Partial foot amputations may not always be worth the risk of complications

To the Editor: Dillon and colleagues present a challenging perspective on the evidence comparing partial foot amputation (PFA) and below-knee amputation (BKA) outcomes.1,2 Australia’s diabetes-related major amputation rates have only recently reduced to international levels3 and we fear that any oversimplistic perspectives may be detrimental to these improved rates and, importantly, to our patients. Thus, we believe these articles1,2 should be read cognisant of some important points.

First, the authors correctly identify that 75% of Australia’s amputations are PFAs (toe, ray or transmetatarsal amputations [TMAs]),4 yet base their PFA arguments nearly entirely on TMA literature.1,2 TMAs are complex procedures and make up just 5%–10% of PFAs.4 Thus, we believe the article should be primarily read as a comparison between TMA and BKA outcomes.

Second, the authors correctly report higher ipsilateral reamputation risks for TMAs compared with BKAs;1,2 however, they omit lower contralateral amputation risks5 and somewhat dismiss well reported lower mortality risks.1,2,5

Last, the authors conclude “very similar functional outcomes” from data comparing methodologically different TMA studies with BKA studies or data within heterogeneous and underpowered studies.1,2 These definitive interpretations may be misleading, especially given the statistically significant functional benefits of TMAs compared with BKAs, as reported in the higher impact studies the authors cite.2,6

We thank Dillon et al for highlighting such a large, yet silent, burden of disease and hope this letter will provide more balance to this crucial life-changing decision facing 8000 Australians and their clinicians this year.4

Partial foot amputations may not always be worth the risk of complications

In reply: We appreciate the opportunity to reply to two letters submitted in response to our article.1

Both letters agree that our perspective piece was mainly based on evidence about the outcomes for people with transmetatarsal amputation, noting that most people undergo amputation of the toe(s) or toes and metatarsals. As highlighted in our supporting work,2 there are comparatively few investigations focusing on outcomes for people with digital, ray, tarsometatarsal and transtarsal amputation. Despite this, we stand by our interpretation that the rates of complications and reamputation seem very similar across levels of partial foot amputation.1,2 To illustrate, a study that stratified large numbers of people by level of partial foot amputation found that the rates of ipsilateral reamputation were not statistically different in groups with either toe, ray or mid-foot (ie, transmetatarsal, Lisfranc and Chopart) amputation.3 Given these data, we argue that our synthesis of published outcomes on the rates of reamputation and other complications for people with different levels of partial foot amputation was reasonable. Our article should not be considered a comparison between the outcomes of transmetatarsal and transtibial amputation.

We do not believe that current data show that toe amputations are becoming more common in Australia. The age-standardised incidence of toe amputation remained stable between 2000 and 2010, while the incidence of partial foot amputation at the toe and metatarsal level and transmetatarsal level increased.4

We are not advocating that more transtibial amputations should be considered to minimise the risk of complications and further amputations. Rather, clinicians should consider the emerging evidence when communicating the perceived benefits to patients; particularly given that this evidence challenges long-held beliefs.2

We are grateful for the opportunity to promote discussion and highlight awareness of the need for further research into outcomes for people facing difficult decisions about limb loss.

Age, CKD and other kidney messages

Chronic kidney disease in the elderly is common, potentially harmful and amenable to nuanced management

Every March for the past 8 years, the International Society of Nephrology (ISN) and the International Federation of Kidney Foundations have jointly organised World Kidney Day (WKD; http://www.worldkidneyday.org). The purpose of WKD is to increase the awareness of kidney disease among politicians, the general public, general practitioners, physicians, nephrologists and other health care workers. WKD has been taken up with gusto in an increasing number of countries around the world, including Australia, and it is evident that the messages are being heard and to some extent have influenced policy. This year’s WKD will be held on 13 March, around the theme of “Chronic kidney disease (CKD) and aging”. Is this a message as substantive as those of previous WKDs?

Previous messages have been standouts. In 2007, the message was that kidney disease is common (affecting 10% of adults worldwide), harmful (not only from complications of CKD and end-stage kidney disease [ESKD], but also from a substantially increased risk of premature death, especially from cardiovascular causes) and treatable.1 In 2009 and 2010, the nexus between kidney disease and hypertension and diabetes, respectively, was stressed. Hypertension is a major risk factor for CKD and a key therapeutic target.2 The prediction that there will be 1.5 billion hypertensive people on our planet by 20252 is indeed a sobering one! Diabetes, especially type 2, is now the commonest cause of CKD and ESKD in most countries3 — and things are only going to get worse before they get better. By 2025, there will be almost 400 million people worldwide with type 2 diabetes3 and a similar number with impaired glucose tolerance, many of whom will go on to develop CKD. CKD, especially in the presence of proteinuria, is a principal risk factor for cardiovascular disease.4 Cardiovascular risk rises proportionally as kidney function declines; for example, Stage 3 CKD independently carries an almost 50% increased risk of cardiac death, a risk greater than that of diabetes or previous cardiovascular disease. Considering all stages of CKD together, there is a 100-fold greater chance of premature death (especially cardiovascular) than of developing ESKD. Importantly, interventions designed to slow CKD progression and reduce proteinuria appear also to reduce cardiovascular risk.

What began as a risky experiment about 50 years ago has now become routine practice in more than 80 countries around the world; there is no doubt at all that renal transplantation is the best way to replace kidney function in patients with ESKD.5 But, currently, only 10% of global need for kidney transplantation is met, restricted by economic considerations, insufficient donors, too small a trained workforce, immunological barriers and ethical considerations.5 Last year’s WKD focused on acute kidney failure (AKF). The prevalence of AKF is increasing worldwide and most cases are preventable,6 yet prevention and dialytic support during AKF are pipedreams for many countries. In response, the ISN has launched an ambitious program called “0 by 25” with the lofty aim that by 2025 no one should die of untreated AKF in the poorest parts of Africa, Asia and South America.

