Management of prediabetes and type 2 diabetes with acarbose

Chang-Yu Pan, China

Lifestyle modification as a long-term treatment for prediabetes?

Lifestyle modification should be first-line treatment for prediabetes However, the success of lifestyle modification in trials is difficult to reproduce in practice Lifestyle modifications in clinical trials are intensively monitored and managed, while in practice there are a number of challenges to overcome1,2 In many cases, pharmacological intervention is required
1. Punzalan C, et al. Ethn Dis 2006;16(Suppl. 1):S7988. 2. Marrero DG. Endocr Pract 2006;12(Suppl. 1):11820.

Acarbose the first and only OAD approved for prediabetes therapy

Approved for treating postprandial hyperglycaemia in individuals with IGT Approved first in China 6 August 2002 Now approved in 25 countries

Acarbose reduces postprandial hyperglycaemia

Dysglycaemia, without acarbose
Intestinal glucose resorption

Without acarbose

With acarbose

Blood glucose

Dysglycaemia, with acarbose

NGT

2 Hours

2 Hours

Zick R, Schnitger F. Mainz: Verlag Kircheim; 2001.

STOP-NIDDM acarbose reduces the risk of developing type 2 diabetes

Relative reduction in the incidence of type 2 diabetes

36%
p=0.0003 vs placebo (based on two consecutive positive OGTTs)

Increase in the reversion to normal glucose tolerance

35%
vs 31% placebo, p<0.0001
Chiasson JL, et al. Lancet 2002;359:20727.

Chinese Prevention Study acarbose reduces the risk of type 2 diabetes

35%

28%

25%

28%

No intervention
37% NGT IGT Type 2 diabetes 12% 45% 71% 43% 47%

Lifestyle intervention

6%

Acarbose

23%

88%

Metformin

Yang WY, et al. Chin J Endocrinol Metab 2001;17:1316.

Acarbose is an effective monotherapy for type 2 diabetes

HbA1c
0 Change in HbA1c (%) 1.1 0.5 0.8 1.0 n=2,831 n=2,838 2.3 n=2,238 3.0 30 randomised, placebo-controlled trials 1.5 4.0
Van de Laar F, et al. Diabetes Care 2005;28:15475.

Fasting Postprandial
0 Change in plasma glucose (mmol/L)

1.0

2.0

Acarbose is an effective monotherapy for type 2 diabetes

0.8 0.6 Change in variable 0.4 0.2 0 0.2 0.4 0.6 0.8 0.10
Chan JCN, et al. Diabetes Care 1998;21:105861.

1hPG (mmol/L) FPG (mmol/L) HbA1c ITT (%)

Acarbose

Placebo
All p<0.05

HbA1c Per protocol (%)

BMI (kg/m2)

Acarbose has an excellent safety profile

Adverse events reported over 16 weeks Adverse events Drug-related AEs (%) Gastrointestinal AEs (%) flatulence distension diarrhoea Withdrawals owing to AEs (n) Placebo n=132 18 6 4 2 3 Acarbose n=126 36 16 14 10 2

Compliance with therapy (%)

96

98

Pan CY, et al. Diab Res Clin Pract 2003;61:18390.

Acarbose treatment of ethnic Chinese type 2 diabetes patients

Two Post-Marketing Surveillance studies in China and Taiwan assessed efficacy, safety and acceptance of acarbose in patients with type 2 diabetes in daily clinical practice
Baseline characteristics Age (yrs) BMI (kg/m2) FBG (mg/dL) 2h-PG (mg/dL) HbA1C (%) China1 (n=2,480) 57.6 24.6 179.4 268.5 8.9 Taiwan2 (n=1,558) 61.5 25.5 223.6 297.2 9.9

1. Su S-O, et al. Chin J Endocrinol Metab 2006;22:6a15. 2. Hung Y-J, et al. Clin Drug Invest 2006;26:55965.

Acarbose has excellent safety and efficacy profiles in ethnic Chinese type 2 diabetes patients
China1 (n=2,480) Taiwan2 (n=1,558)

FBG reduction (mg/dL)

