Endocrinology

In reply: Readers will probably deduce that Paul J Sambrook is no relation of Philip N Sambrook. The Australian Broadcasting Corporation, which aired The 7:30 Report that Paul Sambrook and colleagues refer to, subsequently acknowledged in writing that there were a number of factual errors in the original program. Under these circumstances, a right of reply was entirely appropriate. There is ongoing debate about the incidence of osteonecrosis of the jaw (ONJ), but as the modelling used in our study1 did not involve any assumptions about this, it is irrelevant to our findings. The studies by Lo et al2 and Mavrokkoki et al3 did not report incidence of ONJ — they reported prevalence. Moreover, one of the coauthors of the letter by Paul Sambrook et al (above) has published that the estimates by Mavrokkoki et al, being from a retrospective postal survey, must be viewed with caution.4 The Lo et al study was approved by an institutional review board of the United States Food and Drug Administration (FDA), not “funded and conducted” by the FDA, as Sambrook and colleagues state in their letter. There have been numerous studies of the effects of vertebral fractures and osteoporosis on quality of life. The authors claim that ONJ causes greater interference to a patient’s life than osteoporosis or vertebral fractures, but cite no references to justify this bald assertion. The US court case of Boles v Merck & Co5 was not an “independent study” (as implied in the last paragraph of the letter by Sambrook et al), but a legal proceeding that is being appealed. One of the coauthors of the letter was a paid expert for the plaintiff. ONJ is a serious complication of bisphosphonate therapy in the small proportion of affected individuals. We agree that patients need to be informed of the risks of therapy, but they also need to be informed of the consequences of not taking therapy (ie, the benefits forgone) to make a really informed decision. Our article was intended to let patients understand what those consequences might be. The courts are certainly not the place for informed debate. And the media should appreciate that unbalanced reporting can have significant consequences.

Philip N Sambrook · Jiang S Chen · Judy M Simpson · Lyn M March

Objective: To document diabetes health services use and indices of glycaemic management of young people with type 1 diabetes from the time of their first contact with adult services, for those living in regional areas compared with those using city and state capital services, and compared with clinical guideline targets.Design, setting and subjects: Case note audit of 239 young adults aged 18–28 years with type 1 diabetes accessing five adult diabetes services before 30 June 2008 in three geographical regions of New South Wales: the capital (86), a city (79) and a regional area (74).Main outcome measures: Planned (routine monitoring) and unplanned (hospital admissions and emergency department attendance for hypoglycaemia or hyperglycaemia) service contacts; recorded measures of glycated haemoglobin (HbA1c), body mass index (BMI), and blood pressure (BP).Results: Routine preventive service uptake during the first year of contact with adult services was significantly higher in the capital and city. Fewer regional area patients had records of complications assessment and measurements of HbA1c, BMI and BP across all audited years of contact (HbA1c: 73% v 94% city, 97% capital; P < 0.001). Across all years, regional area patients had the highest proportion of HbA1c values > 8.0% (79% v 62% city, 56% capital) and lowest proportion < 7% (4% v 7%, 22%) (both P < 0.001). Fewer young people made unplanned use of acute services for diabetes crisis management in the capital (24% v 49% city, 50% regional area; P < 0.001). In the regional area, routine review did not occur reliably even annually, with marked attrition of patients from adult services after the first year of contact.Conclusion: Inadequate routine specialist care, poor diabetes self-management and frequent use of acute services for crisis management, particularly in regional areas, suggest service redesign is needed to encourage young people’s engagement.

Lin Perry PhD, MSc, RN · Katharine S Steinbeck MB BS, FRACP, PhD · Janet S Dunbabin BAg(Sc), PhD · Julia M Lowe MB ChB, FRCP, MMedSci

Results of two new trials will drive further research into the “andropause hypothesis” Two important research articles, published in a recent issue of the New England Journal of Medicine (NEJM), bracket the topic of prescribing testosterone for older men.1,2 Testosterone treatment for older men is based on considering male ageing as analogous to either menopause or pathologically based hypogonadism. The former is a false analogy — menopause has a unique natural history featuring complete failure of female reproductive hormones in mid-adult life, contrary to all other human hormonal systems which decline gradually and modestly with ageing. The latter is based on the superficial resemblance of non-specific symptoms in ageing men with those of most hormonal deficiencies or chronic diseases. This “andropause hypothesis” is not well substantiated, with the 2004 United States Institute of Medicine’s authoritative review3 concluding that available evidence did not justify a major study of testosterone replacement in older men comparable to the Women’s Health Initiative (WHI) study of oestrogen replacement in menopause. Nevertheless, the past two decades have seen an approximately 20-fold increase in testosterone prescribing despite no proven new indications. This is largely confined to the US, with minimal changes in Australia4 and other regional markets; however, that bandwagon could certainly be viewed as having left the station, fuelled by heavy direct-to-public drug advertising in the US. One of the NEJM articles reports the European Male Ageing Study (EMAS) — a large observational study of male ageing involving more than 3300 men aged 40 years and over from population-based sources in eight European cities, and the European counterpart to the seminal Massachusetts Male Ageing Study (MMAS).1 The EMAS evaluated the relationship of non-specific physical and mental symptoms to serum testosterone levels, an approach originating from clinic-based studies5,6 and used in the analysis of the population-based data of the MMAS,7 to which the EMAS adds a large sample size. Crucially, the statistical power of this study can neither overcome its logical flaws nor the inconsistency between its findings and conclusions. After noting statistically insignificant associations of low testosterone levels with clinically relevant physical or psychological features, the researchers focus on three sexual symptoms — erectile dysfunction, frequency of morning erections and sexual desire. Each symptom shows a weak association with serum testosterone levels, featuring a shallow breakpoint (at levels of 8–11 nmol/L) together with high false-positive and negative rates. Although the only consistent significant association is between all three sexual symptoms and a serum testosterone level threshold of 8 nmol/L, the researchers inexplicably propose a “definition” of “late-onset hypogonadism” requiring the presence of all three sexual symptoms plus a serum testosterone level of less than 11 nmol/L. The proposal is further undermined by the study’s findings that all the associations of the three sexual symptoms with low serum testosterone levels are nullified by adjustment for age, obesity and co-existing illnesses, indicating that they are attributable to confounding rather than any authentic correlation. The study’s authors, in effect, overinterpret cross-sectional data to imply causality. Such quasi-longitudinal interpretation is especially unsafe when blood test results are not steady for the population. This is the case for serum testosterone, with evidence of downward temporal trends in America and Europe,8 probably due to progressive population increases in obesity. The impact of implied causality should not be underestimated — despite its ritual caveats against testosterone prescribing, this article is likely to encourage more overuse of testosterone. The article resonates with past mistakes, notably the decades of excessive oestrogen prescribing, encouraged by overinterpreted observational studies and curbed only by the first placebo-controlled randomised trial of hormonal replacement therapy. Lest we sleepwalk down that same path, let us hope that it will not take decades before the “andropause hypothesis” undergoes rigorous testing. The second NEJM article reports the early termination of a randomised, placebo-controlled clinical trial for excess adverse cardiovascular effects associated with testosterone supplementation.2 The study evaluated the somatic benefits of 6 months of daily use of testosterone gel in frail men over 65 years with low serum testosterone levels. As expected, this population had a high prevalence of cardiovascular disease, which would explain their low serum testosterone levels as a non-specific effect of chronic illness. The progressive excess of adverse cardiovascular effects in testosterone-treated men (23 men receiving testosterone v 5 receiving placebo in the trial’s total of 209 men) was unexpected but persisted despite the use of various definitions of adverse cardiovascular events (the original definition was broad and included unexplained syncope and peripheral oedema). As the study design was conventional in regard to testosterone dosage, titration and monitoring, these findings show a low cardiovascular safety margin for testosterone supplementation in frail older men. They differ from the findings of previous comparable placebo-controlled studies of testosterone use in older men, which reported no excess cardiovascular events,9 even in 12-month studies of men with cardiac failure.10 Nevertheless, these adverse findings cannot be considered surprising given the earlier onset and greater severity of cardiovascular disease in men, together with the refutation of the long-dominant hypothesis that oestrogen provides women with a degree of cardiovascular protection.11 As this second article2 highlights, the effects of a treatment that excessively increases risk for the most common cause of death — cardiovascular disease — overwhelm even substantial improvements in less common or non-fatal disorders. Hence, the study’s finding of a benefit (improved limb muscular strength) was overshadowed by adverse cardiovascular profiles, as has happened with other treatments, such as the WHI’s reductions in bone fractures and colorectal cancer, and the highly effective, gastric-sparing cyclooxygenase-2 (COX-2) inhibiting analgesics and the oral antidiabetic glitazones. A corollary is that overinterpreting the regular association of low serum testosterone in men with cardiovascular disease as a risk factor that might be ameliorated — rather than as a consequence — led to a misplaced focus on prostate cancer as the major risk of testosterone treatment in older men. Taken together, these two studies can be construed as pressing the accelerator and the brakes at the same time on testosterone prescribing for older men . . . with probably the usual effect of spinning wheels. However, several reflections arise for Australian clinical practice. First, Australia’s national guidelines for testosterone use,12 developed in 2000 and adopted by the Pharmaceutical Benefits Scheme as the criteria for subsidised testosterone prescriptions, are vindicated. They aim to restrict testosterone prescribing for age-related androgen deficiency without hindering it for pathologically based androgen deficiency. European and US guidelines (produced in 2005 and 2006, respectively) were republished recently, essentially unchanged.13,14 The northern hemisphere guidelines, in contrast to Australia’s, blur the distinction between pathologically based and age-related androgen deficiency, loosen the diagnostic criteria and lack regulatory force. Thus they minimise the diagnostic hurdle, leading to the perverse outcome of potentially encouraging rather than deterring unproven overuse of testosterone. Second, the EMAS definition of “late-onset hypogonadism” is not suitable for implementation in practice. Findings of the MMAS confirm clinical experience and are reflected in all clinical guidelines:12-14 serial serum testosterone levels in older men are sufficiently variable7 to require the results of at least two blood samples taken weeks apart to establish a sustained low level of serum testosterone. Hence, a definition reliant on a sample of single testosterone measurements is likely to be highly error-prone, due to regression to the mean and other sources of variability. It also relies on testosterone measurements by mass spectrometry, a superior technology not yet available in Australian pathology laboratories despite recognised limitations of testosterone immunoassays.15 Similarly, the so-called “free” testosterone variable, also used in the study but not recommended, is calculated by an inaccurate formula unsuitable for individual diagnosis.16 Third, reflection on these two NEJM articles makes evident the need to reinforce bans on direct-to-public advertising of testosterone supplementation. This critical protection depends on industry self-regulation. Without this protection, an avalanche of misguided testosterone prescribing awaits us, analogous to the massive, unregulated marketing of non-proprietary impotence drugs advertised on billboards and in the media, apparently beyond regulatory reach. Finally, testosterone prescribing for older men is best restricted to clinical trials where ethical oversight ensures appropriate design and warnings to participants. Age alone may not prove a valid indication, but this should not limit essential further research within the framework of placebo-controlled clinical trials aiming to define the benefits and risks of testosterone use in patients with the comorbidities of ageing, such as obesity, diabetes, metabolic syndrome and other chronic conditions.