So is 2014’s WKD message as weighty as its antecedents (Box)? The latest message concerns CKD and ageing.7 Just like the body that surrounds them, kidneys age; a contemporary question is whether this ageing represents progressive CKD. Another key question is whether the automatic reporting of estimated glomerular filtration rate (eGFR) has spawned an epidemic of worried but well elderly people. The answer to the second question is yes and no. Otherwise healthy elderly people with a mild reduction in eGFR are likely to see out their years without any increased risk. However, whatever the cause of impaired eGFR, especially in the presence of proteinuria and with a rate of decline more rapid than expected for age alone, there will be increased risk.8 Despite their age, elderly patients with CKD will benefit from therapies aimed at slowing disease progression, better controlling metabolic derangements, reducing cardiovascular complications and allowing informed choices about ESKD therapy. That greater life expectancy does not necessarily equate with increased years of good health probably applies more to patients with CKD than any other ageing population. But treatment of selected older patients can increase survival, whether that treatment is conservative, dialytic or by transplantation. Older patients have less chance of undergoing transplantation, usually because of their comorbidities, but they can respond well, and various strategies (such as use of marginal and older donors) have increased the donor pool. Older patients with limited comorbidities can do well on dialysis, with improved survival; yet those with comorbidities may do better with non-dialytic, conservative therapy. So messages about CKD are just as important for older patients, and their wise application among older patients may do more for global health than among younger age groups.

What should developed countries be doing to lessen the global burden of kidney disease? Many developed countries must focus on their own groups at high risk of kidney disease, such as the Aboriginal population in Australia. In addition, they can play a key role in helping low-to-middle income countries tackle their kidney disease burden. The ISN directs a large proportion of its budget and efforts towards transformational capacity-building programs, including its Fellowship,9 Sister Renal Centre and other programs.10,11 By an increasing contribution to these programs, Australia can play a key role in the global response to kidney disease.

Important global messages* about kidney disease

2007	CKD is common, harmful and treatable
2009	Hypertension is a major risk factor for CKD
2010	Diabetes is a major risk factor for CKD
2011	CKD is a principal risk factor for cardiovascular disease
2012	Transplantation is the best therapy for ESKD, but is in short supply
2013	AKF is common and preventable
2014	CKD in the elderly is common, and amenable to discerning management

* Messages of World Kidney Day. CKD = chronic kidney disease. ESKD = end-stage kidney disease. AKF = acute kidney failure.

Notifying a doctor of a first hypoglycaemic episode is associated with a lower rate of recurrence among inpatients with diabetes

To the Editor: Hypoglycaemia is a common problem in inpatients with diabetes and is associated with morbidity and mortality.1,2 We conducted a retrospective single-centre cohort study to evaluate the management (notifying a doctor and taking appropriate preventive actions, defined as altering the hypoglycaemic agent that led to the event or commencing dextrose in appropriate cases by the doctor) of the first hypoglycaemic episode and its impact on recurrence and length of stay.

We evaluated the first hypoglycaemic episode (capillary glucose level < 3.5 mmol/L) of all 915 patients with diabetes admitted to our inpatient ward over 3 months, from January to March 2012. One hundred patients experienced one or more hypoglycaemic episodes and, of these, 57 experienced recurrences. For 19 patients, a doctor was notified of the first episode. Recurrence was seen in six of these patients, compared with 51 of the 81 patients for whom
a doctor was not notified of the
first episode (P = 0.013). Severe hypoglycaemia (< 2.5 mmol/L) was seen in 11/19 patients during the
first episode in the doctor-notified group and in 18/81 patients in the doctor-not-notified group. Age, hypoglycaemic agents, symptoms and after-hours occurrence were similar between groups.

Twelve patients were admitted twice during this time. For 10 of the readmitted patients, a doctor was not notified during the first admission and, for 11 patients, a doctor was not notified during the second admission. Of the doctor-not-notified patients, five and seven in the first and second admissions, respectively, experienced a recurrence. However, none of the doctor-notified patients experienced a recurrence.

Appropriate preventive action was taken for 14/19 patients in the doctor-notified group, compared with 28/81 patients in the doctor-not-notified group (P = 0.002). Recurrence occurred in 21 of the 42 patients for whom appropriate action was taken, compared with 36 of the 58 patients for whom it was not taken (P = 0.31).

Recurrent hypoglycaemia was associated with longer length of stay: 13.5 days v 7.5 days for a single occurrence (P = 0.035).

In our study, 10% of patients hospitalised with diabetes had a hypoglycaemic episode, which is similar to previously documented rates.3 The association between notifying a doctor of the first hypoglycaemic event and a lower recurrence rate highlights the importance of notification and appropriate management of the
first episode. The association with longer length of stay is similar to that previously observed.4 A causal effect is difficult to infer due to many confounding factors and the retrospective nature of the study. As expected, there was an association between appropriate action and doctor notification. The lack of association between appropriate action and recurrences may be due
to small sample size or other factors that were not classified as appropriate action.

A three-word slogan: stop the bloat

Would it be too hysterical to declare a “diabetes emergency”? Perhaps not. An estimated 280 people develop diabetes mellitus each day in Australia, adding to the estimated 1.7 million people with the condition. This number is expected to almost double by 2030 (http://www.diabetesaustralia.com.au/Understanding-Diabetes/Diabetes-in-Australia). One in five people
with diabetes do not even know they have it (http://www.abs.gov.au/ausstats/abs@.nsf/mf/4364.0.55.005). Despite the tardiness in acting on diabetes here and globally, which Leeder details in his editorial (doi: 10.5694/mja13.10973), people are now scrambling to turn back the numbers.

In terms of meaningful diagnosis and management, let alone cure, diabetes has long proved recalcitrant for both individuals and communities. Its social and economic cost now threatens to outpace Australia’s health budget for tertiary, secondary and primary prevention of diabetes and its complications. With an estimated 3.5 million people in Australia now affected by diabetes or prediabetes, Zimmet (doi: 10.5694/mja13.10972) highlights the urgent need for a response to the “epidemic”. This word is used pointedly — he compares the scale of the problem to that of the typhoid and cholera scourges of the 19th century. It is an enormous Australian, and global, challenge. There is much to think about and act on when the World Diabetes Congress convenes in Melbourne in December.

Not surprisingly, diabetes features in cutting-edge therapeutics and in research, but also in ethical debates. Cohen and colleagues discuss the action and application of glucagon-like peptide-1 receptor agonists in glycaemic control (doi: 10.5694/mja12.11856); it remains to be seen what clinical role they will eventually play. In our ethics series, Han and Craig describe research using cord blood-derived stem cells to attenuate islet cell autoimmunity in type 1 diabetes (doi: 10.5694/mja12.10835). However, along with Stewart and colleagues (doi: 10.5694/mja12.11668), they also note the complicated ethical considerations in cord blood banking for therapeutic or research purposes.

