Practice Update: Endocrinology | Volume 1. Number 2. 2016

Practice Update: Endocrinology | Volume 1. Number 2. 2016

VOL. 1 • No. 2 • 2016

ISSN 2206-4656

RESEARCH NEWS AND VIEWS FROM ELSEVIER

FORMERLY CLINICAL ENDOCRINOLOGY NEWS

Diabetes landscape

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in Australia is fast evolving

OPINION

...no matter how compelling, observational data and biological plausibility do not necessarily predict the ability of a therapeutic manipulation of a biomarker to alter clinical outcomes. Dr Peter Libby

One of the biggest conversation points in diabetes these days is

around the impact of the newer diabetes drugs on cardiovascular mortality, the role of epigenetics in diabetes, and the potential impact of an artificial pancreas system on patients with type 1 diabetes.

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DIABETES FDA revises recommendation

for metformin use in patients with chronic kidney disease Hypoglycaemia remains a most challenging obstacle

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OBESITY Overweight, obesity leads to higher mortality 8 METABOLIC & ENDOCRINE DISORDERS 10 CARDIOVASCULAR COMPLICATIONS Encourage intake of whole, not refined, grains 13 CHRONIC KIDNEY DISEASE Exercise caution in certain patients 14 My approach to the patient with memory loss who needs a statin

Life-years lost to diabetes Diabetes Research and Clinical Practice

Prevalence of diabetic retinopathy in newly diagnosed type 2 diabetes Diabetologia Based on fundus photographs, researchers observed that 13% of participants with newly diagnosed type 2 diabetes had DR.

BMI and mortality risk The Lancet Mortality risk increased log-linearly with BMI for BMI >25 kg/m 2 ; the hazard ratio per 5 kg/m2 higher BMI was1.29 to 1.39, depending on the continent.

LDL levels and major adverse cardiac events in ischaemic heart disease treated with statins JAMA Internal Medicine In patients with ischaemic heart disease who are compliant with statin therapy, LDL levels ≤100 mg/dL are associated with reduced risk of MACE. 11

Life-years lost to diabetes decreased as age at diabetes diagnosis increased; those diagnosed before 20 years of age lost 20 years whereas those diagnosed after 80 years of age lost no years.

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DIABETES

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EXPERT OPINION FDA revises recommendation for metformin use in patients with chronic kidney disease Dr Silvio Inzucchi, Professor of Medicine at the Yale University School of Medicine in New Haven, Connecticut, discusses the recent change to the package label for metformin relating to its use in patients with chronic kidney disease. T he US Food and Drug Administration just recently decided to change the package label for metformin as related to use in

EDITORIAL Managing Editor Anne Neilson anne.neilson@elsevier.com Editor Carolyn Ng carolyn.ng@elsevier.com Designer Jana Sokolovskaja j.sokolovskaja@elsevier.com

renal function were overly restrictive and pre- vented the use of this important, effective, and cheap medication in hundreds of thousands of patients in the US. Although lactic acidosis is a serious and potentially life-threatening condi- tion, it is actually no more common in patients prescribed metformin. Moreover, surveys showed high rates of metformin use in patients with mild to moderate chronic kidney disease, despite the earlier FDA guidelines in place since drug ap- proval in 1995. Despite this fact, lactic acidosis rates were not observed to have increased. In fact, when a metformin-treated patient develops lactic acidosis, it is almost always due to some other event, such as a major cardiac event or sepsis. So, metformin is felt to be an “innocent bystander” in these cases. Here are the essential changes (very similar to those in use in the UK): • Base assessment on eGFR, not serum creatinine. • Obtain eGFR before starting metformin and annually; more frequently in those at risk for renal impairment (eg, the elderly). • Metformin can be used when the eGFR is <60 mL/min but remains contraindicated in patients with an eGFR <30. • Don’t start metformin in patients with an eGFR in the 30–45 range. • If the eGFR falls <45 in someone on metform- in, assess the overall benefits and risks before continuing treatment. Stop metformin if the eGFR falls <30. • Hold metformin before iodinated contrast pro- cedures if the eGFR is 30–60; also if there is any liver disease, alcoholism, or heart failure; or if intra-arterial contrast is used. Recheck the eGFR 48 hours after the procedure; restart metformin if renal function is stable. The recent FDA communication certainly does not mean that the drug can be used in those with advanced renal disease. It remains a drug abso- lutely contraindicated when the eGFR is <30.

My only criticism of the new guidelines is that they do not include recommendations for dose adjustment in those with an eGFR 30–45. This is what our group had recommended in two reviews published on this topic. 3,4 Therein we advised that the dose be cut in half when an eGFR of 45 was reached to minimise any chance of getting to a toxic level in patients with that degree of kidney disease. I’d also caution not to use the drug if renal function is or expected to become unstable. This FDA decision is a very important one for those of us managing patients with type 2 diabetes. It has been estimated that somewhere around 800,000 to 1.6 million patients will now be eligible for metformin in the US. Indeed, how often do we wish we could continue metformin in someone who’s developed mild CKD? The al- ternative often is a more expensive and/or riskier medication. So, I and many of my colleagues are very enthusiastic about this change. References 1. Food and Drug Administration. Metformin-containing drugs: drug safety communication – revised warnings for certain patients with reduced kidney function. Available at: www.fda.gov/Safety/MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ucm494829. htm. Accessed on April 12, 2016. 2. Food and Drug Administration. FDA drug safety com- munication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with re- duced kidney function. Available at: www.fda.gov/Drugs/ DrugSafety/ ucm493244.htm . Accessed on April 12, 2016. 3. Lipska KJ, Bailey CJ, Inzucchi SE. Diabetes Care 2011;34:1431-1437. 4. Inzucchi SE, Lipska KJ, Mayo H, et al. JAMA 2014; 312:2668-2675.