David J Handelsman MB BS, FRACP, PhD

We report a series of cases of thyroid dysfunction in adults associated with ingestion of a brand of soy milk manufactured with kombu (seaweed), and a case of hypothyroidism in a neonate whose mother had been drinking this milk. We also report two cases of neonatal hypothyroidism linked to maternal ingestion of seaweed made into soup. These products were found to contain high levels of iodine. Despite increasing awareness of iodine deficiency, the potential for iodine toxicity, particularly from sources such as seaweed, is less well recognised. Clinical recordsCases of thyroid dysfunction associated with ingestion of soy milkIn November 2008, a 36-year-old woman (Patient 1, Box 1) presented with a mildly elevated serum thyroid-stimulating hormone (TSH) level detected during screening for in vitro fertilisation. As she tested negative for thyroid antibodies, her urinary iodine level was measured to exclude iodine deficiency; this level was markedly elevated at 4445 μg/L (reference range [RR], < 200 μg/L). The source of the excess iodine was unclear until the patient did an internet search and identified that the soy milk she had been drinking (Bonsoy) contained kombu1,2 — a type of seaweed. The patient ceased drinking the soy milk, which resulted in rapid normalisation of her TSH level. Three months later, a 38-year-old man (Patient 2, Box 1) presented with florid thyrotoxicosis. Minimal uptake of technetium on a thyroid scan and absence of TSH receptor antibodies essentially excluded Graves disease. The scan result, in combination with his elevated urinary iodine level (1278 μg/L), indicated that iodine toxicity was the most likely cause of the thyrotoxicosis. He drank brands of soy milk other than Bonsoy, but also drank Bonsoy in takeaway coffee. After he ceased drinking all soy milk, his symptoms rapidly abated and his serum TSH level normalised 3 months later. No further cases of suspected iodine toxicity were seen until approximately 1 year later, when six additional patients presented to one of us (B A C) over a 6-week period (Patients 3–8, Box 1). These patients presented with thyroid conditions ranging from subclinical hyperthyroidism to florid thyrotoxicosis. Patient 3 had already been diagnosed with thyrotoxicosis due to underlying iodine toxicity (urinary iodine level, 11 427μg/L); however, the source of excess iodine was not identified until she sought a second opinion. One month after she ceased consuming Bonsoy milk (which she had been consuming for the previous 8 years), her serum TSH level normalised. An aliquot of Bonsoy milk was analysed for iodine content using a plasma mass spectrometer (Department of Biochemistry, Royal Prince Alfred Hospital, Sydney, NSW), which showed an iodine concentration of 25 000 μg/L. In comparison, the levels of iodine in other soy milks that were analysed ranged from 15 μg/L to 281 μg/L (Box 2). Two weeks later, the same laboratory received a second aliquot of Bonsoy milk for analysis, due to a case of neonatal hypothyroidism. The newborn screening program had identified a baby with an elevated TSH level (28 mIU/L; RR, < 20 mIU/L; heel-prick blood sample). Additional testing 19 days after birth showed further elevation of the baby’s serum TSH level (163 mIU/L), as well as a low level of serum free thyroxine (3.7 pmol/L; RR, 10–25 pmol/L). Exposure to exogenous iodine from a maternal source was suspected because of the marked rise in serum TSH level. Urinary iodine levels were subsequently found to be elevated in both the mother (5415 μg/L) and the baby (9797 μg/L). During the last trimester of pregnancy, the mother had been drinking about 500 mL of Bonsoy milk daily. She had been breastfeeding since delivery. The iodine concentration of the second aliquot of this soy milk (27 580 μg/L) was similar to that of the previously analysed sample. The baby was initially treated with thyroxine but, after the mother ceased ingesting the soy milk, the baby’s thyroid function normalised. Independent analysis of the soy milk (Division of Analytical Laboratories, NSW Health, Sydney, NSW) again revealed an extremely high iodine concentration (31 000 μg/L). Cases of neonatal hypothyroidism associated with maternal ingestion of seaweed soupTwo cases of neonatal hypothyroidism related to maternal ingestion of seaweed have been reported recently by two of us (P J E and M M J).3 The first case involved a Korean mother who, during pregnancy and the puerperium, consumed soup made with overseas-bought dried seaweeds. Her baby, born at 36 weeks’ gestation, had a normal TSH level at the time of newborn screening (heel-prick blood sample). However, the baby subsequently developed jaundice and, at 3 weeks of age, a repeat TSH test showed elevation of the baby’s serum TSH level (39 mIU/L; RR, 0.4–5.0 mIU/L) as well as a low level of serum free thyroxine (9.7 pmol/L; RR, 13–30 pmol/L) and an elevated urinary iodine level (690 μg/L). The baby was initially treated with thyroxine but, after the mother ceased ingesting seaweed soup, the baby’s thyroid function normalised. Dried samples of two different seaweed compounds, analysed by a commercial pathology company (Sullivan Nicolaides Pathology, Brisbane, QLD), showed iodine concentrations of 291 μg/g and 424 μg/g. The second case involved an infant born at 27 weeks’ gestation who had a normal TSH level at the time of newborn screening, and an elevated serum TSH level (24 mIU/L; RR, 0.06–7.14 mIU/L) when a routine repeat TSH test was carried out at 1 month of age. This infant’s mother had also been ingesting seaweed soup — made with Heng Fai seaweed, imported from China, to increase her breast milk supply. The baby’s urinary iodine level at the time of maternal seaweed ingestion was elevated (454 μg/L). The iodine concentration in the mother’s breast milk at the time of seaweed ingestion was elevated at 878 μg/L; 4 weeks after she ceased consuming the seaweed, the concentration dropped to 188 μg/L. NSW Health was notified and testing of the Heng Fai seaweed by the NSW Food Authority revealed high levels of iodine (4450 μg/g), which resulted in voluntary withdrawal of Heng Fai seaweed by the importers in March 2010.4 DiscussionIodine toxicity causes a spectrum of thyroid disorders, ranging from hyperthyroidism to hypothyroidism.5,6 Reasons for the variable effects are unclear, but may relate to age, pre-existing autoimmune thyroid disease, and amount and duration of iodine ingestion.5,6 The adults described here did not appear to have underlying nodular goiters or Hashimoto disease (Box 1). In iodine toxicity, thyroid technetium uptake scans usually show absent or low technetium uptake in thyrotoxicosis and increased technetium uptake in neonatal hypothyroidism. Graves disease and autonomous nodular thyroid disease are more common causes of thyrotoxicosis but can be excluded primarily by scan results, lack of a goitre and absence of TSH receptor antibodies. However, as urinary iodine levels are not routinely measured in clinical practice, iodine toxicity may be underdiagnosed. This series of cases of thyroid dysfunction led to a national recall of Bonsoy milk on 24 December 2009,7 and the distributer agreed to voluntary withdrawal of the product from sale in Australia. This brand of soy milk was fermented in seaweed, which is thought to improve the flavour, and is promoted as having wide-ranging health benefits.1 The NSW Health alert for Bonsoy milk stated that in a child, ingestion of only 5 mL, and in an adult, only 30 mL, would exceed the safe upper limit of iodine intake.8,9 It is unclear whether changes to the manufacturing process of the Bonsoy product may have increased its iodine content. However, after removal of kombu from the manufacturing process, the iodine content was reduced markedly (15 μg/L) and the product returned to the Australian market in April 2010. The World Health Organization was notified of the iodine toxicity of the Bonsoy milk, which was withdrawn from sale in a number of other countries.10 Between January and June 2010, 48 retrospective Australian cases of thyroid dysfunction associated with this brand of soy milk were also notified to local public health authorities (Katrina Knope, Coordinating Epidemiologist, OzFoodNet, Office of Health Protection, Department of Health and Ageing, June 2010, personal communication). A cluster of cases of thyrotoxicosis, linked to iodine toxicity from an unidentified soy milk, was also reported in New Zealand in 2005.11 The common practice by women from Japan and Korea of ingesting seaweed made into soup, sometimes in large quantities, to promote wellbeing in the mother and stimulate breast milk supply, does not appear to be widely known in the medical community. However, due to iodine transmission through breast milk, transient or even persistent hypothyroidism has been reported in neonates born to mothers who undertake this practice.12,13 If left undiagnosed and untreated, neonatal hypothyroidism can have devastating clinical consequences, including impaired intellectual development. Although newborn screening tests will help to identify hypothyroidism during the first week of life, there is no subsequent routine screening of thyroid function in term babies whose TSH level may not increase until after 1 week of age, as seen in one of the neonatal cases described here and in a Korean study of preterm infants.12 Our findings demonstrate the importance of: considering iodine toxicity in patients who present with thyrotoxicosis in the absence of TSH receptor antibodies and low or absent uptake on a thyroid technetium uptake scan; measuring urinary iodine level in cases where thyrotoxicosis is not explained by conditions such as autoimmune or nodular thyroid disease; and actively seeking a history of maternal seaweed consumption during pregnancy and lactation in cases of neonatal hypothyroidism. Finally, although iodine deficiency is a documented and serious concern in Australia,14,15 these cases highlight the risks of excess iodine intake from dietary sources. The food industry is not strictly regulated (eg, imported products are not usually tested to confirm their contents), and contamination of food and drink is only detected when unusual or severe clinical events ensue. There is a strong public health argument for monitoring iodine levels in imported foods and commercially available seaweed preparations. 1 Characteristics of a cluster of eight adult patients in whom thyroid dysfunction was attributed to consumption of Bonsoy, a brand of soy milk manufactured with seaweed, November 2008 to December 2009* Sex; age (years) SerumTSH level (mIU/L) Serum fT4 level (pmol/L) Serum fT3 level (pmol/L) Serum TRAb test result Serum TPO/Tg Ab test result Technetium uptake on thyroid scan Urinary iodine level (μμg/L) Thyroid ultrasound result RR 0.4–3.5 9–19 2.5–5.7 0.5%–3.5% < 200 Patient 1 F; 36 4.63 9.7 Not done Not done Negative Not done 4 445 Not done Patient 2 M; 38 < 0.02 59.4 16 Negative Negative Negligible 1 278 Normal size, single nodule (3 mm diameter), normal vascularity Patient 3 F; 46 < 0.005 50 39 Negative Negative < 0.5% 11 427 Mild enlargement, reduced vascularity Patient 4 F; 36 < 0.04 30 12 Negative Negative 0.5% 777 Normal Patient 5† F; 37 < 0.0005; 12.4 29; < 5 5.6; 3.4 Negative Negative Not done 6 208 Normal Patient 6‡ F; 29 0.04 16 4.9 Negative Negative 0.5% 48 Tiny nodules (< 3 mm diameter) Patient 7 F; 33 0.08 18 6.6 Negative Negative 1.3% 5 022 Normal Patient 8 M; 47 0.07 17 4.9 Negative Negative 0.1% 320 Single nodule (5 mm diameter) TSH = thyroid-stimulating hormone. fT4 = free thyroxine. fT3 = free triiodothyronine. TRAb = TSH receptor antibody. TPO/Tg Ab = thyroid peroxidase and thyroglobulin antibodies. RR = reference range. F = female. M = male. * Reported daily intake of Bonsoy milk ranged from < 100 mL/day to 1000 mL/day. † Patient 5 had blood tests for thyrotoxicosis performed at 5.5 months postpartum, and repeated at 7 months postpartum (when she had developed hypothyroidism). ‡ Patient 6 ceased consumption of the Bonsoy milk about 2–3 months before testing. 2 Iodine concentration in various milks, assayed in December 2009* Brand Iodine (μμg/L) Soy milks Bonsoy 25 000, 27 580 Sanitarium So Nice 27 Vitasoy 19 Coles Soy Drink 19 So Natural Original 15 Other milks Woolworths Lite (low-fat cows milk) 281 Pura Milk (full-fat cows milk) 215 So Good Rice Milk 29 * All testing was carried out at the Department of Biochemistry, Royal Prince Alfred Hospital, Sydney, NSW.

