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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

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Table of ContentsExecutive Summary...............................................................................................31. Introduction...................................................................................................52. What Are the Epidemiological Trends for Europe and the World?...............83. What is the Control Strategy?.....................................................................134. What is Known of the Affordability, Feasibility, and Sustainability of

the Control Strategy?..................................................................................145. Why Does the Disease Burden Persist?.......................................................156. What Can Be Learnt from Past/Current Research into Pharmaceutical

Interventions for this Condition?.................................................................177. What is the current “pipeline” of products that are to be used for this

particular condition?...................................................................................228. What is the Current Status of Institutions and Human Resources

Available to Address the Disease?...............................................................239. Ways Forward from a Public Health Viewpoint with Regard to Public

Funding........................................................................................................25Endnotes..............................................................................................................28

Annexes

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http://mednet3.who.int/prioritymeds/report/annexes/diabetes_annexes.doc


Executive SummaryBurden of DiseaseDiabetes 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 DiabetesPersons 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.

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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.

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 actionHeat stable insulinFewer side effects (e.g., hypoglycemia)

Continuous glucose-monitoring devicesMeasurement in real timeNon-invasive or minimally invasiveClosed loop Glucose monitorsData download to physician via web

Drugs for prevention of specific complicationsACE inhibitors for nephropathyRigorous control of lipids with new generation statinsFixed dose combinations for cross risk factors (e.g “polypill”)Nerve growth agonists for neuropathies

Islet transplantationStem cellsIslet 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

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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.

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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;

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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.

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1.1 Types of DiabetesThere 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 insulin-dependent 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

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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.

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Figure 6.4.1: Type 1 Diabetes Incidence per 100000 persons per year

Type 1 Diabetes (Incidence per 100000) (year 2000)

0 10 20 30 40 50

ChinaTaiwan

IndonesiaJapan

ThailandJordan

BangladeshIndia

Sri LankaPoland

EgyptLithuaniaSlovenia

FranceSlovakiaGreece

Czech RepublicHungary

ItalyAustriaCyprusEstoniaBelgium

LuxembourgSpain

PortugalAustraliaGermany

NetherlandsMalta

New ZealandIreland,

DenmarkUSA

United KingdomSwedenFinland

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

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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

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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 age-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)

DM PrevalenceNumber of people with DM (000's) in

the 20-79 age-group

Total DM Prevalence per 1000 persons

CountryPopulation (20-

79) (000's)

% Age group Male Female Total in specified

age groups

Austria 6,041 3.8 20-79 99.9 132.4 232.3 38Belgium 7,458 4.1 20-79 135.3 172 307.4 41Cyprus 518 4.9 20-79 11.3 14 25.3 49Czech Republic 7,624 11.7 * all 890.5 117Denmark 3,853 6.2 * 60-74 561.7 146Estonia 1,014 4.5 20-79 18 27.6 45.6 45Finland 3,731 5.5 * 45-64 158.7 43France 41,927 4.0 20-79 729.8 926.9 1,656.80 40Germany 61,874 4.2 20-79 1,133.20 1,466.8

02,600.00

42Greece 7,991 5.9 20-79 209.7 258.5 468.2 59Hungary 7,431 6.6 20-79 203.2 288.2 491.5 66Ireland, Republic of 2,514 3.2 20-79 36.2 44 80.2 32Italy 43,910 7.1 20-79 1,452.90 1,672.4

03,125.40

71Lithuania 2,603 3.2* all 84.1 32Luxembourg 316 3.8 20-79 5.4 6.7 12.1 38Malta 273 9.9 35-69 20.8 76Netherlands 11,494 3.6 20-79 192.8 223.1 415.9 36Poland 27,136 5.7 20-79 659.2 897.9 1,557.10 57Portugal 7,309 5.4 20-79 167.9 229 397 54

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Slovakia 3,784 8.6* all 324.7 86Slovenia 1,486 8.0* all 119.5 80Spain 29,899 6.1* 10 to 74 2,018.30 68Sweden 6,341 6.4* all 570.3 90United Kingdom 41,638 3.5 20-79 646.4 820.4 1,466.80 35

Total328,165 5.4 5,701.20 7,179.9

017,630.

20 54* = crude value

Source: Diabetes Atlas, International Diabetes Federation

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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)

0.0

2.0

4.0

6.0

8.0

10.0

12.0

0-4 5-14 15-29 30-44 45-59 60-69 70-79 80+

EU10 -M

EU15 F

World- M, F

EU10-F

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 diabetesType 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

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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.