chronic kidney disease (CKD) patients. 1,2 This was in response to two citizen petitions that were filed with the agency in 2013, one from our group. The prior label restricted its use to men with serum creatinine <1.5 mg/dL and women with serum creatinine <1.4 mg/dL. Evidence has emerged over the past 20 years that the prior guidelines for those with impaired EXPERT COMMENTARY By Prof Sof Andrikopoulos T he FDA’s decision to change the package label for metformin for its use in patients with eGFR <60 mL/min (but >30 mL/ min) is a positive one. It’s important to note that there is no evidence suggesting that using metformin when eGFR <60 but >30 is harmful as long as the dose of metformin is titrated, the patient is closely monitored and the patient’s kidney function is measured annually. If these measures are taken, as most endocrinologists would, then it’s very useful to use metformin. It’s an effective drug and we know it’s a safe drug. I’ve had discussions with the Therapeutic Goods Administration about changing the pack- age label of metformin in Australia, in line with that in the US, and the TGA is currently review- ing this. Prof Sof Andrikopoulos is President of the Australian Diabetes Society, Head of the Islet Biology and Metabolism Research Group at the Department of Medicine, University of Melbourne, Editor-in-Chief

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Dr Silvio Inzucchi is Professor of Medicine (Endocrinology); Clinical Director, Section of Endocrinology; Director, Yale Diabetes Center;

Director, Endocrinology and Metabolism Fellowship, Yale School of Medicine, New Haven, Connecticut.

of the Journal of Endocrinology and Journal of Molecular Endocrinology.

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JOURNAL SCAN Teenage girls with type 1 diabetes have poorer metabolic control than boys and face more complications in early adulthood Journal of Diabetes and Its Complications Take-home message As adults, more females had retin- opathy, P < 0.05. Females had higher mean HbA 1c values at diagnosis, 11.2 vs

was found in adolescent females, and they had a higher frequency of mi- crovascular complications. Improved paediatric diabetes care is of great im- portance for increasing the likelihood of lower mortality and morbidity later in life. Teenage girls with type 1 diabetes have poorer metabolic control than boys and face more complications in early adulthood. J Diabetes Compli- cat 2016;30:917–922, Samuelsson U, Anderzén J, Gudbjörnsdottir S, et al.

10.9% (99 vs 96 mmol/mol), P < 0.03, during adolescence, 8.5 vs 8.2% (69 vs 66 mmol/mol) P < 0.01, but not as young adults. CONCLUSIONS Worse glycaemic control

• The goal of this study was to evaluate differences in metabolic control between adolescent males and females with type 1 diabetes. Investigators categorised HbA 1c values into three groups: < 7.4% (57 mmol/mol); 7.4% to 9.3% (57–78 mmol/mol); and > 9.3% (78 mmol/mol). Females were over- represented in the highest HbA 1c group (51.7% vs 46.2% expected) and underrepresented in the lowest HbA 1c group (34.2%; P < 0.001). As young adults, females were more likely to have retinopathy (P < 0.05). Increased HbA 1c values in females compared with males were seen at diagnosis (11.2% vs 10.9%) and in adolescence (8.5% vs 8.2%), but not as young adults. • Adolescent females with type 1 diabetes have worse glycaemic control than males with type 1 diabetes. This difference resolves in young adulthood, but young adult females have higher rates of retinopathy.

RESULTS When dividing HbA 1c values in three groups; < 7.4% (57 mmol/mol), 7.4–9.3% (57–78 mmol/mol) and >9.3% (78 mmol/mol), there was a higher proportion of females in the highest group during adolescence. In the group with the highest HbA 1c values during adolescence and as adults, 51.7% were females, expected value 46.2%; in the group with low HbA 1c values in both reg- istries, 34.2% were females, P < 0.001.

AIMS To compare metabolic control between males and females with type 1 diabetes during adolescence and as young adults, and relate it to microvas- cular complications. METHODS Data concerning 4000 adoles- cents with type 1 diabetes registered in the Swedish paediatric diabetes quality registry, and above the age of 18 years in the Swedish National Diabetes Reg- istry was used.

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EXPERT OPINION Diabetes landscape in Australia is fast evolving Interview with Prof Sof Andrikopoulos

it could very well be that if we have better gut health we may be able to prevent a lot of the chronic diseases we see today. Closing the loop in type 1 diabetes We’re making huge strides in type 1 diabetes with the closed loop system, or the artificial pancreas, being so close to reality. The artificial pancreas, which combines an insulin pump with glucose and a continuous glucose monitor, will reduce glycaemic excursions, preventing an increase in HbA 1c and complications as a result of better plasma glucose control. I find this absolutely fascinating. The artificial pancreas will save lives; it will not only prevent diabetes complications but actually save lives. References 1. Zinman B, Wanner C, Lachin JM, et al. N Engl J Med 2015; 373:2117–2128. 2. Marso Sp, Daniels GH, Brown-Frandsen K, et al. N Engl J Med 2016; 375:311–322. 3. Department of Health. Australian National Diabetes Strategy 2016–2020. Commonwealth of Australia 2015. Canberra: DoH 2016. www.health.gov. au/internet/main/publishing.nsf/content/3AF935DA210DA043CA257EFB 000D0C03/$File/Australian%20National%20Diabetes%20Strategy%20 2016-2020.pdf (accessed 8 August 2016). 4. Sonnenburg JL and Bäckhed F. Nature 2016;535:56–64.