Bronwyn A Crawford PhD, MB BS, FRACP · Christopher T Cowell MB BS, FRACP · Phillip J Emder BSc(Med), MB BS, FRACP · Diana L Learoyd PhD, MB BS, FRACP · Elizabeth L Chua PhD, MB BS, FRACP · John Sinn MB BS, MMed(ClinEpi), FRACP · Michelle M Jack PhD, MB BS, FRACP

Primary hyperparathyroidism (PHT) complicated by osteitis fibrosa cystica (OFC) — the “classical” form of PHT — is rarely seen today. A 41-year-old woman of Sri Lankan descent presented with persistent pain in her right distal forearm 2 days after chopping vegetables. X-ray revealed a fracture through a lucent lesion within the midshaft of the right ulna. A whole-body bone scan showed numerous abnormalities of the major long bones consistent with OFC (Figure, A). Skeletal x-rays showed widespread lytic lesions with osteopenia and subperiosteal erosions, illustrated here by x-ray of the right hand (Figure, B) where marked subperiosteal bone resorption can be seen; note the ill-defined phalangeal cortex (thick arrow) and erosion of the terminal tufts of the distal phalanges (thin arrow). Skull x-ray showed “salt-and-pepper” demineralisation (Figure, C), best appreciated by the lack of visible vascular markings on the calvarium; lytic lesions are present (arrows). The serum calcium level was 4.22 mmol/L (reference range, 2.13–2.63 mmol/L). Our patient was successfully treated with a parathyroidectomy — 5 months after surgery, bone turnover markers were normal, and 14 months after surgery, bone mineral density, tested at the hip, had increased by 22%.

Anna Lih · Mridula Lewis · John Carter

Objective: To determine the cost-effectiveness of routine administration, irrespective of blood pressure (BP), of a fixed-dose combination of perindopril and indapamide to patients with type 2 diabetes mellitus.Design, setting and participants: Prospective cost-effectiveness analysis within the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial, an international, multicentre, randomised controlled trial of 11 140 participants with type 2 diabetes randomly allocated to receive perindopril plus indapamide (4 mg–1.25 mg/day) or placebo.Main outcome measures: Health-related quality-of-life measured by the EuroQol-5D, resource utilisation, and cost-effectiveness (cost per death averted at 4.3 years’ average follow-up, and estimated cost per life-year gained, by extrapolation).Results: The mean health-related quality-of-life score of survivors was 0.80 (on a 0–1 scale [death to full health]), with no difference between treatment groups. Active treatment reduced hospital admissions for coronary heart disease and coronary revascularisation by 5%. For the Australian participants, perindopril–indapamide cost A$1368 per patient during the trial period, but reduced total hospitalisation costs by A$410 and other medication costs (mainly other BP-lowering drugs) by A$332. The absolute reduction in all-cause mortality for the active treatment group was 1.1%, giving a cost per life saved of A$49 200. Lifetime extrapolation gave an estimated cost per life-year saved of A$10 040 (discounted at 5% per year).Conclusion: The combination of perindopril and indapamide in patients with type 2 diabetes appears to be cost-effective.Trial registration: United States National Library of Medicine NCT00145925.

Paul P Glasziou MB BS, PhD · Philip M Clarke MEc, PhD · Jan Alexander · Mohana Rajmokan MSc · Elaine Beller BSc, MAppStat · Mark Woodward PhD · John Chalmers MD, PhD, FRACP · Neil Poulter MSc, FRCP · Anushka A Patel FRACP, PhD

To the Editor: Chen and colleagues1 published a risk assessment tool for type 2 diabetes (AUSDRISK) based on the Australian Diabetes, Obesity and Lifestyle Study (AusDiab).2 We tested AUSDRISK’s performance in an independent cohort of 1494 women enrolled in the Geelong Osteoporosis Study (1994–1997; 77% participation),3 comprising an age-stratified sample of women randomly selected from the Barwon Statistical Division and followed prospectively over a decade.4 In 2004–2008, of 1015 surviving study participants aged 25 years or older at enrolment, 800 (79%) returned for follow-up assessment. We excluded 261 women who did not have a fasting plasma glucose (FPG) test result at both baseline and follow-up assessments, and 33 with baseline diabetes. The remaining 506 women formed the cohort on which the AUSDRISK tool was tested. Diabetes was defined by one or more of three criteria: FPG level ≥ 7.0 mmol/L, treatment with insulin or oral hypoglycaemic agents, or self-report. Demographics, ethnicity and lifestyle factors were documented by questionnaire. Participants were described as “active” if they described their mobility as “moves, walks and works energetically, and participates in vigorous activity”; otherwise, they were considered “inactive”. As our baseline questionnaire did not document a history of high glucose levels, we performed two analyses: one assuming no participants had this history, and a second identifying participants with baseline impaired fasting glycaemia (FPG level, 6.1–6.9 mmol/L). The study was approved by the Human Research Ethics Committee, Barwon Health. Using the final AUSDRISK model,1 we allocated points for baseline characteristics according to sex, age, ethnic background, parental history of diabetes, history of high blood glucose (FPG level, ≥ 6.1 mmol/L), use of antihypertensive medications, current smoker status, physical inactivity, and waist circumference. The predictive power of AUSDRISK was determined using the area under the receiver operating characteristic curve (AROC). Using a total AUSDRISK score ≥ 12 as the criterion for prediction of diabetes, we evaluated the performance of AUSDRISK by calculating its sensitivity, specificity and positive predictive value (PPV) in our cohort. Ninety-eight participants had an AUSDRISK score ≥ 12 (or 106 if those with impaired fasting glycaemia were scored for a history of high blood glucose). Statistical analyses were performed using Stata software, version 9 (StataCorp, College Station, Tex, USA). Twenty-eight participants (5.6%) developed incident diabetes during the period of follow-up (13 with FPG ≥ 7.0 mmol/L, 14 receiving treatment with insulin or hypoglycaemic agents, and seven self-reporting the condition). If we assumed that none of the participants had a history of high blood glucose levels, the AROC for AUSDRISK in the Geelong cohort (0.78 [95% CI, 0.72–0.85]) was comparable with that in the AusDiab cohort (0.78 [95% CI, 0.76–0.81]).1 In our study, the sensitivity of the AUSDRISK tool was 50.0% (95% CI, 30.6%–69.4%), specificity was 82.4% (95% CI, 78.7%–85.7%) and PPV was 14.3% (95% CI, 8.0%–22.8%). Recognising baseline impaired fasting glycaemia increased AUSDRISK’s predictive power (AROC, 0.81 [95% CI, 0.74–0.88]; sensitivity, 60.7% [95% CI, 40.6%–78.5%]; specificity, 81.4% [95% CI, 77.6%–84.8%]; and PPV, 16.0% [95% CI, 9.6%–24.4%]). Study limitations were that we only evaluated women, we did not collect data on a history of high blood glucose levels, diabetes was diagnosed in the absence of an oral glucose tolerance test, and criteria for inactivity differed from those used in the AusDiab study. Our population was older than that of the AusDiab study and would probably have had a higher prevalence of diabetes, influencing our PPV result. Not surprisingly, including individuals with impaired fasting glycaemia increased the point estimates for AROC, sensitivity and PPV. In conclusion, our data independently demonstrate the limited predictive value of AUSDRISK for women over a 10-year period.

Julie A Pasco · Mark A Kotowicz · Margaret J Henry · Geoffrey C Nicholson

CorrectionAcknowledgements omitted: In “A multimodal intervention to improve fragility fracture management in patients presenting to emergency departments” in the 2 August 2010 issue of the Journal (Med J Aust 2010; 193: 149-153), the acknowledgements were omitted. The following text should be inserted before “Competing interests”: Acknowledgements: We wish to thank the following for their contribution to our project: the National Health and Medical Research Council’s National Institute of Clinical Studies and Australian Department of Veterans’ Affairs Fellowship Program; the North Metropolitan Area Health Service, Perth (Sir Charles Gairdner Hospital, Osborne Park Hospital and area rehabilitation and aged care staff); and physicians and general practitioners involved in developing the consensus guidelines. The html and pdf versions of this article have been corrected.

Charles A Inderjeeth · Denise A Glennon · Kate E Poland · Katherine V Ingram · Richard L Prince · Victoria R Van · C D’Arcy J Holman