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.

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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 elderlyThere 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 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 womenPopulations 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

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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.

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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 2Environmental 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 non-insulin analogues should be the primary control agents.3.3 Reducing mortality and morbidity by dealing with co risk factorsIf 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 factorsStrategy BenefitGlycemic control Reduces microvascular diseaseBlood pressure control Reduces macro/micro vascular eventsLipid Control Reduces coronary events/mortalityAspirin use Reduces myocardial infarctionACE 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

6.4-18


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 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 anti-hypertensives 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 BurdenThe 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

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http://mednet3.who.int/prioritymeds/report/FinalRep/CardioREPFIN.doc


4.2 Feasibility of Control StrategyPrimary 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

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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.

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5.2 Type 2

Type 2 persists because there is no cure or preventative agentDiabetes 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 concernAlthough 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 agents60. 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 countriesThis 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 ii 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;

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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 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.

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Table 6.4.4: Non insulin therapeutics

Therapeutic

SulphonylureasChlorpropamide,acetohexamide, tolazamide, tolbutamideglibenclamide/glyburindeglipizide/glimepiridegliclazide

MeglinitidesRepaglinide (Prandin, NovoNorm)Nateglinide (Starlix, Novartis/Yamanouchi/Aventis Starsis, Fastis)Mitiglinide Servier Phase d-phenyalanine derivativenateglinide

Biguanides (e..g., Metformin)(Glucophage tm USA)

ThiazolidinedionesRosiglitazone (Avandia®)Pioglitazone (Actos®)

Alpha glucosidase inhibitorsAcarbose®

Benefits

Optimal efficacy in early stages

Less risk of hypoglycemia than insulin or sulphonylureas

Faster onset than sulphonylureas

Minimal risk ofHypoglycaemia; weight neutral

Useful in limiting postprandial spike in blood glucose; few side effects

Harms

Long term use may desensitise beta cells: weight gain.

Hypoglycemia; multiple daily doses required

GI disturbancesWeight gainedema

GI disturbances

Comments

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

Useful in limiting postprandial spike inglood glucose

Little weight gain is a benefit for cardiovascular outcomes

Monitoring liver functionrequired- troglitazone was removed from the market due to effects on liver

Beneficial effects on serum triglycerides

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 diabetes-today’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.

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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 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: InsulinsTherapeuticHuman or recombinant human Insulin

Intermediate acting insulinNPHLente Insulin

Long acting insulin analoguesInsulin glargine (Aventis)

Insulin detemir (LevemirTM: Novo Nordisk

Fast acting insulin analoguesInsulin Lispro (Eli Lilly)Insulin Aspart (Novo Nordisk)

Biphasic insulin analogues

CommentsRarely achieves tight and long term control over glucose

Does not mimic basal insulin secretion

Approved in EU and Switzerland. Little weight gain observed in trials

Lispro: reversing amino acid 28/29 in B chainAspart: replacing proline at position B28

Insulin analogues+human insulin NPH

Long term effects of insulin on lung tissue not clear, no pulmonary insulins commercially

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Pulmonary delivered insulin

available yet

6.2 Alternate delivery methods are possible6.2.1 Inhalation TherapyTo 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 long-term 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

iii Amiel SA &Alberti KGMM, 2004, Inhaled insulin: May prove to be a panacea, BMJ 2004;328:1215-1216

iv Zamanini A, Newson RB, Maisey M, Feher MD. Injection related anxiety in insulin treated diabetes. Diab Res Clin Pract 1999:46: 239-46

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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 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 TransplantationPancreatic 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 insulin-requiring 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

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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 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).

Table 6.4.6: USA Diabetes Clinical Trials Phase Type 1 Type 2 Other

v See Insulin Dependent Diabetes Trust International, at www.iddtinternational.org, last accessed 28 April 2004.

