Edwin A M Gale

Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials: A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association

Diabetes is defined by its association with hyperglycemia-specific microvascular complications; however, it also imparts a two- to fourfold risk of cardiovascular disease (CVD). Although microvascular complications can lead to significant morbidity and premature mortality, by far the greatest cause of death in people with diabetes is CVD. Results from randomized controlled trials have demonstrated conclusively that the risk of microvascular complications can be reduced by intensive glycemic control in patients with type 1 (1,2) and type 2 diabetes (3–5). In the Diabetes Control and Complications Trial (DCCT), there was an ∼60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated group (goal A1C <6.05%, mean achieved A1C ∼7%) and the standard group (A1C ∼9%) over an average of 6.5 years. The relationship between glucose control (as reflected by the mean on-study A1C value) and risk of complications was log-linear and extended down to the normal A1C range (<6%) with no threshold noted. In the UK Prospective Diabetes Study (UKPDS), participants newly diagnosed with type 2 diabetes were followed for 10 years, and intensive control (median A1C 7.0%) was found to reduce the overall microvascular complication rate by 25% compared with conventional treatment (median A1C 7.9%). Here, too, secondary analyses showed a continuous relationship between the risk of microvascular complications and glycemia extending into the normal range of A1C, with no glycemic threshold. On the basis of these two large controlled trials, along with smaller studies and numerous epidemiologic reports, the consistent findings related to microvascular risk reduction with intensive glycemic control have led the American Diabetes Association (ADA) to recommend an A1C goal of <7% for most adults with diabetes (6), recognizing that more or less stringent goals may be appropriate for certain patients. Whereas many epidemiologic studies and meta-analyses …

Prediction of IDDM in the General Population: Strategies Based on Combinations of Autoantibody Markers

Strategies for assessing risk of progression to IDDM, based on single and combined autoantibody measurement, were evaluated in 2,855 schoolchildren (median age 11.4 years) and 256 children with newly diagnosed IDDM (median age 10.2 years), recruited to a population-based study in the Oxford region. In 256 children with IDDM, levels of antibodies ≥97.5th centile of the schoolchild population were found in 225 (88%) for islet cell antibodies (ICAs), in 190 (74%) for antibodies to GAD, in 193 (75%) for antibodies to protein tyro-sine phosphatase IA-2 (IA-2), and in 177 (69%) for autoantibodies to insulin (IAAs). Estimates of risk of progression to IDDM within 10 years, derived by comparing the distribution of antibody markers in the two populations (schoolchildren and children with IDDM), were 6.7% (ICAs), 6.6% (GAD antibodies), 5.6% (IA-2 antibodies), and 4.8% (IAAs) for schoolchildren with levels above the 97.5th centile, increasing to 20, 23, 24, and 11%, respectively, for antibody levels >99.5th centile. Most children with IDDM had multiple antibody markers, and 89% of those diagnosed over age 10 years had ≥2 antibodies above the 97.5th centile, as compared against 0.7% of schoolchildren, in whom this combination gave a 27% 10-year estimated risk of IDDM. Risk increased but sensitivity fell as combined antibody thresholds were raised, or the number of antibodies above the threshold was increased. Strategies based on detection of ≥2 antibodies with primary testing for GAD and IA-2 antibodies and second line testing for ICAs and/or IAAs were evaluated. Detection of at least two markers selected from GAD antibodies ≥97.5th centile and/or IA-2 antibodies ≥99.5th centile and/or ICAs ≥97.5th centile identified 0.25% of schoolchildren and 83% of children with newly diagnosed IDDM, with an estimated risk of 71% (95% CI 57–91). Although confirmation from prospective studies is still needed, this analysis suggests that antibody combinations can predict diabetes in the general population.

European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes

BACKGROUND Results of studies in animals and human beings suggest that type 1 diabetes is preventable. Nicotinamide prevents autoimmune diabetes in animal models, possibly through inhibition of the DNA repair enzyme poly-ADP-ribose polymerase and prevention of beta-cell NAD depletion. We aimed to assess whether high dose nicotinamide prevents or delays clinical onset of diabetes in people with a first-degree family history of type 1 diabetes. METHOD We did a randomised double-blind placebo-controlled trial of nicotinamide in 552 relatives with confirmed islet cell antibody (ICA) levels of 20 Juvenile Diabetes Federation (JDF) units or more, and a non-diabetic oral glucose tolerance test. Participants were recruited from 18 European countries, Canada, and the USA, and were randomly allocated oral modified release nicotinamide (1.2 g/m2) or placebo for 5 years. Random allocation was done with a pseudorandom number generator and we used size balanced blocks of four and stratified by age and national group. Primary outcome was development of diabetes, as defined by WHO criteria. Analysis was done on an intention-to-treat basis. FINDINGS There was no difference in the development of diabetes between the treatment groups. Of 159 participants who developed diabetes in the course of the trial, 82 were taking nicotinamide and 77 were on placebo. The unadjusted hazard ratio for development of diabetes was 1.07 (95% CI 0.78-1.45; p=0.69), and the hazard ratio adjusted for age-at-entry, baseline glucose tolerance, and number of islet autoantibodies detected was 1.01 (0.73-1.38; p=0.97). Of 168 (30.4%) participants who withdrew from the trial, 83 were on placebo. The number of serious adverse events did not differ between treatment groups. Nicotinamide treatment did not affect growth in children or first-phase insulin secretion. INTERPRETATION Large-scale controlled trials of interventions designed to prevent the onset of type 1 diabetes are feasible, but nicotinamide was ineffective at the dose we used.

