PracticeUpdate: Endocrinology

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OPINION

The analysis demonstrated the difficulty of maintaining haemoglobin A1c to goal over 3 years, even in a clinical trial setting. 6

CONFERENCE EASD 2016

Unexpectedly, in the SUSTAIN-6 study, a small safety study of the once-weekly GLP1 analog semaglutide, semaglutide significantly reduced the risk of cardiovascular death, MI, or stroke by 26% compared with placebo in 3297 patients with diabetes and at high cardiovascular risk. 11

Pregnancy outcomes of women with gestational

diabetes are worse but most differences are due to higher body weight 5 Even in a clinical trial setting, keeping HbA1c at goal for 3 years is difficult 6 Platelets from poorly controlled type 2 diabetes

patients show impaired ability to protect against

cardiac ischaemia/ reperfusion injury

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DIABETES Insulin infusion and glucose monitoring: a guideline for diabetes technologies 10 OBESITY Double diabetes does not have to mean double complications 13 FEATURE ARTICLE Improved glycaemic control with closed-loop insulin in pregnant diabetic women 15

Increased mortality in people with impaired glucose tolerance after the onset of diabetes Diabetes Care This study demonstrates that a large portion of the increased mortality risk in patients with impaired glucose tolerance is attributable to development of type 2 diabetes.

Optimized mealtime insulin dosing for fat and protein in type 1 diabetes: application of a model-based approach to derive insulin doses for open-loop diabetes management Diabetes Care Regardless of carbohydrate content, the fat and protein content of meals appears to increase insulin requirements in patients with type 1 diabetes. 11

Magnitude of weight loss and changes in physical fitness linked with long-term cardiovascular disease outcomes in overweight diabetics The Lancet Diabetes & Endocrinology In this secondary analysis of the Look AHEAD trial, investigators found that greater weight loss and greater change in fitness level was associated with reduced cardiovascular disease.

Metformin beneficial for overweight due to antipsychotics in children with autism JAMA Psychiatry In children and adolescents with ASD and weight gain due to antipsychotics, metformin may be effective for weight reduction.

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NEWS

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Awhey/guar “preload” improves postprandial glycaemia and HbA in type 2 diabetes In well controlled patients with type 2 diabetes, 12 weeks’ treatment with a low dose whey/guar preload taken twice daily before meals has been shown to reduce postprandial blood glucose. T his outcome of a 12-week, single-blind, randomised, placebo-controlled trial was

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

of age; body mass index 29.5 ± 5.1 kg/m 2 ; haemoglobin A1c 6.5 ± 0.5%; 24 managed by diet alone and 23 by metformin) received 150 mL flavoured shakes contain- ing either 20 g whey protein and 5 g guar (90 kcal), or flavoured placebo (0 kcal), 15 minutes before two meals each day, for 12 weeks. No other specific dietary advice was given. During the first day (week 1) and last day (week 12) of treatment, pa- tients attended the laboratory after an overnight fast and consumed the whey/guar or placebo preload shake 15 minutes before a mashed potato meal (368.5kcal: 61.4 g carbohy- drate, 7.4 g protein, and 8.9 g fat) labelled with 13C-octanoic acid. Venous blood was sampled

frequently for measurement of glu- cose, and gastric 50% emptying time was calculated by quantifying breath 13C over 240 minutes. Haemoglo- bin A1c was measured on the first and last day of treatment. Gastric emptying was slower after the whey/guar preload than after pla- cebo at the beginning of treatment (gastric 50% emptying time: whey/ guar 192.4 ± 9.2 minutes, placebo 167.2 ± 7.2 minutes, P < 0.05), though this effect was attenuated after 12 weeks (gastric 50% emp- tying time: whey/guar 177.2 ± 8.6 minutes, placebo 163.7 ± 7.5 min- utes, difference not significant). Postprandial blood glucose concen- trations were lower after the whey/ guar preload than after placebo at both the beginning (P <  0.0001) and end (P< 0.0001) of treatment, without any attenuation of this effect at 12 weeks. During both week 1 (r = –0.58, P = 0.0001) and week 12 (r = –0.57, P = 0.0001) an inverse relationship was observed between blood glucose at 60 minutes and gastric 50% emptying, so that when gastric emptying was more relatively rapid, the glycaemic response was greater. Haemoglobin A1c decreased by 0.1 ± 0.1% (1.0 ± 0.6 mmol/ mol) with the whey/guar preload and increased by 0.2 ± 0.1% (2.0 ± 0.8 mmol/mol) with placebo (P = 0.005). No meaningful changes in body weight were observed in ei- ther group (placebo –0.4 ± 0.3 kg, whey/guar –0.4 ± 0.3 kg). Dr Rayner concluded that in well controlled patients with type 2 diabetes, 12 weeks’ treatment with a low-dose whey/guar preload taken twice daily before meals was shown to reduce postprandial blood glucose, was associated with a slow- ing of gastric emptying, and led to a modest improvement in haemoglo- bin A1c.

