Controversies and consensus regarding vitamin D deficiency in 2015: whom to test and whom to treat?

Controversy persists regarding who should be tested and who should be treated for vitamin D deficiency

Controversy continues to surround vitamin D testing, the diagnosis and clinical significance of vitamin D deficiency, and the benefits — or lack thereof — of vitamin D supplementation. Over 2000 peer-reviewed articles have been published on these topics within the past 12 months, generating much debate and discussion in the scientific literature and lay media.

The role of vitamin D in skeletal and extraskeletal health

Vitamin D has an established and important role in skeletal health through its actions in mediating intestinal calcium absorption and, therefore, its effects on extracellular calcium homeostasis and bone mineralisation. Consequently, severe vitamin D deficiency results in under-mineralisation of bone (osteomalacia in adults, rickets in children) that requires treatment with vitamin D and calcium supplementation. Vitamin D deficiency is also associated with secondary hyperparathyroidism and increased bone turnover, which may contribute to osteoporosis and fracture risk.

Since the publication of a landmark randomised, placebo-controlled trial that showed that vitamin D (cholecalciferol) and calcium supplementation reduced hip and non-vertebral fractures in a group of elderly, vitamin D-deficient women,1 the correction of vitamin D deficiency and assurance of adequate calcium intake have been cornerstones of osteoporosis management. Indeed, most of the evidence for the fracture reduction efficacy of the antiresorptive therapies currently prescribed has been from clinical trials in which the study participants were vitamin D- and calcium-replete or supplemented as needed.

However, whether vitamin D and calcium supplementation is required in the majority of patients treated for osteoporosis has been challenged. Some studies have suggested that the efficacy of antiresorptive therapies is independent of baseline vitamin D status or calcium intake,2 but these conclusions were based, in part, on post-hoc secondary analyses in people who, in the majority, did not have vitamin D deficiency, using bone density as the primary end point. Moreover, a recent trial sequential meta-analysis demonstrated that vitamin D supplementation alone did not reduce total or hip fracture risk, but co-supplementation with vitamin D and calcium did, with sensitivity analyses suggesting that elderly institutionalised patients might benefit the most.3 Therefore, while it is unclear whether serum vitamin D concentration itself is a useful marker of osteoporosis risk,4 and vitamin D supplementation alone may not improve skeletal outcomes in many patients at risk of osteoporosis who might be otherwise calcium sufficient, there is evidence that older individuals at increased risk of vitamin D deficiency should be targeted for supplementation with both vitamin D and calcium to reduce fracture risk.

Even more controversial is the role of vitamin D in extraskeletal diseases such as cancer, atherosclerosis, diabetes, infections and neurodegenerative diseases. Vitamin D receptors are expressed in many non-skeletal tissues where conversion of 25-hydroxyvitamin D (25(OH)D) to active metabolites through local enzymatic action can potentially result in a wide variety of paracrine or autocrine effects,5 ranging from antiproliferation to immunomodulation. Numerous epidemiological studies show an inverse relationship between 25(OH)D concentrations and a wide range of illnesses, but these observational data are limited by possible reverse causation, residual confounding, and classification and publication biases.6 Illness can result in the contraction of outdoor activities, reduced sunlight exposure and, accordingly, low 25(OH)D concentration may be a consequence, rather than a cause, of disease.

Low vitamin D may be a marker of ill health

To minimise the impact of reverse causation, a recent systematic review examining the relationship between 25(OH)D concentration and ill health analysed prospective and nested case–control studies where the disorder of interest was not previously diagnosed and only studies that measured 25(OH)D concentrations, rather than predicted vitamin D status according to sunlight exposure or dietary intake, were included, to limit classification bias.7 The authors confirmed that most prospective observational studies showed an inverse association between 25(OH)D concentrations and a number of diverse health outcomes. However, to minimise residual confounding and determine causality, analysis of the randomised trials of vitamin D supplementation was also undertaken. This showed, almost universally, that vitamin D supplementation had little or no effect on the occurrence, severity and clinical course of these illnesses — even after subgroup analyses of subjects with vitamin D deficiency who received adequate dose supplementation. The discrepancy between the observational and interventional trial findings suggests that low 25(OH)D may be a marker, rather than a cause, of ill health — perhaps reflecting the effects of inflammation and the negative acute phase response of vitamin D-binding protein.

Interestingly, among the interventional trial data, a small survival benefit was seen in a subgroup of frail older women, a sizeable proportion of whom were in institutional care. This again suggests that frail older patients at increased risk of significant vitamin D deficiency might benefit from supplementation. Vitamin D supplementation in older patients — using cholecalciferol but not ergocalciferol — was also found to be associated with a modest reduction in overall mortality in another recently published meta-analysis.8

Benefits of vitamin D supplementation may not exceed the costs of unnecessary testing

Taken together, the current evidence suggests that the main beneficial effects of vitamin D supplementation relate to musculoskeletal, rather than extraskeletal, health outcomes, with the subset of frail older patients with the highest likelihood of vitamin D deficiency being those most likely to benefit. Nonetheless, the exponential increase in vitamin D testing and supplement use in recent years, not just in Australia but worldwide, has raised justifiable concerns that many vitamin D measurements are being undertaken without evidence-supported indications6 and many individuals are being supplemented with little evidence for benefit. Australian Medicare billing data have shown a remarkable 94-fold increase in vitamin D testing between 2000 and 2010, with repeat testing accounting for nearly half the test numbers, despite only a 0.5-fold increase in bone mineral density testing over the same period.9

Royal College of Pathologists of Australasia position statement on vitamin D testing

In response to these concerns about possible inappropriate “over-testing”, the Royal College of Pathologists of Australasia (RCPA) convened a working party and, in 2013, published a position statement to clarify the role of vitamin D testing in the context of vitamin D deficiency, with guidelines about who should be tested and when repeat testing should be performed.10

The RCPA recommendations, broadly consistent with the current evidence, advocate selective testing as an appropriate case-finding strategy in individuals at increased risk of vitamin D deficiency, and their suggested clinical indications for vitamin D measurement support this conclusion. Specifically, the routine screening of healthy adults is not recommended, with the caution that doing so might reveal a significantly sizeable group with low vitamin D levels that could lead to treatment without clear evidence of benefit and perpetuate unnecessary repeat testing. The statement also affirms the use of 25(OH)D as the best marker of vitamin D status but acknowledges that variability exists between the current assay methods. Progress is presently being made to overcome some of these methodological limitations (eg, interference from heterophilic antibodies, inefficient separation of analyte from binding protein) and improve standardisation, through the use of international serum-based reference standards, the adoption of a reference method and the introduction of an international vitamin D certification program administered by the US Centers for Disease Control and Prevention.

The recommended 25(OH)D target treatment threshold of 50 nmol/L (at the end of winter), supported by Australian5 and international guidelines, is based on skeletal health outcomes and surrogate end points. The RCPA position statement emphasises the current lack of consistent evidence for the benefit of vitamin D supplementation in the treatment and prevention of many extraskeletal illnesses. Based on the serum half-life of 25(OH)D and basic pharmacokinetic principles, repeat vitamin D testing should occur no earlier than 3 months after the commencement of supplementation or a change in dose, and no further testing may be required once the target 25(OH)D concentration is achieved.