Physicians need to be aware of this newly described complication Every year, thousands of Australians are prescribed bisphosphonates for the treatment of osteoporosis. They are highly effective agents, with numerous large clinical trials demonstrating a significant reduction in the risk of osteoporotic fractures as early as 6 months after commencement of therapy. Bisphosphonates such as risedronate, alendronate, etidronate, pamidronate and zoledronic acid have an excellent safety profile, although gastro-oesophageal irritation or transient flu-like symptoms may occur in patients receiving oral or intravenous bisphosphonates, respectively. Other side effects, such as renal impairment, uveitis and osteonecrosis of the jaw, have been described but are extremely rare. Since 2005, there have been several reports suggesting another potential side effect of long-term bisphosphonate therapy, namely the development of unusual fractures of the subtrochanteric or diaphyseal femur.1-4 Two initial case series described these femur fractures in a total of 12 patients (11 female) receiving current alendronate therapy. The mean age of these patients was 63 years and the mean treatment duration with alendronate was 6 years.2,4 The fracture pattern appeared morphologically distinct from the more common osteoporotic hip fracture and hence, in 2008, the term “atypical femur fracture” was introduced to describe a combination of three highly characteristic features: (i) a transverse or oblique fracture line occurring in (ii) an area of cortical thickening with (iii) a medial unicortical beak5 (Box). A further peculiar feature was the location of these atypical fractures in the subtrochanteric or mid-shaft femur, which is normally considered the strongest part of the femur. In 2007–2008, three retrospective analyses confirmed the predominance of this particular fracture pattern among bisphosphonate users.6-8 The largest of these included a study of 70 patients with non-hip femoral fractures, of whom 25 were receiving alendronate.6 The atypical fracture pattern was strongly associated with alendronate use, with a reported odds ratio of 139 (95% CI, 19–939; P < 0.001). The authors again noted that these fractures were associated with a longer duration of alendronate use (on average 4.4 years longer than patients without atypical fractures) and appeared to affect younger rather than older women. Most recently, a large 5-year retrospective study of non-hip femoral fractures found strong evidence supporting a potential association between oral bisphosphonate use and the occurrence of atypical fractures.9 Of 152 non-hip femoral fractures, 20 were classified as atypical following a detailed review of individual radiographs. Of the 20 patients, 17 had been receiving long-term therapy with either alendronate (n = 15) or risedronate (n = 2). According to this study, oral bisphosphonate use imparted a 37-fold increased risk of atypical versus typical osteoporotic fracture, with the atypical fracture pattern being 96% specific to oral bisphosphonate use.9 Other potential risk factors for developing atypical fractures include prolonged use of glucocorticoids,2,4,9,10 hormone replacement therapy,2 use of selective oestrogen receptor modulators,4 rheumatoid arthritis9,10 and vitamin D deficiency.9 The occurrence of groin or thigh pain, sometimes manifesting months before the acute fracture, has been described by several authors,1,4,7,8 with one group reporting its occurrence in 13 out of 17 (76%) atypical fracture cases.8 The pain is attributed to the development of unilateral stress fractures and should be viewed as an early warning sign in patients receiving bisphosphonate therapy. Several authors have also noted the occurrence of these fractures bilaterally.1-3,8-10 Attempts to elucidate the precise incidence of these fractures or to confirm their association with bisphosphonates on an epidemiological or observational scale have proved elusive. In 2009, a registry-based cross-sectional study of 11 944 patients failed to demonstrate a greater frequency of subtrochanteric or diaphyseal femoral fractures in patients receiving alendronate.11 Similarly, in 2010, a secondary analysis of three large randomised bisphosphonate trials including 14 195 patients concluded that subtrochanteric femoral fractures were very rare and statistically not associated with bisphosphonate use.12 However, these studies, did not assess individual fracture radiographs but, rather, relied on written reports, all of which were created many years before the recognition of the atypical fracture pattern as a distinct entity. Hence, although these studies indicate that subtrochanteric or diaphyseal femur fractures in patients receiving bisphosphonates are very rare, they do not provide definitive information on the potential association between bisphosphonate use and the occurrence of atypical fractures. The subtrochanteric location of these femoral fractures may offer potential insight into their biomechanical evolution. The theory of bisphosphonate-related severe suppression of bone turnover, with the development of a transverse fracture in the area of maximal weight-related stress, is supported by a number of bone biopsy studies2,4,13 but remains controversial due to the lack of clear causal evidence. In conclusion, the evidence supporting an association between bisphosphonate use and atypical fractures remains preliminary, with the failure of large epidemiological and observational studies to substantiate such an association. Certainly, these fractures are rare and their biomechanical evolution remains unclear. With all of this in mind, physicians should remember that bisphosphonates are highly beneficial in the management of osteoporosis and that their anti-fracture effects by far outweigh the risks posed by this rare, potential reaction. However, they should also be aware of the possibility of atypical femur fractures in patients receiving prolonged oral bisphosphonate therapy, and maintain a low threshold for investigating those who report otherwise unexplained thigh or groin pain. Atypical and typical osteoporotic fractures of the femur A: Radiograph demonstrating the characteristic appearance of an atypical femoral fracture: a transverse or oblique (< 30°) fracture line in an area of cortical thickening with a medial unicortical beak. The biomechanical theory of severe suppression of bone turnover with an insufficiency fracture and secondary cortical thickening at the area of maximal weight-related stress has been proposed. The patient had been receiving alendronate for 7 years before the spontaneous development of this fracture. B: Radiograph demonstrating a typical osteoporotic spiral fracture involving the diaphyseal femur.

Christian M Girgis MB BS(Hons) · Markus J Seibel MD, PhD, FRACP

Objective: To implement and evaluate a multimodal intervention to improve osteoporosis treatment in patients with a fragility fracture.Design, setting and participants: Strategies to improve the management of patients discharged from an emergency department after presentation with fragility fracture were implemented prospectively in a large tertiary public hospital. Patients were surveyed by post to assess their awareness of osteoporosis and of the need for treatment. General practitioners and hospital clinicians completed an online questionnaire about their attitudes to osteoporosis and its management. A simplified consensus guideline was developed for local use. Our study was conducted between 1 October 2007 and 31 October 2008.Main outcome measures: Rates of referral of patients for osteoporosis review; rates of investigation and treatment.Results: Although most GPs (259/306 [85%]) accepted that it was their responsibility to assess and treat their patients and inform them of their osteoporosis risk, only 35/87 patients (40%) indicated awareness of their risk. After implementation of our project, the rate of bone mineral densitometry investigations improved from 6/200 (3%) to 39/87 (45%) (P < 0.05). The number of patients receiving calcium and vitamin D supplementation increased from 24/200 (12%) (for both supplements) to 29/87 (33%) and 32/87 (37%), respectively (P < 0.05). Initiation of specific treatments increased from 12/200 (6%) to 26/87 (30%) (P < 0.05). Referral of eligible patients to the Fragile Bone Clinic for osteoporosis review improved from 20/500 (4%) to 51/194 (26%). After being contacted by a fracture liaison nurse, 84% of these patients presented for osteoporosis review in the clinic.Conclusions: A major key to improving osteoporosis management is to actively identify all patients at risk and proactively engage and encourage them to seek assessment and management. A multimodal strategy involving a dedicated fracture liaison nurse may offer the greatest potential for improving education and patient follow-up and treatment.

Charles A Inderjeeth MB ChB, MPH, FRACP · Denise A Glennon MB BS, FRACP · Kate E Poland MB BS · Katherine V Ingram MB BS, FRACP · Richard L Prince MB BS, MD, FRACP · Victoria R Van BHSc · C D’Arcy J Holman MB BS, MPH, PhD

Objective: To examine the impact of a national current affairs television program about the association between osteonecrosis of the jaw and bisphosphonates on subsequent prescription use, fractures and deaths.Design and setting: National Pharmaceutical Benefits Scheme prescription data for 9 months after the television program were used to estimate the impact of reduced bisphosphonate use on fractures and mortality.Main outcome measures: Prescription rates, fractures and deaths.Results: The estimated reduction of 29 633 in the number of bisphosphonate prescriptions may have resulted in 70 hip fractures, 60 other fractures and 14 deaths that would otherwise have been prevented over the 9-month period of the study.Conclusion: Although it is important for patients to be informed of the risks of medication, media coverage that does not present a balanced view has the potential to do more harm than good.

Philip N Sambrook MD, LLB, FRACP · Jiang S Chen PhD · Judy M Simpson BSc, PhD · Lyn M March PhD, FRACP

Neuroendocrine tumours (NETs) are increasing in both incidence and prevalence and, as a group, are more prevalent than either gastric, pancreatic, oesophageal or hepatobiliary adenocarcinomas, or any two of these cancers combined. Clinical awareness of the protean and intermittent symptoms of NETs (eg, sweating, flushing, diarrhoea, and bronchospasm) is critical for timely diagnosis; however, the classical carcinoid syndrome is relatively uncommon. The most useful diagnostic test for gastrointestinal NETs is measurement of plasma chromogranin A (CgA) levels. Disease extent is assessed by both anatomical imaging, and nuclear imaging with radiolabelled somatostatin analogues. Pathological evaluation comprises tumour–node–metastasis classification, a minimum pathological dataset, CgA and synaptophysin immunostaining, as well as mitotic count or Ki-67 index (a marker of cell proliferation) to define grading. Resection of the primary lesion and as much metastatic disease as possible increases the efficacy of medical therapy. Other management strategies include hepatic embolisation and peptide receptor radionuclide therapy. Patients with tumours expressing somatostatin receptors should be treated with somatostatin analogues. Depending on the tumour grade, other effective agents include cytotoxics, tyrosine kinase inhibitors, and antiangiogenics. The overarching requirement for best management of patients with NETs is to ensure that they have ready access to experienced multidisciplinary clinician groups located within centres of appropriate subspecialty expertise.

Irvin M Modlin MD, PhD, DSc · Steven F Moss MB BS, MD, MRCP · Kjell Oberg MD, PhD · Robert Padbury MB BS, PhD, FRACS · Rodney J Hicks MB BS, MD, FRACP · Bjorn I Gustafsson MD, PhD · Nicholas A Wright MD, PhD · Mark Kidd PhD

Objective: To compare the efficacy and safety of a 10-day, high-dose v a 3-month, continuous low-dose oral cholecalciferol course in a vitamin D deficient population. The primary end points were the change in serum 25-hydroxyvitamin D (25(OH)D) concentrations at 3 months and the development of hypercalcaemia and hypercalciuria. Design, setting and participants: Fifty-nine vitamin D deficient inpatients (serum 25(OH)D ≤ 50 nmol/L) were enrolled in a prospective, randomised, open-label trial. Participants were randomly assigned to a high-dose regimen of cholecalciferol 50 000 IU daily for 10 days or a 3-month, continuous low-dose cholecalciferol regimen of 3000 IU daily for 30 days, followed by 1000 IU daily for 60 days. Both groups received calcium citrate 500 mg daily. Results: Twenty-six patients completed the study within 3 ± 1 months. The mean increases in serum 25(OH)D were similar in both the high- and low-dose groups (to 55 v 51 nmol/L, respectively; P = 0.9). There was no significant difference in the proportion of subjects who attained serum 25(OH)D concentrations > 50 nmol/L between the high- and low-dose groups (9/10 v 13/14, respectively; P = 1.0). Hypercalciuria (urine calcium > 7.5 mmol/day) occurred in three patients (two low-dose, one high-dose), while renal impairment worsened in one patient. No patient developed hypercalcaemia (corrected calcium > 2.6 mmol/L), vitamin D toxicity (25(OH)D > 200 nmol/L) or nephrolithiasis during the study. Conclusion: Both the 10-day, high-dose and the 3-month, low-dose cholecalciferol regimens effectively increased serum 25(OH)D to within the normal range. The high-dose regimen may be an effective and cheap alternative for patients with vitamin D deficiency. Trial registration: Australian Clinical Trials Registry ACTRN 12607000338460.