Diabetes and gender.

Abstract It is often assumed that there is little or no sex bias within either Type I (insulin-dependent) or Type II (non-insulin-dependent) diabetes mellitus. This review considers evidence that sex effects of interest and importance are present in both forms of the disease. Type I diabetes is the only major organ-specific autoimmune disorder not to show a strong female bias. The overall sex ratio is roughly equal in children diagnosed under the age of 15 but while populations with the highest incidence all show male excess, the lowest risk populations studied, mostly of non-European origin, characteristically show a female bias. In contrast, male excess is a consistent finding in populations of European origin aged 15–40 years, with an approximate 3:2 male:female ratio. This ratio has remained constant in young adults over two or three generations in some populations. Further, fathers with Type I diabetes are more likely than affected mothers to transmit the condition to their offspring. Women of childbearing age are therefore less likely to develop Type I diabetes, and – should this occur – are less likely to transmit it to their offspring. Type II diabetes showed a pronounced female excess in the first half of the last century but is now equally prevalent among men and women in most populations, with some evidence of male preponderance in early middle age. Men seem more susceptible than women to the consequences of indolence and obesity, possibly due to differences in insulin sensitivity and regional fat deposition. Women are, however, more likely to transmit Type II diabetes to their offspring. Understanding these experiments of nature might suggest ways of influencing the early course of both forms of the disease. [Diabetologia (2001) 44: 3–15]

Combined Analysis of Autoantibodies Improves Prediction of IDDM in Islet Cell Antibody-Positive Relatives

Prediction of insulin-dependent diabetes mellitus (IDDM) is still largely based on islet cell antibodies (ICAs), but it may be improved by combined analysis with other humoral markers. We examined autoantibodies to insulin (IAAs), glutamic acid decarboxylase (GAD), and Mr 37,000 and Mr 40,000 fragments of islet antigens (37 and 40 kDa) together with ICA subtypes in 101 family members with ICAs ≥10 Juvenile Diabetes Foundation units (JDF U) followed for up to 14 years, of whom 18 have developed IDDM. Life-table analysis showed a 43% risk of IDDM within 10 years for those with ICAs ≥10 JDF U, rising to 53% for those with ICAs ≥20 JDF U. The risk for ICAs ≥10 JDF U was 62% in the family members in the youngest age quartile (<13.2 years) and fell with increasing age to 4% in those >40.7 years of age (P = 0.03). ICAs ≥10 JDF U combined with IAAs gave a risk of 84% (P = 0.03 compared with IAA−), and ICAs ≥10 JDF U combined with GAD antibodies gave a risk of 61% (P = 0.018). The risk for ICAs >10 JDF U with antibodies to 37-kDa antigen was 76% (P < 0.0001). Risk increased with the number of autoantibodies, from 8% for ICAs alone to 88% with >3 autoantibodies (14 cases detected) (P < 0.0001). The increased risk associated with multiple antibodies was observed independent of age. The median time to diagnosis in those with antibodies to 37- and/or 40-kDa antigen was 1.5 years, compared with 7.2 years in those with IAAs and GAD antibodies in the absence of antibodies to 37/40 kDa. The intensity and range of the autoantibody response offers better overall prediction of diabetes than any single autoantibody specificity, although antibodies to 37-/40-kDa antigens may prove to be useful markers of early clinical onset. We found that 78% of future cases of IDDM in ICA+ relatives came from the 27% with multiple autoantibodies and estimate that 88% of individuals within this category will need insulin treatment within 10 years. We propose a simple predictive strategy based on these observations.

Mortality After Incident Cancer in People With and Without Type 2 Diabetes: Impact of metformin on survival

OBJECTIVE Type 2 diabetes is associated with an increased risk of several types of cancer and with reduced survival after cancer diagnosis. We examined the hypotheses that survival after a diagnosis of solid-tumor cancer is reduced in those with diabetes when compared with those without diabetes, and that treatment with metformin influences survival after cancer diagnosis. RESEARCH DESIGN AND METHODS Data were obtained from >350 U.K. primary care practices in a retrospective cohort study. All individuals with or without diabetes who developed a first tumor after January 1990 were identified and records were followed to December 2009. Diabetes was further stratified by treatment regimen. Cox proportional hazards models were used to compare all-cause mortality from all cancers and from specific cancers. RESULTS Of 112,408 eligible individuals, 8,392 (7.5%) had type 2 diabetes. Cancer mortality was increased in those with diabetes, compared with those without (hazard ratio 1.09 [95% CI 1.06–1.13]). Mortality was increased in those with breast (1.32 [1.17–1.49]) and prostate cancer (1.19 [1.08–1.31]) but decreased in lung cancer (0.84 [0.77–0.92]). When analyzed by diabetes therapy, mortality was increased relative to nondiabetes in those on monotherapy with sulfonylureas (1.13 [1.05–1.21]) or insulin (1.13 [1.01–1.27]) but reduced in those on metformin monotherapy (0.85 [0.78–0.93]). CONCLUSIONS This study confirmed that type 2 diabetes was associated with poorer prognosis after incident cancer, but that the association varied according to diabetes therapy and cancer site. Metformin was associated with survival benefit both in comparison with other treatments for diabetes and in comparison with a nondiabetic population.

