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Chapter 6.4: Diabetes
Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Background Paper
Diabetes
By Warren Kaplan
7 October 2004
6.4-1
Chapter 6.4: Diabetes
Table of Contents
Executive Summary ............................................................................................................................. 3
1.
Introduction ................................................................................................................................ 5
2.
What Are the Epidemiological Trends for Europe and the World? ................................... 8
3.
What is the Control Strategy? ................................................................................................. 13
4.
What is Known of the Affordability, Feasibility, and Sustainability of
the Control Strategy? ............................................................................................................... 14
5.
Why Does the Disease Burden Persist? ................................................................................. 15
6.
What Can Be Learnt from Past/Current Research into Pharmaceutical
Interventions for this Condition? ........................................................................................... 17
7.
What is the current “pipeline” of products that are to be used for this particular
condition? .................................................................................................................................. 22
8.
What is the Current Status of Institutions and Human Resources
Available to Address the Disease? ......................................................................................... 23
9.
Ways Forward from a Public Health Viewpoint with Regard to Public Funding .......... 25
Endnotes .............................................................................................................................................. 28
Annexes
6.4-2
Chapter 6.4: Diabetes
Executive Summary
Burden of Disease
Diabetes profoundly affects the quality of life and represents a life-long burden on a patient’s
social support system. Although the present document is primarily concerned with therapeutic
interventions, the key public health message about diabetes is that with the right provision of
care and patient empowerment, a full and health life is possible for many (although not all)
people with diabetes.
The impact of diabetes and its sequelae is enormous. In the United States:
 Diabetes is the leading cause of new blindness in people aged 20–74 years;
 Diabetes is the leading cause of kidney disease requiring dialysis;
 As a result of the effects of diabetes on nerve and peripheral vascular tissue, diabetes is
the most common cause of amputation;
 Diabetes patients suffer heart disease 2 to 4 times more frequently than non-diabetic
persons;
 Diabetes patients suffer strokes 2 to 4 times more frequently than non-diabetic persons;
 The rate of congenital malformation in offspring of diabetic mothers may be as high as
10 percent, and fetal mortality occurs in 3 to 5 percent of pregnancies.
It has been estimated that 300 million persons will have diabetes by the year 2025 (about 5.4% of
the world’s projected population). Type 2 diabetes affects nearly 10% of the adult population in
developed countries. The projected increase in prevalence will be four times higher in the
developing than in the developed world. In 2025, the countries with the largest number of
people with diabetes will be India, China and the United States. Given the burden and
associated costs of diabetes, the ongoing epidemic represents a major public health problem
demanding effective control. The European burden of diabetes is increasing although there are
widely differing estimates. Population based studies based on males and females between 39–88
years reported 3.6% known people with diabetes in the Netherlands, 6.4% in Denmark and 8.0%
in Italy.
The economic burden of diabetes is staggering, in large part because of the number of
associated complications . Direct medical and indirect (lost productivity due to disability and
premature death) expenditures in the United States in 1997 were estimated at nearly $100 billion.
Total direct medical costs for Type 2 diabetes in a survey of 8 EU countries was estimated at 29
Billion Euros a year.
There is a large gap between diabetes prevalence and treatment rates. It has been estimated that 30-50% of
diabetes cases remain undiagnosed. Onset of the disease occurs on average 4–7 years before diagnosis.
Type 2 diabetes develops gradually and at earlier stages is often not severe enough for the patient to notice
any of the classic symptoms of diabetes. Nevertheless, such patients are at increased risk of developing
macrovascular and microvascular complications.
Treatment Options: Types of Diabetes
Persons with 1 diabetes must deal with a life of insulin replacement and the complications of
diabetes. At present, there is no real ability to provide effective, long term, tight glycemic control
with exogenous insulin. We need more insight into basic biology and new therapeutic
innovations for cure and insulin delivery. Few could argue that such a discovery of a
preventative or curative agent would represent a milestone for Type 1 diabetes. No treatment
has been shown to safely prevent type 1 diabetes in humans, although islet transplantation and
new immunosuppressive regimens show that the disease can potentially be cured.
6.4-3
Chapter 6.4: Diabetes
Persons with Type 2 diabetes may be at the mercy of industrialization which is indeed
responsible for some of the increasing incidence of Type 2 diabetes, leading to obesity, physical
inactivity and consumption of high fat diet. There is solid scientific basis for advocating
preventive measures to slow the onslaught of Type 2 diabetes. Management of Type 2 diabetes
has always been centered on control of the energy economy of the body, i.e., achieving a
negative calorie balance if weight loss is required and/or optimal intake of carbohydrates and
lipids. Current treatment for Type 2 diabetes is quite variable and often staged to the progress
of the disease. Current treatment of Type 2 diabetes is far from satisfactory. Evidence suggests
that controlling obesity and physical inactivity can prevent, or at least delay, the development of
disease in many genetically susceptible individuals. Success in actually controlling these risk
factors on a large scale has been limited. There are considerable gaps in our understanding of
optimal applications of existing and new therapies, particularly since many patients will have
co-morbidities that require polypharmacy.
The commercial market for diabetes therapeutics will ensure that there will be no shortage of
private research funding for the immediate future although opportunities exist for public
funding of diabetes research. Both private and public funders should consider the following
priority areas:
Insulin/insulin analogues with improved pharmacokinetics/delivery mechanisms
Long term action
Heat stable insulin
Fewer side effects (e.g., hypoglycemia)
Continuous glucose-monitoring devices
Measurement in real time
Non-invasive or minimally invasive
Closed loop Glucose monitors
Data download to physician via web
Drugs for prevention of specific complications
ACE inhibitors for nephropathy
Rigorous control of lipids with new generation statins
Fixed dose combinations for cross risk factors (e.g “polypill”)
Nerve growth agonists for neuropathies
Islet transplantation
Stem cells
Islet cell xenotransplantation (use of beta cells from a different species)
Encapsulation methods for beta cells
Improved immunosuppressants
Clinical trial improvements
 An infrastructure should be created to facilitate diabetes clinical trials. This need is
especially pressing in diabetes research in which clinical trials to “hard end points” may
take many years and even decades, and where clinical trials are established de novo,
requiring a tremendous input of energy and resources. A diabetes trial network could
provide a stable infrastructure for the long-term and complex clinical trials required for
the study of diabetes. It is important to develop and maintain an informational registry
of patients for study and perform clinical trials in diabetes and its complications.