reported at the EASD 2016 meeting. Chris K. Rayner, PhD, of the University of Adelaide, Australia, explained that his team has shown that whey “preloads,” taken before meals for up to 4 weeks, slow gastric emptying and reduce postprandial glycaemia in type 2 diabetes. Guar also slows carbohydrate absorp- tion. Dr  Rayner and colleagues evaluated the effects of 12 weeks’ treatment with a whey/guar preload on gastric emptying, postprandial blood glucose, and overall glycaemic control (haemoglobinA1c), in type 2 diabetes. Forty-seven patients with type 2 diabetes (26 males; age 64 ± 7 years

SALES Commercial Manager Fleur Gill fleur.gill@elsevier.com

Whey “preloads,” taken before meals for up to 4 weeks, slow gastric emptying and reduce postprandial glycaemia in type 2 diabetes. Guar also slows carbohydrate absorption.

Account Manager Linnea Mitchell-Taverner l.mitchell-taverner@elsevier.com

DISCLAIMER PracticeUpdate Endocrinology provides highlights of key local and international conferences with timely and relevant news, expert opinions and journal article reviews for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier Australia will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Please consult the full current Product Information before prescribing any medicationmentioned in this publication. For an annual print and/or digital subscription of PracticeUpdate Endocrinology , email news. au@elsevier.com or visit elseviermedcomms. com.au To share your feedback with us, email news. au@elsevier.com Conference news, expert opinions and journal article reviews are sourced from PracticeUp- date.com PracticeUpdate provides professional research, expert insights, and education resources in a single online destination. PracticeUpdate content is selected by medical experts in endocrinology for its relevance, timeliness, and importance. It is guided by world-renowned editorial and advisory boards that represent community practitioners and academic specialists with cross-disciplinary expertise. For in-depth insights that matter, discover PracticeUpdate.com today. ISSN 2206-4656 (Print) ISSN 2206-4664 (Online)

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CONFERENCE COVERAGE

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52nd annual meeting of the European Association for the Study of Diabetes 12–16 SEPTEMBER 2016 • MUNICH, GERMANY

Myocardial dysfunction in diabetes, pregnancy outcomes of women with

gestational diabetes, keeping HbA1c at goal, and overuse of acetylsalicylic acid in diabetes were just a handful of the many scientific and clinical presentations at the 52nd annual meeting of the European Association for the Study of Diabetes (EASD). The PracticeUpdate Editorial Team reports.

Though liraglutide + insulin is effective in type 1 diabetes, a high hypoglycaemia rate limits its use Liraglutide 1.8 and 1.2 mg, as an adjunct to insulin, has been shown to lead to greater reductions in haemoglobin A1c, body weight, and total insulin dose than placebo. Higher rates of symptomatic hypoglycaemia limit its utility for a broad population of patients with type 1 diabetes, however. T his outcome of ADJUNCT ONETM, a 52-week double-blind, multinational treat-to-target trial in adults with type A1c were significantly larger for liraglutide 1.8 and 1.2 mg than for placebo (estimated treatment differences 95% CI 1.8 mg: –0.20% [–0.32; –0.07], 1.2 mg: –0.15% [–0.27; –0.03], 0.6 mg: –0.09% [–0.21; 0.03]).