In the climate of rising costs and limited resources, it behoves clinicians to ensure that their requests for vitamin D measurement and their prescription of vitamin D supplements are evidence-based, or at least supported by established guidelines and expert consensus, to avoid unnecessary and inappropriate testing, the medicalisation of otherwise healthy low-risk individuals and the treatment of patients who will not clearly benefit from supplementation.

The rationalisation of vitamin D measurement could foreseeably begin with education initiatives to increase general awareness and appreciation of the current evidence and guidelines for appropriate testing and supplementation. This could be followed by audit of local practice to provide data and feedback to improve and streamline guideline- and evidence-supported test requests and subsequent management. Such initiatives are preferable to imposing limitations on test frequency and prescriptive enforcement of indications for testing. The results of ongoing large prospective randomised clinical trials,1 1 such as the current Australian D-Health trial (http://dhealth.qimrberghofer.edu.au), will hopefully further clarify the role of vitamin D supplementation in the prevention and management of skeletal and non-skeletal disorders, including its effects on mortality risk, in various patient and individual subgroups.

[Perspectives] Fergus Cameron: getting the big picture in childhood diabetes

Fergus Cameron’s father encouraged him to study medicine because he thought “I’d do better in medicine rather than in business”, recalls Cameron. It turned out to be a good call. After decades as a clinician researcher, Cameron finds himself as Head of the Diabetes Services and Deputy Director of the Department of Endocrinology Unit at the Royal Children’s Hospital Melbourne (RCH), as well as a diabetes research group leader at the Murdoch Children’s Research Institute.

Pancreatic adenocarcinoma presenting as first-onset diabetic ketoacidosis

Clinical record

A 47-year-old African American man was brought by his partner to the emergency department of a peripheral hospital with increasing confusion and a 1-week history of asthenia, anorexia and significant weight loss. Significant thirst, polyuria and nausea were not indicated by the corroborative history. He had no previous medical history and did not regularly take any medications. He had never smoked and his alcohol consumption was moderate. He had not travelled overseas recently. The patient’s mother and maternal grandfather had both died of pancreatic cancer while still young, but this was not known at the time of his initial presentation.

The patient weighed 89 kg, with a body mass index of 26.0 kg/m2. His vital statistics were: heart rate, 130 beats/min; blood pressure, 99/60 mmHg; respiratory rate, 20 breaths/min; pulse oximetry, 98% on room air; and tympanic temperature, 36.7ºC. He had ketotic breath and signs of severe hypovolaemia. Incoherent responses and disorientation with respect to both time and place were exhibited during neurological examination, but no focal neurological deficits. Cardiovascular, respiratory and abdominal examinations showed nothing unusual.

The results of his initial laboratory tests are listed in the Box. They were consistent with the diagnosis of first-onset diabetic ketoacidosis (DKA) and profound hyperosmolar hypernatraemia. His estimated free water deficit was about 20 litres. His serum pancreatic enzyme levels were elevated, as were his C-reactive protein levels and white blood cell count. Chest radiography, electrocardiography, a urine drug screen, cerebral computed tomography (CT) and urine and blood cultures showed nothing unusual.

In light of the above findings, the patient was resuscitated with intravenous fluids, and insulin infusion was commenced for the treatment of DKA. Heparin was administered for the prophylaxis of venous thrombosis. He was then transferred to the intensive care unit of a tertiary referral centre for further investigation and care. His ketosis had resolved by Day 3 in the intensive care unit, and his serum sodium levels had gradually returned to normal by Day 6. At the same time, his mental functioning improved. The results of assays for diabetes-relevant autoantibodies (anti-glutamate decarboxylase and anti-islet cell antibodies) were negative, his glycosylated haemoglobin (HbA1c) level was 10.9% (reference interval (RI), 4.0%–6.0%) and his C-peptide concentration was 1377 pmol/L (RI, 200–1200 pmol/L).

The elevated pancreatic enzyme levels prompted further investigation of his abdomen and pelvis with CT; the patient’s acute renal dysfunction precluded the administration of intravenous contrast. The scan revealed a bulky pancreatic head with surrounding lymphadenopathy and multiple non-specific hypodensities in the liver. There was no radiological evidence of acute pancreatitis. Abdominal ultrasonography revealed numerous hypoechoic liver lesions consistent with metastatic disease. Levels of carbohydrate antigen 19-9 were markedly elevated (983 kU/L; RI, ≤ 37 kU/L), while the concentration of carcinoembryonic antigen was 18.1 µg/L (RI, 0–2.5 µg/L).

Despite adequate fluid replacement, the patient remained oliguric and developed deteriorating uraemia, so that haemodialysis was initiated. This facilitated further investigation with contrast-enhanced triple-phase hepatic CT, which confirmed a 25 × 23 × 17 mm heterogeneous head of pancreas mass, together with multiple hypodense liver lesions (Figure). Ultrasound-guided fine-needle aspiration biopsy of a liver lesion was performed. The cytological profile and immunohistochemical characteristics of the biopsy sample were consistent with metastatic adenocarcinoma, probably of pancreatic origin.

Palliative chemotherapy was considered, but the clinical condition of the patient deteriorated after the development of a pulmonary embolus and disseminated intravascular coagulopathy. He died on Day 35. Consent for an autopsy was not given.

Discussion

The hallmark of diabetic ketoacidosis (DKA) is the triad of hyperglycaemia, ketonaemia and metabolic acidosis. The pathogenesis of DKA involves a relative insulin deficiency and an excess of counterregulatory hormones.1 Interplay between these factors results in reduced glucose utilisation and increased gluconeogenesis, together with increased lipolysis and ketogenesis.

DKA is classically associated with type 1 diabetes mellitus (DM1) but it has been increasingly recognised that it may also occur in type 2 diabetes mellitus (DM2).2 Pancreatic adenocarcinoma presenting as DKA, however, is rare; only two other cases have been reported. The first involved a 75-year-old woman with longstanding DM2 who presented with DKA; pancreatic adenocarcinoma was later diagnosed.3 The second case was in a 36-year-old woman with a history of gestational diabetes; she presented with DKA associated with a pancreatic abscess that was later found to include pancreatic adenocarcinoma.4

Our patient was an otherwise healthy man who presented with first-onset DKA that led to the diagnosis of metastatic pancreatic adenocarcinoma. Despite the absence of a history of clinical symptoms, the elevated HbA1c and C-peptide levels, together with the absence of insulin autoantibodies, suggest that our patient may have had undiagnosed DM2. Further, our patient was African American, and an elevated incidence of DKA in African Americans with DM2 has been reported. In fact, studies have found that up to half of African American and Hispanic patients who developed DKA had features of DM2, referred to as “ketosis-prone DM2”.5,6 It has been hypothesised that the association of ketosis-prone DM2 with these ethnic groups reflects a genetic susceptibility to transient reductions in insulin production.5 The ethnicity of the two previous patients with pancreatic adenocarcinoma-associated DKA was unfortunately not reported.

