The control of the glucose triad  - challenges

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Contents

Oral antidiabetics: Clinical effectiveness and limitations

Inadequate achievement of treatment goals

The long-term effectiveness of current therapies

Current Therapies for Type 2 Diabetes Overview

Type 2 diabetes is a chronic, progressive disease that is difficult to manage in the long-term

The main classes of oral antidiabetics include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues) reduce hepatic glucose production (biguanides) delay digestion and absorption of intestinal carbohydrate (alpha-glucosidase

inhibitors) reduce insulin resistance (thiazolidinediones)

Oral antidiabetics are heterogeneous in terms of mode of action, efficacy, safety profile and tolerability

The frequent need for escalating therapy reflects progressive loss of pancreatic beta-cell function, usually in the presence of obesity-related insulin resistance

Krentz AJ, Bailey CJ. Drugs. 2005;65(3):385-411.

Sulphonylureas

Mode of Action Sulphonylureas increase endogenous insulin secretion

Efficacy Decrease fasting plasma glucose 60-70 mg/dL (3.3-3.9 mmol/L) Reduce HbA1c by 1.0-2.0%

Safety and Tolerability Hypoglycaemia Weight gain No specific effect on plasma lipids or blood pressure Generally the least expensive class of medication

Medications in this Class First generation sulphonylureas: chlorpropamide (Diabinese), tolazamide,

acetohexamide (Dymelor), tolbutamide Second generation sulphonylureas: glibenclamide, glimepiride (Amaryl), glipizide

(Glipinase, Minodiab), gliclazide

Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411.

Sulphonylureas Therapeutic Considerations

Potential risk of hypoglycaemia; predisposing factors include:

age restricted carbohydrate intake renal and hepatic dysfunction potentiating effects of alcohol and drugs in common use

Hypoglycaemic action of SUs is more likely in the elderly, debilitated, or malnourished patients

May increase hyperinsulinaemia and weight gain

Melander A. Diabet Med. 1996 Sep;13(9 Suppl 6):S143-7.

Glinides

Mode of Action Glinides stimulate insulin secretion (rapidly and for a short duration)

in the presence of glucose

Efficacy Decreases peak postprandial glucose Decreases plasma glucose 60-70 mg/dL (3.3-3.9 mmol/L) Reduce HbA1c 1.0-2.0% Dosed with each meal

Safety and Tolerability Hypoglycaemia (although may be less than with sulphonylureas if patient

has a variable eating schedule) Weight gain No significant effect on plasma lipid levels Better tolerated at higher levels of serum creatinine than sulphonylureas

Medications in this Class: repaglinide (Prandin), nateglinide (Starlix)

Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411.

-Glucosidase Inhibitors

Mode of Action Alpha-glucosidase inhibitors block the enzymes that digest starches in the small

intestine

Efficacy Decrease peak postprandial glucose 40-50 mg/dL (2.2-2.8 mmol/L) Decrease fasting plasma glucose 20-30 mg/dL (1.4-1.7 mmol/L) Decrease HbA1c by 0.5-1.0%

Safety and Tolerability Flatulence or abdominal discomfort No specific effect on lipids or blood pressure No weight gain Contraindicated in patients with inflammatory bowel disease

or cirrhosis

Medications in this Class: Glucobay, Glyset

Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411.

MetforminEfficacy and Adverse Events

Mode of Action Metformin decreases hepatic glucose production and increases insulin-mediated

peripheral glucose uptake (primary effect)

Efficacy Decrease fasting plasma glucose 60-70 mg/dL (3.3-3.9 mmol/L) Reduce HbA1c 1.0-2.0%

Safety and Tolerability Diarrhoea and abdominal discomfort Lactic acidosis if improperly prescribed Causes small decrease in LDL cholesterol level and triglycerides No specific effect on blood pressure No weight gain, with possible modest weight loss Contraindicated in patients with impaired renal function (Serum Cr >1.4 mg/dL for

women, or 1.5 mg/dL for men)

Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411.