Professor Andrikopoulos speaks with Carolyn Ng on the evolving landscape in the treatment of type 2 diabetes, a need for a national strategy to prevent diabetes, exciting research that could better our understanding of diabetes as a chronic disease, and the prospect of an artificial pancreas system and its impact on patients with type 1 diabetes. O ne of the biggest conversation points in diabetes these days is around the impact of the newer diabetes drugs such as empagliflozin and liraglutide on cardiovascular

We need to implement the recommendations of the Aus- tralian National Diabetes Strategy to prevent the burden of diabetes, not just on the health system in Australia but also on the country’s economy. We are well aware of the statistics: there are 1.7 million people in Australia with diabetes; 280 in- dividuals are diagnosed with diabetes each day; and the indirect cost to the national economy is $14.6 billion annually in loss of income as a result of the disease. These are big numbers. Prevention of diabetes is therefore a conversation we need to have. The key stakeholders – the Australian Diabetes Society, Australian Diabetes Educators Association, Royal Australasian College of Physicians, and the Department of Health – need to come together and come up with a national strategy for the prevention of diabetes. Getting to the root of diabetes While there is evidence of a strong genetic predisposition, we don’t as yet know the exact causes of diabetes. In type 1 diabetes, we know that there are major genetic loci that are more prevalent in people getting type 1 diabetes. In the last 15–20 years, that genetic load has reduced and there seems to be a lot of environmental factors that may be contributing to the accelerated rate of type 1 diabetes such as insulin resistance or overweight. Can we prevent type 1 diabetes? I think we can by fully understanding the mechanism of the disease: why the body’s immune system attacks and kills beta cells resulting in insulin deficiency which then causes diabetes. The topic of epigenetics and its role in predisposing someone to diabetes, whether type 1 or type 2, is of particular interest to me. First, what are the epigenetic changes that cause type 2 diabetes and second, what are the environmental influences that cause epigenetic changes. Can we as clinicians intervene? Can we reduce or remove these environmental influences; avoid the epigenetic changes and thereby prevent the onset of diabetes? Another emerging research area is looking into the gut mi- crobiota and how these predispose us to chronic diseases such as diabetes. An interesting paper published in Nature 4 recently reported that gut microbiota can influence human metabolism, predisposing to obesity and potentially triggering diabetes. So

mortality. The EMPA-REG OUTCOME trial 1 for example reported that patients with type 2 diabetes taking empagliflozin had a 38% significantly (P < 0.001) lower risk of death from CV disease compared with patient on placebo. This is big result. The other big study is the LEADER trial 2 , results of which were released at the recent American Diabetes Association meeting. It reported similarly positive outcomes among type 2 diabetes patients taking liraglutide – a marked reduction in death from CV disease compared with patients on placebo. These are significant results in that it’s the first time we’re seeing glucose-lowering drugs confer CV protection. The ques- tion now then is how do we use these drugs in the treatment algorithm? For the Australian Diabetes Society, our main chal- lenge is informing ourselves to apply what we now know from these studies in the appropriate management of our patients with type 2 diabetes. Both empagliflozin and liraglutide are approved in Australia, with empagliflozin also subsidised on the Pharmaceutical Benefits Scheme as second-line and triple therapy, and as add-on to insulin. The question that remains to be answered is whether we can use these clinical trial data and apply them to all patients with diabetes? The entry point for these clinical trials is that patients have had to have a prior CV event or a strong predisposition to CV events. Does this mean that these drugs are only useful in diabetes patients with established CV disease or can they be used to prevent patients from a CV event? National strategy needed for diabetes prevention Preventing diabetes is still a challenge at a national level. The Australian National Diabetes Strategy 2016–2020 3 document has dedicated a whole section on the prevention of diabetes. Is it appropriate to talk to patients about lifestyle modification at the prediabetes stage? It probably is. Can we use pharmaco- therapy to prevent the conversion of prediabetes to diabetes? Well we currently don’t have any drug that is indicated for prediabetes. Do we need a national strategy for the prevention of diabetes? I think we do.

Professor Sof Andrikopoulos is President of the Australian Diabetes Society, Head of the Islet Biology and Metabolism Research Group at the Department of Medicine, University of Melbourne, and Editor-in- Chief of the Journal of Endocrinology and Journal of Molecular Endocrinology.

Meeting of minds at the 2016 ADS–ADEA annual meeting

Prof Andrikopoulos says an interesting topic that will be dis- cussed at this year’s meeting, one topic of many, is on the use of technology in the management of diabetes. “We are excited to host a number of high profile international speakers including Professor John Pickup of the King’s College London, a technology specialist who’ll be talking about the closed loop pumps making headlines in diabetes. We’ll also be discussing clinical data from the latest trials such as the LEADER trial; so hot topics and very timely discussions that will be relevant to healthcare professionals with an interest in diabetes.” The ADS–ADEA 2016 Annual Scientific Meeting will be held at the Gold Coast, 24–26 August. For more information visit www.ads-adea.org.au

JOURNAL SCAN Text message support increases weight loss in patients with prediabetes Diabetes Care Take-home message • In this randomised controlled trial, researchers analysed the ef- ficacy of text message support in achieving weight loss in 163 patients offered diabetes prevention program classes. Patients in the text message group lost more weight compared with the control group (mean 2.6 vs 0.6 pounds; P = 0.05). Furthermore, a higher rate of patients in the text message group achieved 3% weight loss (38.5% vs 21.5%; P = 0.02). • Text message support improved weight loss in patients with prediabetes, highlighting the importance of engaging patients in weight loss programs. Abstract

JOURNAL SCAN Life-years lost to diabetes Diabetes Research and Clinical Practice Take-home message

at diagnosis from 20.0 years for those diagnosed before age 20 years to no difference for those diagnosed after 80 years. Hazard ratios for mortal- ity decreased from 3.03 (95%CI 2.41–3.80) for those with diabe- tes diagnosed before 20 years to 1.04 (95% CI 0.78–1.39) for those diagnosed after 80 years. The estimate of life-years lost associated with diabetes was much higher among those with pre-existing cardiovascular dis- ease (20.3 years) than among those without cardiovascular disease (8.5 years). CONCLUSIONS The effect of diabetes on survival depends on age at first diagnosis of diabetes and the presence of pre-existing diseases. The life- years lost are higher for those with diabetes diagnosed at younger ages. This study pro- vided the updated estimates of life-years lost associated with diabetes in the United States. Life-years lost associated with diabetes: An individually matched cohort study using the US National Health Inter- view Survey data . Diabetes Res Clin Pract 2016;118:69–76, Z Wang, M Liu.

