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In the BMJ of December 14th 2002, Annabel Ferriman reviews the
breach of the industry’s advertising code by Novartis in promoting their
drug nateglinide.1 In a meeting sponsored by Novartis, data from the
DECODE study was interpreted as supporting the contention that treatment
of post-prandial hyperglycaemia may reduce the mortality in patients with
type 2 diabetes.2 On behalf of the DECODE-study we would like to make some
clarifying comments.
The DECODE-study was initiated in January 1997 by two authors of this
letter (KB-J and JT). The rationale was that the American Diabetes
Association and the World Health Organisation were planning to revise the
diagnostic criteria for diabetes. It was unclear how the proposed revision
would impact on the epidemiology of diabetes and on the vital prognosis of
individuals classified as having diabetes, or the intermediate states of
impaired glucose tolerance and the newly introduced category impaired
fasting glucose. Thus we invited centres within Europe, in the name of the
European Diabetes Epidemiology Group, to contribute with data from their
epidemiological surveys which had used an Oral Glucose Tolerance Test
(OGTT). The aim was to evaluate the impact of the revised diagnostic
criteria on the
• Prevalence of diabetes
• Phenotypic characterisation of individuals classified as diabetic and
their cardiovascular risk profile
• Morbidity and mortality (all cause and vascular causes).
Special emphasis was put on the comparisons between fasting versus 2-hour
post-challenge plasma glucose values, for diagnostic purposes.
More than 40 centres have provided their data for a joint
collaborative statistical analysis.
The findings of the study have been published in more than 15 papers
in peer reviewed journals. The key-findings include:
• About one third of those screened diabetic on a 2h glucose will have
normal fasting glucose, one third an impaired fasting glucose while one
third will have a diabetic fasting glucose3. One third of all subjects who
will be screened as diabetic (based on fasting or 2h glucose) will have a
non-diabetic fasting glucose
• All cause mortality and vascular mortality are more closely associated
to post-load plasma glucose values than to fasting plasma glucose2, 4
• An at-risk cardiovascular profile is more closely associated to post-
load plasma glucose values than to fasting plasma glucose5
• In asymptomatic people without a history of diabetes, the increased risk
of total and cardiovascular mortality associated with fasting glucose in
univariate analysis is mostly explained by the concomitant 2h glucose
level in multivariate analysis.5
These observations led us to suggest that the OGTT should be
maintained for diagnostic purposes, at least in certain groups of at-risk
individuals, and this suggestion was followed by the WHO in their final
recommendation for revised diagnostic criteria for diabetes.6
We are aware that the observational data from the DECODE-study have
been used to support the view that treatment of post-prandial
hyperglycaemia could lead to a reduced cardiovascular morbidity and
mortality. We cannot agree with this inference from our data since
observational data cannot be directly taken as an indication of the
treatment effect. The DECODE study is by far the largest data base which
has analysed the consequences of hyperglycaemia; subjects all had the
standardised and recommended oral glucose load, which is known to be non-
physiologic but is nonetheless commonly agreed. It is not possible to
assume that lowering of hyperglycaemia would lead to a similar reduction
in morbidity and mortality. While some theoretical assumptions about the
potential effect size can be derived from such large prospective studies,
the final judgement on the effect of risk factor lowering can only be
derived from randomised controlled clinical trials. Further the DECODE
study was only able to observe the effects of post-challenge
hyperglycaemia, not post-prandial hyperglycaemia.
There is currently no data on the effects of lowering plasma glucose
in people with asymptomatic hyperglycaemia. We know that lifestyle
intervention and certain antidiabetic drugs can lower post-prandial and
post-challenge glucose, but whether these available interventions would
lead to a reduced cardiovascular morbidity and mortality is not known.
There are ongoing studies to resolve this question, but results will only
be available some years hence.