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http://www.clinicaltrials.gov/

http://www.iddtinternational.org/


I (8) 5 (62%) 2 (25%) 1 NeuropathyII (20) 10 (50%) 9 (45%) 1 LADAIII (12) 5 (42%) 5 (42%) 1 Gestational

1 NeuropathyIV (2) 1 (50%) 1 (50%)

Table 6.4.7: Selected Pharmacological Interventions for Diabetes Under Development

Class Mechanism of ActionMorpholinoguanidines Glucose dependent release of endogenous

insulin from beta cellsImidazolines80 Blockage of inhibition of endogenous insulin

releasePhophodiesterase inhibitors81 Releases endogenous insulin Succinate esters82 Enhances release of endogenous insulinD chiro inositol83 Improves insulin signalling in target tissuesAlpha lipoic acid 84 Increases glucose uptakeGlucagon like peptides-1 (GLP-1)Exendin-4 (GLP-1 homolog)

Enhances endogenous insulin release

Amylin agonists Enhances endogenous insulin releaseVanadium salts 85

Dipeptidyl peptidase inhibitors (DPP4 inhibitors)

Insulin mimetic

Inhibition in vivo stabilizes important enzymes and peptides involved in maintaining blood glucose

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There are many companies involved in research and development of diabetes medicines.

Amylin Pharmaceuticals Aventis Bayer AGBoehringer Ingelheim GmbH Bristol Myers Squibb

Calyx TherapeuticsHoffmann La Rocher LTd. GlaxoSmithKline plc

Inhale TherapeuticsEli Lilly Company Merck Metabolex IncNovartis Pharma AG Novo Nordisk

Peptor CorporationPfizer Inc Sanofi Synthelabo Takeda IndustriesFujisawa Healthcare Proctor and Gamble

EndotherapeuticsAnnex 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 FundingOverall, 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

vi 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.

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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.

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 6th 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 self-tolerance 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 FundingNot 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.

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http://www.easd.org/


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

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.

1 Venkat Narayan KM, EW Gregg, A Fagot-Campagna, MM Engelgau and F. Vinicor, 2000, Diabetes-a common, growing, serious, costly and potentially preventable public health problem, Diabetes Res. and Clinical Practice, 50:S77-S84.).

2 Wingard, DC, Barrett-Connor, E., 1995. Heart disease and diabetes. In Diabetes in America, NIH Publication 95-1468, 429-448).

3 Shepard, J., 2002, Diabetes in tomorrow’s world: dark clouds do have silver linings, Diabetes, Obesity and Metabolism, 4: 351-355).

4 Devasenan D, Liu E, Eisenbarth GS, 2004, BMJ 328: 750-754

5 Atkinson, MA, Eisenbarth GS, 2001, Type 1 diabetes: new perspectives on disease pathogenesis and Treatment, Lancet, 358: 222-229.

6 Zimmet P, Alberti KG, Shaw J. 2001 Global and Societal implications of the diabetes epidemic. Nature 414: 782–87.

7 Amos, AF, McCarty DJ, Zimmet P., 1997. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet. Med., 14: S1-85.

8 Alberti, KGMM. 2001. Treating type 2 diabetes- today’s targets, tomorrow’s goals., Diabetes, Obesity and Metabolism 3: S3-S10.

9 American Diabetes Association, 2003, Treatment of Hypertension in Adults with Diabetes, Diabetes Care, 26: S80-S82.

10 Diabetes Atlas, Second Edition, 2003, International Diabetes Federation.

11 Harris MI, Hadden WC, Knowler WC, Bennet PH. 1987 Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in US population aged 20–74 years. Diabetes 36: 523–34.

12 Kramers P. 2001, Design for a set of European Community Health Indicators. Report of the ECHI Project. Bilthoven: Netherlands Institute of Public Health (RIVM).

13 Fleming DM, Schellevis FG, Van Casteren V. 2004. The prevalence of known diabetes in eight European countries Eur. J. Public Health, 14: 10-14.

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http://www.researchandmarkets.com/

http://www.researchandmarkets.com/

http://www.ims-global.com/insight/news


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

14 Onkamo P, Vonnen S, Karvonen M, Tuomilehto J. 1999. Worldwide increase in incidence of Type 1 diabetes - the analysis of the data on published incidence trends. Diabetologia 42: 1395–1403.

15 LaPorte RE, Tajima N, Kerblom HK, et al. 1985. Geographic differences in the risk of insulin-dependent diabetes mellitus: the importance of registries. Diabetes Care; 8 (suppl 1): S101–07.

16 Anonymous. EURODIAB ACE Study Group. 2000. Variation and trends in incidence of childhood diabetes in Europe. Lancet; 355: 873–76.

17 Green A, Gale EA, Patterson CC, for the EURODIAB ACE study. 1992. Incidence of childhood-onset insulin-dependent diabetes mellitus: the EURODIAB ACE study. Lancet; 339: 905–09.