• This matched case-control study looked at years of life lost to diabetes in the United States; adults with diabetes had a lifespan 10.5 years shorter than matched controls. Life-years lost to diabetes decreased as age at diabetes diagnosis increased; those diagnosed before 20 years of age lost 20 years whereas those diagnosed after 80 years of age lost no years. In people with pre-existing CVD, 20.3 life-years were lost compared with only 8.5 years in those without CVD. • “Life-years lost to diabetes varies by age at diagnosis and comorbidities, and the results of this study provide clini- cians with estimates that are useful for counselling patients, prognostication, and weighing health risks.” Abstract

compared with 38.5% in the inter- vention group (95% CI 27.7–49.3) (absolute difference 17.0%; P value 0.02). Mean glycated haemoglo- bin (HbA 1c ) increased by 0.19% or 2.1 mmol/mol (95% CI -0.1 to 0.5%) and decreased by 0.09% or 1.0 mmol/mol (95% CI -0.2 to 0.0%) in the control group and inter- vention participants, respectively (absolute difference 0.28%; P = 0.07). Stratification by language demonstrated a significant treat- ment effect in Spanish speakers but not in English speakers. CONCLUSIONS Text message sup- port can lead to clinically significant weight loss in patients with pre- diabetes. Further study assessing effect by primary language and in an operational setting is warranted. Text message support for weight loss in patients with pre- diabetes: a randomized clinical trial . Diabetes Care 2016 Aug 01;39:1364-1370, HH Fischer, IP Fischer, RI Pereira, et al.

invitation to DPP classes as de- fined by the Centers for Disease Control and Prevention, or to the text message-augmented intervention group, which also received text messages adapted from the DPP curriculum for 12 months. RESULTS Mean weight decreased 0.6 pounds (95% CI -2.7 to 1.6) in the control group and 2.6 pounds (95% CI -5.5 to 0.2) in the inter- vention group (P = 0.05). Three percent weight loss was achieved by 21.5% of participants in the control group (95% CI 12.5–30.6),

OBJECTIVE Although the benefits of in-person Diabetes Prevention Program (DPP) classes for diabe- tes prevention have been dem- onstrated in trials, effectiveness in clinical practice is limited by low participation rates. This study explores whether text message support enhances weight loss in patients offered DPP classes. RESEARCH DESIGN AND METHODS English- and Spanish-speaking patients with prediabetes (n = 163) were randomised to the control group, which only received an

status, pre-existing cardiovas- cular disease and pre-existing cancer. All-cause mortality from original surveys to 31 December 2011 and median survival ages were estimated for those with diabetes and their matched controls. RESULTS Overall median survival age for adults with diabetes was 10.5 years shorter than that for matched controls without diabetes. Estimated life-years lost associated with diabetes decreased with increasing age

AIM Previous estimates of life- years lost to diabetes are highly inconsistent. This study pro- vided the updated estimates of life-years lost to diabetes in the United States. METHODS Each of a nation- ally representative sample of 21,829 adults with diabetes in the US National Health Inter- view Survey 1997–2009 was individually matched to one without diabetes by age, sex, race, survey year, BMI, smoking

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EXPERT COMMENTARY Compassion vs empathy By Dr David Rakel “When a person feels accepted for who they are and what they do – no matter how unhealthy – it allows them the freedom to consider change rather than needing to defend against it.” T his quote by Steve Berg-Smith is true for treating oth-

had a moderate non-proliferative diabetic retinopa- thy. Diabetic retinopathy was proliferative in 0.3%. No cases of severe non-proliferative diabetic retin- opathy or diabetic maculopathy were found. Thirty (14.9%) of 202 and six (7.2%) of 83 individuals with and without concomitant arterial hypertension, re- spectively, had diabetic retinopathy (OR 2.54, 95% CI 1.06–7.14). Visual acuity did not differ between individuals with and without diabetic retinopathy. CONCLUSIONS/INTERPRETATION In this large European study, the prevalence of diabetic retinopathy in screening-detected type 2 diabetes was 13%. Only a very small proportion of participants with detected diabetic retinopathy needed treatment. Prevalence of diabetic retinopathy in screening- detected diabetes mellitus: RESULTS from the Gutenberg Health Study (GHS) . Diabetologia 2016 Jun 17;[Epub ahead of print], Ponto KA, Koenig J, Peto T, et al. Mindful self-compassion intervention improves depression, distress, and HbA1c in people with diabetes Diabetes Care Take-home message • This randomised controlled trial evalu- ated the effect of an 8-week mindful self-compassion program on depression, diabetes-related distress, and HbA 1c in patients with type 1 or type 2 diabetes mellitus. The results revealed that par- ticipants in the program had significantly fewer depressive symptoms, reduced distress, and improved HbA 1c during the study period and at follow-up. • This study suggests that promoting self- compassion improves overall emotional well-being as well as specific metabolic markers in diabetic patients. Abstract OBJECTIVE Mood difficulties are common among patients with diabetes and are linked to poor blood glucose control and increased complications. Evidence on psychological treatments that improve both mood and meta- bolic outcomes is limited. Greater self-compas- sion predicts better mental and physical health in both healthy and chronically ill populations. Thus, the purpose of this randomised con- trolled trial (RCT) was to evaluate the effects of self-compassion training on mood and meta- bolic outcomes among patients with diabetes. RESEARCH DESIGN AND METHODS This RCT tested the effects of a standardised 8-week mindful self-compassion (MSC) program (n = 32) relative to a wait-list control condition (n = 31) among patients with type 1 and type 2 diabetes. Measures of self-compassion, de- pressive symptoms, diabetes-specific distress, and HbA 1c were taken at baseline (preinter- vention), at week 8 (postintervention), and at 3-month follow-up. RESULTS Repeated-measures ANOVA using intention to treat showed that MSC training increased self-compassion and produced statistically and clinically significant reduc- tions in depression and diabetes distress in the intervention group, with results maintained at 3-month follow-up. MSC participants also averaged a clinically and statistically meaning- ful decrease in HbA 1c between baseline and follow-up of > 10 mmol/mol (nearly 1%). There were no overall changes for the wait-list con- trol group. CONCLUSIONS This initial report suggests that learning to be kinder to oneself (rather than being harshly self-critical) may have both emo- tional and metabolic benefits among patients with diabetes. Kindness matters: A randomised controlled trial of a mindful self-compassion interven- tion improves depression, distress, and HbA 1c among patients with diabetes. Diabe- tes Care 2016 Jun 22;[Epub ahead of print], Friis AM, Johnson MH, Cutfield RG, et al.