1.8 mg: 1.31 [1.07; 1.59], 1.2 mg: 1.27 [1.03; 1.55], 0.6 mg: 1.17 [0.97; 1.43]). No significant differences were observed for severe hypoglycaemic episodes (1.8 mg [45], 1.2 mg [31], 0.6 mg [40], placebo [57]). Sig- nificantly more hyperglycaemic episodes with ketosis >1.5 mmoL/L were seen with 1.8 mg [77] than for placebo [37], but not for 1.2 mg [44] or 0.6 mg [54]. Eight diabetic ketoacido- sis episodes occurred (1.8 mg [3], 1.2 mg [1], 0.6 mg [4], placebo [0]). The most frequently reported adverse events with liraglutide were nausea and vomiting. Dr Mathieu concluded that liraglutide 1.8 and 1.2 mg, as an adjunct to insulin, led to greater reductions in haemoglobin A1c, body weight, and total insulin dose than placebo. Higher rates of symptomatic hypoglycaemia limit its clinical utility for a broad population of patients with type 1 diabetes, however. She added, “There might still be a role for glucagon-like peptide 1 receptor agonists as adjunct therapies in people with type 1 dia- betes. In real life, the benefits on weight and haemoglobin A1c outweigh the risk of hypo- glycaemia. And in real life, doses of insulin can be adapted more rapidly to glycaemia than in a clinical trial.”

At baseline, mean age, type 1 diabetes duration, haemoglobin A1c, and body weight were 44 years, 21 years, 8.2%, and 86.2 kg, respectively. Fifty-two percent of subjects were women, 28% were on continuous subcutane- ous insulin treatment, 7% had severe hypogly- caemia in the past year, 6% had hypoglycaemic unawareness, and 17% had a fasting C-peptide ≥ 0.03 nmoL/L. HaemoglobinA1c was reduced 0.34–0.54% across groups at week 52. Despite the treat- to-target design, reductions in haemoglobin The benefits on weight and haemoglobin A1c outweigh the risk of hypoglycaemia. And in real life, doses of insulin can be adapted more rapidly to glycaemia than in a clinical trial.

1 diabetes in suboptimal glycaemic control (haemoglobinA1c 7–10%) was reported at the EASD 2016 meeting. Chantal Mathieu, MD, of Katholieke Uni- versiteit, Leuven, Belgium, and colleagues set out to determine whether adjunct treatment with liraglutide, a glucagon-like peptide-1 analog, improves glycaemic control and re- duces insulin requirements and body weight in type 1 diabetes. Subjects (n = 1398) were randomised 3:1 to once-daily subcutaneous injections of lira- glutide (1.8, 1.2, or 0.6 mg) or placebo as an adjunct to insulin. Primary endpoints were change in haemoglobin A1c, fasting body weight, and total insulin dose. The secondary endpoint was the incidence of symptomatic hypoglycaemic episodes.

Reductions in body weight were significantly larger for all liraglutide groups than for placebo (estimated treatment differences and 95% CI 1.8 mg: –4.9 kg [–5.7; –4.2], 1.2 mg: –3.6 kg [–4.3; –2.8], 0.6 mg: –2.2 kg [–2.9; –1.5]). Reductions in total insulin dose were sig- nificantly larger for liraglutide 1.8 and 1.2 mg than for placebo (estimated treatment ratios and 95% confidence intervals 1.8 mg: 0.92 [0.88; 0.96], 1.2 mg: 0.95 (0.91; 0.99), 0.6 mg: 1.00 [0.96; 1.04]). Significantly more symptomatic hypogly- cemic episodes (severe or plasma glucose <56 mg/dL and hypoglycaemic symptoms) were seen for liraglutide 1.8 and 1.2 mg than for placebo (estimated rate ratios and 95% CI

PRACTICEUPDATE ENDOCRINOLOGY

EASD 2016

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Platelets frompoorly controlled type 2 diabetic patients lost not only their ability to protect against ischaemia/reperfusion injury but also induced an increase of infarct size and lactate dehydrogenase release, amarker of necrosis. >9

The analysis demonstrated the difficulty of maintaining haemoglobin A1c to goal over 3 years, even in a clinical trial setting. >6

The findings support the concept that (micro)vascular structural brain damage precedes the clinical diagnosis of type 2 diabetes andmay contribute to the cerebral complications of prediabetes and type 2 diabetes. >8

Pregnancy outcomes of women with gestational diabetes are worse but most differences are due to higher body weight

Though the pregnancy outcomes of women with World Health Organization (WHO) classified gestational diabetes have been shown to be worse than those with normal glucose tolerance, most of the differences were explained by the higher body weight of these women, finds a retrospective database analysis.