It has traditionally been assumed that the development of DKA in people with DM2 requires a stressful precipitating event. Recent studies, however, have found that there were no obvious triggers in up to 25% of people with DM2 who developed DKA.7 For our patient, there was no identifiable trigger apart from his pancreatic adenocarcinoma. It is possible that a pancreatic adenocarcinoma may itself have either paracrine or paraneoplastic effects that disrupt normal pancreatic endocrine function. Indeed, it has been shown that even transient insulinopaenia is sufficient to elicit DKA in ketosis-prone African American patients.8 It is not known whether this played a role in our patient, as insulin and C-peptide levels were not assayed when he was initially examined.

Finally, the diagnosis of pancreatic adenocarcinoma in our patient was somewhat fortuitous, as initial abdominal imaging was undertaken to investigate the elevation in his serum pancreatic enzyme levels. A definitive diagnosis was further delayed by the patient’s acute renal dysfunction, which had initially precluded the use of intravenous contrast. A high degree of clinical suspicion of primary pancreatic disease is thus required when patients with features of DM2 present with first-onset DKA, especially if there are no apparent clinical triggers. Abdominal imaging may be warranted in these cases to look for less obvious precipitating events.

Lessons from practice

Diabetic ketoacidosis (DKA) has classically been associated with type 1 diabetes but there is now increasing recognition of its occurrence in type 2 diabetes.
It was previously assumed that relative insulinopaenia or stressful precipitating events were required to trigger DKA. Recent studies, however, indicate that there was no obvious precipitating factor in up to 25% of DKA cases in people with type 2 diabetes.
DKA is more common in people from certain ethnic groups (including African Americans and Hispanics) with type 2 diabetes, termed ketosis-prone type 2 diabetes.
If patients with type 2 diabetes present with DKA without any apparent trigger, abdominal imaging may be warranted to look for less obvious precipitating events.

Arterial phase of triple-phase computed tomography of the patient’s liver with oral contrast agent. Representative axial section showing hypodense head of pancreas mass (arrow).

Biochemical parameters of the patient immediately after his admission to hospital

Parameter

Value

Reference interval

7.21

7.36–7.44

Paco2, mmHg

35–45

Pao2, mmHg

80–100

Actual bicarbonate, mmol/L

22–30

Base excess, mEq/L

– 14

– 2 to +2

Lactate, mmol/L

2.3

0.5–1.6

Sodium, mmol/L

166*

135–145

Potassium, mmol/L

4.8

3.5–5.0

Chloride, mmol/L

108

97–109

Bicarbonate, mmol/L

24–32

Urea, mmol/L

27.9

3–8

Creatinine, µg/L

391

70–110

Calcium, mmol/L

2.52

2.10–2.60

Corrected calcium, mmol/L

2.54

2.10–2.60

Glucose, mmol/L

64.8

3.0–7.7

Ketone (point-of-care), mmol/L

7.7

< 3

Osmolality, mEq/L

480

280–300

Albumin, g/L

38–48

Protein, g/L

62–80

Alanine aminotransferase (ALT), IU/L

5–55

Aspartate aminotransferase (AST), IU/L

5–55

Alkaline phosphatase (ALP), IU/L

165

30–130

γ-Glutamyl transferase (GGT), IU/L

130

< 60

Bilirubin, µmol/L

< 21

Amylase, IU/L

653

20–120

Lipase, IU/L

1207

13–60

Haemoglobin, g/L

178

130–170

Platelets, × 109/L

300

150–400

White cell count, × 109/L

23.1

4–10

Neutrophils, × 109/L

18.9

2.0–7.0

Lymphocytes, × 109/L

0.9

1.0–3.0

Monocytes, × 109/L

1.4

0.2–1.0

* Serum sodium corrected for hyperglycaemia is 192 mmol/L, using the formula in Banerji, et al.9

The imperative to prevent diabetes complications: a broadening spectrum and an increasing burden despite improved outcomes

While the diabetes epidemic continues to gather pace globally, there is cause for both optimism and concern with regard to diabetes complications. A recent Australian study, in which data from a national diabetes registry collected from 1997 to 2010 was interrogated, showed that mortality rates in diabetes are decreasing,1 in line with secular decreases seen globally. Recent overseas data also show that life expectancy in type 1 diabetes is improving, yet the risk of death from any cause or from cardiovascular causes remains at least twofold higher for such patients compared with the general population.2 Thus, mortality outcomes are improving in people with diabetes and, overall, are better aligning with those of the general population. For example, Australian data indicate that between 1997 and 2010, the diabetes-related death rate for all Australians declined by 20%.3

These data, however, relate particularly to older adults, who generally now lose very few years of life due to diabetes. In contrast, in younger adults with type 1 and type 2 diabetes, mortality has remained high compared with age-matched controls.1,4 Further, subgroups including Indigenous Australians, some people born overseas and those living outside major cities of Australia have notably higher diabetes-related death rates.3 The data on complications suggest that improved strategies should now be directed to these subgroups to reduce the within-diabetes differential in mortality outcomes.

Superimposed on the general decreases in mortality rates are indications that the rates of the more severe complications in people with diabetes are also declining. Recent analysis of large US databases has shown that rates of myocardial infarct, stroke and amputation are falling.5 These secular improvements may in part be due to the earlier detection of type 2 diabetes in recent years, resulting in a less severe patient phenotype being studied — a form of lead-time bias. Nevertheless, a major factor has been the improved treatment of people with diabetes, especially in terms of modifiable risk factors; improvements in lipid levels, blood pressure and blood glucose levels and reduced background rates of smoking have each likely played a role.1 Screening and detecting diabetes complications, by history-taking and clinical examination plus dedicated screening for vascular complications, may have also contributed to improved outcomes.

Such optimism, however, gives way to concern; the combination of improvements in survival in those with diabetes and an increase in new diabetes diagnoses (related to unchecked obesity and an ageing population) are contributing to increased diabetes prevalence and disease burden.6 Thus, although the incidence of complications is declining, these benefits are overwhelmed by the sheer numbers of people affected by diabetes. This includes increasing projected numbers of younger patients with diabetes who have a high lifetime risk of complications.7 With current trends, the community burden of diabetes complications is set to increase. Therefore, a net result of our treatment success is an increase in current and projected population disability in people with diabetes (Appendix 1).8 Disability-adjusted life-years (DALYs) are projected to rise for diabetes; it has been predicted that diabetes will have the highest national disability score for any chronic illness from 2016.8 In addition, there are increasing direct health and resource costs attributed to diabetes, estimated at $1.5 billion for the 2008–09 financial year, which represents an 86% increase over an 8-year period.9 With this increasing burden, the challenge has never been greater to prevent diabetes and related complications.

Epidemiology of diabetes complications in Australia: clinical implications

Despite recent advances, complications of diabetes are a significant cause of morbidity and mortality. Diabetes is the most common cause of end-stage renal failure and of working-age blindness in Australia. However, it is notable that at any time point, most people with diabetes do not have any diabetes complications (Box 1).10 About one-third will have one or two complications, and only a minority will have more than two. The proportion of people with a severe complication is much lower — less than 5% each year for conditions including myocardial infarct, blindness, end-stage renal disease and severe hypoglycaemia.

These data inform us that, for most patients, we will be attempting to prevent onset of diabetes complications, and screening for their occurrence to better target and intensify therapy for complications that are detected. This is an important message; the opportunity currently exists to prevent onset of complications in most patients. In other patients, preventing the worsening of complications will be the aim. In those with severe end-stage complications, and in the absence of possible organ transplantation, the focus will be on palliation and active management of adverse symptoms caused by diabetes and its management.