With regard to the above, a structure should be created to facilitate drug to drug
comparative clinical trials.
6.4-4
Chapter 6.4: Diabetes
1.
Introduction
The word “diabetes “ is from the Greek for “siphon” and this clinical description sometime in
the second century AD is graphic:
“Diabetes is a dreadful affliction, not very frequent among men, being a melting down of
the flesh and limbs into urine. The patients never stop making water and the flow is
incessant, like the opening of aqueducts. Life is short, unpleasant and painful, thirst
unquenchable, drinking excessive, and disproportionate to the large quantity of urine,
for yet more urine is passed…” (Aretaeus the Cappadocian, translated by Francis
Adams 1856- Source Book of Medical History, 1960 Dover Publications)
The urine of some people with diabetes was described as tasting like honey, being sticky and
attractive to ants. The word “mellitus” is the latin word for honey. During the eighteenth and
early nineteenth centuries, diabetes became recognized as a metabolic disorder but only in 1888
did von Mering and Minkowski make the crucial observation that removal of the pancreas lead
to diabetes in dogs. The active principle could not be isolated for several more decades. In 1922,
Banting and Best published their first paper describing use of pancreatic extracts to successfully
lower glucose in dogs lacking a pancreas.
Diabetes mellitus is a syndrome of disorders that are characterized by hyperglycemia (chronic
high blood sugar ) resulting from defects in secretion of insulin, the ineffective metabolic action
of insulin (i.e., insulin resistance) or both. Pathophysiologically, endogenous insulin deficiency
of Type 1 should be distinguished from impaired insulin sensitivity and impaired beta cell
function in Type 2 diabetes. The hyperglycermia of diabetes is associated with potentially
devastating long-term damage, dysfunction, and failure of various organs, especially the eyes,
kidneys, nerves, heart, and blood vessels. Long-term complications of diabetes include
retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral
neuropathy with pain and risk of foot ulcers and amputation. 1 People with diabetes are at
increased risk of cardiovascular , peripheral vascular, and cerebrovascular diseases. 1 Indeed, it
has been estimated that more than 50% of individuals with Type 2 diabetes (the most common
form in developed countries) face the prospect of dealing with ischaemic heart disease. 2 Up to
25% of all Type 2 people with diabetes in England have clinically significant evidence of
microvascular disease at initial presentation. 3 Thus, public health systems cannot deal with
diabetes without dealing with its associated co-morbidities.
Diabetes profoundly affects the quality of life and represents a life-long burden on a patient’s
social support system. The impact of diabetes and its sequelae is enormous, as the following key
points. In many countries1, 11:
 Diabetes is the leading cause of new blindness in people aged 20–74 years;
 Diabetes is the leading cause of kidney disease requiring dialysis;
 As a result of the effects of diabetes on nerve and peripheral vascular tissue, diabetes is
the most common cause of amputation;
 Diabetes patients suffer heart disease 2 to 4 times more frequently than non-diabetics;
 Diabetes patients suffer strokes 2 to 4 times more frequently than non-diabetics;
 The rate of congenital malformation in offspring of diabetic mothers may be as high as
10 percent, and fetal mortality occurs in 3 to 5 percent of pregnancies.
This report is a review of primarily pharmaceutical interventions for diabetes but it must be
recognized that prevention of diabetes mellitus through changes in behavior such as diet and
exercise should be the first line of intervention.
6.4-5
Chapter 6.4: Diabetes
1.1
Types of Diabetes
There are several pathogenic processes involved in the most common forms of diabetes that lead
to excess blood glucose and these for a continuum of disease progression. These range from
autoimmune destruction of the insulin-producing beta cells of the pancreas (leading to
insufficient insulin production) to abnormalities that result in the body becoming resistant to the
insulin it produces. This resistance results from inadequate insulin and/or diminished tissue
responses to insulin. Poor insulin secretion and defects in insulin action frequently coexist in the
same patient, and it is often unclear which abnormality is the primary cause of the high blood
sugar levels. The vast majority of cases of diabetes fall into two broad categories.
1.1.1 Type 1 diabetes: This is immune-mediated and has been variously called insulindependent diabetes, or juvenile-onset diabetes. It results from a cellular-mediated autoimmune
destruction of the pancreatic beta-cells that produce insulin.
Immune markers of immune destruction are present in 85–90% of individuals with Type 1
diabetes. There have been many purported associations with various environmental factors that
might trigger Type 1 diabetes, but so far only congenital rubella syndrome has been
conclusively associated with the disease.4
However, Type I diabetes clearly has genetic associations. Genes for type 1 diabetes provide
both susceptibility towards, and protection from, the disease. Few true “Type 1 genes” have
been identified. The most important nucleotide sequences are located within the major
histocompatibility complex (MHC) HLA class II region on chromosome 6. The specific
contribution of these genes to the pathogenesis of type 1 diabetes is unclear. 5
In Type 1 diabetes, rates of beta -cell destruction are variable, being rapid in some individuals
(mainly infants and children) and slow in others6 (mainly adults). Many individuals with type 1
diabetes eventually become completely dependent on exogenous insulin for survival as there
eventually will be an absolute deficiency of insulin secretion because all beta cells are inactive. It
is often many years between the onset of beta cell destruction and the presence of overt
hyperglycemia.
Type 1 diabetes accounts for a minority of all diabetes but accounts for the majority of diabetes
mellitus in younger age groups for most countries. 10 Overall, about 8-9 times as many people
have Type 2 diabetes than Type 1. It has been estimated that the annual global increase of new
cases of Type 1 diabetes is about 3%. 10 The almost universal increasing trend in younger ages
is not likely due to changes in the genetic background. 10 Data on global incidence and
prevalence of Type 1 diabetes suggests that there are large variations- due in part to unreliable
data, variations in risk genes and other variables. Figure 6.4.1 is a summary of Type 1 diabetes
incidence per 100000 persons for the year 2000 for selected countries around the world. The data
was obtained from reference 10. We note that amount of Type 1 diabetes at any one time (i.e.,
prevalence (per 100000)) generally follows the same geographic ranking as in Figure 6.4.1, with
minor variations. There is little or no reliable data from Sub-saharan Africa. In the Eastern
Mediterranean, Egypt accounts for about one quarter of the estimated total number of prevalent
cases. The United Kingdom, Germany and the Russian Federation account for most of the
prevalent cases, although the largest rates of new cases per year can be found in some of the
Scandinavian countries (See Figure 6.4.1) and reference 10.
6.4-6
Chapter 6.4: Diabetes
Figure 6.4.1: Type 1 Diabetes Incidence per 100000 persons per year
Type 1 Diabetes (Incidence per 100000) (year
2000)
Finland
Sweden
United Kingdom
USA
Denmark
Ireland,
New Zealand
Malta
Netherlands
Germany
Australia
Portugal
Spain
Luxembourg
Belgium
Estonia
Cyprus
Austria
Italy
Hungary
Czech Republic
Greece
Slovakia
France
Slovenia
Lithuania
Egypt
Poland
Sri Lanka
India
Bangladesh
Jordan
Thailand
Japan
Indonesia
Taiwan
China
0
10
20
30
40
50
Source: International Diabetes Federation, Diabetes Atlas, 2nd edition
1.1.2 Type 2 diabetes: Type 2 diabetes, is also referred to as non-insulin-dependent diabetes,
or adult-onset diabetes. The cause of Type 2 diabetes is a combination of resistance to the action
of insulin and an inadequate secretion of insulin as a normal compensatory response to
increased blood glucose. At least initially, and often throughout their lifetime, these individuals
do NOT need insulin treatment to survive, in large part because autoimmune destruction of
beta-cells does not occur. However, many patients with Type 2 diabetes are obese, and obesity
itself causes some degree of insulin resistance.7 The risk of developing Type 2 diabetes also
increases with age and lack of physical activity. 8 It occurs more frequently in individuals with
hypertension or abnormal blood lipids, and its frequency varies in different racial/ethnic
subgroups. 9 Diabetes is a leading cause of death, new cases of end stage renal disease,
amputations, blindness and cardiovascular disease. 1
6.4-7
Chapter 6.4: Diabetes
Type 2 diabetes constitutes about 85 to 95% of all diabetes in developed countries and for an
even higher percentage in developing countries. It is now a serious global public health problem.
2.
What Are the Epidemiological Trends for Europe and the World?
Diabetes mellitus (primarily Type 2) is a large burden to society and the rise in new patients
with Type 2 diabetes in Western and Central Europe and the USA over the next few decades
must be acknowledged. See Section 2.3.
2.1 It has been estimated that 300 million persons will have diabetes by the year 2025 (which
would be a staggering 5.4% of the world’s projected population). The projected increase in
prevalence will be four times higher in the developing than in the developed world. 10 In 2025,
the countries with the largest number of people with diabetes will be India, China and the
United States. Given the burden and associated costs of diabetes, the ongoing epidemic
represents a major public health problem demanding effective control. The prevalence of all
forms of diabetes increases with age and reaches about 10% by age 60 in most populations. 11 In
both developed and developing countries, diabetes affects people in their economically
productive years and it affects those who are economically disadvantaged (elderly, racial/ethnic
minorities) 1, 11
2.2 The European burden of diabetes is increasing. Indeed, diabetes mellitus has been proposed
as one of the European Community health indicators in the European Union sponsored program
on Health Monitoring.12 The available information on prevalence of diabetes (all types) in
Europe is best characterized as being inconsistent, with widely differing estimates. Population
based studies based on males and females between 39–88 years reported 3.6% known people
with diabetes in the Netherlands, 6.4% in Denmark and 8.0% in Italy. 13 This study 13 used the
numbers of patients presenting with diabetes in a 12 month period (1999/2000) to GPs in
established European sentinel practice surveillance networks in eight European countries.
Estimates of prevalence were standardized to the 1998 European population. but NO distinction
made between Types 1 and 2 diabetes. Table 6.4.1 below is taken directly from Table 5 of
reference 13.
Are there really more known people with diabetes in Belgium than elsewhere? The reliability of
the denominator is critical: the Belgian population was estimated from consultation frequencies
(all ages), in the individual GP practices, which were compared with national data. The number
of general practitioners and the total number of consultations bore a similar proportion to
national equivalent data. There is a potential for overestimation of the numerator because
patients may consult more than one doctor. Persons under 45 years account for 60% of the total
population but less than 15% of diabetes cases. The nature of general practice is such that
prevalence estimates in persons aged 45 years and over are probably based on high levels of case
ascertainment in all networks with few false positives. With the exception of Belgium, the age6.4-8
Chapter 6.4: Diabetes
standardized prevalence in males varied between 40 and 70, and in females between 45 and 77
per 1000.
We performed an independent estimate using diabetes mellitus prevalence data for the
expanded European Union (minus Latvia) from the International Diabetes Federation 10 in the
age group 20-79, although some countries only have data for other age groups, as shown in
Table 6.4.2. Prevalence estimates in Table 6.4. 2 are subject to the same reliability limitations as
discussed above and these data are based on population prevalence studies using an oral
glucose tolerance test, and so estimate known and unknown diabetes. As Table 6.4.1 shows that
prevalence is uniformly about 20-30% higher in females than males, this is also suggested by
Table 6.4.2 but there is no showing in Table 6.4.2 of Belgium being an “outlier”. Indeed the
highest prevalence in the expanded EU can be found in the Czech Republic with a remarkable
10% (over 100 cases per 1,000 persons of all ages). The high prevalence in Denmark (146 cases
per 1,000 persons) is undoubtedly due to the fact that only ages 60-74 are represented in the
dataset.
Table 6.4.2 Prevalence estimates of diabetes mellitus - European Region (2000)
Number of people with
DM (000's) in the 20-79
age-group
DM Prevalence
Country
Austria
Belgium
Cyprus
Population
(20-79)
(000's)
6,041
Age
group
%
Male
Total DM
Prevalence per
1000 persons
Female
Total
3.8
20-79
99.9
132.4
232.3
7,458
4.1
20-79
135.3
172
307.4
518
4.9
20-79
11.3
14
25.3
Czech Republic
7,624
Denmark
3,853
6.2 *
60-74
Estonia
1,014
4.5
20-79
Finland
3,731
5.5 *
45-64
France
41,927
4.0
20-79
729.8
926.9
1,656.80
Germany
61,874
4.2
20-79
1,133.20
1,466.80
2,600.00
Greece
7,991
5.9
20-79
209.7
258.5
468.2
Hungary
7,431
6.6
20-79
203.2
288.2
491.5
Ireland, Republic of
2,514
3.2
20-79
36.2
44
80.2
43,910
7.1
20-79
1,452.90
1,672.40
3,125.40
2,603
3.2*
all
Luxembourg
316
3.8
20-79
Malta
273
9.9
35-69
Netherlands
11,494
3.6
20-79
192.8
223.1
415.9
Poland
27,136
5.7
20-79
659.2
897.9
1,557.10
Portugal
7,309
5.4
20-79
167.9
229
397
Slovakia
3,784
8.6*
all
Slovenia
1,486
8.0*
all
29,899
6.1*
10 to 74
6,341
6.4*
all
41,638
3.5
20-79
328,165
5.4
Italy
Lithuania
Spain
Sweden
United Kingdom
Total
11.7 *
all
* = crude value
Source: Diabetes Atlas, International Diabetes Federation
6.4-9