ers and ourselves. This study of type 1 and 2 diabetics showed that an 8-week mindfulness and self-compassion course reduced depression, diabe- tes-associated stress, and HbA 1c levels by almost 1% 3 months after enrolment in this 8-week course com- pared with a “usual care” control group.

Self-acceptance and kindness not only improves depression, coping, and diabetic control but can also reduce clinician burnout.

Diabetes is associated with self-critical thoughts such as, “I need to eat better, exercisemore, and lose weight.” This can lead to distress, depression, and worsening diabetic control. Compassion training has been associated with lower cortisol, increased heart rate variability, decreased IL-6 (inflam- mation), decreased stress, and lower HbA 1c levels. Compassion training also stimulates oxytocin (the love hormone) and natural endorphins. What is compassion training? Two main ingredients of the compassion training provided in this study were self-kindness (rather than self-criticism) and common hu- manity (rather than isolation). This second point is a key difference between empathy and compassion. Practicing empathy can lead to empathy distress or empathy fatigue because the training requires that we feel the suffering of another person where the two people involved are separate: me and you. Compassion training on the other hand teaches a common humanity, where two people are more one than separate. When I support you through your suffering, I support myself because we are both part of the same humanity (compassion) vs I feel your suffering (heavy) and I am going to help you through it (empathy). This may sound like psychological and philosophical babble, but there is promising evidence to back this up. In 2014, Klamicki and colleagues showed study participants videos of human suffering before and after empathy training (“I feel your pain”) and compassion training (loving-kindness training, for self and

others). The researchers looked at positive and negative affect and functional MRI after participants watched videos of human suffering. Negative affect worsened after empathy training and then improved after compassion training. Positive affect changed little after empathy training but went up significantly after compassion training. Functional MRI of the brains of these study participants showed that compassion training activated the centres associate with love, reward, and affiliation. Those activated with empathy were associated with pain. 2 Self-acceptance and kindness not only improves depression, coping, and diabetic control but can also reduce clinician burnout if we see our work as a service to all humanity in which we are an intricate part. References 1. Berg-Smith S. Heart of behavior change: Client-centered education. 2015; www. doh.wa.gov/portals/1/Documents/8100/HeartOfBehaviorChange.pdf . Accessed July 4, 2016. 2. Klimecki OM, Leiberg S, Ricard M, Singer T. Soc Cogn Affect Neurosci 2014;9:873–879.

Dr David Rakel is Associate Professor at the Department of Family Medicine and Director at the University of Wisconsin Integrative Medicine, University of Wisconsin School of Medicine and Public Health.

JOURNAL SCAN Prevalence of diabetic retinopathy in newly diagnosed type 2 diabetes Diabetologia Take-home message • In this observational population-based study, researchers investigated the prevalence of diabetic retinopathy (DR) at the time of diagnosis of type 2 diabetes. Of the 14,948 participants inves- tigated, 347 had newly diagnosed type 2 diabetes detected during the screening. Based on fundus photographs, researchers observed that 13% of participants with newly diagnosed type 2 diabetes had DR. The majority of DR in these participants was mild non-proliferative (12%), but 0.6% of participants had moderate DR and 0.3% had proliferative DR. • Up to 13% of individuals with type 2 diabetes have DR at the time of diagnosis, underscoring the importance of diabetes screening. Abstract

between 35 and 74 years. We determined the weighted prevalence of diabetic retinopathy by as- sessing fundus photographs. Screening-detected type 2 diabetes was defined as an HbA1c concen- tration of 6.5% (47.5 mmol/mol) or more, no medical diagnosis of diabetes and no intake of insulin or oral glucose-lowering agents. RESULTS Of 14,948 participants, 1377 (9.2%) had diabetes mellitus. Of these, 347 (25.2%) had newly diagnosed type 2 diabetes detected by the screen- ing. Overall, the weighted prevalence of screening- detected type 2 diabetes was 2.1%. Fundus photos were evaluable for 285 (82.1%) participants with newly diagnosed diabetes. The weighted preva- lence of diabetic retinopathy in screening-detected type 2 diabetes was 13.0%; 12% of participants had a mild non-proliferative diabetic retinopathy and 0.6%

determine the prevalence of diabetic retinopathy in patients with newly diagnosed (screening-detected) type 2 diabetes. METHODS The Gutenberg Health Study is a popu- lation-based study with 15,010 participants aged

AIMS/HYPOTHESIS Individuals with type 2 diabetes mellitus may experience an asymptomatic period of hyperglycaemia, and complications may already be present at the time of diagnosis. We aimed to