A constellation of comorbidities: the broadening complications spectrum

To date, prevention and management of diabetes complications have focused on the long-term end-organ blood glucose-related microvascular complications (nephropathy, retinopathy and neuropathy) and macrovascular complications (cardiovascular disease [CVD], cerebrovascular disease and peripheral vascular disease), and on foot disease, as these are major causes of morbidity and premature mortality. However, the spectrum of diabetes complications is not restricted to these “traditional” forms.

The acute complications of diabetes, such as diabetic ketoacidosis or hyperosmolar coma, are part of the complications spectrum. Increasingly, “non-traditional” diabetes-related complications are being recognised, given their frequent co-occurrence with and in some cases their exacerbation by diabetes, as well as their impact on outcomes for individuals with diabetes. These include complications related to insulin resistance and the metabolic syndrome, including obstructive sleep apnoea, polycystic ovary syndrome, gout, the common diastolic dysfunction in diabetic cardiomyopathy, and non-alcoholic fatty liver disease (NAFLD). Indeed, NAFLD is more common in people with type 2 diabetes, and diabetes accelerates NAFLD to its more severe form of non-alcoholic steatohepatitis.11

Certain infections and some cancers (eg, colorectal, breast, liver and pancreas cancers) are linked to the metabolic syndrome, and cancer is an increasingly prevalent cause of death in patients with diabetes.1 Given increased longevity, diabetes-related cognitive impairment leading to dementia is becoming a clinically significant problem for our ageing population,12 as is heart failure. Periodontal disease13 and low testosterone in men with type 2 diabetes14 are also prevalent but less well recognised. In people with type 1 diabetes, related autoimmune diseases require regular consideration in care; these include thyroid disease (Hashimoto disease and Graves disease), coeliac disease, premature ovarian failure and Addison disease.15

Further, in considering the “biopsychosocial model”, prevalence of major mood state disorder (especially clinical depression) is elevated in people with diabetes compared with the general population.16 Also, forms of eating disorders are clearly increased in type 1 diabetes,17 as is the diabetes-specific psychological condition of “diabetes-related distress”, which links to the emotional burden, and demands in regimen, of having diabetes. Clinicians should be aware of such complications and comorbidities in patients and that management may fall beyond traditional diabetes paradigms. In addition, these are variably included in health economic analyses and, if accounted for, health costs of complications are likely to be greater.

Clinical lessons from studies of the pathogenesis of diabetes complications

The pathogenesis of tissue and organ diabetes complications is challenging to study as clinical disease usually takes many years to develop and progress. In addition, the propensity to develop diabetes complications is not entirely predictable from clinical profiles and risk factors alone. Genomic risk profiling in diabetes complications is not yet a clinical tool. Nevertheless, clinicians should be alert to family histories of complications as a clue to enhanced complications susceptibility, particularly for diabetic renal disease.18

Progress has been made in defining how chronic high blood glucose levels can, via cell and tissue intermediates such as advanced glycation end-products or growth factors, lead to inflammation and/or fibrosis in an organ and subsequent loss of function.19 In addition, there has been some success in targeting intermediates downstream of glycaemia to attenuate organ complications.20 For example, fenofibrate has been shown to have clinical utility in preventing some diabetes complications, most notably the progression of diabetic retinopathy,21 probably through mechanisms including antioxidant and peroxisome proliferator-activated receptor-α modulating effects. Further, in patients with severe vision threatening retinopathy, blockade of vascular endothelial growth factor (VEGF) bioactivity through intraocular antibody strategies can not only prevent blindness in those with diabetic macular oedema but also improve visual acuity.22 These findings show that if blood glucose control has not prevented severe diabetes complications in a particular patient, other clinical interventions might salvage a threatened organ.

Prevention of diabetes complications: glucose in perspective

The evolving glucocentric approach

Only late last century through randomised controlled trials targeting glycaemia was it shown that metabolic control matters in diabetes complications. In type 1 and type 2 diabetes, prevention of onset and progression of microvascular complications of diabetes was realised by chronic control of blood glucose levels.23,24 Subsequently, the epidemiological follow-up cohorts of the Diabetes Control and Complications Trial (DCCT)25 and the UK Prospective Diabetes Study (UKPDS)26 showed that macrovascular complications can be prevented by tight chronic glycaemic control in type 1 and type 2 diabetes, respectively. These studies also showed that early glucose control delivers sustained benefit in reducing the risk of onset and progression of diabetes complications across subsequent years and decades. From these observations, the concept of “metabolic memory” or “legacy effect” of early blood glucose control arose.25,26

Subsequent randomised controlled trials of chronic glycaemia — such as the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE),27 the Veterans Affairs Diabetes Trial (VADT)28 and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial29 have collectively shown that microvascular complications can also be prevented by tight chronic glycaemic control. These studies enrolled patients with more advanced diabetes than the DCCT and the UKPDS and did not show benefit in macrovascular disease or mortality. In addition, the ACCORD trial showed that harm as well as good can occur when a therapeutic strategy to intensively target blood glucose levels is used in patients with more advanced disease.29 Although the causality has not been defined for the ACCORD trial findings, together these studies of chronic glycaemia have led to the concept of individualisation of blood glucose targets to improve the benefit-to-risk ratio in people with diabetes.30

Specific regulation of postprandial glucose and its importance in terms of risk of complications in diabetes is unclear, according to a recent review by the International Diabetes Federation.31 The observational Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study showed a relationship between postprandial dysglycaemia and risk of CVD,32 while the Study to Prevent NIDDM (STOP-NIDDM Trial), which used acarbose to target postprandial dysglycaemia, showed benefit in terms of CVD but was underpowered to do so.33 Although it has not yet been shown whether targeting postprandial glucose has a benefit in terms of complications prevention above glycated haemoglobin (HbA1c) reduction alone, achieving an HbA1c level of ≤ 53 mmol/mol can only be safely realised in a patient by considering postprandial glucose levels and fasting levels.

Challenges in maintaining chronic glycaemic control

The decline in β-cell function that is usual in type 2 diabetes, and the increasing risk of hypoglycaemia in type 1 diabetes over time or after antecedent hypoglycaemia, antagonise the goal of durable glycaemic control. For type 1 diabetes, the hypoglycaemia risk is especially increased and related to autonomic dysfunction affecting the release of counter-regulatory hormones (glucagon and adrenalin). If insulin therapy cannot be further optimised, a higher HbA1c target may be required with the unavoidable compromise being a higher risk of complications. For type 2 diabetes, the need for clinicians to continue to overcome therapeutic inertia in the intensification of treatment is critical; in particular, clinicians must impress on patients the usual need for titrated pharmacotherapy in addition to lifestyle interventions.

Major challenges that add complexity to care for people with diabetes include new medicines and combinations. Expansion of treatments on the Pharmaceutical Benefits Scheme and under the Therapeutic Goods Administration requires that health professionals are continually upskilled through evidence-based education in the use of medicines for diabetes. Similarly, it remains to be seen whether the newer agents available for type 2 diabetes, including therapies based on incretin and sodium–glucose cotransporter-2 — which show varying but largely beneficial effects on non-glycaemic risk profiles in preliminary studies, including body weight and blood pressure reductions — will translate into benefits relating to complications in clinical trials. Data from cardiovascular trials involving newer hypoglycaemic agents that are currently underway, and postmarketing data for these agents, should shed light on this.