18


27.6


5.4




561.7
45.6


6.7

890.5
158.7
84.1
12.1





20.8
324.7
119.5
2,018.30
570.3
646.4
820.4
1,466.80
5,701.20
7,179.90
17,630.20
in specified age
groups
38
41
49
117
146
45
43
40
42
59
66
32
71
32
38
76
36
57
54
86
80
68
90
35
54
Chapter 6.4: Diabetes
This gender difference in prevalence can also be shown when burden of disease is measured as
DALYs per 1,000 population within age groups as in Figure 6.4.2. In the EU15, the total diabetes
burden shifts from men (line below EU15F) to women after the age of 70, as might be expected
from the overall aging of the population combined with longer female life span. The newer EU
countries have a lower overall diabetes burden, with women contributing more to the burden
than men.
Figure 6.4.2
Diabetes Mellitus (DALYs per 1000 by age)
12.0
EU15 F
World- M, F
10.0
8.0
6.0
4.0
EU10 -M
2.0
EU10-F
0.0
0-4
5-14
15-29
30-44
45-59
60-69
70-79
80+
2.3
Several specific epidemiologic issues exist with the main types of diabetes
and these are relevant for the purposes of this review.
2.3.1 Increases in Type 1 diabetes
Type 1 diabetes seems to be increasing in almost all populations, with the increase particularly
high in nations with a low incidence of this disease. Significantly, the incidence of Type 1
diabetes is expected to be about 40% higher in 2010 than in 1997. 14 There is an enormous
international variation in rates of Type 1 diabetes, especially among different ethnic
populations.15 16 See also Figure 6.4.1. The two areas with the highest incidence rates, Finland
and Sardinia, are 3000 km from each other, whereas Estonia, bordering Finland, has an incidence
rate of about one-quarter of its neighbor.17 Such variations in disease incidence are increasingly
being seen to follow these ethnic and racial distributions, which indicates that we should not
rely on a model that accounts only for geographic position. The explanation for these wide
disparities in risk within ethnic groups probably lies in differences in genes or environment.
Strategies for prevention and long term management will of necessity vary as well.
The EURODIAB collaborative study 17 a registry consortium involving 44 centers representing
most European countries and Israel, indicates an annual rate of increase in Type 1 diabetes
incidence of 3–4%, but in some central and eastern European countries (most notably those of
the former communist bloc), the increase is far more rapid. 18 Furthermore, examination of the
rates of Type 1 diabetes as a function of the age at onset showed rates of increase of 6·3%, 3·1%,
and 2·4% in populations of children aged 0–4 years, 5–9 years, and 10–14 years, respectively.
These findings support the impressions of health-care professionals that they are seeing more
and more cases of type 1 diabetes, especially in younger children. The incidence of type 1 disease
thus shows a trend towards earlier onset.
6.4-10
Chapter 6.4: Diabetes
2.3.2 Increases in Type 2 diabetes:
Despite its high frequency, Type 2 diabetes is hard to quantify accurately, since estimates will
vary according to access to diagnostic facilities, the diagnostic definitions, the means of
ascertainment, the nature and age-structure of the population under consideration, the ability to
distinguish between type 1 and type 2 diabetes, and the longevity of those affected. The
approach for assessing diabetes prevalence recommended by the WHO is population-based
studies using the oral glucose tolerance test. The vast majority of people with diabetes identified
this way will have Type 2 diabetes, although in theory further tests could be done to identify
those with auto-immune destruction of beta cells. The effect of access to diagnostic facilities,
definitions and so on, will make a difference only in accessing the prevalence of know diabetes.
Genes that predispose to cardiovascular disease and obesity in Europe and North America are
also widespread in other areas and, presumably as a function of a more sedentary lifestyle,
changes in eating habits and growing affluence, there has been an alarming increase in Type 2
diabetes, in body weight and obesity in much of the world. 18 Predictably, the proportion of
people in developing countries with Type 2 diabetes (and its attendant sequelae) is putting an
increasing strain on health care systems in developing countries. 19 20 Several worrying trends
are associated with the burden of Type 2 diabetes which should inform further discussion within
the EU.
2.3.2.1. Over the past 10 years, more women of childbearing age, adolescents, and even children have
developed type 2 diabetes 21 22
As with adults, obesity in childhood causes hypertension, abnormal lipid metabolism, chronic
inflammation, and insulin overproduction. 23 This clustering of cardiovascular disease risk
factors, known as the “insulin resistance syndrome”, has been identified in children as young as
5 years of age. Being overweight in childhood increased the risk of death from ischaemic heart
disease in adulthood two-fold over 57 years. 24 Type 2 diabetes, once virtually unrecognised in
adolescence, now accounts for as many as half of all new diagnoses of diabetes in some
adolescent populations. 24 This condition is almost entirely attributable to the pediatric obesity
epidemic, though heredity and lifestyle factors affect individual risk . The emergence of type 2
diabetes in children cannot be good news, in view of its macrovascular (heart disease, stroke,
limb amputation) and microvascular (kidney failure, blindness) sequelae.25
In both Type 1 and Type 2 diabetes, it is important to improve glucose control for children as,
given their age and the operational problems involved in taking medications, the level of control
achieved in adolescents may not equal that obtained in adults. Furthermore, current treatment
approaches for achieving glycemic control are not optimal. Intensive treatment regimens also
have side effects, such as weight gain and increase in the risk of severe low blood sugar . Both of
these may be seen to limit compliance, and this carries its own risks. Hence, many children with
diabetes go on to develop the long-term complications of the disease.22
The increasing prevalence of type 2 diabetes in the young may be thwarted by the standard first
line actions that should be advocated- more physical activity and changing dietary habits.
2.3.2.2 Diabetes in the elderly
There may be several distinct subsets in the population of elderly people with diabetes
including those with “typical” Type 2 diabetes, those with beta cell loss purely as the result of
aging, those with diabetes secondary to other diseases or interventions, i.e., steroids, and those
with delayed onset of autoimmune Type 1 diabetes, the latter now called “latent autoimmune
diabetes of the adult” or LADA . 26 Population studies have documented that as many as 80% of
known elderly people with diabetes may remain inadequately treated. 27 Furthermore, impaired
tolerance for glucose and excess insulin levels appear to be independently associated with
declining cognitive function. 28 This is disconcerting because, in addition to the wide range of
6.4-11
Chapter 6.4: Diabetes
traditional diabetes complications, the healthcare systems caring for the diabetic elderly will
have to confront increased risk of cognitive decline, physical disability, falls and fractures, and
other conditions associated with geriatric syndromes. 29 30 31 Several large prospective studies
have associated diabetes with cognitive decline and clinical dementia. 32 33
Indeed, the greatest absolute increase and total numbers of diabetes cases are actually occurring
among the elderly. Polypharmacy is common among the elderly because of the desire to
simultaneously manage glycemia, hyperlipidemia, hypertension, and other associated
conditions. Yet polypharmacy can affect cognitive ability, physical functioning, and depression
through drug-drug or drug-disease interactions. As one might expect, those with impaired
cognitive function might be less likely to manage their own diabetes and had a greater level of
use of health and social services. 34 There may even be a link between diabetes and Alzheimer’s
disease since several recent studies have suggested that Type 2 diabetes is associated with a
higher incidence of dementia and Alzheimer's disease. 35 A recent review concluded that
diabetes is probably a risk factor for Alzheimer's disease mainly through the cerebrovascular
disease that diabetes causes.36
2.3.2.3 Diabetes and women
Populations with the highest prevalence of type 2 diabetes also have the highest rates of diabetes
in young women. World Health Organization data from 1992 showed the prevalence of diabetes
in women of child-bearing age (20–39 years) to be highest in native Americans, Micronesians,
rural Fijians, and aboriginal Australians, all of whom have very high populations rates of type 2
diabetes.37 In adolescents, type 2 diabetes has been increasingly noted in native Canadian and
American populations38, Mexican-Americans, African-Americans, Japanese people, and Libyan
Arabs.39 An interesting study of sibling pairs argues for the role of the in-utero environment.40
Siblings born after the mother’s diagnosis of diabetes had a higher risk of diabetes than those
born before the diagnosis. This finding contrasted with siblings born to fathers with diabetes, in
whom there were no significant differences between the siblings. If Type 2 diabetes in pregnancy
does contribute to the increasing rate of type 2 diabetes in the population, knowledge of whether
we can change or modify these rates by improved glycaemic control during pregnancy will be
important.41
Cardiovascular disease (CVD) occurs frequently in men and women with diabetes mellitus but
normally, premenopausal women without diabetes are generally protected from CVD. 42 It has
been argued that diabetes removes this protective effect of gender on CVD but it is not