At the community health level, the factors associated with diabetes go right down to the fundamentals of society and culture. The risks of disease are well known to stratify according to sociodemographic characteristics. Tackling social determinants, quickly knowing which strategies work and appropriately channelling resources should be central missions of health policy and deserve prominent airing in debates before the upcoming federal election. In our pre-election series, Redman and Wells (doi: 10.5694/mja13.10885) and Baum (doi: 10.5694/mja13.10873) discuss these important objectives. The research by Wickramasinghe and colleagues investigating the effect of team care and management plans on biochemical measures of diabetes control (doi: 10.5694/mja13.10161) reinforces the central role of organised and effective primary care. Any health policy put forward in the election campaign needs to recognise that both societal factors and health care delivery contribute to overall population health.

Clinical and public health research over the past few decades increasingly serves to show how fast health and health care problems develop. Continued health care reform in this context is a necessity. Bennett (doi: 10.5694/mja13.10839) outlines reform achievements since the formation of the National Health and Hospitals Reform Commission, as well as current and future challenges to Australian health care and what should be done about them. “Reform fatigue” may not be an option.

As the competition for the community’s vote nears its end, the MJA offers those who would lead us an opportunity to look beyond slogans to what is likely to make or break Australia’s health. In the case of diabetes, we ask them not to abrogate their responsibilities to those affected. This is one problem that is amenable to “solutions”. Like typhoid and cholera two centuries ago, there is real opportunity in Australia, with appropriate public health strategies, to cut the overall burden of disease and the toll that it exacts.

Can we avert a diabetes catastrophe in Australia?

Diabetes is likely to cement its place as the fastest growing epidemic in history

At the present time, one person is dying of diabetes every seven seconds, but the news can only talk about victims of hurricanes with houses flying in the air.

Nassim Taleb, Antifragile: things that gain from disorder1

During the past three decades, the number of people with diabetes has more than doubled globally, making it one of the most important public health challenges for all nations.2 During this time, the Medical Journal of Australia (MJA) has had a consistent history of highlighting the “rise and rise” of diabetes as a major public health threat.

In a 1985 MJA editorial, the sparse information on diabetes epidemiology, and its socioeconomic and public health effects on Indigenous and non-Indigenous communities, was highlighted.3 This was in spite of evidence on overseas trends that predicted a future epidemic. Ten years later, in another MJA editorial, it was noted that the predictions were being largely ignored by public health planners.4

In 1999–2000, the first national study of diabetes, the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) was conducted.5 It revealed that about 1 million Australians were affected by diabetes and 60% of adults were overweight or obese.6

In a 2006 MJA editorial, my coauthor and I pointed out that Australia was already in the throes of an unprecedented epidemic of diabetes and obesity.7 In 2007, the federal government announced a 4-year $103 million program for prevention of type 2 diabetes. However, it was poorly designed and the funding stopped in 2011. In 2008, in an address to the Sydney Institute, Prime Minister Kevin Rudd had stated:

If current trends continue, by 2020, diabetes will be the leading cause of disease for men and the second leading cause for women.8

The global diabetes epidemic can be compared with the cholera and typhoid epidemics of the 19th century and the HIV/AIDS epidemic of the 20th century. There are now 370 million people with diabetes worldwide, and this number is predicted to reach 500 million by 2030.9

Testament to the global recognition of this scenario is the landmark and unanimous 2006 United Nations General Assembly resolution which declared diabetes an international public health issue.10 This has been followed by a recent call from the World Health Assembly to reduce avoidable mortality from non-communicable diseases, including diabetes, by 25% by 2025.11

Regrettably, Australia has not seen coordinated action on this epidemic.12 We have not had a national diabetes strategy and action plan for a decade.13 Government attempts at preventing type 2 diabetes have had minimal success, and since the Prime Minister’s warning on diabetes was made, Australia has moved even closer to a “diabetes apocalypse”.

At least 1.5 million people in Australia now have diabetes, and 2 million have prediabetes.12 Consequently, about 30% of Australia’s adult population is directly affected by this important cardiovascular risk factor.

Diabetes strikes at the heart of our Indigenous population — the remote Northern Territory town of Alice Springs is close to becoming the world’s capital of diabetes in terms of prevalence.13 Diabetes is ripping through our Indigenous communities at a frightening pace, causing one of the highest rates of diabetic kidney disease in the world.

We have a frightening national scenario, from the personal individual costs of diabetes through to the costs of medical care and the adverse effects on national productivity.12,14 A recently released report from the Australian Institute of Health and Welfare15 notes that in the 2008–09 financial year, estimated expenditure for diabetes allocated by health care sector totalled over $1507 million, which was 2.3% of all allocated health care expenditure. An additional $153 million was spent on government programs and subsidies, research and gestational diabetes programs. Notably, while expenditure for all diseases increased by 60% between 2000–01 and 2008–09, that for diabetes increased by 86% in the same period. These costs are likely to be an underestimate and would have increased substantially since then.

The June 2013 launch of a new National Diabetes Strategy and Action Plan by Diabetes Australia at the National Press Club was designed to raise awareness of the urgency of addressing the diabetes agenda before the forthcoming federal election. The plan highlights the major issues requiring action and sets out five key goals, all with an emphasis on prevention:

prevent complications — through optimal management and earlier diagnosis
prevent more people from developing type 2 diabetes
reduce the impact of diabetes in pregnancy for women and children
reduce the impact of diabetes on Aboriginal and Torres Strait Islander people
strengthen prevention through knowledge and evidence.14

From a preventive aspect, there is now a focus on early life developmental events, particularly the early life impact on the fetus and the epigenetic effects of risk factors during pregnancy, including hyperglycaemia.2 It is clear that these epigenetic changes can result in intergenerational changes to risk of diabetes, creating a vicious cycle. This is a new target for prevention of type 2 diabetes.

In December 2013, the World Diabetes Congress returns to Australia after 25 years. Over 10 000 delegates are expected from developed and developing nations and they will be looking for answers on how to address this epidemic. Much has changed: we have an enviable record in diabetes research, education and care, despite the failure of governments to face the rolling epidemic head on.