The multifactorial approach

In parallel with the trials examining glycaemia are key clinical trials such as the Collaborative Atorvastatin Diabetes Study (CARDS),34 Heart Protection Study (HPS),35 the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND),36 which have shown the importance of managing key lipid parameters and blood pressure in curtailing diabetes complications. In contrast to glycaemia, the achievement of blood pressure and lipid targets remain generally stable over time. The Steno-2 Study and follow-up study showed the significant benefit of a multifactorial approach targeting all CVD risk factors in concert, especially in people with albuminuria.37 The results of these studies emphasised that the relative impact of glycaemic control on macrovascular disease is quite modest, and that a major multifactorial emphasis on managing blood pressure, lipid levels and smoking cessation is essential in type 1 and type 2 diabetes.

Outcomes in complications screening and risk factor management

Practical strategies and related methods to aid complications outcomes in diabetes are provided in Box 2.38,39 Systematic practice of such evidence-based medicine will lead to improved patient outcomes. As reflected in recent data, the major concern is the gap between current evidence using available therapies and delivery of evidence-based care (although the gap is decreasing).40According to national data, most people with diabetes continue to not receive the complete annual cycle of care for diabetes complications screening and many are not achieving the targets (albeit generic) established in national evidence-based diabetes clinical care guidelines for blood glucose levels, blood pressure and lipid levels (Appendix 2).10 It is expected that through improved national data capture processes and diabetes complications screening programs, documented outcomes regarding managing these reversible risk factors and the related diabetes complications will also improve.40,41 Each clinical practice needs to have systematised approaches to diabetes care, and each patient needs to have his or her care personalised in goal setting and delivery to optimise diabetes complications outcomes.

Clinicians need to know the current best clinical evidence to practise and adapt for each patient. The increased availability of user-friendly evidence-based clinical care guidelines in diabetes and complications in both type 1 and type 2 diabetes across the lifecycle facilitates this process.39,42 Increasingly, these guidelines acknowledge that a generic approach has value, although a one-size-fits-all approach does not work for many patients and health care delivery settings. Thus, quality clinical care guidelines developed by the National Health and Medical Research Council include clinical practice points to help personalise care by adapting the evidence to individual patients with diabetes. Examples include type 1 diabetes, paediatric diabetes and complicated type 2 diabetes (eg, diabetic foot ulceration), which are each best managed directly by a multidisciplinary care specialist team including an endocrinologist or diabetologist, diabetes educator and nutritionist. In contrast, most patients with type 2 diabetes can be managed at a local and primary health care team level, with request for timely specialist consultation only in specific cases.

Obstetric care in diabetes requires a separate strategy that involves preconception planning (in patients with pre-existing diabetes) and high-risk pregnancy care (including in patients with gestational diabetes). This topic is beyond the scope of this article.

Diabetes complications now and into the future

As understanding of diabetes complications improves, approaches to not only prevent onset and progression but to reverse complications and loss of organ function will become increasingly possible. Some potential initiatives are addressed in Appendix 3. In the interim, improved trends in clinical outcomes tell us that there is much to be achieved by systematically applying the current evidence base and clinical tools to prevent and manage complications for the increasing number of people affected by diabetes (Box 3).

1 Prevalence and incidence of diabetes complications (type 1 and type 2 diabetes combined), according to a National Association of Diabetes Centres audit and benchmarking report, 201110

	Proportion

Prevalence of traditional complications (any severity)
0	61.7%
1 or 2	30.0%
3 or more	8.3%
Incidence of severe complications in previous 12 months
Myocardial infarct	4.0%
Coronary artery bypass grafting, angioplasty or stent	2.7%
Stroke	1.6%
New blindness	0.9%
End-stage renal disease	0.4%
Lower limb amputation	0.7%
Severe hypoglycaemia	4.8%

2 Strategies and methods to prevent and treat diabetes complications*

Complications strategy, and parameter or complication

Summarised intervention or assessment methods

Diagnose diabetes in a timely manner

Use current clinical care guidelines to screen for type 2 diabetes, including glycated haemoglobin level where indicated (now approved on the Medicare Benefits Schedule)

Engage the patient with diabetes in self-care

Develop a rapport and use chronic care models to aid self-care adherence; consider e-health initiatives (eg, medical appointment reminders)

Intensively target and manage major reversible multifactorial risk factors for organ complications*

Chronic glycaemia

Glycated haemoglobin generic target: ≤ 53 mmol/mol†

Lipid levels

LDL-C generic target: < 2.0 mmol/L†

Blood pressure

Blood pressure generic target: ≤ 130/80 mmHg†‡

Smoking cessation

Include quit smoking programs

Sustained weight loss if indicated

Calorie-controlled nutrition approach and focus on exercise

CVD absolute risk

Consider reduction in absolute CVD risk (eg, statin therapy is recommended for patients at high risk of CVD irrespective of LDL-C level unless contraindicated or clinically inappropriate)

Screen for traditional complications, generally at least annually

Eyes

Perform dilated fundus examination and test visual acuity

Kidneys

Test for albuminuria and estimated glomerular filtration rate

Peripheral nerves, including feet

Clinically assess by using a 10 g monofilament, testing reflexes, applying a tuning fork, and looking for skin and mechanical foot abnormalities

Cardiovascular

Clinically assess, especially by history-taking

Cerebrovascular

Clinically assess (eg, check for carotid bruit)

Peripheral arterial

Clinically assess (eg, check foot pulses)

Once a particular complication is detected, consider: increased frequency of specific complication reassessment; specific end-organ therapy for the complication, including antiplatelet and anticoagulant strategies in macrovascular disease; specialist referral

Retinopathy

Consider fenofibrate therapy in patients with type 2 diabetes and ophthalmologist referral for those with mild or higher grade of retinopathy

Nephropathy

Commence angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker therapy as tolerated in patients with albuminuria; consider nephrologist referral for patients with estimated glomerular filtration rate < 30 mL/min/1.73 m2 and those with macroalbuminuria

Neuropathy

Refer patients with moderate or high risk of foot ulcer to a podiatrist for education and pressure offloading; ulcers should be managed with high-risk foot service care

Ischaemic heart disease

Refer patients with evidence of ischaemic heart disease to a cardiologist and stratify patients by urgency of review

Transient ischaemic attack or stroke

Refer at-risk patients to a neurologist; assess by carotid duplex ultrasound

Peripheral arterial disease

Consider referring patients to a vascular surgeon, especially those with claudication or rest pain

Consider presence of other complications§

Depression, diabetes distress

Assess by administering the Patient Health Questionnaire-2 or Problem Areas in Diabetes Questionnaire

Diabetic gastroparesis

Assess by history-taking; perform gastric-emptying study or a generic trial of prokinetic agents

Erectile dysfunction

Assess by history-taking; trial medical therapy; consider surgical interventions

Establish a hypoglycaemia prevention and therapy plan (especially for those receiving insulin therapy)

Educate in hypoglycaemia prevention and treatment

Provide advice on balancing carbohydrate intake, exercise and insulin doses, and on frequency and timing of blood glucose monitoring; provide a specific hypoglycaemia self-treatment plan and an emergency plan

Assess for lack of hypoglycaemia awareness, severe hypoglycaemia history

Assess by history-taking; if present, consider referring patients to an endocrinologist, diabetes educator or diabetes centre

Establish a sick day management plan (for hyperosmolar non–ketotic coma or diabetic ketoacidosis)

Self-care education during intercurrent illness

Provide advice on frequency of self-monitoring of blood glucose and ketones, oral intake and insulin doses; provide an emergency plan

LDL-C = low-density lipoprotein cholesterol. CVD = cardiovascular disease. * Adapted from General practice management of type 2 diabetes — 2014–1538 and National evidence-based clinical care guidelines for type 1 diabetes in children, adolescents and adults.39 † Targets should be individualised, achieved and then maintained. ‡ The general blood pressure target in these guidelines remains ≤ 130/80 mmHg despite it being relaxed in some recent guidelines. § Common examples only are given.