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EXPERT COMMENTARY Hypoglycaemia remains a most challenging obstacle By Dr Raimund Herzog T o this day, hypoglycaemia remains the most challenging obstacle in the achievement of tight glycaemic control All-cause mortality and cardiovascular disease associated with prior history of hypoglycaemia in type 1 diabetes Diabetes Care Take-home message

hypoglycaemia-associated autonomic failure that heightens the risk for subsequent severe hypoglycaemic episodes differs from that in patients experiencing large excursions into the hyperglycaemic and hypoglycaemic range. While the latter might – as an important ca- veat – present to our practice with the same average plasma glucose and A1c, they will be much more likely to be frequently admitted to the emergency roomwith severe hypoglycaemic episodes. It is contingent upon us as clinicians to identify these patients early to make appro- priate adjustments to their insulin regimens to reduce the risk of adverse outcomes. It is contingent upon us as physician scientists to try to identify and develop predictive biomarkers that will allow early identification – and ide- ally treatment – of contributing inflammation, endothelial dysfunction, and other factors in these patients who are at particular risk for car- diovascular events and death from other causes. This study by Lu and colleagues is an excellent example of how carefully collected national health insurance data (in this case from Taiwan) help assess the specific circumstances of severe hypoglycaemia-associated morbidity and mortality in a type 1 diabetic patient population.

in type 1 diabetic patients. The more wide- spread use of continuous glucose monitors has revealed more hypoglycaemic episodes in this population than we ever knew of when relying on finger-stick glucose measurements alone. Investigators over the past several years have identified additional complications of severe hypoglycaemia, which go beyond its incapaci- tating effects on the brain such as impaired cognition, seizures, loss of consciousness, and permanent brain injury. Cardiovascular com- plications and increased all-cause mortality were recently highlighted in large studies of type 1 and type 2 diabetic patients experienc- ing frequent hypoglycaemia under intensive diabetes control. This study by Lu and colleagues is an excel- lent example of how carefully collected national health insurance data (in this case fromTaiwan) help assess the specific circumstances of severe hypoglycaemia-associated morbidity and mor- tality in a type 1 diabetic patient population. The investigators report a significant association between severe hypoglycaemia and cardiovas- cular and all-cause mortality during the year immediately preceding the events, while only all-cause mortality was associated with severe hypoglycaemia occurring between 1 and 3 and 3 and 5 years prior to the event in question. One can envision a scenario where frequent mild recurrent hypoglycaemia and the ensuing

• The goal of this case-control study was to investigate the association between severe hypoglycaemia and future risk for all-cause mortality and cardiovascular disease (CVD) in people with type 1 diabetes. Researchers found that individuals who had severe hypogly- caemic events less than a year prior had an increased risk for all-cause mortality and CVD (ORs, 2.74 and 2.02, respectively). Additionally, individuals who had severe hypoglycaemic events within 1 to 3 years or 3 to 5 years before death had an increased risk for all-cause mortality (OR, 1.94 and 1.68, respectively). • Severe hypoglycaemic events in patients with type 1 diabetes were associated with increased CVD risk for up to 1 year, and risk for all-cause mortality remained elevated for up to 5 years after a hypoglycaemic event.

Abstract OBJECTIVE This study investigated the effects of severe hypoglycaemia on risks of all-cause mor- tality and cardiovascular disease (CVD) incidence in patients with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS Two nested case-control studies with age- and sex-matched control subjects and using the time-density sam- pling method were performed separately within a cohort of 10,411 patients with T1DM in Taiwan. The study enrolled 564 nonsurvivors and 1,615 control subjects as well as 743 CVD case sub- jects and 1,439 control subjects between 1997 and 2011. History of severe hypoglycaemia was identified during 1 year, 1–3 years, and 3-5 years before the occurrence of the study outcomes. Conditional logistic regression analyses were performed to estimate the odds ratio (OR) and 95% CI of the study outcomes. RESULTS Prior severe hypoglycaemic events with- in 1 year were associated with higher risks of all- cause mortality and CVD (adjusted OR 2.74 [95%

CI 1.96–3.85] and 2.02 [1.35–3.01], respectively). Events occurring within 1–3 years and 3–5 years before death were also associated with adjusted ORs of 1.94 (95% CI 1.39–2.71) and 1.68 (1.15–2.44), respectively. Significant dose-gradient effects of severe hypoglycaemia frequency on mortality and CVD were observed within 5 years. CONCLUSIONS Although the CVD incidence may be associated with severe hypoglycae- mic events occurring in the previous year, the risk of all-cause mortality was associated with severe hypoglycaemic events occurring in the preceding 5 years. Exposure to repeated severe hypoglycaemic events can lead to higher risks of mortality and CVD. A population-based study of all-cause mortal- ity and cardiovascular disease in association with prior history of hypoglycemia among patients with type 1 diabetes. Diabetes Care 2016 Jul 06;[EPub ahead of print], Lu CL, Shen HN, Hu SC, et al.

Dr Raimund Herzog is Assistant Professor in Endocrinology at Yale School of Medicine.

EXPERT COMMENTARY Short-term investigations not set up to assess long-term safety, clinical outcomes

By Dr Silvio Inzucchi T his is the very latest meta-analysis concerning non-insulin therapies for type 2 diabetes, funded by the Agency for Healthcare Research and Quality (AHRQ) of the US De- partment of Health and Human Services. TheAHRQ evaluates and prioritises medical evidence in an effort to promote safer, higher-quality, and more equitable and affordable care. The paper assessed the relative efficacy of drugs as monotherapy and in combination with metformin and incorporated 204 individual studies. Its main findings should not be surprising. HbA 1c reduc- tions were similar across most monotherapies as well as when drugs were combined with metformin, with the exception of the DPP-4 inhibitors, which are somewhat less potent. There was a notable absence of recently reported large randomised trials, including EMPA-REG OUTCOME and LEADER, likely because these trials did not specifically compare a single drug with another but instead assessed the CV effects of an agent vs standard care. Metformin provides a cardiovascular (CV) mortality benefit to sulfonylureas. Metformin, DPP-4 inhibitors, GLP-1 receptor ago- nists, and SGLT2 inhibitors are either weight-neutral or result in some weight loss, whereas sulfonylureas and TZDs lead to weight gain. Sulfonylureas increase the risk of hypoglycaemia. GI side effects are more common with metformin and GLP-1 agonists. Genital mycotic infections are increased with SGLT2 inhibitors. Unfortunately, most of the studies in this meta-analysis were short-term investigations and were not set up to assess long-term

empagliflozin and the GLP-1 agonist liraglutide, respectively) vs standard care. Those investigations demonstrated reduced CV events in the active therapy arms and may influence future guidelines to recommend that they be used preferentially after metformin when CV disease is already established.

