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MANAGEMENT OF TYPE 2 DIABETES AND NEW NICE GUIDELINES Dr SUNIL ZACHARIAH CONSULTANT ENDOCRINOLOGIST

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Page 1: Consultant presentations

MANAGEMENT OF TYPE 2 DIABETES AND NEW NICE GUIDELINES

Dr SUNIL ZACHARIAH CONSULTANT ENDOCRINOLOGIST

Page 2: Consultant presentations

INTRODUCTION

• The epidemic of type 2 diabetes and the recognition that achieving specific glycaemic goals can substantially reduce morbidity have made the effective treatment of hyperglycemia a top priority

• Intensive glycaemic control has been demonstrated to have a powerful beneficial effect on diabetes-specific microvascular complications, including retinopathy, nephropathy and neuropathy

• Development of new classes of blood glucose-lowering medications to supplement the older therapies has increased the number of treatment options

Page 3: Consultant presentations

GLYCEMIC GOALS OF THERAPY

• DCCT (Diabetes Control and Complications Trial), UKPDS (UK Prospective Diabetes Study) and Stockholm Diabetes Study in Type 1 diabetes have helped to establish the glycaemic goals of therapy that result in improved long term outcomes

• Most recent glycemic goal recommended by the American Diabetes Association is HbA1c<7%, whereas International Diabetes Federation recommends HbA1c<6.5%

Page 4: Consultant presentations

• Results of ACCORD study, which had the primary objective of decreasing CVD with interventions aimed at achieving HbA1c<6% vs. interventions aimed at achieving hbA1c<7.9%, showed excess CVD mortality in the intensive treatment group.

• ADVANCE study did not demonstrate any excess CVD mortality with HbA1c<6.5%

• Individualize target• Take into consideration factors such as life

expectancy, risk of hypoglycemia, presence of CVD

Page 5: Consultant presentations

HbA1c

• Check 2-6 monthly (according to individual needs) until stable on unchanging therapy

• 6 monthly once blood glucose level and blood glucose-lowering therapy are stable

Page 6: Consultant presentations

Lifestyle interventions

• Weight loss as little as 1 kg will ameliorate hyperglycemia

• ? Anti-obesity medications

• NICE guidelines regarding bariatric surgery

Page 7: Consultant presentations

‘Diabesity epidemic’

• Increase in prevalence of diabetes is closely linked to marked increase in obesity

• Obesity lies in the causative pathway to glucose intolerance and is a major factor in progression from IGT to type 2 diabetes

• Every 1 kg increase in weight is associated with a 9% relative increase in diabetes prevalence

Page 8: Consultant presentations

TRENDS IN INACTIVITY

Page 9: Consultant presentations

Physical inactivity as 4th primary risk factor for all-cause mortality

Page 10: Consultant presentations

Impact of bariatric surgery on type 2 diabetes

• 60 Obese patients (BMI>40), with recently diagnosed T2DM [Australia]

• Between 2002-2006• 30 received lifestyle interventions, 30 had gastric

banding, along with usual diabetes care• Remission of T2DM (HbA1c<6.2%) while taking

no medications occurred in 73% of surgical group but only 13% of conventional group.

• At 2 year follow-up surgical group lost 20.7% weight while conventional group lost 1.7%

Page 11: Consultant presentations

• Impact of bariatric surgery on diabetes does not appear to be purely as a result of weight loss

• Significant improvements in insulin resistance are observed in the first week after surgery before any appreciable weight loss has occurred

• ?effects on gut hormones

Page 12: Consultant presentations

PATIENT EDUCATION

• Structured education is an integral part of diabetes care

• Ideally offer it preferably through a group education programme, to every person and/or their carer at and around the time of diagnosis, with annual reinforcement and review

• Programme should meet the quality criteria laid down by DOH and Diabetes UK Patient Education Working Group