3 Key learning points

By applying current readily available evidence-based knowledge to individual patients with diabetes, much can be done to prevent onset and progression of diabetes complications.
Primary care physicians have a major role in diagnosing diabetes in a timely manner and then intensively managing risk factors for diabetes complications.
Clinicians need to recognise the import of early glucose control, and an individualised and targeted multidisciplinary approach, in complications prevention. Focusing exclusively on glucose levels is insufficient to attenuate risk; a multifactorial approach with attention to cardiovascular risk factors is optimal.
Detecting diabetes complications by systematic screening can aid targeting of therapies to improve outcomes relating to complications.
Engaging patients in self-care, including through a diabetes health care team and e-health, can improve adherence to therapy and outcomes.
In the future, it is envisaged that more sensitive markers for detecting complications subclinically and options to screen for a broader range of diabetes complications, combined with improved tissue-specific therapies, will further improve complications outcomes.

Odds, risks and appropriate diagnosis of gestational diabetes

The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) diagnostic process and criteria for gestational diabetes mellitus (GDM) are designed to identify women at increased risk of a range of adverse pregnancy outcomes related to maternal hyperglycaemia; in particular, excessive fetal growth and fetal hyperinsulinaemia.1 The relationship between maternal hyperglycaemia and adverse outcomes is continuous, and more than one elevated glucose level from oral glucose tolerance testing equates to higher glucose exposure; however, one elevated glucose value is sufficient to impart a higher risk of pregnancy complications.2

We note with concern the recent article in the Journal by d’Emden, which proposes “a more statistically valid basis for diagnosing GDM”.3 It suggests that the criteria for GDM diagnosis proposed in 2010 by the IADPSG1 would result in up to 50% of women with a single elevated oral glucose tolerance test result being “inappropriately diagnosed with GDM as they do not meet the agreed risk threshold”. We consider these statements to be incorrect and offer the following arguments in rebuttal.

Interpreting odds ratios and confidence intervals

No distinction appears to have been made between “odds” and “risks” in the statistical analysis. This is incorrect4,5 and leads to a variety of erroneous conclusions.

Underlying the arguments in the article is an incorrect interpretation of odds ratios and their 95% confidence intervals (CIs). Odds ratios vary on a non-linear scale from zero to infinity, with 1.0 being the central value (point of no difference). If the 95% CI of an odds ratio does not cross unity, the association described is considered significant at the 5% level.4,5

It is wrong to suggest that 50% of subjects actually carry a risk lower than the reported point estimate. Rather, the confidence limits mean that, were a study to be repeated 1000 times, the actual odds ratio obtained would be expected to be less than the reported lower 95% confidence limit on 25 occasions.

D’Emden proposed that the lower 95% confidence limit should be used in place of the point estimate of the odds ratio in the determination of diagnostic thresholds for GDM. We strongly contend that the lower 95% CI is intrinsically less likely to be a true reflection of the prevailing odds. No statistical support was quoted by d’Emden, and such a method does not appear to be accepted in the literature. In practical terms, had the IADPSG taken this approach, it would have given a similar result to selecting a higher odds ratio threshold, based on the conventional point estimate. The IADPSG specifically chose a point estimate of 1.75 for the determination of thresholds. The consensus process specifically considered and eventually rejected alternative prespecified odds ratio thresholds of 1.5 and 2.0.

Understanding the comparisons made using data

We believe that d’Emden misinterpreted the data that he presented in Box 2.3 The odds ratios shown there, extracted from an article by two of us (A R D and B E M),2 relate to a comparison of women diagnosed post hoc as having GDM by IADPSG criteria according to various combinations of oral glucose tolerance test results ≥ threshold (1, 2 or 3 abnormal values) versus women classified post hoc as not having GDM. They bear no relation to the continuous logistic regression model that was used to determine the IADPSG-recommended diagnostic thresholds. The comparison made is entirely different. For the reasons stated above, it is incorrect to say, for example, that for women with only one elevated glucose value, “50% … did not reach the agreed risk threshold”.

As previously outlined,1 the diagnostic thresholds were defined as the average glucose values at which the odds for the three selected outcomes reached 1.75 times the estimated odds of these outcomes at mean glucose values, based on fully adjusted logistic regression models. Further, an individual woman does not have her “own” odds ratio. She, or her baby, either experience a particular outcome or they do not. As presented previously,2 the comparison after assignment of a diagnostic label at this point should be between groups of women with and without GDM as defined by the recommended criteria.

Changing the criteria may not increase frequency of GDM diagnosis

Outside these statistical concerns, we note that many objections to the IADPSG criteria appear to be founded on a presumption of more frequent GDM diagnoses with a change to the IADPSG approach from historical criteria (in Australia, predominantly the 1991 ad hoc criteria).6 Although an increase in the projected frequency of GDM (from 9.6% to 13.0%) in a cohort of women from Wollongong, New South Wales, was demonstrated with this change in criteria,7 this was predominantly due to increased GDM frequency in women treated in the private sector, suggesting possible sociodemographic influences. Another Australian study, among Indigenous women from Cape York, Queensland, reported a slightly lower GDM frequency (decreased from 14.2% to 13.4%) after a change to IADPSG criteria, but noted a threefold overall increase in GDM due to improved testing practices.8 A cohort study from Vietnam that compared the same criteria also showed a marginally lower GDM frequency (from 20.8% to 20.4%) with a change from the ad hoc criteria to the IADPSG approach.9

The IADPSG criteria include a lower threshold for fasting glucose and a higher 2-hour glucose threshold than the previous Australian ad hoc criteria, and introduce a new 1-hour threshold value. The frequency of GDM detected with IADPSG criteria will inevitably vary between population groups, likely due to different underlying prevalences of fasting hyperglycaemia as opposed to post-glucose load hyperglycaemia across varying ethnicities.

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study

Considering the HAPO study data in particular, post hoc risk ratios for a wide range of outcomes, associated with varying diagnostic thresholds based on prespecified values (1.5, 1.75 and 2.0) of adjusted odds ratios, have been published in detail.10 From review of these published data (summarised in the Box) it can be seen that the use of the IADPSG-recommended odds ratio threshold of 1.75 to determine GDM diagnostic thresholds leads to actual risk ratios approximating or greater than 2.0 when comparing women classified post hoc as GDM versus non-GDM (normal).