The rapid growth of numbers of people with diabetes is placing an increasing burden on our society and is outpacing the resources that we have to deal with the challenge. Our governments and health authorities must address the epidemic now — the only alternative is a disease burden that could overwhelm the national health budget and damage national productivity. The options are: act now or face the consequences.

In Australia, the alarm bells continue to ring loud, yet authorities continue to ignore the warnings. Almost 20 years ago, my coauthor and I called for the establishment of a national diabetes commission to address the epidemic,4 a recommendation again made in the new National Diabetes Strategy and Action Plan.14 The delay in establishing such a commission is a national disgrace. Again I ask, is anyone in Canberra listening?

The history of insulin: the mystery of diabetes

Drawing inspiration from our forebears in scientific inquiry to face emerging global challenges

Adisease as ancient, prevalent and serious as diabetes attracts mythology, and the edges of its history blur. The ancient Greek word diabetes, originally deriving from the verb diabainein, “to pass through”, was the name for a “siphon”, referring to the associated polyuria. Aretaeus of Cappadocia (around the first century CE) was probably an early adopter of the word although another source suggests it was first used by Apollonius of Memphis around 250 BCE. Mellitus, meaning “honey-sweet”, was added by the British physician Thomas Willis in 1675 “after rediscovering the sweetness of urine and blood of patients (first noticed by the ancient Indians)”.1 However, it was not until 1776 that another British physician, Matthew Dobson, identified excess sugar in urine and blood as the cause of their sweetness.1

In 1889, Joseph von Mering and Oskar Minkowski (variously described as physicians or physiologists, depending on the source) in Strasbourg reported that they had been able to render dogs diabetic by removing the pancreas — Minkowski must have been surgically deft, whatever his other professional skills. Mythology has it that their experimental animal keeper noticed ants (or bees in another account) enjoying the urine of pancreatectomised animals. The surgery was performed in pursuit of better understanding of the digestive organs, and this discovery was made serendipitously.2

With increasing attention paid to the pancreas, ideas developed and imagination flourished. Its exocrine and endocrine functions became clearer. Frederick Banting, a 24-year-old orthopaedic surgeon in Toronto, sought to ligate the exocrine outlet to produce atrophy of that part of the pancreas, thus, he hoped, allowing the endocrine part to be studied, undigested by the pancreatic juices. With the aid of a medical student, Charles Best, Banting ligated the pancreatic ducts of a dog. As a result, the exocrine cells in the pancreas atrophied, leaving the insulin-producing islet cells. From the islets, Banting and Best produced pancreatic extracts with which they were able to ameliorate the diabetes produced by surgical removal of the dog’s pancreas. Much work followed, leading to the acrimonious award of the Nobel Prize in Physiology to Banting and head of the department where he did his work, John Macleod.3

The developments since have been phenomenal achievements in what we now call translational research. They have been realised through clinical commitment, academic competition, private enterprise by pharmaceutical companies purifying and mass producing insulin, and government support. The nature of diabetes has continued to yield complex mysteries — what once appeared to be a straightforward deficiency disorder is now known to be exceptionally complex. Insulin resistance and metabolism more generally continue to give rise to fascinating insights.

As a second-year medical student in 1960, I shared the amazement that the A and B chains of insulin had been sequenced, after Frederick Sanger received the Nobel Prize for this remarkable feat in 1958. Since then, of course, we marvel at the complex studies of the insulin molecule and the recombinant technologies that have enabled its mass production and modification.

But diabetes has admitted no easy defeat, and the current global epidemic of type 2 diabetes has shown just how much more we have to learn about the metabolic context of the disease. The seeming simplicity of attributing type 2 diabetes to obesity has begun to yield to a deeper appreciation of the underlying metabolic upheavals that occur in the form of the origin and the expression of this disease. The epidemiology of both type 1 and type 2 diabetes raises questions about regional variations in susceptibility, genetic variability and environmental factors — there is much more to be learned. We know enough to do something, but not enough to do everything.

Insulin reminds us of the power of scientific inquiry and our remarkable contemporary capacity to intervene for good. That tens of thousands of people die worldwide each year for lack of insulin, and 50% of the estimated 200 million people with diabetes remain undiagnosed, should give us pause for thought alongside this celebration. In relation to type 2 diabetes, we face challenges of a different sort, although no less complex. Much has been achieved, but much remains to be done.

Consistently high incidence of diabetic ketoacidosis in children with newly diagnosed type 1 diabetes

To the Editor: Data from the tertiary paediatric hospitals in Brisbane (Royal Children’s and Mater Children’s Hospitals) support Claessen and colleagues’ letter.1

A total of 1091 children aged < 18 years were initially admitted from 1 January 2001 to 31 December 2011 with a new diagnosis of type 1 diabetes (T1D) (Box). Diabetic ketoacidosis (DKA) was defined as venous pH < 7.3 or serum bicarbonate level < 15 mmol/L in association with hyperglycaemia and ketoacidosis. Severity was defined as mild (pH 7.2 to < 7.3, or serum bicarbonate level 10 mmol/L to < 15 mmol/L), moderate (pH 7.1 to < 7.2, or serum bicarbonate 5 mmol/L to < 10 mmol/L) and severe (pH < 7.1, or serum bicarbonate < 5 mmol/L). Overall, 348 of 1091 children (31.9%; 95% CI, 29.1%–34.7%) presented with DKA over the 11 years studied. Initial analysis of trend suggested that the proportion of DKA was increasing over the period (χ2 test for trend, P = 0.005). However, when the 119 children whose DKA status was not recorded were excluded, this trend was no longer significant (P = 0.296), suggesting that the trend observed was a result of case ascertainment bias. To further assess this bias we analysed the period from 1 January 2006 to 31 December 2011 (which had minimal patients with DKA status not recorded), and there was no change in the trend of DKA presentations (P = 0.272).