Kathryn L Hackman MB BS · Claudia Gagnon MD, FRCPC · Roisin K Briscoe BSc(Hons) · Simon Lam MB BS, FRACP, MRCP(UK) · Mahesan Anpalahan MD, FRACP, MRCP(UK) · Peter R Ebeling MB BS, MD, FRACP

Cross-border importation of traditional and prescription medications is common, and many of these drugs are not approved by the Australian Therapeutic Goods Administration. Furthermore, counterfeit versions of prescription medications are also available (eg, weight-loss medications, anabolic steroids, and medications to enhance sexual performance). We describe a 54-year-old man with the first Australian case of severe hypoglycaemia induced by imported, laboratory-confirmed counterfeit Cialis. This serves to remind medical practitioners that counterfeit medication may be the cause of severe hypoglycaemia (or other unexplained illness). Clinical recordA 54-year-old male truck driver was admitted to a regional hospital with profuse sweating, slurred speech, ataxia and confusion. He had a history of heavy smoking and moderate alcohol consumption, but denied taking any medications or using recreational drugs. On the evening before his illness, he had four standard alcoholic drinks. On examination, his blood pressure was 150/97 mmHg, body mass index was 33.3 kg/m2, and his score on the Glasgow Coma Scale was 12/15 (eye response, 3; motor response, 6; and verbal response, 3). The rest of the general and systemic examination was unremarkable. In the emergency department, his blood glucose level indicated severe hypoglycaemia (1.1 mmol/L; reference range [RR], 3.0–6.0 mmol/L). After administering 50 mL of an intravenous infusion of 50% dextrose and giving an intramuscular injection of 1 mg glucagon, his Glasgow Coma Scale score improved to 15/15. Subsequently, apart from a high-carbohydrate diet, he required an intravenous infusion of 5% dextrose at a variable rate for 4 days to maintain euglycaemia. His glucose requirement decreased slowly over the following 4 days. He was extensively investigated for hypoglycaemia while in hospital. All other haematological and biochemical parameters, except β-hydroxybutyrate, insulin and C-peptide, were normal. His serum insulin and C-peptide levels, measured on Day 1 and Day 2, were abnormally elevated relative to his low blood glucose level (ie, for the low blood glucose level in this case, the serum insulin level would be expected to be lower). The serum insulin and C-peptide levels had normalised by Day 9 (Box). The serum β-hydroxybutyrate level, measured on Day 2, was particularly low at 0.05 mmol/L (RR, < 0.20 mmol/L), consistent with insulin excess. Magnetic resonance imaging of the pancreas gave negative results for insulinoma. A plasma sulfonylurea screening test, first done on Day 9, gave a negative result. No conclusive diagnosis about this self-limiting hypoglycaemic episode was made during admission. The patient was discharged after making a full recovery. He was advised to self-monitor his capillary blood glucose level and was referred to the endocrinology clinic at our hospital for further evaluation. He attended the endocrinology clinic 2 weeks after discharge. In view of his self-limiting hypoglycaemic episode, specific enquiry was made about the use of oral medication that may have caused the hypoglycaemia. He admitted that, an hour before developing the symptoms, he took a sexual performance-enhancing medication. This was the first time he had taken any medication of this type. The medication had been bought in Vietnam by a friend. This raised the suspicion of contaminated or counterfeit medicine as the cause of the hypoglycaemia. The medication from Vietnam was in a bottle labelled “Cialis 50”. When compared with Cialis manufactured by Eli Lilly, gross differences in packaging, labelling and dose strength were noticed. High-performance liquid chromatography performed by the Australian Therapeutic Goods Administration (TGA) confirmed that one tablet of counterfeit Cialis 50 contained 152.8 mg of glibenclamide and 0.5 mg of sildenafil. The TGA and Eli Lilly Australia were subsequently officially notified. DiscussionThis is the first report of a laboratory-confirmed counterfeit Cialis tablet in Australia. There have been recent warnings about this counterfeit drug and other similar sexual performance-enhancing medications on several health websites.1-4 Cialis (tadalafil), a phosphodiesterase-5 (PDE-5) inhibitor, is a pharmaceutical drug manufactured and marketed by Eli Lilly. It can be obtained only with a prescription, and is dispensed in 5 mg, 10 mg and 20 mg, but not 50 mg, doses. Our case reveals the poor quality-control measures used during the manufacturing process of counterfeit Cialis, which not only contained a lethal dose of a sulfonylurea, but also a subtherapeutic amount of a different agent from the PDE-5 inhibitor class. Glibenclamide is not known to have any sexual performance-enhancing effect, and hypoglycaemia is not a known adverse reaction of tadalafil. Consumption of counterfeit medicines may be harmful. As many countries have not yet enacted deterrent legislation, counterfeiters often do not need to fear prosecution.5 Medicines for erectile dysfunction or sexual enhancement have a huge global market, and this is not the first report of this adverse reaction. An outbreak of hypoglycaemia, secondary to ingestion of sexual performance-enhancing drugs, including counterfeit Cialis and other unlicensed drugs, was reported recently from South-East Asia.6 These drugs also contained high doses of glibenclamide and low doses of sildenafil. The World Health Organization estimates that up to 1% of medicines available in the industrialised countries, and 10% globally, may be counterfeit.7 In Australia, the TGA is an effective regulatory authority; however, despite the regulations, overseas travel and internet purchasing may allow counterfeit medicines to be imported. Under the “Personal import scheme”, many complementary medicines can be legally imported without import permits.8 Additionally, drugs from the PDE-5 inhibitor class, such as tadalafil, which are prescription-only medicines, are not listed under “Prohibited imports and exports (drugs and precursor chemicals)” and so can be purchased on the internet with a prescription from Australia.9 A universal cyberlaw or some other form of international convention is needed to regulate promotion and sales of these types of products on the internet. The WHO acknowledges that increasing international trade in pharmaceuticals, as well as sales via the internet, has further facilitated the entry of counterfeit products into the supply chain. To combat this, in 2006 the WHO helped to create the International Medical Products Anti-Counterfeiting Taskforce (IMPACT).5 Consumers are encouraged to use web sources like the TGA, Health on the Net Foundation, and the WHO to get useful and reliable online health information on medicinal products.10-12 Based on this case, we suggest that health warnings about counterfeit sexual performance-enhancing medications should be published on the TGA website. Glucose, insulin and C-peptide levels during admission Day 1 Day 2 Day 9 Glucose (RR, 3.0–6.0), mmol/L 2.4 2.8 4.7 Insulin (RR, 2–23), mU/L 17 11 0.3 C-peptide (RR, 0.3–1.4), nmol/L 2.6 Not done 0.7 RR = reference range.

Santosh K Chaubey MB BS, MD · Kunwarjit S Sangla MB BS, FRACP · Emershia N Suthaharan MB BS, MD · Yong M Tan MB BS, FRACP, FRCP(Edin)

Objective: To audit and describe the effects of participation in the Dose Adjustment for Normal Eating (DAFNE) course on clinical outcomes in people with type 1 diabetes mellitus (T1DM).Design, setting and participants: Audit of clinical outcomes before and 1 year after DAFNE training for 145 people with T1DM who participated in courses at seven Australian diabetes centres between February 2005 and March 2007. Participants had been diagnosed with T1DM at least 1 year before and were beyond the “honeymoon phase”, with glycated haemoglobin (HbA1c) < 12% and no severe diabetes complications. They were aged over 17 years and able to understand written and spoken English.Intervention: A 5-day structured education program covering T1DM management with an emphasis on unrestricted diet, precise carbohydrate estimation and prandial insulin dosing using insulin-to-carbohydrate ratios.Main outcome measures: Glycaemic control (HbA1c levels), weight, severe hypoglycaemia, and quality of life scores on general (Hospital Anxiety and Depression) and diabetes-specific (Problem Areas in Diabetes) scales.Results: Mean HbA1c fell from 8.2% to 7.8% (95% CI for change, − 0.5% to − 0.2%; P < 0.0001) and weight from 75.1 to 74.2 kg (95% CI for change, − 1.6 to − 0.2 kg; P = 0.012). Severe hypoglycaemia was less frequent after DAFNE training (P = 0.0001). Quality of life improved (P < 0.0001 for both scales).Conclusions: One year after participation in the DAFNE program of structured education, people with T1DM showed improved glycaemic control, reduced incidence of severe hypoglycaemia, slightly reduced weight and improved quality of life. The DAFNE course offers one means of improving clinical outcomes in T1DM.

H David McIntyre MB BS, FRACP · Brigid A Knight BSc, GradDipNutrDiet · Dianne M Harvey BSc, GradDipDietetics · Marina N Noud MNurs, DipEd, CDE · Virginia L Hagger MPH, RN-CDE, GradDipVet · Kristen S Gilshenan BMaths(Hons), BInfoTech

Recent research has confirmed that Australian children and pregnant women are mildly iodine deficient. A considerable proportion of the pregnant population is moderately to severely iodine deficient. Even subclinical hypothyroidism in the mother, occurring as a consequence of iodine deficiency, can cause irreversible brain damage in the fetus, making it essential to avoid iodine deficiency in pregnancy. The proposal of Food Standards Australia and New Zealand (FSANZ) — Mandatory Iodine Fortification for Australia (P1003) — has been implemented. FSANZ openly admits P1003 is inadequate for covering the needs of pregnant women. Therefore, health professionals and the public must be properly informed about the limitations of this proposal. Views differ about the most effective measures to prevent iodine deficiency in Australia. We propose that women planning a pregnancy, and pregnant and lactating women should be advised to take an iodine supplement. Women with pre-existing thyroid disease should exercise caution and seek medical advice before taking a supplement.

Gisselle Gallego BPharm, PhD · Stephen Goodall BSc, MSc(Health Econ), PhD · Creswell J Eastman MD, FRACP, FAFPHM

The 21st century has the most diabetogenic environment in human history with the number of people with diabetes worldwide increasing to 380 million by 2025. The fastest rate of increase will be in developing countries. Diabetes is now the major cause of end-stage kidney disease globally; 20%–40% of people on dialysis are diabetic. In Australia, the number of people with type 2 diabetes starting dialysis increased fivefold between 1993 and 2007. We must act now at local, national and international levels to prevent type 2 diabetes; screen for early diabetic kidney disease; increase public awareness of kidney disease; treat with medications proven to reduce kidney disease progression; and promote research into and trialling of new therapies. The problem is global yet requires local action. World Kidney Day on 11 March 2010 is a time to intensify action on diabetic kidney disease and to continue to do so until this huge but largely preventable health burden is controlled.

Robert C Atkins MSc, DSc, FRACP · Paul Z Zimmet PhD, MD, FRACP

Incorrect internet address. In “AUSDRISK: an Australian Type 2 Diabetes Risk Assessment Tool based on demographic, lifestyle and simple anthropometric measures” in the 15 February 2010 issue of the Journal (Med J Aust 2010; 192: 197-202), there was an error in the second-last paragraph of the Discussion (page 201). The internet address for the AUSDRISK patient-friendly questionnaire should have been <http://www.bakeridi.edu.au/aus_diabetes_risk>.

Lei Chen · Dianna J Magliano · Beverley Balkau · Stephen Colagiuri · Paul Z Zimmet · Andrew M Tonkin · Paul Mitchell · Patrick J Phillips · Jonathan E Shaw

Objective: To develop and validate a diabetes risk assessment tool for Australia based on demographic, lifestyle and simple anthropometric measures.Design and setting: 5-year follow-up (2004–2005) of the Australian Diabetes, Obesity and Lifestyle study (AusDiab, 1999–2000).Participants: 6060 AusDiab participants aged 25 years or older who did not have diagnosed diabetes at baseline.Main outcome measures: Incident diabetes at follow-up was defined by treatment with insulin or oral hypoglycaemic agents or by fasting plasma glucose level ≥ 7.0 mmol/L or 2-hour plasma glucose level in an oral glucose tolerance test ≥ 11.1 mmol/L. The risk prediction model was developed using logistic regression and converted to a simple score, which was then validated in two independent Australian cohorts (the Blue Mountains Eye Study and the North West Adelaide Health Study) using the area under the receiver operating characteristic curve (AROC) and the Hosmer–Lemeshow (HL) χ2 statistic.Results: 362 people developed diabetes. Age, sex, ethnicity, parental history of diabetes, history of high blood glucose level, use of antihypertensive medications, smoking, physical inactivity and waist circumference were included in the final prediction model. The AROC of the diabetes risk tool was 0.78 (95% CI, 0.76–0.81) and HL χ2 statistic was 4.1 (P = 0.85). Using a score ≥ 12 (maximum, 35), the sensitivity, specificity and positive predictive value for identifying incident diabetes were 74.0%, 67.7% and 12.7%, respectively. The AROC and HL χ2 statistic in the two independent validation cohorts were 0.66 (95% CI, 0.60–0.71) and 9.2 (P = 0.32), and 0.79 (95% CI, 0.72–0.86) and 29.4 (P < 0.001), respectively.Conclusions: This diabetes risk assessment tool provides a simple, non-invasive method to identify Australian adults at high risk of type 2 diabetes who might benefit from interventions to prevent or delay its onset.