Measures selected by the IADPSG

D’Emden stated that neonatal adiposity (defined as per cent body fat > 90th centile) was not a predefined outcome of the HAPO study. Although not mentioned in the primary HAPO results article,11 it was clearly identified as a primary outcome from the earliest descriptions of HAPO study methods.12 Full data regarding per cent body fat and cord C-peptide were available for 73% of the total HAPO cohort of 23 316 neonates, representing the largest dataset of this type ever collected.

The inclusion of cord C-peptide > 90th centile as one criterion used for the determination of diagnostic thresholds was criticised on the basis that “it is not a routine test performed in clinical practice”. We would strongly dispute that this should be a primary reason for inclusion or exclusion of a particular measure in the definition of GDM. In fact, all the selected measures (birthweight > 90th centile, per cent body fat > 90th centile and cord C-peptide > 90th centile) are based on understanding of the pathophysiology connecting maternal hyperglycaemia to pregnancy complications. They are measures of key features of diabetic fetopathy (excess growth, excess adiposity and hyperinsulinism, respectively). Their inclusion relates directly to this nexus and we strongly contend that this is well grounded, irrespective of current clinical practice, which arguably may fall short of qualifying as a gold standard.

D’Emden also suggested that these measures were selected by the IADPSG “because they had had the greatest difference between the at-risk group and the normal group”. As participants in the IADPSG consensus process, we categorically deny this assertion. By definition, any consensus process is post hoc, as it must consider information that has already been collected. Although HAPO study investigators were involved in the consensus process, they comprised a minority of the IADPSG consensus panel, which was clearly distinct from the HAPO group. Therefore, they were not constrained to the use of primary HAPO outcome variables in selection of diagnostic thresholds. We can affirm that the measures selected and the nature of further statistical calculations were decided a priori. Further, until the thresholds were selected, there were no at-risk and normal groups to compare, so this assertion is incorrect.

Conclusion

The thresholds recommended by the IADPSG, although greatly influenced by the HAPO study, also took into consideration other available epidemiological data13–16 as well as the inclusion criteria and results of the two major randomised clinical trials in this area.17,18 In common with any dichotomous classification of essentially continuous variables, the thresholds for GDM diagnosis are, by nature, arbitrary. Further, pregnancy complications have multiple potential underlying causes. No set of criteria for diagnosing GDM could ever fully separate women at risk and not at risk of pregnancy complications. However, the IADPSG criteria do represent a considered consensus view from an expert group and are underpinned by high-level statistical expertise.

The World Health Organization agreed to adopt the IADPSG criteria,19 which have been accepted for local implementation in Australia by a consensus group including the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, the Australian Diabetes Society, Royal College of Pathologists of Australia and the Australasian Diabetes in Pregnancy Society. From January 2015, the criteria were introduced into clinical practice in Queensland, the Australian Capital Territory and variably across other states. Other local groups such as the Royal Australian College of General Practitioners have dissented, making complete local agreement unlikely. However, we continue to support the underlying methods used to develop the IADPSG consensus criteria and contend that they represent a well reasoned approach to the diagnosis of GDM.

Risk ratios for pregnancy outcomes in women with GDM versus women without GDM*

Outcome	Non-GDM (%)	GDM (%)	Risk ratio

Birthweight > 90th percentile	8.3	16.2	1.95†
Cord C-peptide > 90th percentile	6.7	17.5	2.62†
Neonatal per cent body fat > 90th percentile	8.5	16.6	1.96†
Pre-eclampsia	4.5	9.1	2.02†
Preterm delivery (< 37 weeks’ gestation)	6.4	9.4	1.47†
Primary caesarean section	16.8	24.4	1.45†
Shoulder dystocia and/or birth injury	1.3	1.8	1.44‡

GDM = gestational diabetes mellitus. * When using the International Association of the Diabetes and Pregnancy Study Groups recommended threshold values derived from a 75 g oral glucose tolerance test for GDM diagnosis (fasting, ≥ 5.1 mmol/L; 1-hour, ≥ 10.0 mmol/L; 2-hour, ≥ 8.5 mmol/L) applied to the Hyperglycemia and Adverse Pregnancy Outcome study cohort. † P < 0.001. ‡ P < 0.01.

Odds, risks and appropriate diagnosis of gestational diabetes: comment

In my opinion, McIntyre and colleagues have misunderstood the primary point I raised in my earlier article in the Journal.1 My concern was not the increased number of women diagnosed with gestational diabetes mellitus (GDM), but the accuracy of the diagnostic thresholds. Although I suggested that many women in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study with one elevated blood glucose level may not be at risk, I also stated that additional women with two or more blood glucose levels marginally below the new thresholds will be at risk. The authors’ comment that an increased odds ratio has the same effect confirms that they misunderstood my concern.

My concerns about the combined primary end point were valid and I acknowledge the response provided — but is cord C-peptide > 90th centile a true adverse neonatal outcome?

I agree that thresholds should be determined by fully adjusted models.

However, no data have been provided to refute the assertion that many women with only one elevated blood glucose level may not be at risk. Each blood glucose threshold has been determined independently and not adjusted for normal blood glucose levels.2 The thresholds should accurately define patients at risk in the HAPO study,3 so the number of women diagnosed should approximate the total number of cases of GDM (since a woman can only have one case of GDM per pregnancy). Of 23 316 participants, 3746 (16.1%) were diagnosed with GDM. There were 1935 women with an elevated fasting blood glucose level, 1928 with a raised 1-hour blood glucose level, and 1309 with a raised 2-hour blood glucose level — 5172 cases of GDM (22.2%) in total, or 38% more cases than women diagnosed with GDM.2,4 This occurs because women with two or more elevated blood glucose levels are double- or triple-counted as diagnoses. Women with two or more elevated levels have the highest rate of adverse outcomes.4 These women contribute disproportionately to the total number of adverse events for each parameter.

There is an expectation that the lower limit of the confidence interval should exceed the diagnostic odds ratio threshold, given that the minimal odds ratio of groups of these women should be 1.75. This raised additional concerns1 that many women with only one elevated blood glucose level will belong to blood glucose level categories at reduced risk, when the overall odds ratio of these cohorts is equivalent to the risk threshold.4

This is not a new problem. It confronted the Framingham statisticians who stated “analyses that fail to examine risk factors in combinations usually greatly overestimate the population-attributable risks associated with individual risk factors”,5 which is exactly the situation for women with one elevated blood glucose level only. They also stated that “multivariable risk assessment also avoids overlooking high-risk CVD [cardiovascular disease] candidates with multiple marginal risk factors and avoids needlessly alarming persons with only 1 isolated risk factor”,5 which is also the situation for women with two or more blood glucose levels just below the diagnostic thresholds in contrast to those with a single marginally elevated blood glucose level. It is reasonable to question the recommended implementation of the current thresholds.2 Subgroup analysis of the 22 152 women with two normal blood glucose levels is a valid suggestion.

The HAPO study has a wealth of data.3 Clinicians require tools that accurately diagnose women at risk. The interaction of blood glucose parameters is similar to the interaction of cardiovascular risk factors; a single cholesterol threshold does not define absolute risk for all people. We have a great opportunity to develop a risk model that would more accurately identify women at risk, based on the three blood glucose levels, age, weight, ethnicity and other parameters. This would make the most of the data from this excellent study. It has been done for cardiovascular disease, why not for GDM?