A recent Australian study aimed at increasing awareness of T1D resulted in a decreased number of children presenting with DKA in the intervention region (15/40 to 4/29; P < 0.03), while in the control region there was no significant reduction in the rate of DKA over the same period (46/123 to 49/127).2

We confirm the high rates of DKA in children first admitted with a diagnosis of T1D to tertiary paediatric hospitals in Brisbane, and this has not decreased over
the past decade. Given that DKA is associated with significant morbidity and mortality, combined with recent evidence that improved awareness of T1D can decrease DKA rates at presentation, it seems appropriate to initiate public awareness campaigns on a larger scale.3

Diabetic ketoacidosis (DKA) status and severity in children first admitted to hospital with a diagnosis of type 1 diabetes

The rationale for combining GLP-1 receptor agonists with basal insulin

The progressive nature of type 2 diabetes mellitus (T2DM) dictates the need for an individualised, stepped interventional approach. The current approach to treatment intensification includes the addition of increasingly complex insulin regimens that involve prandial insulin dosing. However, the more intensively diabetes is treated with many of the current treatment options, the greater the risk of hypoglycaemia, weight gain and, possibly, cardiovascular mortality.1–3 One of the key challenges in patient management is how to achieve glycaemic goals while mitigating these risks.

Pharmacological approaches aimed at enhancing the incretin effect in T2DM have been pursued.4 Two main classes of incretin therapies are now in use: glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1 receptor agonists mimic the effects of endogenous GLP-1; they stimulate glucose-medicated insulin secretion and suppress glucagon secretion (Box 1). But, unlike DPP-4 inhibitors, they have the additional clinical benefits of delaying gastric emptying and decreasing appetite.

The Therapeutic Goods Administration has approved the use of some incretin therapies (the DPP-4 inhibitor saxagliptin and two GLP-1 receptor agonists, exenatide and lixisenatide) as adjunctive therapy in patients with T2DM who have inadequate glycaemic control while taking oral hypoglycaemic therapy and basal insulin. To date, these therapies have not been listed on the Pharmaceutical Benefits Scheme for this indication. Data on the combination of DPP-4 inhibitors and basal insulin have recently been reviewed elsewhere;5 they reduce glycated haemoglobin (HbA1c) levels but have no significant effect on weight. The pharmacological rationale and clinical evidence for combining GLP-1 receptor agonists with basal insulin are presented below.

Pharmacological rationale

Basal insulins provide control of fasting glucose; however, their utility in the control of postprandial glucose excursions is limited. Current treatment algorithms advocate the addition of prandial insulin in patients who have not reached their glycaemic targets with basal insulin. T2DM is characterised by impaired insulin secretion, inappropriately high glucagon secretion and increased insulin resistance. Exogenous insulin addresses only one aspect of this pathophysiology. GLP-1 receptor agonists suppress glucagon secretion by α cells, suppress appetite and delay gastric emptying. These effects decrease postprandial glucose excursions, potentially negating the need for prandial insulin. Based on the known mechanisms of action of GLP-1 receptor agonists, their use in combination therapy with basal insulin might offer an alternative approach to aid in maximising HbA1c control, while managing body weight and minimising the risk of hypoglycaemia.

Although all GLP-1 receptor agonists share the same basic mechanism of action, differences in their pharmacokinetics result in variations in their effects on fasting blood glucose and postprandial glucose excursions.6 Data suggest that continuous GLP-1 exposure might down-regulate effects on gastric emptying, with a subsequent impact on postprandial glucose excursions.6 Short-acting GLP-1 receptor agonists (eg, exenatide, lixisenatide), which provide intermittent GLP-1 exposure, have a greater effect on postprandial glucose excursions,7–10 suggesting that their use could, in theory, better complement the activity of basal insulin. Short-acting GLP-1 receptor agonists exert their most pronounced postprandial glucose effects following the first meal after drug administration. Clinical studies are needed to verify whether there will be any advantage to administering lixisenatide in conjunction with the largest meal of the day.

Clinical evidence

Clinical data from prospective and retrospective studies evaluating the efficacy of exenatide in combination with basal insulin have been summarised in the literature.11 The evidence suggests that this combination provides improvements in HbA1c and postprandial glucose levels, with concomitant weight loss and no marked increase in the risk of hypoglycaemia.11

Retrospective observational and clinical practice studies examining GLP-1 receptor agonists combined with basal insulin have consistently shown improvements in HbA1c levels and body weight, but also increased reports of gastrointestinal side effects.12 Despite their limitations, collectively, these studies provide insight into real-world use of this combination over a period of up to 4 years. They also demonstrate frequent use of this combination in clinical practice before it has received regulatory approval in other markets. For example, the Association of British Clinical Diabetologists real-world audit, in which 315 contributors from 126 centres across the United Kingdom provided data, showed that of the 4857 patients treated with exenatide, 1921 (39.6%) had used it in combination with insulin before this combination was registered.13 Patients on combination therapy comprised those for whom insulin had been continued at exenatide initiation (n = 1257) as well as those for whom insulin was started after exenatide initiation (n = 664). The latter were not included in the data analyses. Over the 12-month period of the audit, adding exenatide to patients continuing on insulin resulted in a mean HbA1c level reduction of 0.51%, weight reduction of 5.8 kg, an insulin dose reduction of 42 units/day and 16.6% of patients stopping insulin use.

Systematic reviews of prospective interventional data, from studies of differing sizes and durations, conclude that the use of GLP-1 receptor agonists as add-on therapy to basal insulin has demonstrable advantages in terms of additional lowering of HbA1c levels without major risk for hypoglycaemia, lower basal insulin requirements, decreased postprandial glucose levels (with or without fasting plasma glucose decreases) and weight loss.12,14 The effects of adding exenatide once weekly to insulin glargine have not yet been assessed in a clinical trial. Box 2 provides a summary of available data from randomised controlled clinical studies in which this combination has been evaluated for 6 months or more.15–20

The question of whether there is a continuing role for GLP-1 receptor agonists when prandial insulin becomes necessary has not yet been answered. Randomised controlled trials (RCTs) have only included patients using basal insulin; however, observational studies have included patients using basal alone,21 basal plus prandial,22 or premixed insulin.23 Of note, in studies that included prandial or premixed insulin, the doses of prandial insulin in particular were decreased, whereas doses of basal insulin generally remained constant, lending further support to the rationale for combining a GLP-1 receptor agonist with basal insulin.

Potential concerns

The potential benefits of combining a GLP-1 receptor agonist with basal insulin need to be weighed against tolerability, safety and costs (Box 3). In addition, fixed dosing schedules and the potential impact on the absorption of other drugs should be taken into account.