immediately obvious why this should be so.43 A recent review, controlled for age, hypertension,
hypercholesterolemia and smoking suggests that most of the observed differences in risk for
CVD mortality between men and women with diabetes mortality are mediated by "traditional"
cardiac risk factors and not from diabetes itself.43 Thus, actively focusing on these factors and
treating aggressively may prevent many of these complications.
2.3.2.4 Mismatch between treatment strategy and actual prevalence
There is a large gap between diabetes prevalence and treatment rates. It has been estimated that
30-50% of diabetes cases remain undiagnosed and this mismatch can be as high as 90% in parts
of urban Africa. 10 Onset of the disease occurs on average 4–7 years before diagnosis. Type 2
diabetes develops gradually and at earlier stages is often not severe enough for the patient to
notice any of the classic symptoms of diabetes. 1-9 Nevertheless, such patients are at increased
risk of developing macrovascular and microvascular complications.
6.4-12
Chapter 6.4: Diabetes
3.
What is the Control Strategy?
Is there an effective package of control methods assembled into a “control strategy” for most
epidemiological settings?
3.1
Type 1: Simply put, people with Type 1 diabetes are condemned to life of insulin
replacement and the complications of diabetes. At present, there is very limited ability to
provide effective, long term, tight glycemic control of exogenous insulin.
3.2
Type 2
Environmental and lifestyle changes resulting from industrialization may be responsible for
some of the increasing incidence of Type 2 diabetes. Physical activity and consumption of a high
fat diet lead to obesity. These first two factors can potentially be changed. 43, 48 Insulin resistance
can be improved by behavior modification and drug treatment. There is solid scientific basis for
advocating preventive measures to slow the onslaught of diabetes. Major primary prevention
trials have demonstrated that we can prevent or delay 25–60% of new type 2 diabetes44, 45.
Approximately one case of diabetes can be prevented or delayed for every six to seven patients
with impaired glucose tolerance receiving intensive lifestyle supervision (reduced caloric intake
and optimal utilization of carbohydrates and lipids) over an approximate 3-year period. 46, 47, 48
Thus, clinical trials have shown that lifestyle interventions were the most effective, with drug
therapy (metformin and acarbose) also being effective but with lower reductions in
incidence. Therefore, the development and evaluation of other drugs in prevention of Type 2
diabetes is an area of importance.
In short, management of Type 2 diabetes has always been centered on control of the energy
economy of the body, i.e., achieving a negative calorie balance if weight loss is required
and/or optimal intake of carbohydrates and lipids. Most patients are quite reticent to progress
to injectable insulin replacement therapy (See Section 5.2) because of the perceived 'failure'
on their part to control the disease. We reiterate that diet and exercise and then oral noninsulin analogues should be the primary control agents.
3.3
Reducing mortality and morbidity by dealing with co risk factors
If pharmacological interventions are needed, several current treatments have proven efficacy in
reducing mortality and morbidity due to complications of the disease. Such strategies, and their
expected benefit, are shown in Table 6.4.3 (adapted from reference 11)
Table 6.4.3. Pharmacological Strategies to alter diabetes co risk factors
Strategy
Benefit
Glycemic control
Reduces microvascular disease
Blood pressure control
Reduces macro/micro vascular events
Lipid Control
Reduces coronary events/mortality
Aspirin use
Reduces myocardial infarction
ACE inhibitor use
Reduces nephropathy
Cardiovascular disease (CVD) risk factor treatment is at least as effective as it is in persons
without diabetes, although the greater absolute risk of diabetic subjects gives them greater
absolute benefit from the interventions. One difficulty may be that patients with diabetes
require a great deal of preventive treatment; subsequently, their rates of compliance with
recommended treatment may be lower than desirable. 49 Providing a fixed dose combination
(FDC) pill containing three or four agents may obviate this problem.
Hypertension is an extremely common comorbid condition in diabetes, affecting 20–60% of
patients with diabetes, depending on obesity, ethnicity, and age.55 In type 2 diabetes,
hypertension is often present as part of the insulin resistance syndrome also including central
6.4-13
Chapter 6.4: Diabetes
obesity and inappropriate lipid levels. There is a strong epidemiological connection between
hypertension in diabetes and adverse outcomes of diabetes. 55
The Heart Protection Study Collaborative Group from Oxford presented data from the Heart
Protection Study (HPS) of cholesterol lowering in the UK and there were highly significant
reductions in the rate of first major coronary events, strokes, and revascularisations, both in
diabetic patients and in those without diabetes. 50
Drug makers should look into cross-risk factor FDCs. One way to tackle this issue would be the
development of a fixed dose of several drugs in a single pill to treat several cardiovascular risk
factors in one. This is potentially a high-risk strategy for the pharmaceutical industry, but a
clearly low-cost intervention for generic companies, as key elements of a combination therapy,
such as ACE inhibitors, statins and aspirin, are already generically available. A recently
published and controversial paper outlined a strategy to combine aspirin, a statin, three antihypertensives and folic acid in one pill for patients with vascular disease and those over the age
of 55 years.51
The objective of this “polypill’ is to simultaneously reduce four key
cardiovascular risk factors: LDL cholesterol, blood pressure, serum homocysteine and platelet
function. The paper argued that a Polypill has the ability to reduce ischemic heart disease by
88% and stroke by 80%. Furthermore, it is estimated that side-effects and adverse events would
only warrant withdrawal of the pill in 1-2% of patients and fatal side-effects are estimated to
occur in less than one in 10,000 users. This “polypill” FDC treatment for secondary prevention of
cardiovascular disease is addressed in the paper by Neall et al. See Chapter 6.3
4.
What is Known of the Affordability, Feasibility, and Sustainability
of the Control Strategy?
4.1
Economic Burden
The economic burden of diabetes is staggering, in large part because of the number of
associated complications . A recently published study evaluated more than 7000 Type 2 diabetes
patients in 8 European countries. 56 Total direct medical costs in these countries was estimated at
29 Billion Euros a year. The estimated average yearly patient cost was 2834 Euros and
hospitalisation accounted for over one half of the direct costs. Drug costs for managing the
disease were relatively low, as oral drug therapy for glycemic control was about 4% of overall
costs. 52 Another estimate of direct medical costs of Type 2 diabetes in Switzerland estimated
annual per patient costs at about 2201 Euros and total country-wide expenditures of about 2.2%
of total healthcare expenses. 53 Direct medical and indirect (lost productivity due to disability
and premature death) expenditures in the United States in 1997 were estimated at nearly $100
billion (about €82 billion).54 This is, incredibly about 10% of all health care expenditures in 1997
and one of every four Medicare dollars. 55
4.2
Feasibility of Control Strategy
Primary prevention of diabetes requires concerted effort with regard to diet, lifestyle, diagnosis,
costs and access. Cure of diabetes requires intensive basic and applied research into the genetic
and metabolic mechanisms. Prevention of diabetes-related complications requires both diet and
lifestyle changes as well as applied and basic scientific efforts. Indeed, one must question
whether the health systems in developing countries are capable of handling the burden of
diabetes, much less other chronic conditions.56 57
6.4-14
Chapter 6.4: Diabetes
5.
Why Does the Disease Burden Persist?
5.1
Type I
Type 1 diabetes persists because there is as yet no identified agent capable of affording
primary prevention. Few could argue that such a discovery of a preventative agent would
represent a milestone for Type 1 diabetes. No treatment has been shown to safely prevent type 1
diabetes in humans.We need more insight into basic biology and new therapeutic innovations
for cure and insulin delivery.. Islet transplantation and new immunosuppressive regimens
show that the disease can potentially be cured. 5 Nonetheless, individuals with Type 1 diabetes
require daily injections of insulin to sustain life and access to insulin is a problem in many
developing countries.
There have been several recent setbacks in prevention of Type 1 diabetes. In the United States,
the diabetes prevention trial (DPT-1) was started in 1994 with the aim of determining whether
antigen based treatment with insulin (oral and parenteral insulin treatment in relatives at high
and moderate risk) would prevent or delay diabetes. These treatments did not slow the
progression to diabetes. The European nicotinamide diabetes intervention trial (ENDIT) also
found no difference in protection from diabetes when participants were assigned to either oral
nicotinamide or placebo treatment 58.
There is, however, an another obstacle facing the diabetes prevention field in general and Type 1
in particular, which has been dubbed the “treatment dilemma”. 5 Animal and human studies
suggest that early intervention is more effective in terms of disease prevention. In contrast, the
ability to identify an individual who will truly develop type 1 diabetes (among an at-risk
population) increases as the individual approaches onset of overt disease so that the process of