Manufacturing a human heel in titanium via 3D printing

3D printing continues to find new uses as more people get familiar with the capabilities of this relatively new manufacturing tool. Professor Peter Choong at Melbourne’s St Vincent’s Hospital proved the adage “chance favours the prepared”. His patient faced losing a foot due to a cancerous heel, so he came up with the idea of a 3D-printed alternative. He engaged medical device company Anatomics to design the implant. The CSIRO’s Lab 22 was contacted due to its capability in 3D printing and, within a week, a foot-saving replacement was used in surgery — a world first.

Using engineering principles and computer-assisted design, Anatomics manipulated the computed tomography data of the patient’s healthy heel to design a device to include muscle attachment points to support the new heel once implanted, internal structures to handle the forces of an adult heel, and porosity to reduce implant weight and facilitate tissue integration.

The CSIRO manufactured the design in its Arcam A1 printer. Using titanium Ti6Al4V powder, the printer produced the device overnight. The CSIRO and Anatomics cleaned and prepared the device for surgery. The collaborative team made several prototypes, refining the designs for form, fit and function. The final version was implanted about 24 hours after manufacturing.

There are a number of learning outcomes from this endeavour. The patient was able to keep his foot, which otherwise would have been amputated. Quality of life was preserved. The state of the art has been advanced and, following the success, more challenging applications can be undertaken with lower risk. And from the manufacturing perspective, investment in digital file manipulation, lower-cost materials and capable equipment will make the technology more accessible.

The effect of fasting diets on medication management

To the Editor: Fasting diets have been used by humans for millennia for religious and medical purposes and are now gaining popularity for wellbeing and weight loss purposes. With increasing use of short- and long-term courses of medication to manage a multitude of conditions, a question that needs to be asked is will fasting diets impact on medication regimens?

The 5 : 2 diet, where calorie intake is unrestricted 5 days a week and limited to 500 calories for women and 600 calories for men 2 days a week, is becoming increasingly popular due to widespread publicity. In humans, there is some evidence that intermittent fasting (mainly alternate day fasting rather than the 5 : 2 regimen) could lead to weight reduction, decreased insulin resistance and prevention of type 2 diabetes.1,2

It is possible that patients who are taking medication and intermittently fasting each week could encounter adverse effects or therapeutic failure. Medications of concern generally fall into two categories: those for which absorption may be significantly altered by administration on an empty stomach, and those for which increased gastrointestinal3 or other4 adverse effects may result when taken on an empty stomach (Box).

For example, the bioavailability of telaprevir when taken while fasting is 27% of that when taken with a standard meal.5 As telaprevir needs to be taken three times a day for 12 weeks for treatment of chronic hepatitis C, treatment failure may result with intermittent fasting.

On a similar note, while the absorption of warfarin is not adversely affected by fasting, it is possible that an altered diet (particularly a diet that is high in vitamin K-containing foods) in patients taking warfarin may lead to volatility in international normalised ratio.6

Caution is warranted for patients with diabetes who wish to embark on these fasting diets, despite the appeal in terms of weight loss and reduced insulin sensitivity.2 Glibenclamide, glimepiride and insulin carry a high risk of hypoglycaemia if continued as normal when fasting.7

We urge all health professionals to consider the possible impact of fasting diets on medications and investigate further where required. Information regarding potential clinical significance of the diet may be evaluated via the full product information for individual medications and through community and hospital pharmacies.

Medications that warrant further investigation in patients undertaking fasting regimens*

Medications for which adverse effects may be increased if taken while fasting

Medications for which there may be clinically significant alterations in absorption if taken while fasting

Corticosteroids, mycophenolate, tacrolimus

Itraconazole capsules, posaconazole

Doxycycline, metronidazole, sodium fusidate, tinidazole, sulfamethoxazole–trimethoprim

Atazanavir, darunavir, tenofovir, etravirine, ritonavir, saquinavir, valganciclovir, telaprevir, boceprevir

Clomipramine, fluvoxamine, paroxetine, venlafaxine

Acitretin, isotretinoin, tretinoin

Amantadine, bromocriptine, levodopa

Albendazole (for systemic infections only), griseofulvin, ivermectin, mebendazole, praziquantel

Baclofen, betahistine, cyproheptadine, dapsone, lithium, sodium valproate, tiagabine

Mefloquine, artemether–lumefantrine, atovaquone

Imatinib

Ivabradine, labetalol

Cinacalcet, spironolactone

* This list is not exhaustive.

Reassessment of the new diagnostic thresholds for gestational diabetes mellitus: an opportunity for improvement

To the Editor: With reference to d’Emden’s recent article,1 we believe the value of an internationally agreed set of guidelines has not been considered.

The World Health Organization endorsed the new diagnostic criteria for the diagnosis of gestational diabetes mellitus (GDM) as suggested by the International Association of Diabetes in Pregnancy Study Groups (IADPSG), and adopted by the Australasian Diabetes in Pregnancy Society (ADIPS),2 the Royal Australian and New Zealand Society of Obstetrics and Gynaecology, the Australian College of Midwives, the Australian Diabetes Society, the Australian Diabetes Educators Association, Austria, Canada, China, Germany, Greece, Israel, Italy, Japan, Poland and some organisations in the United States.

The benefit of an internationally agreed set of guidelines for the diagnosis of GDM cannot be understated. It would allow for a consistent approach to the definition, and provide a consistent baseline on which to answer many of the unanswered questions about GDM. As with all consensus agreements, it is likely to change over time to reflect evolving research.

The potential increase in the number of women diagnosed with GDM has been considered by the IADPSG.3 Given the current diabetes epidemic, the prevalence of GDM should reflect the prevalence of glucose intolerance in the mature adult population.

The new guidelines have been carefully considered by the international community and are consistent with a large observational study and Level 1 evidence from two well conducted clinical trials,3 with controversies raised by d’Emden debated for several years.3 ADIPS supports the common understanding that will be enhanced by international consensus.

Reassessment of the new diagnostic thresholds for gestational diabetes mellitus: an opportunity for improvement

To the Editor: A recent article by d’Emden focused on concerns about the new diagnostic criteria for gestational diabetes mellitus (GDM).1 In his article, he states that “women may be charged higher life insurance premiums because of a prior diagnosis of GDM”.1 A similar unreferenced concern was also expressed in 2013.2

We specifically examined this aspect in an Australian context.3 Twelve life insurance companies, responsible for more than an estimated 90% of the Australian retail life insurance market, were surveyed with a request from a hypothetical applicant. This applicant was a 40-year-old woman, with no current health problems, who had an episode of GDM 10 years earlier and a subsequent normal result on an oral glucose tolerance test. Ten of the twelve companies (83%) responded, and were unanimous that no additional insurance premium would be required.

The new Australasian Diabetes in Pregnancy Society criteria are likely to result in an increased prevalence of GDM.4 Logically, this may lead to an increase in the cost of initial treatment, but this cost may effectively be recovered by better obstetric outcomes.5 Local data are required.

It is inevitable that any change will be accompanied by differences of opinion. Whenever possible, these opinions should not be alarmist.