• Meet the local cultural, linguistic, cognitive and literacy needs

Page 13: Consultant presentations

DIETARY ADVICE

• Integrate with diabetes management plan

• Sensitive to person’s needs, culture and beliefs

• Include high-fibre, low-glycemic index sources of carbohydrate

• Include low-fat dairy products and oily fish

• Control intake of foods containing saturated fats and trans fatty acids

Page 14: Consultant presentations

SELF-MONITORING

• Self-monitoring of plasma glucose should be available

• To those on insulin treatment• To those on oral glucose-lowering medications

to provide information on hypoglycemia• To assess changes in glucose control resulting

from medications and lifestyle changes• To monitor changes during intercurrent illness• To ensure safety during activities, including

driving

Page 15: Consultant presentations

METFORMIN

• Major effect is to decrease hepatic glucose output and lower fasting glycemia

• Typically metformin monotherapy will lower HbA1c by 0.8-1.5%

• Step up metformin over several weeks to minimize risk of gastrointestinal side effects

• Consider trial of Metformin SR if GI tolerability prevents the person continuing with metformin

• Interferes with B12 absorption, but is very rarely associated with anemia

Page 16: Consultant presentations

• Weight stability or modest weight loss• UKPDS demonstrated a beneficial effect of

metformin on CVD outcome• Renal dysfunction with metformin use may

increase the risk of lactic acidosis (less than 1 case per 100000 treated patients)

• If eGFR <45 or creatinine >130, half the dose• If eGFR <30 or creatinine >150, stop metformin

Page 17: Consultant presentations

SULFONYLUREAS

• Lower glycaemia by enhancing insulin secretion• Efficacy is similar to metformin • Major adverse effects are hypoglycemia and

weight gain (2 kg)• NICE guidelines• Prescribe a sulfonylurea with a low acquisition

cost (not glibenclamide) when an insulin secretagogue is indicated

• Educate the patient about the risk of hypoglycemia, particularly if he or she has renal impairment

Page 18: Consultant presentations

THIAZOLIDINEDIONES

• Glitazones are peroxisome proliferator-activated receptor gamma modulators

• Increase the sensitivity of muscle, fat and liver to endogenous and exogenous insulin (“Insulin sensitizers”)

• As monotherapy reduces HbA1c by 0.5-1.4%• More durable effect on glycemic control,

particularly compared with sulfonylyureas

Page 19: Consultant presentations

• Weight gain, fluid retention, with peripheral edema

• 2 fold increased risk of CCF• Increase in adiposity, largely subcutaneous, with

some reduction in visceral fat shown in some studies

• TZDs either have a beneficial (pioglitazone) or neutral (rosiglitazone) effect on atherogenic lipid profiles

• Recent meta-analysis on Rosiglitazone

Page 20: Consultant presentations

NICE guidelines on Glitazones

• Do not start or continue TZDs if the person has heart failure or is at higher risk of fracture

• Continue TZD therapy only if there is a HbA1c reduction of >0.5% in 6 months

• TZD might be preferable to DPP4 inhibitor if the person has marked insulin insensitivity

Page 21: Consultant presentations

GLINIDES

• 2 glinides currently available• Repaglinide and Nateglinide• As monotherapy reduces HbA1c by 1-1.5%• Like the sulfonylureas, the glinides stimulate

insulin secretion, although they bind to a different site within the sulfonylurea receptor

Page 22: Consultant presentations

The action of repaglinide on -cells

ATP-sensitive K+ channel

Voltage-dependent Ca2+ channel

Membranepotential

Ca 2+

ATP

Insulin

Glucose

Ca2+-dependent K+ channel

MetabolismProteinsynthesis

Insulingranules

Na+ channel

Cl- channel

Repaglinide

NUCLEUS

PRANDIN SmPC Aug 2007

Page 23: Consultant presentations

• The risk of weight gain is similar to sulfonylureas, but hypoglycemia may be less frequent

• Mainly to control post-prandial surge• [As patients get closer to HbA1c target, post

prandial glucose becomes the most significant contributing factor]

Page 24: Consultant presentations

ACARBOSE

• NICE: Consider Acarbose for a person unable to use other oral glucose-lowering medications

• Alpha-Glucosidase inhibitor, which reduces the rate of digestion of polysaccharides in the proximal small intestine, primarily lowering post prandial glucose levels without causing hypoglycemia

• Increased delivery of carbohydrate to the colon results in increased gas production and GI side effects (25-45% stoppage)

Page 25: Consultant presentations

INCRETIN-BASED THERAPIES

IR-i

nsu

lin (

mU

/l)

80

60

40

20

–10 –5 60 120 1800

** * * * * *

Time (min)

Incretineffect

Insulin response

Pla

sma g

luco

se (

mm

ol/l)