18 Chockalingam A., 2000. Cardiovascular diseases: India. Let’s not make the same mistakes again. Lancet Perspectives: 356: S9.

19 Zimmet, PZ, Alberti KGMM, 1997. The changing face of macrovascular disease in NIKKM. An epidemic in progress, Lancet 350: 1-4

20 Zimmet, PZ, McCarty D., 1995. The NIDDM epidemic: Global estimates and projection- a look into the crystal ball. Int. Diabetes Fed. Bull., 40: 8-16:

21 Rosenbloom A, Joe J, Young R, Winter W. 1999. Emerging epidemic of type 2 diabetes in youth. Diabetes Care; 22: 345–54.

22 Mokdad AH, Ford ES, Bowman BA, et al. 2000. Diabetes trends in the US:1990–1998. Diabetes Care; 23: 1278–83.

23 Ludwig DS, Ebbeling CB. 2001. Type 2 diabetes mellitus in children:primary care and public health considerations. JAMA; 286:1427–30.

24 Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. 2000. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr; 136: 664–72.

25 . Ebbeling CB, Pawlak DB, Ludwig DS. 2002, Childhood obesity: public-health crisis, common sense cure, Lancet 360: 473–82.

26 Ratnakant, S., ME Ochs, SS Solomon, 2003, Sounding Board: diabetes mellitus in the elderly: a truly heterogenous entity?, Diabetes, Obesity and Metabolism, 5: 81-92.

27 Smith NL et al., 1999. Antidiabetic treatment trends in a cohort of elderly people with diabetes. The Cardiovascular Health Study 1989-1997, Diabetes Care 22: 736-742).

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Glucose monitors 3,276 3,743 4,735 8,072 11.3

Insulin pumps 543 637 749 1,781 18.9

Total 13,513

16,094

17,966

26,812

8.3

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.28 Stolk RP et al., 1997. Insulin and cognitive function in an elderly population, The Torrerdam Study, Diabetes Care 20: 792-795

29 Gregg EW, Engelgau ME, Narayan KMV: 2002. Cognitive decline, physical disability, and other unappreciated outcomes of diabetes and aging (Editorial). BMJ 325:916–917.

30 Strachan MWJ, Frier BM, Deary IJ: 2003. Type 2 diabetes and cognitive impairment. Diabet Med 20:1–2.

31 Nathan DM: 1993. Long-term complications of diabetes mellitus. N Engl J Med 328:1676–1685.

32 Gregg EW,Yaffe K, Cauley JA, Rolka DB, Blackwell TL, Narayan KMV, Cummings SR: 2000. Is diabetes associated with cognitive impairment and cognitive decline among older women? Arch. Intern Med 160:174–180.

33 Fontbonne A, Berr C, Ducimetiere P, Alperovitch A: 2001. Changes in cognitive abilities over a 4- year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study. Diabetes Care 24:366– 370.

34 Sinclair AJ, Girling AJ, Bayer AJ. 2000. Cognitive dysfunction in older subjects with diabetes mellitus: impact on diabetes self-management and use of care services. Diabetes Res Clin Pract 50: 203–12.

35 D Liolitsa, J Powell, S Lovestone, 2002, Genetic variability in the insulin signalling pathway maycontribute to the risk of late onset Alzheimer’s disease, J Neurol Neurosurg Psychiatry; 73:261–266

36 Messier, C.Diabetes, 2003, Alzheimer's disease and apolipoprotein genotype, Experimental Gerontology, 38: 941-946.

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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.

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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

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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.

9.2 Comparative Clinical Trials of Existing Diabetes TreatmentsNew 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 37 WHO Ad Hoc Diabetes Reporting Group. 1992. Diabetes and impaired glucose tolerance in women aged 20–39 years. World Health Stat Q 45: 321–27.

38 Pettitt DJ, Knowler WC, Baird HR, Bennett PH. 1980. Gestational diabetes:infant and maternal complications of pregnancy in relation to thirdtrimesterglucose tolerance in the Pima Indians. Diabetes Care 3:458–64.

39 Omori Y, Minei S, Testuo T, et al. 1994. Current status of pregnancy in diabetic women: a comparison of pregnancy in IDDM and NIDDM mothers. Diabetes Res Clin Pract; 24 (suppl): S273–78.