disease prediction (using various immunologic and metabolic markers) is actually most accurate
relatively late in the disease process.i This results in a conflict, where the most effective
therapies involve early treatment but would be used in a period when disease prediction is poor
so that safe and benign but unnecessary therapy might be used for those who would never
develop type 1 diabetes.
Another challenge relates to clinical trials. In terms of doing clinical trials to test preventive
measures within the general population, the disease frequency and unpredictable time of onset
form major obstacles for design of trials that provide answers in short time frames. Doing
clinical trials in those populations who are at higher risk might prove more cost effective (in
terms of a trial) and efficient, yet in terms of humanitarian benefit, testing interventions on the
general population may be more important because about 85% of newly diagnosed Type 1
patients have no family history of the disease. 5
i The long phase preceding the onset of type 1 diabetes suggests a potential to predict the disease and design trials for
its prevention. See Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, et al. 1996, Prediction of type I
diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes
45:926-33; LaGasse JM, Brantley MS, Leech NJ, Rowe RE, Monks S, Palmer JP, et al.2002, Successful prospective
prediction of type 1A diabetes in schoolchildren through multiple defined autoantibodies: an 8-year follow-up of the
Washington State diabetes prediction study. Diabetes Care 25:505- 11.
6.4-15
Chapter 6.4: Diabetes
5.2
Type 2
Type 2 persists because there is no cure or preventative agent
Diabetes is inexorably linked with a variety of environmental, dietary, lifestyle factors that
require multidisciplinary and concerted action at all levels of society for primary prevention.
Key are the issues of long term glycemic control . Current treatment for Type 2 diabetes is quite
variable and often staged to the progress of the disease. Early on, or in mild forms, diet, weight
loss, and exercise are used to improve insulin sensitivity. If this is inadequate, oral hypoglycemic
agents are added. These may act to further improve insulin action, stimulate more insulin
secretion or alter the absorption of carbohydrates in the diet. If these steps are unsuccessful, the
patient is often placed on insulin, just like the patient with Type 1 diabetes. These approaches
have limited success in controlling elevated glucose levels in patients with Type 2 diabetes (See
Section 6), or in controlling obesity that predisposes to this disease. Thus, current treatment of
Type 2 diabetes is far from satisfactory. Evidence suggests that controlling obesity and physical
inactivity can prevent, or at least delay, the development of disease in many genetically
susceptible individuals. Success in actually controlling these risk factors on a large scale has been
limited. There are considerable gaps in our understanding of optimal applications of existing
and new therapies, particularly since many patients will have co-morbidities that require
polypharmacy. Drug:drug interactions and safety of new agents will be of prime concern. Major
effort and emphasis are still needed on improving strategies of diagnosis and care and on
research into new oral hypoglycaemic drugs. 59
5.2.1 Poor Insulin treatment of Type 2 patients remains a concern
Although available, there appears to be a lack of utilization of insulin therapy in Europe. In a
recent national survey, 86% of Type 2 patients with poorly controlled blood glucose (who
probably required insulin) were still being maintained on oral hypoglycaemic agents 60. The
responsibility for this delay is probably shared by the pharmaceutical industry which markets
oral non-insulins, GPs who care for the vast majority of Type 2 patients, and the distaste
generally for injections among many patients. Indeed, the primary reason for this delay of
insulin therapy may be lack of confidence among primary care physicians to introduce insulin
and manage patients, to the patients` fear of injections usually regarded as a personal failure
after oral treatment.ii
From a public health viewpoint, Type 2 diabetic patients should be offered faster access to active
insulin when oral drugs fail. Nurses, dieticians and other health professionals should receive
sufficient training so as to make health assessment and simple insulin, diet, exercise and other
lifestyle adjustments without having to track down a physician specialist for a signature.
5.2.2 Access to Insulin in developing countries
This report is concerned mainly with priority medicines for important conditions affecting
Europe. Nonetheless, the rising burden of diabetes around the world is a compelling argument
for a brief review of one factor that causes both individual suffering and health system overload,
the lack of access to insulin in places outside the European Union. 61 Fully 75 years after its
discovery, insulin is not routinely available in many parts of the developing world. 62 63 Insulin is
often unavailable in large city hospitals in Africa and may be unavailable in rural areas. A child
with newly diagnosed type 1 diabetes in much of sub-Saharan Africa may live only 1 more
year.64 65 It is well known that the amount available for health care, and in particular for
pharmaceuticals in many developing countries—which have to be purchased with foreign
exchange—may be as little as US$2–3 per person per year.66 The costs of outpatient health care
for type 1 diabetes have been calculated for one African country as around US$229 per person
See, e.g., Zambanini A, Newson RB, Maisey M, Feher MD., 1999. Injection related anxiety in insulin-treated
diabetes. Diabetes Res Clin Pract. 46:239-46;
ii
6.4-16
Chapter 6.4: Diabetes
per year, of which some two-thirds (US$156) is for insulin. 67 In a state-funded health care
system in developing countries, treating one patient with type 1 diabetes might, in effect, be
depriving 75 others of potentially lifesaving antimalarials or antibiotics. The alternative, of
patients buying insulin, may cost the equivalent of 6 months salary per year, for continuous
treatment.68
The problem of finding a suitable “cold chain” to maintain insulin in a refrigerated condition
also contributes to this problem. Developing heat stable insulin should be a prime research
priority. See Section 6.5.
6.
What Can Be Learnt from Past/Current Research into
Pharmaceutical Interventions for this Condition?
6.1
Tight Control of Blood Glucose is Critical but Not Presently Available
At present, all Type 1 and many Type 2 diabetics will require insulin replacement. Oral
insulin analogues are available. Table 6.4.4 summarizes many of these non-insulin
pharmacotherapeutics.
6.4-17
Chapter 6.4: Diabetes
Table 6.4.4: Non insulin therapeutics
Therapeutic
Benefits
Harms
Comments
Sulphonylureas
Chlorpropamide,
acetohexamide, tolazamide,
tolbutamide
glibenclamide/
glyburinde
glipizide/glimepiride
gliclazide
Optimal efficacy
in early stages
Long term use
may desensitise
beta cells:
weight gain.
Secondary treatment failure
common due to progressive
deterioration of beta cells.
No clear evidence that one
sulphonylurea is superior to
any other. Can NOT prevent
progression to insulin
dependence. Requires
functioning beta cells
Meglinitides
Repaglinide (Prandin,
NovoNorm)
Nateglinide (Starlix,
Novartis/Yamanouchi/Aventis
Starsis, Fastis)
Mitiglinide Servier Phase
Less risk of
hypoglycemia
than insulin or
sulphonylureas
Hypoglycemia;
multiple daily
doses required
Useful in limiting
postprandial spike in
glood glucose
d-phenyalanine derivative
nateglinide
Biguanides (e..g., Metformin)
(Glucophage tm USA)
Faster onset than
sulphonylureas
Thiazolidinediones
Rosiglitazone (Avandia®)
Pioglitazone (Actos®)
Minimal risk of
Hypoglycaemia;
weight neutral
GI disturbances
Weight gain
edema
Monitoring liver function
required- troglitazone was
removed from the market
due to effects on liver
Alpha glucosidase inhibitors
Acarbose®
Useful in limiting
postprandial
spike in blood
glucose; few side
effects
GI disturbances
Beneficial effects on serum
triglycerides
Little weight gain is a benefit
for cardiovascular outcomes
Sources: Zinman, B. 2001, A review of the metabolic effects of rosiglitazone, Diabetes, Obesity & Metabolism, 3
(Suppl.1) S34-S43; Evans AJ and Krentz AJ, 2001, Insulin resistance and beta-cell dysfunction as therapeutic targets in
type 2 diabetes, Diabetes, Obesity & Metabolism, 3: 219-229; Kobayashi,M, 1999. Effects of current therapeutic
interventions on insulin resistance, Diabetes, Obesity & Metabolism, 1: S32-S40; Chen J-W, Christianses JS, Lauritzen
T. 2003. Limitations to subcutaneous administration in type 1 diabetes, Diabetes, Obesity & Metabolism, 5: 223-233;
Shepard J. 2002, Diabetes in tomorrow’s world: dark clouds have silver linings, Diabetes, Obesity & Metabolism,
4:351-355; Matthews, DR 2001, Insulin resistance and beta-cell function-a clinical perspective. Diabetes, Obesity &
Metabolism, 3:S28-S33; Garber AJ, 2000, Using dose-response characteristics of therapeutic agents for treatment
decisions in type 2 diabetes, Diabetes, Obesity & Metabolism, 139-147; Alberti, KGMM, 2001, Treating type 2 diabetestoday’s targets, tomorrow’s goals, Diabetes, Obesity & Metabolism, 3: S3-S10; Ogawa S, Takeuchi K, Ito S., 2004.
Acarbose lowers serum triglyceride and postprandial chylomicron levels in type 2 diabetes.Diabetes Obes Metab.
6:384-90.
With regard to insulin replacement therapy in the EU, used as the final stage in achieving
glycemic control if behavioural change and non-insulin analogues fail, major issues lie not in
6.4-18
Chapter 6.4: Diabetes
access to insulin, syringes or blood glucose monitoring, (as it does in developing countries) but
in how to use these tools correctly to achieve near-normal blood glucose levels. 69
Current methods of insulin administration, cannot reproduce the normal beta cell’s ability to
