422RO11NP005

The control of the glucose

triad - challenges

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.

Metformin

Efficacy 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 production 1

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 glucose 2
Decreases fasting plasma glucose 2
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 monotherapy 2,3
No weight gain3
No clinically relevant changes in WBC count 2
Nausea and headache amongst the most common reported adverse events in clinical studies 2,3
Medications in this Class: sitagliptin (Januvia), vildagliptin (Galvus)
GLP-1: glucagon-like peptide, GIP: glucose-dependent insulinotropic polypeptide
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

Inadequate achievement
of treatment goals

Therapeutic Goals are not Always Achieved in

Adults With Diabetes

Patients failing to achieve goal (%)

US Data from NHANES 1999-2002

80

n=998

70

ADA Recommendations

72.6
64

60.4

60
50

50.2

40

35

30
20
10
0

HbA1c
(n=451)

LDL-C
(n=252)

HDL-C
(n=829)

Data from Resnick HE et al. Diabetes Care. 2006;29:531537.

TG
(n=275)

BP
(n=870)

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

Treatment Goals are Progressively Difficult to Meet

in the Long-term
In 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

HbA1c <7%, patients (%)

100

3 years

100

6 years

100

75

75

75

50

50

50

25

25

25

Diet
Glibenclamide
Chlorpropamide
Insulin

Diet
Glibenclamide
Chlorpropamide
Insulin

9 years
n=4075

Diet
Glibenclamide
Chlorpropamide
Insulin

Values are for patients who remained receiving monotherapy and achieved different control targets after
3, 6 and 9 years
Turner RC et al. JAMA. 1999;281(21):2005-2012.

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 effectiveness

of current therapies

Patients on Sulphonylureas may Require

Additional Therapy over Time
In UKPDS 26, after 6 years of therapy with sulphonylureas, 44% of patients required additional
therapy

Proportion of Patients Requiring Additional Therapy

Proportion of patients

1.0
n=294

0.8
0.6
0.4
0.2
0

Time from Randomisation (years)

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).
Matthews DR et al. Diabet Med 1998; 15: 297303.

Monotherapy Can Progressively Lose Efficacy

The incidence of treatment failure at 5 years was 15% with rosiglitazone, 21% with metformin
and 34% with glibenclamide
Glibenclamide

Metformin

Rosiglitazone

Cumulative incidence of
monotherapy failure (%)

40
Hazard ratio (95% CI)
Rosiglitazone vs. metformin, 0.68 (0.55-0.85); p<0.001
Rosiglitazone vs. glibenclamide, 0.37 (0.30-0.45); p<0.001

30

20

10

No. at Risk

1393

1397
1337

957
950
781

844
818
617

324
311
218

Years
1207
1205
1114

1078
1076
958

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

Hypoglycaemia is Often Observed During

Treatment with Oral Antidiabetics
Glibenclamide had a higher rate of patient reported hypoglycaemia compared to rosiglitazone

% Patients Reporting Hypoglycaemia

50
P<0.001

Patients (%)

40

38.7

30
20
10
0

9.8

Rosiglitazone
(n=1456)

11.6

Metformin
(n=1454)

Glibenclamide
(n=1441)

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

Hypoglycaemia is Frequent in Patients on Insulin

Therapy
The prevalence of severe hypoglycaemia is also related to the duration of type 2 diabetes

% Patients with Severe Hypoglycaemia*

50

(n=147)

(n=39)

(n=29)

1-5

6-10

>10

Patients (%)

40
30

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

20
10
0

Duration of Insulin Therapy (years)

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
Henderson JN et al. Diabet Med 2003; 20: 10161021.

Insulin Therapy can Lead to Weight Gain

In this study, patients allocated to insulin gained more weight than patients allocated to
sulphonylurea

Change in Weight in Primary Diet Failure Group

Non-obese
Insulin

Obese
Sulphonylurea*

Insulin

-5

-10

Sulphonylurea*

Metformin

10

n=789
Insulin vs sulphonyurea, p<0.001
-1

Change in weight (kg)

Change in weight (kg)

10

-5

-10

n=831
Insulin vs sulphonyurea, p=0.013
-1

Multicentre, randomised, controlled trial to assess and compare response to sulfonylurea, insulin, or
randomisation
Time in
from
randomisation
metformin over 6Time
yearsfrom
in patients
with newly(years)
diagnosed type 2 diabetes
whom
disease could(years)
and could
not be controlled with diet therapy alone.
*chlorpropamide or glibenclamide
UKPDS 24. Ann Intern Med 1998;128:165-175.

Metformin is Associated with Gastrointestinal

Intolerance

Metformin must be titrated carefully1

High-dose initiation of metformin therapy remains a practical issue 1
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;5:15767. 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 time 1,2
Failure leads to progressive loss of pancreatic -cell function and
increases in HbA1c2
Hypoglycaemia is a commonly observed adverse event 3,4
Weight gain may be frequent with rosiglitazone and glibenclamide 2
Metformin may be associated with gastrointestinal intolerance 5
Elderly patients with diabetes have special therapeutic needs 6

1. Cook MN et al. Diabetes Care 2005; 28:9951000. 2. Kahn SE et al. N Engl J Med 2006;355:2427-43. 3. Henderson JN et al. Diabet
Med 2003; 20: 10161021. 4. Bolen S. et. al. Ann Intern Med 2007;147:386-399. 5. Scarpello JHB, et al. Diabetes Vasc Dis Res
2008;5:15767. 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 hypoglycaemia 3,4,5
Many patients do not meet treatment goals and the majority of
patients do not meet them in the long-term 6

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 effects 9-11

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;348:383393. 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. Pyrl 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.