos (not reliant on

insulin)insulin) Additive effect when combined with Additive effect when combined with

other diabetic treatments, including other diabetic treatments, including insulin. insulin.

DapagliflozinDapagliflozinSide-effectsSide-effects

Urinary tract infectionUrinary tract infection PolyuriaPolyuria Genital fungal infectionGenital fungal infection

Bariatric SurgeryBariatric Surgery

30 Kg weight loss30 Kg weight loss 50% achieve HbA1c < 6.5%50% achieve HbA1c < 6.5% High rate of High rate of remissionremission of diabetes of diabetes But no long term studiesBut no long term studies

Summary of TargetsSummary of Targets

HbA1c < 7.5 % (Metformin)HbA1c < 7.5 % (Metformin)

BP 140 / 80 or less (ACE-I or BP 140 / 80 or less (ACE-I or ARB)ARB)

Cholesterol < 4.0 (Statin)Cholesterol < 4.0 (Statin)

Glycaemic ControlGlycaemic Control Drugs to use Drugs to use

Drug of choice MetforminDrug of choice Metformin

Next Stage Metformin with Sulphonylurea Next Stage Metformin with Sulphonylurea or Pioglitazoneor Pioglitazone or or

Sita/Vilda/Saxa/LinaSita/Vilda/Saxa/Lina


Next Stage Metformin with GLP-1 Next Stage Metformin with GLP-1 injection injection

Final Stage Metformin with basal Final Stage Metformin with basal Insulin Insulin

Consider Dapagliflozin Consider Dapagliflozin

Last resort Bariatric surgery Last resort Bariatric surgery


Drug of choice MetforminDrug of choice Metformin

Next Stage Metformin with Sulphonylurea Next Stage Metformin with Sulphonylurea or Pioglitazoneor Pioglitazone or or Sita/Vilda/Saxa/LinagliptinSita/Vilda/Saxa/Linagliptin

Next Stage Metformin with Exenatide/Liraglutide/Lixisenatide Next Stage Metformin with Exenatide/Liraglutide/Lixisenatide

Final Stage Metformin with basal Insulin Final Stage Metformin with basal Insulin

Consider Dapagliflozin Consider Dapagliflozin

Last resort Bariatric surgery Last resort Bariatric surgery

WSH COST DATAExenatide Success @ 6/12Insulin v Non-Insulin Group

Extra Cost for Exenatide (per person , per month)

Reduction in Cost @ 6 months

Baseline £68.24

On Insulin (86)@ 6/12

£33.90 £34.34

Non-insulin (98)@ 6/12

£54.80 £13.44

Developments in the Treatment of T2DM Dr John Clark.

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Transcript of Developments in the Treatment of T2DM Dr John Clark.