Metformin Summary

As monotherapy, similar glycaemic control as sulphonylureas without stimulating insulin secretion; secondary failure rate similar to sulphonylureas

Does not increase weight

Neutral or beneficial effects on lipids

Does not produce hypoglycaemia when used alone

Most common side effects are GI, which are generally mild to moderate and self-limiting

Adherence to prescribing guidelines is important to minimise risk of lactic acidosis

Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411.

Thiazolidinediones

Mode of Action Thiazolidinediones decrease insulin resistance by making muscle and adipose cells

more sensitive to insulin. They also suppress hepatic glucose production1

Efficacy1

Decrease fasting plasma glucose ~35-40 mg/dL (1.9-2.2 mmol/L) Reduce HbA1c ~0.5-1.0% 6 weeks of treatment needed for maximum effect

Safety and Tolerability2,3

Weight gain, oedema Hypoglycaemia (if taken with insulin or agents that stimulate insulin release) Contraindicated in patients with abnormal liver function or CHF Warnings regarding risk of fractures in women Rosiglitazone: Increase risk of myocardial ischaemic events

Medications in this Class: pioglitazone (Actos), rosiglitazone (Avandia)

1. Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411. 2. Avandi, Summary of Product Characteristics, EMEA, 6 Mar 2008. 3. Actos, Summary of Product Characteristics, EMEA, 6 Sep 2007.

DPP-4 Inhibitors

Mode of Action1

Inhibitor of the protease Dipeptidyl Peptidase IV (DPP-4), the enzyme that degrades incretin hormones such as GLP-1 and GIP

Through this action, DDP-4 inhibitors increase the level of incretins and thus stimulate insulin synthesis and release

Efficacy 0.5 – 1-0 % reduction in HbA1c as monotherapy2,3

Decreases postprandial glucose2

Decreases fasting plasma glucose2

Safety and Tolerability Generally well tolerated, the majority of adverse events reported in clinical studies were mild and

transient3

Low risk of hypoglycaemia when used as monotherapy2,3

No weight gain3

No clinically relevant changes in WBC count2

Nausea and headache amongst the most common reported adverse events in clinical studies 2,3

Medications in this Class: sitagliptin (Januvia), vildagliptin (Galvus)

1. Stonehouse A. Curr Diabetes Rev 2008;4:101-9; 2. Januvia SPC Accessed from http://emc.medicines.org.uk on 26/11/08; 3. Galvus SPC Accessed from http://emc.medicines.org.uk on 26/11/08

GLP-1: glucagon-like peptide, GIP: glucose-dependent insulinotropic polypeptide

Inadequate achievementof treatment goals

Therapeutic Goals are not Always Achieved in Adults With Diabetes

Data from Resnick HE et al. Diabetes Care. 2006;29:531–537.

ADA Recommendations

HbA1c<7%LDL <100 mg/dL (2.6 mmol/l)HDL (male)

>45 mg/dL (1.2 mmol/l)HDL (female)

>55 mg/dL (1.4 mmol/l) TG <200 mg/dL (22.2 mmol/l)BP <130/<80 mm Hg

US Data from NHANES 1999-2002

0

10

20

30

40

50

60

70

80

(n=451)

50.2

HbA1c(n=252)

64

LDL-C(n=829)

72.6

HDL-C(n=275)

35

TG(n=870)

60.4

BP

Pat

ien

ts f

ailin

g t

o a

chie

ve g

oal

(%

) n=998

Treatment Goals are Progressively Difficult to Meet in the Long-termIn UKPDS 49, only a relatively small proportion of patient met HbA1c target levels at 3, 6 and 9 years. This study also found that he number of patients meeting HbA1c target levels decreased with time; the majority of patients needed multiple therapies to attain these glycaemic target levels in the longer term

Turner RC et al. JAMA. 1999;281(21):2005-2012.