40 Dabelea D, Hanson RL, Lindsay RS, et al. 2000. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 49: 2208–11.

41 Feig DS, Palda VA. 2002. Type 2 diabetes in pregnancy: a growing concern Lancet 359: 1690–92.

42 Kanaya AM, Grady D, Barrett-Connor E., 2002. Explaining the sex difference in coronary heart disease mortality among patients with type 2 diabetes mellitus. A meta-analysis. Arch Intern Med 162: 1737–45.

43 Pan XR, Li GW, Hu YH et al. 1997. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 20(4): 537–44.

44 Buchanan TA, Xiang AH, Peters RK et al. 2002. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 51(9): 2796–803.

45 Chiasson JL, Josse RG, Leiter LA et al. 1996. The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance. Diabetes Care 19(11): 1190–3.

46 Tuomilehto J, Lindstrom J, Eriksson JG et al. 2001. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344(18): 1343–50.

47 Knowler WC, Barrett-Connor E, Fowler SE et al. 2002. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 346(6): 393–403.

48 Eriksson KF, Lindgarde F. 1991. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise: the 6-year Malmö feasibility study. Diabetologia 34: 891–8.

49 Bloomgarden ZT. 2003. Cardiovascular Disease and Diabetes, Diabetes Care, 26: 230-237.

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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

50 American Diabetes Assocation, 2003. Management of Dyslipidemia in Adults With Diabetes Diabetes Care, 26: S80-S82.

51 Wald NJ and Law MR. 2003. A strategy to reduce cardiovascular disease by greater than 80%. BMJ 326: 1419-1424.

52 Jonsson B., 2002, Revealing the cost of Type II diabetes in Europe, Diabetologia, 1-14.

53 Schmitt-Koopmann, M. Schwenkglenks, G. A. Spinas, T. D. Szucs, 2004, Direct medical costs of type 2 diabetes and its complications in Switzerland , Eur. J. Public Health, 14: 3-9.

54 American Diabetes Assocation. 1998. Economic consequences of diabetes mellitus in the U.S. in 1997. Diabetes Care. 21: 296-309

55 McKinlay J., Marceau L. 2000. US public health and the 21st century: diabetes mellitus, Lancet 356: 757-761,

56 Ghaffar A, Srinath Reddy K, Singhi M. 2004. Burden of non-communicable diseases in South Asia, , BMJ 328: 807-810.

57 Basnyat, B & Chandika Rajapaksa, L. 2004. Cardiovascular and infectious diseases in South Asia: the double whammy, BMJ 328: 781.58 Couzin J., 2003, Diabetes’ Brave New World, Science 300:1862-1865, available at www.sciencemag.org, last accessed 12 March 2004

59 Cox DJ, Gonder-Frederick LA, Julian DM, Clarke WE 1993. Long-term follow-up evaluation of blood glucose awareness training. Diabetes Care; 17: 1-5.

60 Charbonnel B, Grimaldi A, Detournay D et al. ECODIA. 1999. Prise en charge du diabète de type 2 en France. Ann Endocrinol; 60: 274 (A).

61 McLarty DG, Swai ABM, Alberti KGMM. 1994. Insulin availability in Africa: an insoluble problem? Int Diab Dig; 5: 15–17.

62 Savage A. 1994. The insulin dilemma: a survey of insulin treatment in the tropics. Int Diab Dig; 5: 19–20.

63 Deeb LC, Tan MH, Alberti KGMM. 1994. Insulin availability among International Diabetes Federation member associations. Diab Care; 17: 220–223.

64 Diabetes Epidemiology Research International Study Group. 1992. Childhood diabetes, insulin, and Africa. Diabet Med; 9: 571–73.

65 Castle W, Wicks A. 1980. A follow-up of 93 newly diagnosed African diabetics for 6 years. Diabetologia; 18: 121–23.

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analyses considering such things as hospital admissions (since they are among the major total healthcare costs of diabetes). See Chapter 8.4

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.

66 Yudkin JS. 1999. Tanzania–still optimistic after all these years? Lancet; 353: 1519–21.

67 Chale SS, Swai ABM, Mujinja PGM, McLarty DG. 1992. Must diabetes be a fatal disease in Africa? Study of costs of treatment. BM, 304: 1215-1218.

68 Yudkin JS. 2000. Insulin for the world’s poorest countries, Lancet 355: 919–21.

69 King H, Roglic G. 1999. Global status of diabetes, and recommendations for international action. Int Diabetes Monitor; IFDOR special issue: 38-45.