2h-PG reduction (mg/dL) HbA1C reduction (%) Very good/good efficacy (% of patients) Very good/good tolerability (% of patients)

56.1
111.3 1.9 90.1 89.1

32.0
52.2 1.0 46.0 60.6

Very good/good acceptance (% of patients)

87.1

63.4

1. Su S-O, et al. Chin J Endocrinol Metab 2006;22:6a15. 2. Hung Y-J, et al. Clin Drug Invest 2006;26:55965.

Acarbose has excellent safety and efficacy in dysglycaemic Chinese patients

Another Post-Marketing Surveillance study in China assessed efficacy, safety and acceptance of acarbose in patients with IGT or type 2 diabetes (n=2,550)
Endpoints FBG reduction (mg/dL) 2h-PG reduction (mg/dL) HbA1C reduction (%) Body weight reduction (kg) Very good/good efficacy (% of patients) Effects of acarbose 50mg 3x/day 38.5 92.2 1.4 0.4 92.4

Very good/good tolerability (% of patients)

Very good/good acceptance (% of patients)

91.1
89.8

Pan CY, et al. Clin Drug Invest 2007;27:397405.

Explaining the therapeutic success of acarbose in China

Chinese staple food is rich in carbohydrate Northern China: noodle and cake Southern China: rice and porridge Chinese physicians are well informed Patiently teach how to take acarbose in the correct manner Chinese patients have good compliance Dose: start low, go slow

GI side-effects: aware of GI side-effects management through patient education

The Acarbose Cardiovascular Evaluation (ACE): Rationale

Studies in both Europe and Asia have confirmed the close association between dysglycaemia and CVD ESC/EASD guidelines call for integrated management of dysglycaemia and CVD In STOP-NIDDM, acarbose reduced the risk of developing type 2 diabetes and the risk of a first cardiovascular event in individuals with prediabetes ACE will investigate the effect of acarbose on the risk of a further cardiovascular event in patients with established CVD and prediabetes
Holman RR, Pan CY. 2nd International Congress on Prediabetes and the Metabolic Syndrome, April 25 28 2007.

The Acarbose Cardiovascular Evaluation (ACE): Design

Randomised, double-blind, placebo-controlled trial

Patients with established CVD and prediabetes ~7,500 patients ~150 centres in mainland China and Hong Kong Minimum follow-up of 4 years

Holman RR, Pan CY. 2nd International Congress on Prediabetes and the Metabolic Syndrome, April 25 28 2007.

The Acarbose Cardiovascular Evaluation (ACE): Endpoints

Primary (composite) Time to the first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal MI, or fatal or non-fatal stroke Secondary Time to diagnosis of new-onset type 2 diabetes
Confirmed by two successive diagnostic plasma glucose values (FPG 7.0mmol/L and/or 2hPG 11.1mmol/L), with no intervening non-diagnostic values

Time to occurrence of individual cardiovascular events or death

Holman RR, Pan CY. 2nd International Congress on Prediabetes and the Metabolic Syndrome, April 25 28 2007.

The Acarbose Cardiovascular Evaluation (ACE): Randomisation

Randomised to: Glucobay Matching placebo 50mg three times a day 50mg three times a day

Start low, go slow dose titration

Take tablets at meal-times

CV therapy will be optimised to standard-of-care during the placebo run-in period

Holman RR, Pan CY. 2nd International Congress on Prediabetes and the Metabolic Syndrome, April 25 28 2007.

The Acarbose Cardiovascular Evaluation (ACE): Schedule

ACE will commence in 2007
Visit 1
5 weeks OGTT

ACE results are expected in 2013

Visit 4
1 month

Visit 2
4 weeks Placebo run-in

Visit 3
0 weeks

Visit 5
2 months

Visit 6
4 months

Visits 719
Every 4 months for a minimum of 4 years Close-out

Glucobay CVD Randomisation Placebo

Conclusions
Treating prediabetes with acarbose reduces the risk of developing type 2 diabetes Acarbose is also an effective treatment option for type 2 diabetes Acarbose has an excellent safety profile as a result of its non-systemic mechanism of action The cardiovascular benefits of acarbose will be further investigated by ACE