The most commonly reported adverse events with GLP-1 receptor agonists are gastrointestinal; predominantly nausea, vomiting and diarrhoea. Although these adverse events are reportedly worst at the beginning of treatment and reduce over the duration of the study, they still account for a high proportion of withdrawals from trials.24 A similar gastrointestinal tolerability profile has been noted in studies combining GLP-1 receptor agonists with basal insulin, with nausea being the predominant gastrointestinal adverse event (exenatide, 41% v placebo, 8%;15 lixisenatide, 39.6% v placebo, 4.5%17).

Compared with placebo, higher discontinuation rates due to treatment-emergent adverse events were reported in the basal insulin combination studies with exenatide (9% v placebo, 1%)15 and lixisenatide (9.1% v placebo, 3.2%).17 The current clinical data are limited by the lack of any long-term safety data. In retrospective studies, the frequency of adverse events as a whole was low; however, discontinuation rates due to adverse events were higher (22%–27%) than have been reported in prospective studies.12

GLP-1 receptor agonists do not replace the use of insulin. Identifying responders and non-responders is a clinical challenge; no data are available to aid in predicting who will or will not respond. If patients have not responded within a reasonable time frame, such as 3 months, then the GLP-1 receptor agonist should be stopped. A United States-based retrospective cohort study has shown adherence rates for exenatide and liraglutide to be less than 60%.25 Thus, before stopping therapy it would be pertinent to discuss compliance and administration issues with the patient.

Debate continues as to the true clinical relevance of the possible association between acute pancreatitis and the use of incretin-based therapies. Data from postmarketing reports are conflicting. Two recent studies have examined DPP-4 inhibitors and GLP-1 receptor agonists.26,27 In both studies, the majority of the body of evidence was built on the association between pathological changes of the pancreas and the use of DPP-4 inhibitors. The data presented on GLP-1 receptor agonists were limited in terms of sample size26 or relative risk.27 No cases of pancreatitis have been reported in RCTs of GLP-1 receptor agonists combined with basal insulin.12 Diabetes itself places patients at increased risk of developing pancreatitis; thus, it remains to be determined whether the reports of acute pancreatitis are related to the patient’s underlying disease. The issue has come under considerable regulatory scrutiny around the world but, as yet, no conclusions have been reached. The issue is complex and definitive answers will only come from longer-term data. In the meantime, it is recommended that if pancreatitis is suspected, GLP-1 receptor agonists should be discontinued and, if confirmed, not restarted. GLP-1 receptor agonists should be avoided in patients with a history of pancreatitis.

Conclusion

The available data present a strong pharmacological rationale for the combined use of GLP-1 receptor agonists with basal insulin, and these are supported by positive results from short-term clinical trials. Box 4 summarises practical considerations that Australian clinicians should be aware of when considering the use of GLP-1 receptor agonists in combination with basal insulin. The combination may be of particular value for patients who are overweight and for those in whom hypoglycaemia is an especially worrisome potential adverse effect. Although cost and gastrointestinal side effect profiles should be taken into account when considering this combination, it is likely to be an important therapeutic option for T2DM in the future.

1 Effect of glucagon-like peptide-1 (GLP-1) on insulin release and glucagon secretion

GLP-1 is released within minutes of eating a meal, stimulating insulin release and suppressing glucagon secretion.

2 Randomised controlled clinical studies evaluating glucagon-like peptide-1 receptor agonists as add-on therapy to basal insulin in type 2 diabetes mellitus patients for 6 months or more

Buse et al15

Riddle et al16

Seino et al17

Riddle et al18

Riddle et al19

Rosenstock et al20

Study name

GetGoal-L-Asia

GetGoal-Duo 1

GetGoal-L

HARMONY 6

Design

R, DB, PC, PG, MC;
30 weeks; n = 259

R, DB, PC, PG;
24 weeks; n = 34

R, DB, PC, PG, MC;
24 weeks; n = 311

R, DB, PC, PG, MC;
24 weeks; n = 446

R, DB, PC, PG, MC;
24 weeks; n = 495

R, DB, AC, PG, MC;
26 weeks; n = 557

Intervention

Insulin glargine + exenatide (10 μg twice daily) ± metformin and/or pioglitazone (n = 137)

Metformin + exenatide (5–10 μg twice daily)
+ insulin glargine (0.50 units/kg)
(n = 17)

Basal insulin
± sulfonylurea
+ lixisenatide
(20 μg once daily)
(n = 154)

Insulin glargine
+ lixisenatide
(20 μg once daily)
± metformin and/or thiazolidinedione
(n = 223)

Basal insulin
± metformin
+ lixisenatide
(20 μg once daily)
(n = 328)

Basal insulin ± oral agents + albiglutide* (30–50 mg/week)
(n = 279)

Control

Insulin glargine + placebo ± metformin and/or pioglitazone (n = 122)

Metformin + placebo
+ insulin glargine (0.56 units/kg)
(n = 17)

Basal insulin ± sulfonylurea + placebo (n = 157)

Insulin glargine + placebo ± metformin and/or thiazolidinedione
(n = 223)

Basal insulin ± metformin + placebo (n = 167)

Basal insulin ± oral agents + prandial insulin lispro (n = 278)

Primary end point: mean change in glycated haemoglobin from baseline, %

Exenatide: − 1.74

No data presented

Lixisenatide: − 0.77

Lixisenatide: − 0.71

Lixisenatide: − 0.74

Albiglutide: − 0.82

Placebo: − 1.04

Placebo: + 0.11

Placebo: − 0.40

Placebo: − 0.38

Insulin lispro: − 0.66

Diff: − 0.69 (P < 0.001)

Diff: − 0.88 (P < 0.0001)

Diff: − 0.32 (P < 0.0001)

Diff: − 0.36 (P < 0.0002)

Diff: − 0.16 (P < 0.0001)