Lei Chen MD, MMed · Dianna J Magliano BAppSci(Hons), MPH, PhD · Beverley Balkau PhD · Stephen Colagiuri MD, FRACP · Paul Z Zimmet MD, PhD, FRACP · Andrew M Tonkin MB BS, MD, FRACP · Paul Mitchell MD, PhD, FRANZCO · Patrick J Phillips MB BS, MA, FRACP · Jonathan E Shaw MD, MRCP, FRACP

To the Editor: We write to encourage policy debate over newborn screening for congenital adrenal hyperplasia (CAH). Classical CAH is a severe, life-threatening disease affecting about one in 15 000 liveborn infants in Australia.1 An inexpensive screening test for newborns is available, but this test is not included in the current newborn screening program in Australia. Three-quarters of children with CAH have the severe salt-wasting type that typically presents with failure to thrive, and progresses to severe hyponatraemic, hyperkalaemic dehydration and shock due to an adrenal crisis within weeks of birth. CAH is the most common cause of ambiguous genitalia in neonates (due to virilisation from adrenal androgens in utero); girls with CAH may be incorrectly assigned as boys unless the diagnosis is made without delay. CAH can be easily detected in neonates before the onset of illness by an established heel-prick newborn screening test that has good specificity and sensitivity, especially when used together with second-tier testing. Screening for CAH has been available for 30 years internationally, and is used in all American states, New Zealand and many countries in Europe, Asia and Latin America. Newborn screening reduces mortality and incorrect sex assignment.2 Case reports from Australia3 and overseas4 have shown that undiagnosed CAH is a cause of apparent sudden infant death syndrome. These deaths could have been prevented if newborn screening was in place. A pilot study in New South Wales showed that newborn screening for CAH prevented salt-wasting crises and their potential long-term consequences.1 The cost-effectiveness of newborn screening is difficult to measure, and there is little published evidence on this subject. Although a recent study suggested that CAH screening is not cost-effective,5 the only outcome assessed was mortality; other benefits of early diagnosis and intervention — including reduced morbidity and psychological impact — were not assessed. Newborn screening for CAH is not expensive; the cost per test within the laboratory is about $2, and the incremental cost per infant is in line with other newborn screening tests. In a recent survey, the Australasian Paediatric Endocrine Group found that 91% of paediatric endocrinologists considered provision of newborn screening for CAH in Australia to be very important. The Newborn Screening Joint Subcommittee of the Human Genetics Society of Australasia unanimously supports the inclusion of newborn screening for CAH in all Australian states. Two Australian parent and patient advocacy organisations — the CAH Support Group Australia, and Caring and Living as Neighbours — also strongly support the proposal for adding newborn screening for CAH to the current screening program. Despite clear predicted benefits and agreement among key stakeholders and expert advisers, no state in Australia currently screens for CAH. It is the state governments — guided by the Australian Health Ministers’ Advisory Council — who decide on funding for newborn screening tests, and who should be accountable for acting against the weight of expert opinion and systematic evidence.

Garry L Warne · Katrina L Armstrong · Thomas A Faunce · Bridget M Wilcken · Avihu Boneh · Elizabeth Geelhoed · Maria E Craig

To the Editor: Our positive experience with insulin pump therapy (IPT) in children without private health insurance contrasts with that of Thong and colleagues,1 who found that IPT did not significantly reduce glycated haemoglobin (HbA1c) levels in uninsured adults. IPT improves metabolic control, reduces the risk of microvascular complications and improves quality of life in children with type 1 diabetes mellitus.2,3 Private health insurance fully rebates the cost of an insulin pump, but many uninsured Australian children with type 1 diabetes are denied access to IPT because their family cannot afford the $8000 purchase price of an insulin pump. The other major impediment to using IPT is the paucity of access to skilled local IPT teams. In November 2008, to improve access to IPT, the federal government introduced a means-tested subsidy (to a maximum of $2500 per child) to be administered through the $5.5 million Type 1 Diabetes Insulin Pump Program.4 By 30 June 2009, the program had subsidised only 31 children for insulin pump purchase (unpublished correspondence from the Hon Mark Butler MP, Parliamentary Secretary for Health, to Mr Darren Chester MP, Member for Gippsland, July 2009). The largest user of this scheme, Gippsland Paediatrics (a private practice in rural Victoria), commenced IPT in 11 of the 31 children. Through local service clubs and other charitable institutions, we raised the funds required to pay the $5500 balance for all 11 children.5 Six other financially disadvantaged Gippsland Paediatrics patients had obtained insulin pumps through grants or community fundraising before the government subsidy program was introduced. Thus we have experience of 17 children, aged between 4 and 18 years (mean, 10.8 years) who were recipients of “donor” pumps. This sample represents about a quarter of the local children with type 1 diabetes and almost two-fifths of the 46 patients we have commenced on IPT. To evaluate the metabolic outcome of IPT for these 17 children, we conducted a retrospective analysis of glycaemic control by comparing the average level of HBA1c during the 12 months before commencing IPT with the most recent HbA1c level. The pre-IPT mean HbA1c level of children using the donor pumps was 9.2% (SD, 1.45%), which fell to 7.6% (SD, 0.83%) (P < 0.001) after a mean IPT duration of 10.2 months (SD, 6.1 months). In children aged 12 years or under (10 patients), the mean HbA1c level fell from 9.0% (SD, 0.94%) to 7.6% (SD, 0.43%) (P < 0.001) after a mean IPT duration of 11.9 months (SD, 7.6 months). In the remaining seven patients, aged 13–18 years, the mean HbA1c level fell from 9.4% (SD, 2.0%) to 7.8% (SD, 1.43%) (P = 0.03) after a mean IPT duration of 7.6 months (SD, 1.4 months). Gippsland Paediatrics uses the RADICAL (Rural Australian Diabetes — Inspiring Control Activity & Lifestyle) model of care.6 The model consists of a collocated multidisciplinary team, including a general paediatrician, diabetes educator and counsellor, with the patient and family receiving proactive emotional support, consistency of personnel, and point-of-contact HbA1c testing. We individualise our approach through regular case conferences and try to match therapy with desired lifestyle. Our study demonstrated that, using this model, IPT improves glycaemic control in uninsured children targeted by government policy — at least in the short term. To improve short-term health and reduce long-term diabetic complications in families who cannot afford insulin pumps, government programs need to make IPT more accessible to those families and support local multidisciplinary IPT teams.2