70 Owens DR, Zinman B., Bolli GB. 2001. Insulins today and beyond Lancet 358: 739–46.

71 Harsch IA, Eckhart GH, Konturek PC. 2001. Syringe, pen, inhaler- the evolution of insulin therapy. Med Sci Monit, 7(4): 833-836 72 Pickup J, Keen J. 2002. Continuous Subcutaneous Insulin Infusion at 25 Years Evidence base for the expanding use of insulin pump therapy in type 1 diabetes, Diabetes Care 25: 593–598.

73 Rohrscheib, M., Robinson, R. Eaton, RP. 2003. Non-invasive glucose sensors and improved informatics-the future of diabetes management, Diabetes, Obesity and Metabolism, 5:280-284.

74 Coon B, An LL, Whitton JL, von Herrath MG. 1999. DNA immunization to prevent autoimmune diabetes. J Clin Invest 1999;104:18994.

75 Von Herrath MG, Whitton JL. 2000. DNA vaccination to treat autoimmune diabetes. Ann Med ;32:28592.

76 Owens DR. Zinman B, Bolli G. 2003. Alternative routes of insulin delivery, Diabet. Med. 20, 886–898.

77 Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. 2000. Islet transplanation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343:230–238.

78 American Diabetes Association. 2003. Insulin Administration, Diabetes Care 26: S1-S124.

79 National Institutes of Health, National Library of Medicine, www.clinicaltrials.gov, last accessed 21 April 2004.

80 Efanov, AM, Zaitsev, SV, Mest, H-J et al., 2001. The novel imidazoline compound BL11282 potentiates glucose induced insulin secretion in pancreatic beta cells in the

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Comparative clinical head to head trials to compare efficacy, side effects and cost effectiveness is required using full pharmacoeconomic analyses.

9.3 Comparative Advantage of the EUThose 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 actionHeat stable insulin

absence of modulation of KATP channel activity, Diabetes 50: 797-802

81 Sano R, Miki T, Suzuki, Y. et al., 2001. Analysis of the insulin sensitive phosphodiesterase 3B gene in type 2 diabetes, Diabetes Res. Clin. Pract., 54: 79-88.

82 Fahien, LA & MacDonald, MJ, 2002, The Succinate Mechanism of Insulin Release, Diabetes 51: 2669-2676

83 Baumgartner, JW, 2003, SHIP2: an emerging target for treatment of Type 2 diabetes mellitus, Curr. Drug Targets, 3:291-298.

84 Bernkop-Schnurch, Reich-Rohrwig E., Marschutz, M. et al., 2004, Development of a sustained release dosage form for alpha lipoic acid.II. Evaluation in human volunteers, Drug. Dev. Ind. Pharm., 30: 35-42.

85 Badmaev, V., Prakash, S. & Majeed, M. 1999. Vanadium: a review of its potential role in the fight against diabetes, J. Altern. Complementary Medicine, 5: 273-291.

86 Nerup, J., PA Halban, 2000/ The EFSD and the future of diabetes research in Europe, Diabetologia 43: 1453-1454.

87 Kovac, C., 2002. Professor warns of “brain drain” of diabetes researchers from Europe, BMJ 325: 564.

88 Community Research and Development Information Service, http://www.cordis.lu/lifescihealth/major/home.htm)

89 Community Research and Development Information Service, http://www.cordis.lu/lifescihealth/workprogramme.htm)

92 Diabetes Prevention Trial—Type 1 Diabetes Study Group. 2002. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N. Engl. J Med. 346:1685–1691

93 Newgard CB. 2002. While Tinkering With the B-Cell. . . Metabolic Regulatory Mechanisms and New Therapeutic Strategies American Diabetes Association Lilly Lecture, 2001 Diabetes 51: 3141–3150.

94 Li Bassi, L., Bertele, V., and Garrattini. S., 2003. European Regulatory policies on medicines and public health needs., Eur. J. Public Health, 13: 246-251.

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Fewer side effects (e.g., hypoglycemia)Continuous glucose-monitoring devices

Measurement in real timeNon-invasive or minimally invasiveClosed loop Glucose monitorsData download to physician via web

9.4 Delivery of CareSince 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 interventions coordinated between all levels of government, health care agencies, multidisciplinary health care teams, professional organisations, and patient advocacy groups are needed.

Endnotes

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terms of reference for engagement of a...

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