precisely control blood glucose and other metabolic variables. Tight control of blood glucose
levels in patients with Type 1 diabetes can reduce the progression and incidence of
microvascular complications but trying to create tight control of blood glucose demands a
stringent daily regimen with multiple measurements of blood glucose and multiple insulin
injections or use of an insulin pump. To date, there is still very limited success in identifying
readily applicable methods for truly effective tight blood glucose control . The onset of action of
subcutaneous. injected regular insulin is too slow, and the duration of its action is too long to
mimic the insulin secretion pattern of a healthy individual during a carbohydrate-containing
meal. 70 Similarly, intermediate/long-acting insulin preparations are often unable to provide a
stable, continuous baseline insulin level. The need for insulins with faster onset and shorter
duration of action, and long-acting preparations with a more flat time-action profile and less
variable bioavailability became apparent in the 1990s. 75 Table 6.4.5 lists the presently available
insulins that can be used by people with diabetes whose blood sugar cannot be otherwise
controlled by diet, exercise, or oral agents.
Table 6.4.5: Insulins
Therapeutic
Comments
Human or recombinant human
Insulin
Rarely achieves tight and long
term control over glucose
Intermediate acting insulin
NPH
Lente Insulin
Does not mimic basal insulin
secretion
Long acting insulin analogues
Insulin glargine (Aventis)
Insulin detemir (LevemirTM:
Novo Nordisk
Approved in EU and
Switzerland.
Little weight gain observed in
trials
Fast acting insulin analogues
Insulin Lispro (Eli Lilly)
Insulin Aspart (Novo Nordisk)
Lispro: reversing amino acid
28/29 in B chain
Aspart: replacing proline at
position B28
Biphasic insulin analogues
Insulin analogues+human
insulin NPH
Pulmonary delivered insulin
Long term effects of insulin on
lung tissue not clear, no
pulmonary insulins
commercially available yet
6.4-19
Chapter 6.4: Diabetes
6.2
Alternate delivery methods are possible
6.2.1 Inhalation Therapy
To date, attempts to exploit the nasal, oral, gastrointestinal and transdermal routes have been
mainly unsuccessful. The lungs have a large internal surface area so that they offer potential for
the delivery of polypeptide drugs. Current pulmonary drug delivery systems include a variety
of pressurized metered dose inhalers, dry powder inhalers, nebulizers and aqueous mist
inhalers. Most experience with inhaled insulin has been obtained using either dry powder
formulation in the Nektar Pulmonary Inhaler/Exubera tm device (Nektar Therapeutics Inc., San
Carlos, CA, Aventis, Bridgewater, NJ, Pfizer, NY) or a liquid aerosol formulation in the AERx®
Insulin Diabetes Management System (Aradigm Corp., Hayward, CA, NovoNordisk A/S,
Copenhagen, Denmark). Inhalation is the first non-subcutaneous route of insulin administration
for widespread use.
Several questions have to be carefully investigated, the most important being the possible longterm effects of insulin inhalation for the lung, since insulin is known to have growth-promoting
properties. There is still no available clinical data concerning the efficiency of the inhaled insulin
in patients with pulmonary diseases which may cause problems in absorption of inhaled insulin
due to smaller lung surface area. Inhalable insulin therapy requires larger doses of insulin in
comparison to subcutaneous insulin to achieve the same systemic effect, so the
pharmacoeconomics of this therapy need to be clarified, too. 71 Attempts to use the buccal
mucosa and skin are also continuing.
The bioavailability is 10-15% and the dose equivalent about three times that of injected insulin. A
Cochrane review of randomised controlled trials comparing inhaled with injected short acting
unmodified human insulin used for prandial insulin replacement, in conjunction with a basal
injected insulin, concluded that inhaled insulin provided equivalent control to fully injected
regimens.iii The advantages of inhaled over injected insulins to date relate to patients'
preferences. Inhaled insulin could have huge potential advantage if it encouraged adherence
and resulted in more patients with diabetes achieving treatment targets. Few people like
injections.iv In the developed world, inhaled insulin could have an impact if healthcare
professionals start to use insulin much earlier and more aggressively in type 2 diabetes. In the
developing world, cultural taboos against injection treatments are important so inhaled insulin
may be expected to provide more health benefit—but is not likely to be more affordable or
available than the currently inadequate supplies of injected insulin.
6.2.2
Pumps
Presently, drug delivery pumps are available72 Continuous subcutaneous insulin infusion (CSII)
is used in selected type 1 diabetic subjects to achieve strict blood glucose control. Review of
controlled trials shows that, in most patients, mean blood glucose concentrations and glycated
hemoglobin percentages are either slightly lower or similar on CSII versus multiple insulin
injections. However, hypoglycemia is markedly less frequent than during intensive injection
therapy.77
What is likely to represent a major milestone is the discovery that interstitial glucose reflects
blood glucose with a sufficiently short lag time to be of clinical use. 78 The first generation of
practical, “closed loop” devices that continuously monitor cutaneous interstitial glucose are
being introduced into practice. These devices use a number of strategies for sampling interstitial
glucose, including the placement of a subcutaneous sensor 78 or use of an electric current to
iii
Amiel SA &Alberti KGMM, 2004, Inhaled insulin: May prove to be a panacea, BMJ 2004;328:1215-1216
Zamanini A, Newson RB, Maisey M, Feher MD. Injection related anxiety in insulin treated diabetes. Diab Res Clin
Pract 1999:46: 239-46
iv
6.4-20
Chapter 6.4: Diabetes
bring glucose to the skin surface by iontophoreses. 78 As of 2003, sixteen companies in the U.S.
were developing or investigating non-invasive blood glucose instrumentation. 73
6.3
Vaccines
Since Type 1 diabetes is a condition with a pathological immune activation, one strategy for
vaccine development is to reduce the auto-immune beta cell destruction by administration of
small amounts of the same antigens that are the target of the aberrant immune response. This is
called “tolerization”. 74 75 The National Institute of Allergy and Infectious Diseases (NIAID) is
in clinical trials with a vaccine for tolerization using a synthetic, metabolically active form of
insulin. (See Annex 6.4 Table 1)
6.4
Transplantation
Pancreatic transplantation will remain limited to those patients receiving a kidney transplant
and immunotherapy. Islet cell transplantation is at an early, though encouraging stage following
the availability of new less toxic immunosuppressive agents. 76 The fundamental concept is that
transplantation of pancreatic islets might allow better regulation of insulin delivery to diabetic
patients. Recently, a breakthrough occurred in this field in the form of a series of human islet
transplants done by Shapiro et al. 77 at the University of Edmonton. In this study, patients
received human islets, taken from two to three pancreases per recipient, via injection. Patients
also received a nonsteroidal immunosuppressive agents. This resulted in a finding of insulin
independence in seven consecutive patients over an average time of 12 months. However,
broad-based application of this type of surgery to the millions of individuals with insulinrequiring diabetes is also not possible due to the limited number of suitable donor organs—
estimated to be in the range of several thousand pancreases per year. Furthermore,
transplantation requires long-term immunosuppression with its attendant risks in order for the
graft to be protected from the immune system.
6.5
Heat Stable Insulin
“Vials of insulin not in use should be refrigerated. Extreme temperatures (<36 or >_86°F, <2 or >30°C)
and excess agitation should be avoided to prevent loss of potency, clumping, frosting, or precipitation.” 78
This statement by the American Diabetes Assocation succinctly illustrates a key component of
the “access” issues relating to insulin, particularly in the developing world. Information
obtained from some insulin manufacturers v can be summarized as follows:
CP Pharmaceuticals Ltd: A single vial may be used repeatedly over a 3 month period, as long as
the vial is maintained at the correct storage temperature of 2 to 8 degrees C. If the vial is stored
outside the refrigerator [at room temperature] then the 3 month period is reduced to 28 days.
Insulin in cartridges is stable for up to 4 weeks once open if stored at 25 degrees C.
Novo Nordisk Pharmaceuticals Ltd: Unopened insulins are stable until the expiry date if stored
in a refrigerator. Once opened, insulin in vials is stable for up to 3 months in the refrigerator and
6 weeks at 25 degrees C. Insulin in cartridges is stable for up to 4 weeks once opened if stored at
25 degrees C. “ Brief exposure” to temperature extremes may not reduce the efficacy of insulin
but the company suggests that if the temperature ranges are exceeded, people “should consider
discarding…” the insulin. In this regard, it seems obvious that repeated exposures to high
temperatures without refrigeration will only accelerate the degradation of insulin efficacy. Novo
Nordisk gives the following permitted exposure times for various temperatures. ii
Insulin preparations should not be exposed to temperatures between:
 -20 to –10 degees C for more than 15 minutes
 -10 to –5 degrees C for more than 30 minutes
 -5 to +2 degrees C for more than 2 hours
v
See Insulin Dependent Diabetes Trust International, at www.iddtinternational.org, last accessed 28 April 2004.
6.4-21
Chapter 6.4: Diabetes