safety or clinical outcomes. There was a notable absence of recently reported large randomised trials, including EMPA- REG OUTCOME and LEADER, likely because these trials did not specifically compare a single drug with another but in- stead assessed the CV effects of an agent (the SGLT2 inhibitor

Monotherapy vs metformin-based combination therapy for type 2 diabetes Annals of Internal Medicine Take-home message

that DPP-4 inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycaemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP- 1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors. LIMITATION Most studies were short, with limited ability to assess rare safety and long- term clinical outcomes. CONCLUSION The evidence supports met- formin as first-line therapy for type 2 diabetes, given its relative safety and beneficial effects on haemoglobin A1c, weight, and cardiovas- cular mortality (compared with sulfonylureas). On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: A systematic review and meta-analysis. Ann Intern Med 2016;164:740–751, Maruthur NM, Tseng E, Hutfless S, et al.

• A meta-analysis of 179 trials and 25 observational studies of head-to-head mono- therapy or metformin-based combinations compared the effectiveness and safety of various monotherapies and selected metformin-based combinations in adults with type 2 diabetes. • Compared with sulfonylureas, metformin was safer and had more beneficial effects on haemoglobin A1c, weight, and cardiovascular mortality. Benefits with add-on therapies to metformin appeared to be similar to those observed with monotherapies.

search updated through December 2015). STUDY SELECTION Paired reviewers indepen- dently identified 179 trials and 25 observa- tional studies of head-to-head monotherapy or metformin-based combinations. DATAEXTRACTION Two reviewers independently assessed study quality and serially extracted data and graded the strength of evidence. DATA SYNTHESIS Cardiovascular mortality was lower for metformin versus sulfonylu- reas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascu- lar complications was insufficient or of low strength. Reductions in haemoglobin A1c values were similar across monotherapies and metformin-based combinations, except

BACKGROUND Clinicians and patients need updated evidence on the comparative effec- tiveness and safety of diabetes medications to make informed treatment choices. PURPOSE To evaluate the comparative ef- fectiveness and safety of monotherapy (thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodi- um-glucose cotransporter 2 [SGLT-2] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) and selectedmetformin-based com- binations in adults with type 2 diabetes. DATA SOURCES English-language studies from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, indexed from inception through March 2015 (MEDLINE

PRACTICEUPDATE ENDOCRINOLOGY

DIABETES

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EXPERT COMMENTARY LH does not affect set survival, mean glucose By Dr Silvio Inzucchi L H did not significantly affect infusion set survival or mean glucose. Achieving optimal We found this paper interesting in that it goes against conventional wisdom. The traditional teaching has been that patents should avoid lipohypertrophic areas from prior insulin injections.

else but for cosmetic reasons. In my experience, the lipohypertrophy tends to regress if that region is not used for a few months.

lipohypertrophic areas from prior insulin injections. This represents a local hypertrophy of fat cells from repeated exposure to insulin. The teaching has been that insulin ab- sorption characteristics are altered, with inadequate or delayed absorp- tion due to decreased vascularity of such areas. This study focused on insulin absorption via subcutaneous infu- sion (ie, insulin pump), using its

infusion set performance requires research into factors affecting set survival. Additionally, the recom- mendation for duration of set change may need to be individualised. We found this paper interesting in that it goes against conventional wisdom. The traditional teaching has been that patents should avoid

Duration of infusion set survival in lipohy- pertrophy vs nonlipo- hypertrophied tissue in patients with type 1 diabetes Diabetes Technology & Therapeutics Take-home message • The authors of this study evalu- ated the effect of lipohypertro- phy on the duration of insulin infusion set survival in 20 pa- tients with type 1 diabetes (T1D) who had an area of lipohyper- trophied tissue >3 cm. They found no significant difference in infusion set survival duration or failure rate between infusion sets in lipohypertrophied tissue and those in non-lipohypertro- phied tissue. • Lipohypertrophied tissue does not appear to affect insulin infu- sion set survival in T1D. Abstract BACKGROUND Improved insulin infu- sion set survival and faster insulin action are important issues for pump users and for the develop- ment of an artificial pancreas. The current recommendation is to change infusion sets every 3 days. Our objectives were to determine the effect of lipohypertrophy (LH) on infusion set survival and continuous glucose monitoring glucose levels. RESEARCH DESIGN AND METHODS In this multicentre crossover trial, we recruited 20 subjects (age 28.1±9.0 years) with type 1 diabetes (dura- tion 17.5 ± 8.8 years) and an area of lipohypertrophied tissue >3 cm. Subjects alternated weekly wearing a Teflon infusion set in an area of either LH or non-LH for 4 weeks. Sets were changed after (a) failure or (b) surviving 7 days of use. RESULTS The least-squares mean duration of infusion set survival for sets that lasted <7 days in lipohypertrophied tissue was 4.31 days compared with 4.12 days in nonlipohypertrophied tissue (P = 0.71). The average duration of set survival for individual subjects ranged from 2.2 to 7.0 days. Infu- sion sets in lipohypertrophied tis- sue failed due to hyperglycaemia in 35% of subjects compared with 23% in nonlipohypertrophied tissue (P = 0.22). Both lipohypertrophied and nonlipohypertrophied tissues displayed a general increase in mean daily glucose after the third day of infusion set wear, but daily mean glucose did not differ by tis- sue type (P>0.38 on each day). CONCLUSION LH did not significantly affect infusion set survival or mean glucose. Achieving optimal infusion set performance requires research into factors affecting set survival. Additionally, the recommendation for duration of set change may vival in lipohypertrophy versus nonlipohypertrophied tissue in patients with type 1 diabetes, Diabetes Technol Ther 2016 Jul 01;18(7)429-435, AW Karlin, TT Ly, L Pyle, et al. need to be individualiыed. Duration of infusion set sur-

area. Of course, we cannot say if the same results would be obtained when intermittent injections were used. So, for now, we would still ad- vise avoiding these areas, if nothing

pharmacodynamic properties as its metric. The investigators found absorption to be equivalent when the infusion catheter dwelled in a lipohypertrophic region vs a normal