Mean baseline body weight, kg

Exenatide: 95.4 ± 20.4

No data presented

Lixisenatide: 65.9 ± 13

Lixisenatide: 86.8 ± 20.4

Lixisenatide: 87.4 ± 20

No data presented

Placebo: 93.4 ± 21.4

Placebo: 65.6 ± 12.5

Placebo: 87.3 ± 21.8

Placebo: 89.1 ± 21

Mean change in body weight from baseline, kg

Exenatide: − 1.78

Exenatide: + 0.4

Lixisenatide: − 0.38

Lixisenatide: + 0.28

Lixisenatide: − 1.80

Albiglutide: − 0.73

Placebo: + 0.96

Placebo: + 4.1

Placebo: + 0.06

Placebo: + 1.16

Placebo: − 0.52

Insulin lispro: + 0.81

Diff: − 2.74; P < 0.001

Diff: − 3.7; P < 0.01

Diff: − 0.43; P = 0.08

Diff: − 0.89; P = 0.0012

Diff: − 1.28; P < 0.0001

Diff: − 1.54; P < 0.0001

Mean change in fasting plasma glucose level from baseline, mmol/L

Exenatide: − 1.6

No data presented

Lixisenatide: − 0.42

Lixisenatide: + 0.34

Lixisenatide: − 0.6

Albiglutide: − 0.99

Placebo: − 1.5

Placebo: + 0.25

Placebo: + 0.46

Placebo: − 0.6

Insulin lispro: − 0.72

Diff: − 0.1; P = 0.630

Diff: − 0.67; P = 0.0187

Diff: − 0.12; P = 0.514

Diff: 0

Diff: − 0.27; P = 0.2390

Mean change in morning 2-hour
postprandial glucose level from baseline, mmol/L

Exenatide: − 2.0

No data presented

Lixisenatide: − 7.96

Lixisenatide: − 3.09

Lixisenatide: − 5.54

No data presented

Placebo: − 0.2

Placebo: − 0.14

Placebo: + 0.08

Placebo: − 1.72

Diff: − 1.8; P < 0.001

Diff: − 7.83; P < 0.0001

Diff: − 3.16; P < 0.0001

Diff: − 3.81; P < 0.0001

Insulin dose, units/day

Exenatide: baseline, 49.5; change, h 13

Exenatide: baseline,
nr; change, h 0.50

Lixisenatide: baseline, 24.9; change, i 1.39

Lixisenatide: baseline, 43.3; change, h 3.0

Lixisenatide: baseline, 54; change, i 6

Albiglutide: nr;
change, h 5

Placebo: 47.4;
change, h 20

Placebo: nr;
change, h 0.56

Placebo: 24.1;
change, i 0.11

Placebo: 44.2;
change, h 5.0

Placebo: 58;
change, i 2

Insulin lispro: nr; change, h 7

Discontinuation due to treatment-emergent adverse events

Exenatide: 13 (9%)

No data presented

Lixisenatide: 14 (9%)

No data presented

Lixisenatide: 25 (8%)

No data presented

Placebo: 1 (1%)

Placebo: 5 (3%)

Placebo: 8 (5%)

Number of patients
with hypoglycaemia

Minor events†

Exenatide: 34 (25%)

Exenatide: 9 (53%)

Placebo: 35 (29%)

Placebo: 7 (41%)

Symptomatic events‡

Lixisenatide:
66 (43%)

Lixisenatide:
45 (20%)

Lixisenatide:
87 (27%)

Albiglutide:
61 (22%)

Placebo: 37 (24%)

Placebo: 27 (12%)

Placebo: 35 (21%)

Insulin lispro: 66 (24%)

Major events§

Exenatide: 0

Lixisenatide: 0

Lixisenatide: 1 (0.4%)

Lixisenatide: 4 (1%)

Albiglutide: nr

Placebo: 1 (1%)

Placebo: 0

Insulin lispro: nr

AC = active control. change = average increase or decrease in insulin dose (units/day). DB = double blind. Diff = between-group difference. MC = multicentre. nr = not reported.
PC = placebo controlled. PG = parallel group. R = randomised. * Not currently licensed for use in Australia. † Self-treated or resolved on their own. ‡ Clinical symptoms associated
with prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. § Resulting in loss of consciousness or seizure, or presumed hypoglycaemia that
required the assistance of another person.

3 Potential advantages and concerns of combining a glucagon-like peptide-1 receptor agonist with basal insulin

Advantages:

reduced exogenous insulin requirement
weight maintenance or loss
ability to target both fasting and postprandial hyperglycaemia
relatively low risk of hypoglycaemia

Concerns:

adverse effects
impact on absorption of other drugs
fixed dosing schedules
costs — not currently PBS-listed for this indication

4 Combining glucagon-like peptide-1 (GLP-1) receptor agonists with basal insulin: practical considerations for the Australian clinician

Four GLP-1 receptor agonists are currently registered in Australia:

GLP-1 receptor agonist

Combination with
oral antidiabetic drugs

Combination with
basal insulin

Exenatide* twice daily

TGA approved; PBS listed

TGA approved

Exenatide† once weekly

TGA approved

Liraglutide‡ once daily

TGA approved

Lixisenatide§ once daily

TGA approved

PBS = Pharmaceutical Benefits Scheme. TGA = Therapeutic Goods Administration. * Byetta,
Bristol-Myers Squibb. † Bydureon, Bristol-Myers Squibb. ‡ Victoza, Novo Nordisk. § Lyxumia, Sanofi.

When commencing a GLP-1 receptor agonist in combination with basal insulin, trial and retrospective data suggest that only small reductions in insulin dose (if any) are initially required.
Clinicians must take a proactive approach in warning patients regarding gastrointestinal side effects and intolerance.
GLP-1 receptor agonists do not replace the use of insulin. If patients have not responded within a reasonable time frame, then the GLP-1 receptor agonist should be stopped if compliance and administration issues have been ruled out.

Research using autologous cord blood — time for a policy change

It is now well established that type 1 diabetes is a chronic, multifactorial disease that results from autoimmune-mediated destruction of pancreatic β cells. However, no intervention has successfully prevented the disease to date. Recently, reinfusion of autologous umbilical cord blood has been proposed as a novel preventive therapy and is the focus of an Australian Phase I trial, the Cord Reinfusion in Diabetes (CoRD) pilot study (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363694). However, the use of publicly stored cord blood for research in Australia is currently limited by policy that restricts its use to recognised indications, including allogeneic haematopoietic stem cell transplantation for oncological, haematological, genetic and immunological disorders. There are also specific ethical issues associated with the collection and storage of cord blood, including storage (public v private), informed consent (from whom, when and how?), ownership (does it belong to the child or the parent?), access (exclusive autologous v allogeneic use) and the principle of beneficence.1

A substantial body of research in recent years has been directed towards prevention of type 1 diabetes. Primary prevention has largely targeted putative environmental risk factors such as early introduction of docosahexaenoeic acid or dietary cow milk protein.2 The latter is being investigated in the international randomised controlled Trial to Reduce the Incidence of Type 1 Diabetes in the Genetically at Risk (TRIGR).3 In contrast, secondary prevention trials have targeted immunomodulation through interventions such as nicotinamide and oral or parenteral insulin. While previous trials have failed to demonstrate significant therapeutic benefit,2 and evidence-based guidelines state that no interventions are recommended for use in clinical practice to delay or prevent the onset of type 1 diabetes,4 the role of intranasal insulin is under investigation through the Type 1 Diabetes Prevention Trial.5 Nevertheless, there is a compelling argument to explore novel approaches to the prevention of type 1 diabetes.