The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes

The incidence of childhood type 1 diabetes has risen over the past 50 years. We compared the frequency of HLA class II haplotypes in 194 patients diagnosed more than 50 years ago and 582 age-matched and sex-matched individuals diagnosed between 1985 and 2002. The proportion of high-risk susceptibility genotypes was increased in the earlier cohort (p=0.003), especially in those diagnosed at age 5 years or younger, which is consistent with the hypothesis that the rise of type 1 diabetes is due to a major environmental effect.

Rising incidence of insulin dependent diabetes in children aged under 5 years in the Oxford region: time trend analysis

Abstract Objectives: To monitor incidence of insulin dependent diabetes in children in Oxford health region since 1985, and to look for any evidence of disproportionate increase in children aged under 5. Design: Primary ascertainment of cases of childhood diabetes was by prospective registration of all patients with insulin dependent diabetes diagnosed before age 15 years between 1985 and 1996 and resident in Oxford region at time of diagnosis. This was supplemented by examination of centralised hospital discharge records and death certificates. Secondary case ascertainment was by postal surveys of general practitioners in 1987 and 1996. Setting: Area formerly administered by Oxford Regional Health Authority. Subjects: 1037 children presenting with insulin dependent diabetes under age of 15 years. Main outcome measures: Incidence of insulin dependent diabetes in children aged 0-4, 5-9, and 10-14 years during 1985-95. Results: Overall incidence of diabetes in children aged 0-15 was 18.6 cases/100 000/year and showed an annual increase of 4% from 1985 to 1996. This was mainly due to a rapid increase in children aged 0-4 years, in whom there was an annual increase of 11% (95% confidence interval 6% to 15%, P<0.0001), while the annual increase in those aged 5-9 was 4% (0 to 7%, P=0.05) and in those aged 10-14 was 1% (−2% to 4%, P=0.55). Conclusions: Incidence of insulin dependent diabetes in children aged under 5 years has risen markedly in the Oxford region over the past decade. The cause of the increase is unknown, but environmental influences encountered before birth or in early postnatal life are likely to be responsible. Key messages The incidence of childhood diabetes has increased in Europe and many other parts of the world over the past 20-30 years In the Oxford region we found that the incidence of childhood insulin dependent diabetes increased by 4% per year during 1985-95 Most of this increase was due to an increase of 11% a year in children aged under 5 years, in whom incidence doubled over the study period Environmental factors encountered very early in life are likely to have been responsible for this increase, but the nature of such factors is unknown Attempts at preventing disease should be directed towards intrauterine or early postnatal life

A missing link in the hygiene hypothesis

The incidence of childhood Type I (insulin-dependent) diabetes mellitus has risen in parallel with that of childhood asthma, and the hygiene hypothesis proposes that this is due to reduced stimulation of the immune system by early intercurrent infection. If so, this protective effect is probably mediated by regulatory T lymphocytes. Co-evolutionary partners might have contributed to the development of this form of response, and parasites and the indigenous biota of the gut are plausible candidates. Helminths inhibit the development of atopic disease via induction of regulatory T cells and secretion of Il-10, and pinworms inhibit diabetes development in the non-obese diabetic (NOD) mouse. The most successful human helminth of the western world is the pinworm Enterobius vermicularis, and some 50% of young children in Europe and North America may have been infested around the middle of the twentieth century. Pinworms are benign, usually asymptomatic, and may have immunomodulatory properties that protect against the development of immune-mediated disorders including diabetes and asthma. Their decline in response to improved living conditions might explain a number of features of the epidemiology of childhood atopy and diabetes. The proposed role would be one of immunomodulation rather than disease induction, possibly mediated by interaction with other influences upon the development of the mucosal immune system. This hypothesis could be tested in case-control studies by the development of serological markers or skin testing. If confirmed, identification of the underlying mechanisms could open the way to new forms of immune intervention.

A Critical Analysis of the Clinical Use of Incretin-Based Therapies Are the GLP-1 therapies safe?

There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns reported regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to a potential risk for the increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider the use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative following the contribution by Dr. Butler and colleagues, Dr. Nauck provides a defense of incretin-based therapies and that the benefits clearly outweigh any concern of risk. —William T. Cefalu, MD Editor In Chief, Diabetes Care