8 to 15 degrees C for more than 96 hours
15 to 30 degrees C for more than 48 hours
30 to 40 degrees C for more than 6 hours
Insulin should never be stored above 40 degrees C.
Creation of a truly heat-stable form of insulin ( i.e., capable of being stored above 15 degrees C
for periods), would be a major advance in treatment. The lack of “cold chain” capabilities in
many developing countries lends some urgency in dealing with this pharmacological gap in
diabetes treatment.
7.
What is the current “pipeline” of products that are to be used for
this particular condition?
Clinical trials databases probably provide the most up to date and reliable information in this
regard. Annual reports of pharmaceutical companies are written for investors. We reviewed
information on US clinical trials on the NIH website devoted to clinical trials
(http://www.clinicaltrials.gov) using the search term “diabetes”. 79 We found 456 studies of all
types (behavioral interventions, studies of risk factors, head to head comparative trials,
transplantation trials, studies on obesity, glucose monitors, pharmaceutical interventions, trials
relating to neuropathies, nephropathies and so on). Table 6.4.6 summarizes 42 trials dedicated
to testing pharmaceutical interventions. Annex 6.4 Table 1 has more information on this dataset
along with information on the nature of the therapeutics under trial. The chemical entities tested
in these clinical trials are often given cryptic company designations so it is often impossible to
determine the nature of the tested compound. Nevertheless, certain of these compounds and
their mode of action are already known (Table 6.4.7).
Phase
I (8)
II (20)
III (12)
Table 6.4.6: USA Diabetes Clinical Trials
Type 1
Type 2
5 (62%)
2 (25%)
10 (50%)
9 (45%)
5 (42%)
5 (42%)
IV (2)
1 (50%)
Other
1 Neuropathy
1 LADA
1 Gestational
1 Neuropathy
1 (50%)
Table 6.4.7: Selected Pharmacological Interventions for Diabetes Under Development
Class
Mechanism of Action
Morpholinoguanidines
Glucose dependent release of endogenous insulin from
beta cells
80
Imidazolines
Blockage of inhibition of endogenous insulin release
Phophodiesterase inhibitors81
Releases endogenous insulin
Succinate esters82
Enhances release of endogenous insulin
83
D chiro inositol
Improves insulin signalling in target tissues
Alpha lipoic acid 84
Increases glucose uptake
Glucagon like peptides-1 (GLP-1)
Enhances endogenous insulin release
Exendin-4 (GLP-1 homolog)
Amylin agonists
Enhances endogenous insulin release
85
Vanadium salts
Insulin mimetic
Dipeptidyl peptidase
(DPP4 inhibitors)
inhibitors
Inhibition in vivo stabilizes important enzymes and
peptides involved in maintaining blood glucose
6.4-22
Chapter 6.4: Diabetes
There are many companies involved in research and development of diabetes medicines.
Amylin Pharmaceuticals
Boehringer Ingelheim GmbH
Hoffmann La Rocher LTd.
Eli Lilly Company
Novartis Pharma AG
Pfizer Inc
Fujisawa Healthcare
Aventis
Bristol Myers Squibb
GlaxoSmithKline plc
Merck
Novo Nordisk
Sanofi Synthelabo
Proctor and Gamble
Bayer AG
Calyx Therapeutics
Inhale Therapeutics
Metabolex Inc
Peptor Corporation
Takeda Industries
Endotherapeutics
Annex 6.4 A summarizes the available information (as of late 2003 and early 2004) on the
“pipelines” of some of the above-identified companies.
8.
What is the Current Status of Institutions and Human Resources
Available to Address the Disease?
8.1
Public Funding
Overall, there is an imbalance between the severity and magnitude of diabetes and the amount
of money spent on research. Between 1986 and 2001, the UK “equivalent “ of the NIH, the
Medical Research Council (MRC) increased their total annual research spending from 0.5 to
about 2.5 billion USD (about € 0.4 to €2 billion (Annex 6.4 Figure 3) . These calculations take into
account annual changes in exchange rate. Scaled to the total UK population, per capita annual
MRC expenditure for all biomedical research has doubled over this same time period from about
$3 to about $8 USD per person (€2.5 to €6.5 per person) (Annex 6.4 Figure 3) but we cannot
determine the amount relegated to diabetes research.
The United States provides the most public funding for diabetes research. Annual governmental
appropriations to selected centers in the National Institutes of Health (NIH) are shown in Annex
6.4 Figure 1. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is
the lead governmental agency at the NIH for diabetes. The NIDDK received about 1.5 billion
USD (about €1.2 billion) last year, although it is clear that not all of this went to diabetes
research. Scaled to the total US population, per capita NIDDK appropriation has doubled over
this same time period from about 2 to about 4 USD per person (Annex 6.4 Figure 2). When
scaled to the number of US Type 2 people with diabetes (about 16 million in ages 20-79 in 2002),
the annual per capita NIDDK appropriation is from about 75 to about 90 USD (€61-€73) per
person (years 2000-2002). The combined efforts of major private agencies, most notably the
Juvenile Diabetes Foundation (http://www.jdrf.org) have resulted in an increase in money
specifically spent on diabetes. vi
European resources directed to diabetes are also difficult to quantify but, in our view, the
imbalance is even more pronounced than in the United States. Targeted research for diabetes
exists, but the funding levels are low. In 2001, the European Foundation for the Study of
Diabetes (EFSD: http://www.easd.org) announced a new funding program in Europe in
partnership with Novo Nordisk and the Juvenile Diabetes Foundation International.86 Grants are
funded though the EFSD which has a budget of around 12 million Euros over a 3 year period. 87
Recently, the EFSD and Johnson & Johnson established a new research program into Type 2
diabetes. Between 2002 and 2004, grants of 1 million Euros are to be awarded. Other awards and
the monies involved can be found in Annex 6.4 Table 2.
Recently, the JDRF and the Australian government established a joint effort to evaluate and fund a number of
immunological vaccine therapies for preventing or delaying progress of Type 1 diabetes. The total amount of funding
over a three year period is about $10 million Australian dollars.
vi
6.4-23
Chapter 6.4: Diabetes
The Fifth Framework Programmes (1992-2002) have funded specific programs related to
diabetes. The total funding per year is over 6 million Euros. See Annex 6.4 Table 3.
The European Commission has made diabetes research a priority in the Sixth Framework
Programme as well as in the new Public Health program. 88 The entire funding for the 6th
Framework is at least 1 billion Euros per year over 4 years. One theme of the 6 th Framework is
directed towards investigating genomic approaches for combating various disease, including
diabetes. Exact allocations are not known to us, but the initial budget for genomic research
within the 6th Framework totals about 200 million € (spread over 4 years). 89 Negotiations within
the EU are ongoing for several other projects whose end results may impact diabetes research. In
April 2004, the European Commission awarded 24 institutions nearly 12 million Euros over 5
years to perform an extensive research project on obesity and type 2 diabetes.91 Some other,
still as yet unfunded, projects within the 6th Framework that may be relevant are listed below
1. European Consortium for Stem Cell Research : This project comprises preclinical studies on
embryonic (non-human), fetal and adult stem cells wih potential to differentiate into cell lines
with neural, mesodermal, or epithelial characteristics.
2. Genetics for Healthy Aging The aim of the project is to identify genes involved in healthy
ageing and longevity.
3. Novel approaches to autoimmune diseases: The project targets the restoration of central selftolerance in the thymus. The project would concentrate on type 1 diabetes as a model of
autoimmune disease.
4. Identification of risk genes for atherothrombosis in coronary artery disease : The project will
generate population genetics data that will provide information on the cause of CVD and
atherotrombosis though the identification of genes and gene variants.
8.2
Private Sector Funding
Not only is there an imbalance between the severity and magnitude of diabetes and the amount
of money spent on research, there is a large gap between diabetes prevalence and treatment
rates as many people with diabetes go undiagnosed. Even without accounting for undiagnosed
disease, diabetes costs the UK’s National Health Service 5.5 - 9.4% of its total annual budget.
The commercial market for diabetes therapeutics will ensure that there will be no shortage of
private research funding for the immediate future. The annual market for agents to treat type
2 diabetes is, depending on the analyst, between about $7 to 12 billion in 2003. Various market
research analyses indicate that this market could nearly double within ten years. vii
“Global diabetes market grows”, at www.ims-global.com/insight/news; “Diabetes market overview” at
www.researchandmarkets.com; “Diabetes Market Overview”, at www.researchandmarkets.com, all accessed 28 April
2004.
vii
6.4-24
Chapter 6.4: Diabetes
Table 6.4.8: Worldwide Diabetes Market, through 2007 ($ Millions)
2000
2001
2002
2007
Annual Adjusted
Growth Rate%
2002-2007
Diabetes drugs
9,694
11,714
12,482
16,959
6.3
Glucose monitors
3,276
3,743
4,735
8,072
11.3
543
637
749
1,781
18.9
13,513
16,094
17,966
26,812
8.3
Insulin pumps
Total
Data from Business Communications Company, Inc. (www.bccresearch.com) RB-158 Diabetes
Therapies and Diagnostics: Markets, Technologies, Players,
The oral antidiabetic market will probably exhibit the greatest increase in growth, with the US
market being the main driver. The epidemiologic and clinical reasons for the increase in the
oral antidiabetic market may well be the increase in obesity and Type 2 diabetes on a global
scale, the overall inadequate care in terms of glycemia, and the need to reduce cardiovascular
and other complications in Type 2 people with diabetes. All these reasons clearly present a
medical need and therefore pharmaceutical "gaps" still exist which will remain targets for
drug development.
On a global scale, oral antidiabetic sales are currently worth more than double that of human
insulins and analogues. However, this is largely due to US market dominance - most of the
European countries are exhibiting greater growth and sales in human insulins and analogues
than oral antidiabetics.
There are three major producers of insulin—Eli Lilly, Novo Nordisk, and Aventis (with Pfizer).
Novo Nordisk and Aventis are European-based so there is a significant contribution already to
the diabetes field by European industry.
Given the size of the market, the industry almost certainly recognizes that managing diabetes
will require management of cardiac risk factors such as: better physician and patient education,
improved diagnostic techniques, improved patient compliance with lifestyle modification and
drug therapy, and agents that lower triglycerides (TGs) and increase HDL.
9.
Ways Forward from a Public Health Viewpoint with Regard to
Public Funding
In principle, areas for public funding of diabetes research with regard to pharmaceutical R&D
should initially be aligned with the overall goals of Framework 6 and should be directed to areas
that the pharmaceutical industry may not presently be tackling.
9.1
Gaps between current research and potential research issues which could
make a difference.
6.4-25
Chapter 6.4: Diabetes
Gaps in Basic and Applied Research
A. TYPE 1 Diabetes