Values are for patients who remained receiving monotherapy and achieved different control targets after 3, 6 and 9 years

3 years 6 years 9 years

Hb

A1

c <

7%

, p

ati

en

ts (

%)

0

25

75

100

50

DietChlorpropamide

GlibenclamideInsulin

0

25

75

100

50

0

25

75

100

50

DietChlorpropamide

GlibenclamideInsulin

DietChlorpropamide

GlibenclamideInsulin

n=4075

Inadequate Achievement of Treatment Goals Summary

Many patients do not meet treatment goals and most patients do not meet them in the long-term1

Suboptimal glycaemic control is present in the majority of patients on oral antidiabetic agents2

1. Turner RC et al. JAMA. 1999;281:2005-2012. 2. Willey CJ et al. Am J Manag Care. 2006;12:435-440.

The long-term effectivenessof current therapies

Patients on Sulphonylureas may Require Additional Therapy over TimeIn UKPDS 26, after 6 years of therapy with sulphonylureas, 44% of patients required additional therapy

Matthews DR et al. Diabet Med 1998; 15: 297–303.

Time from Randomisation (years)

Pro

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n o

f p

atie

nts

1.0

0.6

0.4

0

0.8

0.2

0 1 2 3 4 5 6

To assess secondary failure rates of sulphonylureas, the responses in 1305 patients with newly diagnosed type 2 diabetes were randomly allocated to therapy with either chlorpropamide or glibenclamide (UKPDS 26).

Proportion of Patients Requiring Additional Therapy

n=294

No. at Risk

1393 1207 1078 957 844 324 1397 1205 1076 950 818 311 1337 1114 958 781 617 218

Monotherapy Can Progressively Lose EfficacyThe incidence of treatment failure at 5 years was 15% with rosiglitazone, 21% with metformin and 34% with glibenclamide

Kahn SE et al. N Engl J Med 2006;355:2427-43.

Treatment was considered to have failed if a patient had a confirmed or adjudicated level of fasting plasma glucose of more than 180 mg/dL**To convert mg/dL glucose to mmol/l, divide by 18 (e.g. 100 mg/dL is 5.6 mmol/l)

Glibenclamide Metformin Rosiglitazone

Cu

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lati

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ence

of

mo

no

ther

apy

failu

re (

%)

40

20

10

0

30

0

Years

1 2 3 4 5

Hazard ratio (95% CI)Rosiglitazone vs. metformin, 0.68 (0.55-0.85); p<0.001Rosiglitazone vs. glibenclamide, 0.37 (0.30-0.45); p<0.001

Hypoglycaemia is Often Observed During Treatment with Oral AntidiabeticsGlibenclamide had a higher rate of patient reported hypoglycaemia compared to rosiglitazone

Kahn SE et al. N Engl J Med 2006;355:2427-43.

% Patients Reporting Hypoglycaemia

Double-blind, randomised, controlled clinical trial in which rosiglitazone, metformin, and glibenclamide were evaluated as initial treatment for recently diagnosed type 2 diabetes in 4360 patients treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg/dL (10.0 mmol/l). Rosiglitazone vs metformin was not significant.

0

10

20

40

50

Pa

tie

nts

(%

)

9.8

Rosiglitazone(n=1456)

11.6

Metformin(n=1454)

38.7

Glibenclamide(n=1441)

30

P<0.001

Hypoglycaemia is Frequent in Patients on Insulin TherapyThe prevalence of severe hypoglycaemia is also related to the duration of type 2 diabetes

Henderson JN et al. Diabet Med 2003; 20: 1016–1021.

% Patients with Severe Hypoglycaemia*

0

10

20

40

50

Pat

ien

ts (

%)

30

Duration of Insulin Therapy (years)

6-10 >101-5

(n=147) (n=39) (n=29) The frequency of severe hypoglycaemia increased with duration of insulin therapy (p< 0.05, r=0.2)

Retrospective survey of 215 people with insulin-treated type 2 diabetes to quantify the frequency and nature of hypoglycaemia.*Severe hypoglycaemia was defined as episodes requiring assistance

Insulin Therapy can Lead to Weight GainIn this study, patients allocated to insulin gained more weight than patients allocated to sulphonylurea

UKPDS 24. Ann Intern Med 1998;128:165-175.