Peter W Goss

When I took a call from MJA Editor Martin Van Der Weyden asking me to write a “Power of One” article for the Christmas issue of the Journal, I was excited and honoured. Here was an opportunity to reflect on the drivers and influences that led me first into medicine, then diabetes and public health advocacy. Baker IDI Heart and Diabetes Institute, Melbourne, VIC. Paul Z Zimmet AO, MD, PhD, FRACP, FRCP, FAFPHM, FTSE, Director Emeritus and Director of International Research paul.zimmetATbakeridi.edu.au In the beginningThe story starts in the small town of Tarnopol in Poland. My father, Jacob Zimmet, studied medicine in Vienna and graduated in 1935. He returned to an unpaid position in the Tarnopol Hospital — unpaid because Jewish doctors could not be “officially” employed in Poland. Realising there was no future for him there, and having experienced the mounting threat of Nazism in Austria, he applied for visas to Australia and the United States in 1937. The Australian visas arrived first, but my mother, Anna, wanted to burn them. She dreaded leaving their families; but my father was certain war was imminent. So, in December 1938, my parents and Rena, their first child, left for Sydney, arriving in January 1939. World War II broke out in September. The remaining family were taken to concentration camps; there were no survivors except my mother’s younger brother.1 My father found that his medical degree from Vienna, one of the world’s finest universities, was not recognised in Australia because Austria was under German occupation. So, after living virtually penniless in Sydney for 6 months, he moved the family to Adelaide where it would take him only 3 years to requalify, rather than 5 years in Sydney. My parents had to find supporting income and, as my mother had brought a treadle sewing machine from Poland, they established a leather business. Mother sewed, and father skipped lectures at the medical school and bicycled around Adelaide to obtain orders. Arriving on the scene — my start in lifeI was born in 1941, and my father graduated from the University of Adelaide in 1942. He obtained a position as a doctor with BHP, and we moved to Whyalla. It was here that the seeds of my future medical career were planted. My father had a wonderful bedside manner and was adored by his patients. I would accompany him on his rounds in Whyalla and to outlying cattle stations and mining communities like Iron Knob, sitting in the back seat of our old Chevrolet. This was my first taste of medicine. In 1950, we moved back to Adelaide. My father commenced general practice, working from our home so we always had patients around us. It was clearly a powerful influence. In later years, he was very proud that three of his children, Rena, Leon and myself, studied medicine and became Fellows of the Royal Australasian College of Physicians because, with the war interrupting his studies and changes in specialist recognition in Australia, he had been unable to practise as a consultant physician. My youngest sister, Miriam, was smarter and elected instead to join the teaching profession, and she has made a significant contribution to community activities. Today, my father would have been even prouder of my sons, Hendrik (cardiology) and Marcel (paediatrics), who have followed the same path, and another grandson, Adam Zimmet, a cardiac surgeon. Although I always wanted to study medicine, I had a less than impressive school record. Only when I reached the University of Adelaide did I come into my own, obtaining a Commonwealth Scholarship based on my first-year results. However, it was then that my medical career nearly ended. On the first day of second-year medicine, we were introduced to the anatomy dissection room. I lasted for 15 minutes before heading up North Terrace to my father’s consulting rooms to tell him I was ditching medicine! I was marched back to the medical school, and that was that. A fond memory of my student days was the clinic dinner at the end of each rotation when we wined and dined our consultants, but this was not for one of them, Basil Hetzel, who had a remarkable career in medicine.2 For Basil, it was a cup of tea and a sandwich in the ward clinic room! At this stage, I had no career aspirations apart from joining my father’s practice. However, because of the small Jewish community in the area, I moved to Melbourne in 1966 in the hope of finding a wife to bring back to Adelaide. I was offered a second-year residency at the Alfred Hospital but, as I had not consolidated my relationship with my wife-to-be, Vivien, by the end of that year, I needed to stay another year in Melbourne. Luck was on my side, as Don Cameron, who was Registrar of the Diabetes and Metabolic Unit at the time, told me that his boss, Pincus Taft, wanted to know if I was interested in the diabetes job. Thus, serendipity stepped in as a partner to Cupid — it seemed a good opportunity and gave me another year to court my future bride. So began a career in diabetes. The first taste of researchDuring that year (1967), I had my first real taste of the excitement of research. We had a case of intestinal lymphangiectasia with marked hypocalcaemia and tetany that was unresponsive to calcium replacement.3 Hal Breidahl, my consultant, and I were puzzled by this. While on a skiing holiday at Falls Creek, I was listening to the “Farmers Hour” on radio, and the penny dropped! They were discussing how magnesium relieved grass tetany in the local cows. Racing back to Melbourne, I arranged a test of the serum magnesium level, which demonstrated hypomagnesaemia. Following magnesium replacement, the tetany ceased and the serum calcium level rose. Thus arose my first publication, in the British Medical Journal.4 I carried the acceptance letter around in my pocket for months. Fortune smiled on me again and, as luck would have it, my next step profoundly influenced my career direction. Monash University was opening a Department of Medicine at the Alfred — I was determined to be their first registrar, and was subsequently appointed. Even though applications for all the other hospital jobs had closed by this time, Pincus Taft called me to say that Bryan Hudson, Head of the Monash Department of Medicine at Prince Henry’s Hospital, had called to ask why Zimmet had not applied to be his registrar. Pincus ordered me to see the charismatic Bryan immediately, and he told me I was to work for him! Hudson’s department had a powerful team including Henry Burger, Kevin Catt, Ken McLean, and Jack Hansky; Mel Korman was the other registrar. It was a wonderful training experience, not only in endocrinology but across internal medicine. Bryan was a fabulous and caring mentor, but a research career was still far from my mind. However, Bryan insisted that I must do a PhD and dispatched me off to the Monash Department of Biochemistry under the legendary Joe “Ginger” Bornstein (Box 1). My PhD was based around Bornstein’s belief that growth hormone fragments were involved in the regulation of glucose metabolism and insulin sensitivity. I slaved at the bench for 2 years, processing hundreds of litres of urine, and isolated a peptide with hypoglycaemic action5 which, some 35 years later, has commenced clinical trials as a drug for type 2 diabetes.6 Joe was convinced that my research was “cutting edge” and that his hypothesis needed better recognition, so he sent my thesis off to be examined by Professor Rolf Luft, the chairman of the Nobel Committee! My introduction to epidemiologyThe time had come for an “overseas” stint. I chose to work with Harry Keen at Guy’s Hospital in London, as I perceived he was a rising star in the field of diabetes and already a leader in diabetes epidemiology. Intuitively, I believed my PhD work needed a population perspective and that the only way to show its real significance in human diabetes would be to test it in an epidemiological framework. Harry stood out as the person to work with, so, with a Royal Australasian College of Physicians Travelling Scholarship, I headed off to spend a year and a half with him and John Jarrett, another outstanding figure in diabetes epidemiology. That well known pub the Bunch of Grapes was adjacent to the grounds of Guy’s and, between their office, the pub and the laboratory, we threw around many ideas. It was an intensely stimulating environment. Then came my next break, and again chance came into play. It was Christmas 1973 in London, and I was flipping through a pile of old Lancet issues when I came across a 1966 article by the famous New Zealand epidemiologist Ian Prior and his colleagues. They had reported a high prevalence of diabetes in Pacific islanders.7 Pincus Taft had a private practice that included the President of the Pacific island of Nauru, Hammer DeRoburt, and, struck by Prior’s findings, I convinced Pincus that we should undertake a diabetes survey in the Micronesian community of Nauru. This plan became the focus of my attention when I returned to Melbourne. By 1975, we were all set to go. I now had my first experience of the difficulties and logistics of undertaking a survey thousands of miles from home on a remote Pacific island. Nauru was a 7-hour flight from Melbourne and there was only one Air Nauru flight a week (but at least they served Château Mouton Rothschild with the meals!). Imagine our dismay on arriving to find that Air Nauru had left most of our equipment, including the oral glucose loads, at Melbourne Airport! Well, we had to thank the British, as a search through old stocks in the pharmacy left over from the colonial days revealed hundreds of bottles of British Pharmacopoeia 50% glucose, which we diluted and made palatable for the oral glucose loads. We tested 100 people on the first day, and I was stunned by the results — 33% of them had diabetes. Pincus, who I had convinced to join me, was certain it was something to do with incorrect dilution of the glucose, or that the blood glucose methodology was flawed. So sure of this was he that he decided to return to Melbourne, leaving me on Nauru. On the second day, another 33% had diabetes; and so on it went. We finished the survey with a prevalence of over 30%, the highest national figure ever reported anywhere in the world.8 The time was ripe to start warning the world about the potential epidemic of diabetes, a disease that still had “Cinderella” status. In 1976, I presented the Nauru results, reporting the highest diabetes prevalence ever recorded for the first time internationally, at the European Association for the Study of Diabetes (EASD) meeting in Helsinki. I spoke at the opening plenary session to a packed hall, wearing a bright red safari suit (Box 2) that made quite an impression on the audience. Its use was intentional, as I wanted my message to be remembered. I had seen the suit in Aquascutum’s window when I passed through London on my way to Helsinki. I thought that even if the participants forgot my message, they might at least remember the suit! Due to a chance meeting, Nauru provided me with further opportunities in epidemiology. In 1976, the Nauru Government asked me to act as physician to the heads of state attending the South Pacific Forum. While relaxing with my family on the beach at Anibare Bay, I started up a conversation with the only other person there. It was John Hirshman, the World Health Organization Representative for the South Pacific. Incredibly, it emerged that he had been a school classmate of my mother-in-law in pre-war Vienna! John was amazed by my Nauru findings and asked me to become a consultant to the WHO. As a result, I was then asked to undertake surveys in other Pacific Islands over the next few years, including Western Samoa, Fiji, Tuvalu, Kiribati, New Caledonia, Wallis and Futuna, the Cook Islands and Papua New Guinea. In each case, the same pattern emerged of high diabetes rates with modernisation of the islanders’ way of life. I “borrowed” the term “coca-colonisation” from Arthur Koestler9 to explain the impact of Westernisation in causing the high prevalence of diabetes in these Pacific communities. Even so, my predictions of an impending global diabetes epidemic and the potential time bomb in terms of morbidity and mortality were not taken seriously. Of course, sometimes my passionate message was misconstrued, as happened with a leading article in Melbourne’s The Age in 1992, titled “A Western killer let loose in paradise” (Box 3). Unfortunately, the message of the article was largely missed, as a photo of me was printed directly under the headline! But at least I now knew where my career was taking me — headlong into diabetes epidemiology and public health. Uncle Sam and the NIH to the rescueIn 1978, I applied to the National Health and Medical Research Council (NHMRC) to pursue the Nauru studies in greater detail, as it promised to be a goldmine of epidemiology. Requesting a modest $25 000 grant, I was rejected because they were not funding projects offshore. Around that time, the US National Institutes of Health (NIH) became a very strong supporter of diabetes epidemiology. This thrust was led by the enthusiasm and vision of Maureen Harris, from the NIH’s diabetes section, and Peter Bennett, internationally renowned for his research into diabetes in the US Pima Indian population. They suggested I apply to the NIH, as the agency was prepared to support overseas groups if they were undertaking work that would benefit the US. I added an extra zero to my NHMRC application and, in 1979, was fortunate to receive NIH funding. The rest is history, and over the next 20 years I received grants totalling in excess of $10 million for epidemiological studies in Pacific and Indian Ocean nations. From 1979 to 2000, my research was continuously funded by the NIH. It focused on the role of genetic susceptibility, obesity, physical activity, nutrition and sociocultural change in the aetiology of type 2 diabetes. My group also made contributions in the area of type 1 diabetes causation and detection with studies on glutamic acid decarboxylase (GAD), and we developed the first anti-GAD immunoassay for predicting type 1 diabetes.10 With Ian Mackay, and Leif Groop and Tiina Tuomi from Finland, we defined the condition of latent autoimmune diabetes in adults (LADA).10 With Mark Myers and Kalindi Hettiarachchi, I reported that bafilomycin, a food toxin produced in potatoes infected by potato scab, might cause β cell damage11 and type 1 diabetes. The founding of Australia’s first diabetes instituteMy clinical and other research strands came together in 1985 when I founded the International Diabetes Institute (IDI). On the way back to Australia from my stint in the United Kingdom, I had spent time in Denmark with Jørn Nerup at the Steno Memorial Hospital in Copenhagen. I was inspired by this unique facility, which brought together all aspects of diabetes research and care. I came home determined to try to replicate it. From a small base at the Royal Southern Memorial Hospital in Caulfield, my associate physician Matthew Cohen and I gradually built up a team covering diabetes education, care and epidemiology research. The IDI was the result, and it was officially opened by the Governor-General, Sir Ninian Stephen, in 1985 (Box 4). Over the next two decades, the IDI became a major force in diabetes both nationally and internationally and was designated as the first WHO Collaborating Centre for Diabetes. My epidemiology interests next took me to Mauritius in the Indian Ocean. Again we found a very high prevalence of diabetes.12 As the population of Mauritius is tri-ethnic — Asian Indian, Chinese and Creole — it represents almost 70% of the global population, making findings there of global relevance in predicting the chronic disease epidemic.13 A very exciting collaboration with Greg Collier at Deakin University commenced in the mid 1990s. I became aware of Psammomys obesus, a unique animal model of obesity and type 2 diabetes, and imported breeding pairs from Israel. Although better known as the Israeli sand rat, it’s actually a gerbil, having 85%–90% homology with the human genome. In its natural desert habitat, P. obesus remains lean and healthy on a low-energy diet of saltbush.14 However, when given access to standard laboratory chow, the animals develop insulin resistance, obesity, type 2 diabetes and the metabolic syndrome. Greg and I established a wonderful and productive collaboration to explore the genetic aspects of “diabesity”, resulting in numerous publications, patents and an exciting decade of research. Calling the diabetes epidemicBy the mid 1990s, it was even clearer to me that obesity and diabetes were destined to be the most important public health challenges of the 21st century, and that the combined diabesity pandemic was now set to affect most nations. Yet, I was very frustrated and saddened that I still could not get diabetes on the international agenda as a major public health issue. Fortunately, the message hit home in Australia in 1996 with the appointment of a new federal Health Minister. As Shadow Health Minister, Michael Wooldridge had seen a publication, The rise and rise of diabetes in Australia,15 that my Institute had prepared for Diabetes Australia. Struck by this, and after lobbying led by John Carter, a leading Sydney diabetologist, Michael committed the Liberal Party to a pre-election promise of $8 million for tackling diabetes. With the election won, he committed himself to projects that got the ball rolling, including a National Diabetes Strategy and eventually AusDiab, the first ever national diabetes and obesity study in Australia. I was fortunate to serve on a small ministerial advisory committee with John Carter and Stephen Colagiuri. Tim Welborn and I had long been advocates for AusDiab. We put together a national consortium and, with government funding facilitated by Michael, and support from the states, the pharmaceutical industry and some trusts, we were off and running in 2000 (Box 5). AusDiab became the largest national diabetes study in the world. We found that 1 million Australian adults had diabetes, another 2 million had prediabetes, and 60% were overweight or obese.16 The study, and its 5-year follow-up, have produced more than 80 peer-reviewed publications, and the data have been used extensively for health care planning both in Australia and internationally.17 National and international recognitionOur research has received global recognition and I have been fortunate to receive numerous national and international awards, including those from the American Diabetes Association, the EASD, Diabetes UK, the Australian Diabetes Society and the Canadian Diabetes Association, and an Honoris Causa Doctoris from the Complutense University of Madrid in Spain (Box 6). In 2007, I received the global Novartis Award for longstanding contributions in the field of diabetes. In fact, the IDI pulled off a trifecta, as it was a great thrill to see Jonathan Shaw, my Deputy Director, and our collaborating ophthalmologist, Tien Wong, receive the two Novartis Awards for younger investigators the previous year. But one award beat them all. In 2007, I was advised that I was to receive the Honorary Silver Breastplate of the All-Russian Diabetes Association. Further enquiries on my part revealed that this was usually a posthumous award that had gone to distinguished researchers such as Aretaeus (147 bc), Paul Langerhans, Elliott Joslin, and Banting and Best. After I informed the Russians that I was still alive, the award was elevated to a Gold Breastplate. As I was to be in St Petersburg soon after, they dispatched an official delegation from Moscow to make the presentation (Box 7). Vivien and I were rather concerned about how we would ship a large and heavy gold breastplate out of Russia, but we need not have worried — it turned out to be a gold lapel pin! The global epidemic and public health advocacyThe forthcoming and first ever national Health Risk Study proposed for 2010 has had its genesis in AusDiab and our advocacy. We can also take some credit for many of the new initiatives in diabetes, including those directed at preventing type 2 diabetes. The current scale of diabetes and obesity in Australia has serious ramifications. Through all of this diabetes “tsunami”, funding for health professionals to handle the epidemic has fallen very short. In parts of Australia, particularly in our Indigenous community, the prevalence of diabetes and its complications, especially renal failure and amputations, exceed those seen in developing nations and rate among the highest in the world. Prime Minister Rudd recognised this burden in an address to the Sydney Institute last year, stating that diabetes will be the number one disease in Australian men, and number two in women, by 2020.18 The studies in Nauru and Mauritius enabled me to confidently predict the diabetes epidemic that has now evolved,12 and we have estimated that the global number of people with diabetes will rise from 246 million in 2007 to 389 million by 2025.19 It was against this background that, in December 2006, the United Nations (UN) General Assembly unanimously passed Resolution 61/225 declaring diabetes an international public health issue — only the second disease after HIV/AIDS to attain that status. For the first time, governments have acknowledged that a non-infectious disease poses as serious a threat to world health as infectious diseases such as HIV/AIDS, tuberculosis and malaria. The UN resolution recognises that tackling diabetes is likely to be one of the most important challenges for the global public health community in the 21st century. Because of the close link between diabetes and heart disease, about 5 years ago I approached Garry Jennings, then Director of the Baker Heart Research Institute, with the idea of merging our two institutes. The marriage is now happily consummated. Together, as the Baker IDI Heart and Diabetes Institute, we have critical mass and will be a powerful force to face the mounting burden of diabetes and heart disease — two partners in crime. We will continue our strong public advocacy for fundamental alterations to how our lives are organised. Unless we learn the lessons from Nauru and Mauritius, and indeed our own Indigenous community, the epidemics of obesity, diabetes and heart disease will only worsen. ConclusionKey features of my career have been chance and the good fortune to have wonderful and inspirational mentors, a very supportive and loving wife, and two sons, Hendrik and Marcel, who continually challenge my social values and continue the family tradition in medicine, music and debate. I have had a great partnership with that towering figure in diabetes, Sir George Alberti, with whom I have chaired numerous WHO and International Diabetes Federation expert consultations on diabetes and the metabolic syndrome, and with whom I have collaborated, along with Jaakko Tuomilehto, in epidemiological studies. I have had other very supportive colleagues and a strong and dedicated team. In particular, Matthew Cohen and Jonathan Shaw have been devoted partners, as we built the IDI into an influential and innovative force on the world diabetes scene. The merged Baker IDI Heart and Diabetes Institute is now one of the largest forces in heart disease and diabetes research in the world. It has been a long road to travel, assisted by many episodes of chance, to achieve my ambition to see diabetes recognised as a major and serious international health problem and to catalyse action for better treatment and prevention. It has been a particular privilege to be a member of the National Preventative Health Taskforce selected by Nicola Roxon, federal Minister for Health and Ageing. The National Preventative Health Strategy, released in September 2009, embraces much of my own philosophy on preventing the escalation of the obesity-driven diabetes and cardiovascular disease epidemic.20 1 The 50th Anniversary of the Discovery of Insulin Congress, Jerusalem, 1971 L–R: Paul Zimmet, Pincus Taft, Joe “Ginger” Bornstein. 2 The red safari suit, Agra, India, 1976 L–R: Paul Zimmet, Professor Tom Johnson, Professor John Jarrett. 3 Report of a killer in paradise 4 With Governor-General Sir Ninian Stephen, opening the International Diabetes Institute in 1985 5 The AusDiab consortium at the 2003 annual meeting in Melbourne 6 Receiving the Honoris Causa Doctoris from the Complutense University of Madrid, Spain, 2002 7 Receiving the Honorary Gold Breastplate of the All-Russian Diabetes Association, St Petersburg, 2007