An alternative preventive strategy is to modify the regulatory components of the immune system — in particular, Foxp3+ regulatory T cells (Tregs). There is emerging evidence in animal models and in humans to suggest that the loss of normal immunological self-tolerance in type 1 diabetes, a crucial step in its pathogenesis, may be attributable to the failure of Tregs.6 The specific Treg abnormalities involved in type 1 diabetes are yet to be fully elucidated, but may include defects in Treg number and function, and increased resistance to regulation by effector T cells.6

Umbilical cord blood is rich in Tregs, which become functionally suppressive on antigen stimulation,7 and is also a source of haematopoietic and pluripotent stem cells.8 Thus, there is a strong scientific rationale behind the potential for cord blood to prevent or delay the onset of type 1 diabetes. The CoRD trial will examine whether autologous cord blood infusion can prevent type 1 diabetes in high-risk children with serum antibodies to multiple β-cell antigens. In parallel, the trial will study the immunological effects of cord blood infusion. This is the first time such a trial will be undertaken for the prevention of type 1 diabetes in humans, although studies have used autologous cord blood after the onset of type 1 diabetes. In a Phase I trial involving 24 children (median age, 5.1 years) with type 1 diabetes,9 infusion of autologous cord blood after a median diabetes duration of 3 months was associated with a transient increase in total and naive Tregs at 6 and 9 months, respectively. No adverse events were observed. Nevertheless, the intervention did not preserve β-cell function, as C-peptide levels decreased after infusion. However, the time after diagnosis at which the infusion was given may have been important; a rapid loss of β-cell mass has been frequently observed, and this decline may have occurred before the infusion was given. In a pilot study of 15 individuals (median age, 29 years) with type 1 diabetes,10 circulating lymphocytes were cocultured with allogeneic cord blood-derived stem cells and subsequently reintroduced into the circulation. There was a significant improvement in mean fasting C-peptide levels and a reduction in glycated haemoglobin levels and daily insulin requirements, in parallel with an increase in Tregs. The procedure was well tolerated, with no adverse events. These two studies suggest that cord blood may increase the frequency of Tregs in people with type 1 diabetes and may therefore induce immune tolerance. Whether cord blood has the same effect among people with prediabetes is unknown.

There are several fundamental methodological issues that must be addressed in the development of trials such as CoRD, which involve autologous cord blood. Studies that have demonstrated either no or minimal adverse effects in the use of autologous cord blood have involved small study samples.9,10 While the safety of autologous cord blood may also be inferred from the known safety of allogeneic cord blood, further data are required, particularly in the paediatric population. Rates of microbial contamination are low (< 5% in privately banked samples), although such samples are generally not suitable for use. In addition, samples with low total nucleated cell counts may be ineffective;11 however, private banks specify a lower limit of 108 total nucleated cells for storage, thereby reducing the likelihood of inadequate samples being collected.

Despite the clear need for well designed trials to examine the specific therapeutic applications of cord blood, there are important differences in the ways in which public and private banks collect, store and provide access to cord blood, which could affect potential research. Public banks store donated cord blood units for allogeneic use, with around 3000 units stored per year in Australia (about 1% of live births). The rate of collection in public banks is dependent on available funding and only a few hospitals participate in collection nationally. In contrast, private banks provide storage for personal and familial use, for a fee. The storage rate in private banks is around 4000 units per year (Mark Kirkland, Cord Blood Bank Director, Cell Care Australia, personal communication), and growth is estimated at 12%–15% per annum.12 Globally, over a million cord blood units have been stored in private banks. Nevertheless, the chance of using a privately stored cord blood sample is less than 0.01%.13 Although a number of potential therapeutic indications for autologous cord blood have been proposed — such as cerebral palsy, hypoxic–ischaemic encephalopathy,14 congenital hydrocephalus and stroke15 — there are few published data. The number of published clinical trials using autologous cord blood is limited; however, there are 14 ongoing trials registered on ClinicalTrials.gov using both publicly and privately stored cord blood.16

The expansion of cord blood trials, along with high consumer demand for storage, places pressure on regulatory bodies to develop and adapt policies to meet these needs. Although the regulatory framework surrounding cord blood banking in Australia has undergone significant development, issues remain regarding access to publicly donated cord blood. In particular, there is no clear guideline that addresses degifting and use of publicly stored cord blood for autologous reinfusion beyond recognised indications. At present, the use of publicly banked cord blood is essentially limited to well researched and established applications, particularly for haematopoietic reconstitution, and does not extend to research purposes (Anthony Montague, National Cord Blood Network Operations Manager, Australian Bone Marrow Donor Registry, personal communication). These processes are, however, currently under review. Beyond being a policy issue, this raises deeper ethical questions regarding the rights of public donors to access their donated cord blood and equity between public donors and those who privately bank cord blood, particularly as the private industry continues to expand.17,18

While the future applicability of cord blood-based therapeutics, including prevention of type 1 diabetes, is at present unclear, this is an emerging area of research. An evidence base is clearly needed in response to the burgeoning interest in the community for storage of cord blood. However, important questions regarding the storage and use of publicly donated cord blood remain unanswered. Should cord blood banks be permitted to degift altruistically donated samples to enable participation in research? Will novel therapeutic uses for cord blood lead to changes to public cord blood banking policy? Given the likelihood of future cord blood-based clinical trials, the existing framework of cord blood banking policy must be reviewed to meet the needs that will be posed by such research, which may lead the way to expanding novel uses of cord blood.