My type of treatment 1,2

PBS information: NovoRapid ® is listed on the PBS as a drug for the treatment of diabetes mellitus. Levemir ® is listed as a restricted benefit for type 1 diabetes.

Levemir ® is indicated for once- and twice-daily use in type 1 and type 2 diabetes 1

Please review Product Information before prescribing. The Product Information can be accessed at www.novonordisk.com.au Levemir ® (insulin detemir (rys)). Indication: Treatment of diabetes mellitus. Contraindications: Hypersensitivity to insulin detemir or excipients. Precautions: Inadequate dosingmay lead tohyperglycaemiaandDKA.Hypoglycaemiamayoccur ifdosetoohigh inrelationtorequirements(seefullPI).Forsubcutaneousadministrationonly.Avoid I.M.administration. I.V.administration may result in a severe hypo. Mixed with other insulins the action profile of either or both may change. Do not use in infusion pumps. Do not add to infusion fluids. When thiazolidinediones (TZDs) are used in combination with insulin, patients should be observed for signs and symptoms of congestive heart failure, weight gain and oedema; discontinuation of TZDs may be required. No clinical experience during lactation. Children: Levemir can be used in children. Clinical trial experience is available in children with type 1 diabetes aged 2 years and over (see ‘Clinical Trials’ in full PI). Pregnancy: Category A. Levemir can be considered during pregnancy. Clinical trial experience is available in pregnant women with type 1 diabetes (see ‘Clinical Trials’ in full PI). Interactions: Oral antidiabetic drugs (OADs), octreotide, lanreotide, monoamine oxidase inhibitors, nonselective beta-adrenergic blocking agents, angiotensin converting enzyme inhibitors, salicylates, alcohol, anabolic steroids, alpha-adrenergic blocking agents, quinine, quinidine, sulphonamides, oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone, diazoxide, asparaginase, nicotinic acid, oxymetholone and danazol. Studies do not suggest clinically relevant albumin binding interactions between insulin detemir and fatty acids or other protein-bound drugs. Adverse Effects: Hypoglycaemia, injection site reaction. Dosage and Administration: For type 1 diabetes, use in combination with rapid- or short-acting insulin. For type 2 diabetes, use alone or in combination with bolus insulin, OADs, or as add-on therapy to liraglutide. Administer once- or twice-daily as part of a basal-bolus regimen, depending on needs. Adjust dose individually. In combination with OADs or as add on therapy to liraglutide, where optimisation of blood glucose control is not achieved with once daily injection, consideration should be given to adding a mealtime bolus injection of short-/rapid-acting insulin, or to transferring the patient to a pre-mixed insulin (October 2013). NovoRapid ® (insulin aspart (rys)). Indication: Treatment of diabetes mellitus. Contraindications: Hypoglycaemia. Hypersensitivity to insulin aspart or excipients. Precautions: Inadequate dosing or discontinuation of treatment may lead to hyperglycaemia and diabetic ketoacidosis. Where blood glucose is greatly improved, e.g. by intensified insulin therapy, patients may experience a change in usual warning symptoms of hypoglycaemia, and should be advised accordingly. The impact of the rapid onset of action should be considered in patients where a delayed absorption of food might be expected. When thiazolidinediones (TZDs) are used in combination with insulin, patients should be observed for signs and symptoms of congestive heart failure, weight gain and oedema; discontinuation of TZDs may be required. Insulin administration may cause insulin antibodies to form and, in rare cases, may necessitate adjustment of the insulin dose. Pregnancy: Category A. Insulin aspart can be used in pregnancy (see ‘Clinical Trials’ in full PI). Children: NovoRapid ® can be used in children. Clinical experience is available in children aged 2 years and over (see ‘Clinical Trials’ in full PI). Elderly: No safety issues were raised in elderly patients with type 2 diabetes (mean age 70 years) in a PK/PD trial but careful glucose monitoring may be necessary in elderly patients (see ‘Clinical Trials’ in full PI). Interactions: Oral hypoglycaemic agents, octreotide, lanreotide, monoamine oxidase inhibitors, non-selective beta-adrenergic blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol, anabolic steroids, alpha-adrenergic blocking agents, quinine, quinidine, sulphonamides, oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone, diazoxide, asparaginase, nicotinic acid. Adverse Effects: Hypoglycaemia. Dosage and Administration: Dosage as determined by physician. NovoRapid ® should be administered immediately before a meal, or when necessary after the start of a meal. Discard the needle after each injection. NovoRapid ® can be used subcutaneously, intravenously or (10mL vial only) via continuous subcutaneous insulin infusion (‘CSII’). (July 2014). References: 1. Levemir ® Approved Product Information. 2. NovoRapid ® Approved Product Information. Novo Nordisk Pharmaceuticals Pty Ltd. ABN 40 002 879 996. Level 3, 21 Solent Circuit, Baulkham Hills, NSW 2153. NovoCare ® Customer Care Centre (Australia) 1800 668 626. www.novonordisk.com.au. ® Registered trademark of Novo Nordisk A/S. AU/LM/0616/0119c. INK2592-01_CEN. June 2016.

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