–10 –5 60 120 180

10

Time (min)

5

0

15Plasma glucose

Oral glucose load (50 g/400 ml) Isoglycaemic glucose infusion

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

25

90

0

180

270

Pla

sma g

luco

se (

mg/d

l)

Page 26: Consultant presentations

INCRETIN-EFFECT

• The augmented insulin response to oral glucose (the incretin response), is reported to be reduced or abolished in patients with T2DM

• Restoration of the incretin response could improve glycemic control in such patients

Page 27: Consultant presentations

The incretin effect is reduced in patients with type 2 diabetes

0

20

40

60

80

Ins

uli

n (

mU

/L)

0 30 60 90 120 150 180

Time (min)

** *

** **

0

20

40

60

80

0 30 60 90 120 150 180

Time (min)

**

*

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

Patients with type 2 diabetesControl subjects

Intravenous Glucose

Oral Glucose

Ins

uli

n (

mU

/L)

Page 28: Consultant presentations

Incretins and glycaemic control

Adapted from 7. Drucker DJ. Cell Metab. 2006;3:153–165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.

Active GLP-1 and

GIP

Release of incretin gut hormones

Pancreas

Bloodglucose control

GI tract

Glucagon from alpha cells

(GLP-1)Glucose

dependent

Alpha cells

Increased insulin and decreasedglucagon reduce hepatic glucose output

Glucose dependent Insulin

from beta cells(GLP-1 and GIP)

Beta cells

Insulinincreases peripheral glucose uptake

Ingestion of food

DPP-4enzyme rapidly

degrades

incretins

Page 29: Consultant presentations

SITAGLIPTIN

• Licensed for use in T2DM at a dose of 100 mg once a day

• Can be added to metformin, a glitazone, a sulfonylurea or a sulfonylurea+metformin, when current regime does not achieve glycemic control

• HbA1c reduction of 0.5-1%• Weight neutral and low risk of hypoglycemia• Post prandial glucose also reduced (p<0.05) compared

to placebo• Slightly higher rates of constipation, nasopharyngitis and

dizziness

Page 30: Consultant presentations

n=453

n=224

Weeks0 6 12 18 24

% H

bA

1c

7.0

7.2

7.4

7.6

7.8

8.0

8.2

Reduction in HbA1c

of 0.65%

p< 0.001 versus placebo

Placebo + metformin*

Sitagliptin 100 mg o.d. + metformin*

0

24-week Add-on Therapy to Metformin StudyMean change in HbA1c over time9

*Dose of metformin was ≥1,500 mg/day in both arms. All-patients-as-treated populationDiabetes Care, Vol. 29,2006; 2638–2643

Page 31: Consultant presentations

VILDAGLIPTIN

• Licensed at a dose of 50 mg once or twice daily• In T2DM as dual oral therapy• Reduces HbA1c by 0.6-1.1%• Reduces postprandial glucose• Weight neutral and low risk of hypoglycemia• Main side effects are headache,

nosopharyngitis, dizziness

Page 32: Consultant presentations

Vildagliptin produced an additional 1.1% reduction in HbA1c when added to metformin

Vildagliptin 50mg bd + metformin Placebo + metformin

Me

an

ch

an

ge

fro

m b

as

eli

ne

Hb

A1

C (

%)

Time (weeks of treatment)

-1.2

-1.0

-0.8

-0.4

-0.2

0.0

0.2

0.4

4 8 12 16 20 240

-1.1% vildagliptin

vs placebo(p<0.001)

n=n=

143 137 130 126 143143 143 143 143 143

from Bosi et al. Diabetes Care, 2007;30:890–895

Mean baseline HbA1c: 8.3-8.4%

-0.6

Page 33: Consultant presentations

NICE: DPP-4 inhibitors

• Continue DPP-4 inhibitor therapy only if there is a reduction of >0.5% HbA1c in 6 months

• DPP-4 inhibitor is preferable to a Glitazone if• Further weight gain would cause significant

problems• TZDs are contraindicated• Person has a poor response or did not tolerate

TZDs in the past

Page 34: Consultant presentations

Incretins and glycaemic control

Adapted from 7. Drucker DJ. Cell Metab. 2006;3:153–165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.