The DECODE-study has been designed, planned and conducted
independently of any pharmaceutical company. The study has been funded by
the Academy of Finland and unrestricted research grants from Novo Nordisk
and Novartis. Furthermore the National Public Health Institute, Helsinki,
Finland and Steno Diabetes Centre, Gentofte, Denmark have both contributed
financially and through staffing. All members of the Steering Committee
have acted as speakers/lecturers at symposia organised by the
pharmaceutical industry, and Knut Borch-Johnsen is director of the Steno
Diabetes Centre, a hospital providing diabetes care for the Danish
national health care service, but owned by Novo Nordisk.
Knut Borch-Johnsen, MD, Professor, Medical Director Steno Diabetes
Centre, Denmark
Beverley Balkau, PhD, Director of Research, INSERM Unite 258, Paris,
France
Jaakko Tuomilehto, MD, Professor, University of Helsinki, Finland and
National Public Health Institute, Helsinki, Finland
1. Ferriman A. Novartis breached code after doctors say it “invented”
a disease. BMJ 2000;325:1379.
2. The DECODE study group on behalf of the European Diabetes
Epidemiology Group. Glucose tolerance and mortality: comparison of WHO and
ADA diagnostic criteria. Lancet 1999;354:617-621.
3. The DECODE-study group on behalf of the European Diabetes
Epidemiology Group. Is fasting glucose sufficient to define diabetes?
Epidemiological data from 20 European studies. Diabetologia 1999;42:647-
654.
4. The DECODE Study Group, on behalf of the European Diabetes
Epidemiology Group. Glucose Tolerance and Cardiovascular Mortality. Arch
Intern Med 2001;161:397-404.
5. DECODE Study Group on behalf of the European Diabetes Epidemiology
Study Group. Will new diagnostic criteria for diabetes mellitus change
phenotype of patients with diabetes? Reanalysis of European
epidemiological data. BMJ 1998;317:371-375.
6. WHO Consultation. Definition, diagnosis and classification of
diabetes mellitus and its complications. Part 1: diagnosis and
classification of diabetes mellitus. World Health Organization 1999.
Competing interests:
See above.
Competing interests:
No competing interests
24 January 2003
Knut Borch-Johnsen
Professor, Medical Director
Jaakko Tuomilehto, National Public Health Institute, Helsinki, Finland and Beverly Balkau, INSERM Unite 258, France
The DECODE-study, postprandial hyperglycaemia and industry advertising code
In the BMJ of December 14th 2002, Annabel Ferriman reviews the breach of the industry’s advertising code by Novartis in promoting their drug nateglinide.1 In a meeting sponsored by Novartis, data from the DECODE study was interpreted as supporting the contention that treatment of post-prandial hyperglycaemia may reduce the mortality in patients with type 2 diabetes.2 On behalf of the DECODE-study we would like to make some clarifying comments.
The DECODE-study was initiated in January 1997 by two authors of this letter (KB-J and JT). The rationale was that the American Diabetes Association and the World Health Organisation were planning to revise the diagnostic criteria for diabetes. It was unclear how the proposed revision would impact on the epidemiology of diabetes and on the vital prognosis of individuals classified as having diabetes, or the intermediate states of impaired glucose tolerance and the newly introduced category impaired fasting glucose. Thus we invited centres within Europe, in the name of the European Diabetes Epidemiology Group, to contribute with data from their epidemiological surveys which had used an Oral Glucose Tolerance Test (OGTT). The aim was to evaluate the impact of the revised diagnostic criteria on the • Prevalence of diabetes • Phenotypic characterisation of individuals classified as diabetic and their cardiovascular risk profile • Morbidity and mortality (all cause and vascular causes). Special emphasis was put on the comparisons between fasting versus 2-hour post-challenge plasma glucose values, for diagnostic purposes.
More than 40 centres have provided their data for a joint collaborative statistical analysis.