Non-obese Obese

Ch

an

ge

in

we

igh

t (k

g)

Time from randomisation (years)Time from randomisation (years)

-10

-5

0

5

10

-10

-5

0

5

10

n=789Insulin vs sulphonyurea, p<0.001

0 3 5 6-1 1 2 4 0 3 5 6-1 1 2 4

n=831Insulin vs sulphonyurea, p=0.013

Multicentre, randomised, controlled trial to assess and compare response to sulfonylurea, insulin, or metformin over 6 years in patients with newly diagnosed type 2 diabetes in whom disease could and could not be controlled with diet therapy alone.*chlorpropamide or glibenclamide

Change in Weight in Primary Diet Failure Group

Insulin Sulphonylurea* Insulin Sulphonylurea* Metformin

Ch

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Metformin is Associated with Gastrointestinal Intolerance

Metformin must be titrated carefully1

High-dose initiation of metformin therapy remains a practical issue1

Metformin can cause bile salt malabsorption, which increases fluid retention in the large bowel, leading to loose stools and diarrhoea in some patients1

In one study (n=15,453), over a 5-year period an overall discontinuation rate of 7.8% was observed2

1. Scarpello JHB, et al. Diabetes Vasc Dis Res 2008;5:157–67. 2. Rakovac I, et al. Diabet Med. 2005;22:662-4.

The Long-term Effectiveness of Current Therapies Summary

Current oral therapies have a relatively high failure rate over time1,2

Failure leads to progressive loss of pancreatic -cell function and increases in HbA1c2

Hypoglycaemia is a commonly observed adverse event3,4

Weight gain may be frequent with rosiglitazone and glibenclamide2

Metformin may be associated with gastrointestinal intolerance5

Elderly patients with diabetes have special therapeutic needs6

1. Cook MN et al. Diabetes Care 2005; 28:995–1000. 2. Kahn SE et al. N Engl J Med 2006;355:2427-43. 3. Henderson JN et al. Diabet Med 2003; 20: 1016–1021. 4. Bolen S. et. al. Ann Intern Med 2007;147:386-399. 5. Scarpello JHB, et al. Diabetes Vasc Dis Res 2008;5:157–67. 6. Abbatecola AM et al. Drugs Aging 2008;25:913-25.

Conclusions (1)

Diabetes and related-complications is associated with substantial burden on healthcare costs1,2

Most current therapies are limited by treatment failure and side effects such as weight gain and hypoglycaemia3,4,5

Many patients do not meet treatment goals and the majority of patients do not meet them in the long-term6

1. Federation of European Nurses in Diabetes. 2008. Diabetes. The policy puzzle: Is Europe making progress? Available at:http://www.fend.org/news.html. Accessed 22 Sep 2008. 2. Eurostat. Available at: http://epp.eurostat.ec.europa.eu. Accessed on 3 Sep 2008. 3. Krentz AJ, Bailey CJ. Drugs. 2005;65(3):385-411. 4. Kahn SE et al. N Engl J Med 2006;355:2427-43. 5. UKPDS 24. Ann Intern Med 1998;128:165-175. 6. Turner RC et al. JAMA. 1999;281(21):2005-2012.

Conclusions (2)

A wealth of data demonstrate that achieving treatment goals reduces microvascular events1-8

Conflicting results have been reported regarding the benefits of intensive glucose control (IGC) on the risk of CV events, but early IGC appears to have beneficial long-term effects9-11

1. UKPDS. BMJ. 2000;321:405-412. 2. Hanefeld M et al. Diabetologia 1996;39:1577-83. 3. Gaede P et al. N Eng J Med. 2003;348:383-393. 4. Colhoun HM and the CARDS Investigators. Lancet. 2004;364:685-696. 5. Collins R and the Heart Protection Study Collaborative Group. Lancet. 2003;361:2005-2016. 6. Keech A et al. Diabetes Care. 2003;26:2713-2721. 7. Goldberg RB and the CARE Investigators. Circulation. 1998;98:2513-2519. 8. Pyörälä K et al. Diabetes Care. 1997;20:614-620. 9. Holman R. Oral presentation at EASD 2008. 10. Holman RR, et al. N Engl J Med. 2008;359:1577-89. 11. ACCORD Group. N Engl J Med 2008;358:2545-59.