Active GLP-1 and

GIP

Release of incretin gut hormones

Pancreas

Bloodglucose control

GI tract

Glucagon from alpha cells

(GLP-1)Glucose

dependent

Alpha cells

Increased insulin and decreasedglucagon reduce hepatic glucose output

Glucose dependent Insulin

from beta cells(GLP-1 and GIP)

Beta cells

Insulinincreases peripheral glucose uptake

Ingestion of food

DPP-4enzyme rapidly

degrades

incretins

Page 35: Consultant presentations

GLP-1 Analogues

• Exenatide– Synthetic form of Exendin-4, derived from the

salivary secretions of the Gila monster lizard (Heloderma suspectum)

• Liraglutide– Novel long-acting analog obtained by

acylation of GLP-1 with fatty acid chain

Page 36: Consultant presentations

Structure of native GLP-1 and two GLP-1 analogues

97% homology to native GLP-1

53% homology to native GLP-1

Page 37: Consultant presentations

0.1

0.2

Pivotal phase III clinical studies – combined (ITT) exenatide lowered HbA1c

30-wk data; Mean (SE) 1DeFronzo RA, et al. Diabetes Care 2005;28:1092–1100; 2Buse JB, et al. Diabetes Care 2004;27:2628–2635; 3Kendall DM, et al. Diabetes Care 2005;28:1083–1091.

Placebo BD

-0.6

-0.8

247 245 241

8.5 8.5 8.5

0.1

-0.5

-0.9

123 125 129

8.7 8.5 8.6

-0.4

- 0.8-1

-0.5

0

0.5

Baseline

N 113 110 113

8.2 8.3 8.2

H

bA

1c (

%)

* P < 0.002 vs placebo * P < 0.001 vs placebo

*

*

*

*

*

*

* P < 0.0001 vs placebo

SU2MET1 MET + SU3

Exenatide 5 µg BD Exenatide 10 µg BD

Page 38: Consultant presentations

Change in body weight over time, ITT populationExenatide with metformin

-0.3 ± 0.3 kg

-2.8 ± 0.5 kg

-1.6 ± 0.4 kg

Time (week)

ITT population, N = 336 (Placebo, N = 113; exenatide 5 µg, N = 110; exenatide 10 µg, N = 113)*P ≤ 0.05 ** P ≤ 0.001 compared to placeboDeFronzo RA, et al. Diabetes Care 2005;28:1092–1100.

PlaceboExenatide 5 µgExenatide 10 µg

5 10 15 20 25 300-4

-3

-2

-1

0

1

*

***

**

**** **

*

Mea

n (

±SE

) c

han

ge

in b

od

y w

eig

ht

fro

m b

asel

ine

(kg

)

Page 39: Consultant presentations

Open-label extension study – combined 82-week completers data. Exenatide continued to reduce weight

82-wk completers; Mean (SE); Weight was a secondary endpoint Adapted from Blonde L, et al. Poster presented at the American Diabetes Association Meeting 2005 (Abstract 477P)

Baseline body weight98 kg

100 kg100 kg

0 10 20 30 40 50 60 70 80 90-5

-4

-3

-2

-1

0

Mea

n ∆

bo

dy

wei

gh

t (k

g)

Placebo BD (N = 128)Exenatide 5 µg BD (N = 128)Exenatide 10 µg BD (N = 137)

Open-label extension (all patients exenatide 10 µg BD)Placebo-controlled Trials

Time (week)

1

Page 40: Consultant presentations

• 5 mcg or 10 mcg twice daily

• Main side effects are nausea and vomiting, developing antibodies to exenatide

Page 41: Consultant presentations

NICE: EXENATIDE

• Continue exenatide only if a person has a reduction in HbA1c>1% and >3% of initial body weight in 6 months

• Discuss the benefits of exenatide to allow the person to make an informed decision

Page 42: Consultant presentations

LIRAGLUTIDE

• 97% homologous with native human GLP-1• Half life of 11-15 hours• Permitting once daily injection• 1.2 and 1.8 mg/day• Added to metformin plus rosiglitazone, it reduces

HbA1c by 1.5% (p<0.01)• Main side effects are nausea and vomiting

Page 43: Consultant presentations

Starting Insulin therapy

• If other measures do not keep HbA1c to <7.5% (or other agreed target), discuss benefits and risk of insulin treatment

• Initiate with structured programme