The findings of the study have been published in more than 15 papers in peer reviewed journals. The key-findings include: • About one third of those screened diabetic on a 2h glucose will have normal fasting glucose, one third an impaired fasting glucose while one third will have a diabetic fasting glucose3. One third of all subjects who will be screened as diabetic (based on fasting or 2h glucose) will have a non-diabetic fasting glucose • All cause mortality and vascular mortality are more closely associated to post-load plasma glucose values than to fasting plasma glucose2, 4 • An at-risk cardiovascular profile is more closely associated to post- load plasma glucose values than to fasting plasma glucose5 • In asymptomatic people without a history of diabetes, the increased risk of total and cardiovascular mortality associated with fasting glucose in univariate analysis is mostly explained by the concomitant 2h glucose level in multivariate analysis.5
These observations led us to suggest that the OGTT should be maintained for diagnostic purposes, at least in certain groups of at-risk individuals, and this suggestion was followed by the WHO in their final recommendation for revised diagnostic criteria for diabetes.6
We are aware that the observational data from the DECODE-study have been used to support the view that treatment of post-prandial hyperglycaemia could lead to a reduced cardiovascular morbidity and mortality. We cannot agree with this inference from our data since observational data cannot be directly taken as an indication of the treatment effect. The DECODE study is by far the largest data base which has analysed the consequences of hyperglycaemia; subjects all had the standardised and recommended oral glucose load, which is known to be non- physiologic but is nonetheless commonly agreed. It is not possible to assume that lowering of hyperglycaemia would lead to a similar reduction in morbidity and mortality. While some theoretical assumptions about the potential effect size can be derived from such large prospective studies, the final judgement on the effect of risk factor lowering can only be derived from randomised controlled clinical trials. Further the DECODE study was only able to observe the effects of post-challenge hyperglycaemia, not post-prandial hyperglycaemia.
There is currently no data on the effects of lowering plasma glucose in people with asymptomatic hyperglycaemia. We know that lifestyle intervention and certain antidiabetic drugs can lower post-prandial and post-challenge glucose, but whether these available interventions would lead to a reduced cardiovascular morbidity and mortality is not known. There are ongoing studies to resolve this question, but results will only be available some years hence.
The DECODE-study has been designed, planned and conducted independently of any pharmaceutical company. The study has been funded by the Academy of Finland and unrestricted research grants from Novo Nordisk and Novartis. Furthermore the National Public Health Institute, Helsinki, Finland and Steno Diabetes Centre, Gentofte, Denmark have both contributed financially and through staffing. All members of the Steering Committee have acted as speakers/lecturers at symposia organised by the pharmaceutical industry, and Knut Borch-Johnsen is director of the Steno Diabetes Centre, a hospital providing diabetes care for the Danish national health care service, but owned by Novo Nordisk.
Knut Borch-Johnsen, MD, Professor, Medical Director Steno Diabetes Centre, Denmark
Beverley Balkau, PhD, Director of Research, INSERM Unite 258, Paris, France
Jaakko Tuomilehto, MD, Professor, University of Helsinki, Finland and National Public Health Institute, Helsinki, Finland
1. Ferriman A. Novartis breached code after doctors say it “invented” a disease. BMJ 2000;325:1379.
2. The DECODE study group on behalf of the European Diabetes Epidemiology Group. Glucose tolerance and mortality: comparison of WHO and ADA diagnostic criteria. Lancet 1999;354:617-621.
3. The DECODE-study group on behalf of the European Diabetes Epidemiology Group. Is fasting glucose sufficient to define diabetes? Epidemiological data from 20 European studies. Diabetologia 1999;42:647- 654.
4. The DECODE Study Group, on behalf of the European Diabetes Epidemiology Group. Glucose Tolerance and Cardiovascular Mortality. Arch Intern Med 2001;161:397-404.
5. DECODE Study Group on behalf of the European Diabetes Epidemiology Study Group. Will new diagnostic criteria for diabetes mellitus change phenotype of patients with diabetes? Reanalysis of European epidemiological data. BMJ 1998;317:371-375.
6. WHO Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. World Health Organization 1999.
Competing interests: See above.
Competing interests: No competing interests