Paul Z Zimmet

Objectives: To compare the use of evidence-based pharmacological and invasive treatments and 12-month mortality rates between patients with and without diabetes who present with acute myocardial infarction (MI), and to explore the relationship between these treatments and late clinical outcomes.Design and setting: Prospective, nationwide multicentre registry: the Acute Coronary Syndrome Prospective Audit (ACACIA).Patients: Patients presenting to 24 metropolitan and 15 non-metropolitan hospitals with acute coronary syndrome (ACS) and a final discharge diagnosis of acute MI between November 2005 and July 2007.Main outcome measure: All-cause mortality at 12 months.Results: Nearly a quarter of 1744 patients with a final diagnosis of acute MI had a history of diabetes on presentation. Patients with diabetes were older, with a greater prevalence of comorbidities than non-diabetic patients, and were less likely to be treated at discharge with evidence-based medications (aspirin, clopidogrel, a statin and/or a β-blocker) or to receive early invasive procedures. After adjusting for baseline characteristics and therapeutic interventions, diabetes at presentation was independently associated with a higher mortality at 12 months after MI (hazard ratio, 1.79; 95% CI, 1.18–2.72; P = 0.007). Early invasive management and discharge prescription of guideline-recommended medications were associated with a significantly reduced hazard of mortality at 12 months.Conclusion: Patients with diabetes have a higher risk than non-diabetic patients of late mortality following an acute MI, yet receive fewer guideline-recommended medications and early invasive procedures. Increased application of proven pharmacotherapies and an early invasive management strategy in patients with diabetes presenting with ACS might improve their outcomes.Study protocol number (sanofi-aventis): PML-0051.

Joseph Hung FRACP, FACC, FCSANZ · David B Brieger PhD, FRACP, FCSANZ · John V Amerena FRACP, FACC, FCSANZ · Steven G Coverdale MB ChB, FRACP · James M Rankin MB BS, FRACP · Carolyn M Astley RN, BN(Hons) · Ashish Soman MB BS, MRCP(UK) · Derek P Chew MB BS, MPH, FRACP

Tight glycaemic control reduces the risk of development and progression of organ complications in people with type 1 or type 2 diabetes. In this position statement, the Australian Diabetes Society recommends a general target glycated haemoglobin (HbA1c) level of ≤ 7.0% for most patients. This position statement also provides guidelines for the individualisation of glycaemic targets to a tighter or lesser degree, with a recommended target HbA1c level of ≤ 6.0% in some people, or up to ≤ 8.0% in others. Individualisation of the HbA1c target is based on patient-specific factors, such as the type of diabetes and its duration, pregnancy, diabetes medication being taken, presence of cardiovascular disease, risk of and problems from hypoglycaemia, and comorbidities. Management of diabetes also includes: adequate control of other cardiovascular risk factors, including weight, blood pressure and lipid serum levels; antiplatelet therapy; and smoking cessation.

N Wah Cheung MB BS, FRACP, PhD · Jennifer J Conn FRACP, MClinEd, BSc(Hons) · Michael C d’Emden MB BS, PhD, FRACP · Jenny E Gunton MB BS, FRACP, PhD · Alicia J Jenkins MD, FRACP, FRCP · Glynis P Ross MB BS(Hons), FRACP · Ashim K Sinha MB BS(Hons), MD, FRACP · Sofianos Andrikopoulos PhD · Stephen Colagiuri MB BS(Hons), FRACP · Stephen M Twigg MB BS(Hons), PhD, FRACP

To the Editor: Nordin and colleagues raised important issues about prescribing for osteoporosis.1 We agree that the Pharmaceutical Benefits Schedule guidelines for therapy are imperfect, but they do not necessarily lead, as Nordin et al claim, to inappropriate prescribing. For historical reasons, osteoporosis is held to be synonymous with vertebral fractures, but this misrepresents the epidemiology of fractures. Non-vertebral fractures account for 80% of all fractures and 90% of the loss of quality of life and economic costs. Vertebral fractures contribute only 20% of the burden.2 Most fractures arise in the large population at moderate risk with osteopenia — the “bell” of the Gaussian bone mineral density (BMD) distribution, not its “tail”, which comprises those with osteoporosis (defined by a bone densitometry T-score less than – 2.5). Concentrating on vertebral fractures and screening for osteoporosis with bone densitometry, as recommended by Nordin et al, is no solution to this public health problem. Nutritional change and exercise are appealing because they are safe and cost-effective approaches for early intervention, but are supported only by level D evidence (expert opinion).3 Although these approaches are plausible, no trials demonstrate their antifracture efficacy. There are no means of early identification of individuals who will sustain a fracture. Densitometry is neither sensitive nor specific for fracture; most people with osteoporosis do not sustain a fracture, and most fractures arise in people without osteoporosis, who would, paradoxically, be excluded from treatment by screening.4 Bone densitometry should be more accessible for case finding, but its use for screening does not reduce the fracture burden because of this screening paradox. However, Medicare reimbursement for densitometry is available for high-risk individuals (those with premature menopause, other illnesses or who are taking corticosteroids), not just for those aged over 70 years or those with fractures. Restricting treatment on the basis of BMD results is not advocated by the Australian and New Zealand Bone and Mineral Society precisely because it excludes this moderate-risk group from treatment, particularly those with fractures and osteopenia. There is level A evidence (meta-analysis of multiple randomised trials)5 for the antifracture efficacy of bisphosphonates in patients with osteoporosis, and evidence based on single trials6 of their antifracture efficacy in those with osteopenia and prevalent fractures, whose fracture risk is similar to that of people with osteoporosis and no prevalent fracture. There is limited evidence of antifracture efficacy of bisphosphonates in individuals with osteopenia alone.6 Preventing the first fracture is important, and guidelines are deficient in this way. Case finding to estimate absolute risk is the best approach available at this time, using risk factors, remodelling markers and, more recently, microstructural analysis to improve sensitivity and specificity. Rather than inappropriate or overprescribing, evidence suggests underutilisation of drug therapy for osteoporosis.7,8 Osteoporosis remains underdiagnosed, underinvestigated and undertreated, and limiting access to bone densitometry is not supported by the Australian and New Zealand Bone and Mineral Society.

Ego Seeman · Mark A Kotowicz · Peter T Nash · Philip N Sambrook