Studying the natural history of pancreatic immune cells is an important basic research
goal because it represents our best chance of deciphering the underlying disease process
of Type 1 diabetes.

We need disease markers that represent islet-damaging or islet-protective events, such as
numbers and phenotype of circulating islet reactive immune cells. This is especially
important for clinical trials, for prevention or cure of Type 1 diabetes. 92 93 For example,
surrogate markers may enable identification of transplant rejection at the very earliest
stages so that it can be successfully treated. Good surrogate markers could identify
diabetic patients suitable for clinical trials and can be used to follow the course of disease
and test the effectiveness of therapies.
B. TYPE 2 Diabetes

Better animal models representative of human Type 2 diabetes are needed. Development
of atherosclerosis is rare in rodents so small and large animal models of diabetic
complications are required.

We need innovative, non-analgesic therapeutics to reverse or halt nerve damage in
diabetic neuropathies

There ought to be more emphasis on geriatric trials. Much of the large effectiveness
studies in diabetes are conducted among middle-aged populations, and few RCTs have
examined the effect of interventions on cognitive or functional decline.

We lack comparative clinical trials of existing diabetes treatments as they are not
mandated by the existing regulatory framework (See Section 9.2)
C. Drugs for prevention of specific complications
 ACE inhibitors for nephropathy are needed
 We need more rigorous control of lipids with new generation statins
 Research is needed on use of fixed dose combinations for cross risk factors (e.g
“polypill”)
 We need more research and development on nerve growth agonists for neuropathies
D. Islet transplantation
 More research into use of stem cells is needed
 Islet cell xenotransplantation (use of beta cells from a different species)
 Encapsulation methods for beta cells
Overall, we need methods for regeneration of beta cells and stimulation of their growth as,
aside from the obvious clinical benefit, there exists a great disparity between supply and
demand for pancreatic islet harvesting. We need continued development of more specific
and targeted methods for immunoprotection of transplanted cells.
6.4-26
Chapter 6.4: Diabetes
9.2
Comparative Clinical Trials of Existing Diabetes Treatments
New drugs are mainly tested for efficacy and safety against placebo. This results in, as one
review stated, “ … an increasingly long list of products approved for marketing, all with some
proof to be active when compared to placebo” 94 , but with no real way that physicians or
patients can make informed choices about which drug is better, safer or more cost effective than
another. What is lacking are comparative trials and ways of comparing different drugs. Drugs
shown to work better than placebo might actually be inferior to other drugs for the same
indication. In reviewing the future R&D needs as outlined below, we need to bear in mind that
if a new drug is no better than existing ones, the current regulatory and R&D system effectively
allows companies to sell the drug even under these conditions. There are few incentives for the
private sector to undertake such trials. However, from a public health and reimbursement
authority perspective, such trials would be very useful and public funds should be expended on
such trials which should include full pharmacoeconomic analyses considering such things as
hospital admissions (since they are among the major total healthcare costs of diabetes). See
Chapter 8.4


9.3
An infrastructure should be created to facilitate diabetes clinical trials. This need is
especially pressing in diabetes research in which clinical trials to “hard end points” may
take many years and even decades, and where clinical trials are established de novo,
requiring a tremendous input of energy and resources. A diabetes trial network could
provide a stable infrastructure for the long-term and complex clinical trials required for
the study of diabetes. It is important to develop and maintain an informational registry
of patients for study and perform clinical trials in diabetes and its complications.
Comparative clinical head to head trials to compare efficacy, side effects and cost
effectiveness is required using full pharmacoeconomic analyses.
Comparative Advantage of the EU
Those issues best aligned with existing goals of the EU are best suited to the comparative
advantage of the EU. From a “market” viewpoint, the U.S. seems to be focussing on non-insulin
oral antidiabetic medicines. In our view, the European Union comparative advantage lies in its
particular expertise in insulin pump technology and in developing and using new insulin
formulations, and new insulin delivery systems. With these limits in mind, Table 6.4.9 presents
our recommendations for such therapeutic innovations.
Table 6.4.9.
Insulin/insulin analogues with improved pharmacokinetics /delivery mechanisms
Long term action
Heat stable insulin
Fewer side effects (e.g., hypoglycemia)
Continuous glucose-monitoring devices
Measurement in real time
Non-invasive or minimally invasive
Closed loop Glucose monitors
Data download to physician via web
9.4
Delivery of Care
Since we are concentrating on pharmaceutical interventions, we have not reviewed research on
delivery of care to diabetic patients, although this is clearly of critical importance in its overall
public health context. Indeed, diabetes care already accounts for substantial proportions of the
total national health care budgets of western European countries. In particular, controlling the
epidemic of Type 2 diabetes will require changes to the structure of healthcare delivery and
6.4-27
Chapter 6.4: Diabetes
interventions coordinated between all levels of government, health care agencies,
multidisciplinary health care teams, professional organisations, and patient advocacy groups
are needed.
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