mellitus, even after taking into account the weight difference between women with NICE-classified gestational diabetes mellitus and those with normal glucose tolerance. These outcomes support use of the less strin- gent cutoff values recommended by NICE. The data suggests that treatment focused on weight gain during pregnancy might be enough the improve outcomes of these ‘mild’ gestational diabetes cases (WHO-classified gestational diabetes mellitus). Dr Tabak said, “The finding that the moth- er’s weight explains some of the differences in outcomes is hardly surprising. The real prob- lem is to find the right cutoff, where the role of maternal weight becomes less important than that of glycaemia. Our study offers some direction to this problem, but the final answers should come from randomised trials.”

A.G. Tabak, MD, of University College London, UK, and Semmelweis University, Budapest, Hungary, explained that the WHO issued new recommendations for the diagnosis of gestational diabetes mellitus in 2013. The new diagnostic criteria approximately double the prevalence of gestational diabetes versus the previous WHO recommendation. Several professional bodies (including the National Institute for Health and Care Excellence [NICE]) recommended less stringent cutoff values to limit the prevalence of gestational diabetes. Given that the diagnosis of gestational diabetes has been based on the WHO-1999 criteria in the last decade in Hungary, a large proportion of women currently considered to have gestational diabetes remained untreated. Dr Tabak said, “The WHO 2013 diagnostic recommendation of gestational diabetes is based on observational findings of the multinational Hyperglycemia and Adverse Pregnancy Out- comes (HAPO) study. These recommendations lack the support of randomised clinical trials.” He added, “We tried to fill this evidence gap by providing retrospective analytic data on the outcomes of the mildest forms of gestational diabetes.” Dr Tabak and colleagues set out to compare pregnancy outcomes of women with untreated gestational diabetes (according to WHO 2013, WHO–Gestational Diabetes Mellitus and

NICE 2015, and NICE–Gestational Diabe- tes Mellitus) and women with normal glucose tolerance. During a universal screening program in western Hungary, 4828 pregnant women had a 75 g oral glucose tolerance test using three- point glucose determinations in 4 years. Based on these oral glucose tolerance tests, 696 (14.4%) WHO–Gestational Diabetes Mellitus and 478 (9.9%) NICE–Gestational Diabetes Mellitus cases were diagnosed retrospectively. A total of 251 women who were treated for gestational diabetes were excluded from the analysis. Untreated women with gestational diabetes were older and had higher fasting 60-minute, and 120-minute blood glucose, and blood pressure. No difference in marital status or education was found. Women with ges- tational diabetes had higher body weight, though weight gain was similar in all groups (13 kg). WHO–Gestational Diabetes Mellitus newborns had a higher birthweight (144 ± 31 g), Newborns of women who had NICE– Gestational Diabetes Mellitus were of similar birthweight (66 ± 43 g) to controls. Several important outcomes were more frequent in groups classified as having ges- tational diabetes by either criterion including hypertension during pregnancy (see box). No difference in the risk of preeclampsia and malformations was found. After adjustment

for the mothers’ weight at delivery, women with WHO-classified gestational diabetes mellitus had similar outcomes as women with normal glucose tolerance. While for the group with NICE-classified gestational diabetes mellitus, induced delivery and acute caesarean section remained more frequent. Dr Tabak concluded that, though the preg- nancy outcomes of women with WHO-classi- fied gestational diabetes mellitus were worse than those of women with normal glucose toler- ance, most of the differences were explained by the higher body weight of these women. Some outcomes remained worse for women with NICE-classified gestational diabetes

Outcomes that were more frequent in groups classified as having gestational diabetes by either the WHO or NICE criteria. • WHO–Gestational Diabetes Mellitus, odds ratio 1.56, 95% CI 1.03–2.38 • NICE–Gestational Diabetes Mellitus 1.58, 95% CI 0.90–2.78 Induced delivery: • WHO–Gestational Diabetes Mellitus, odds ratio 1.25, 95% CI 0.98–1.60 • NICE–Gestational Diabetes Mellitus 1.54, 95% CI 1.11–2.13 Forceps or vacuum use: • WHO–Gestational Diabetes Mellitus, odds ratio 1.29, 95% CI 1.01–1.64 • NICE–Gestational Diabetes Mellitus 1.35, 95% CI 0.97–1.87 Acute caesarean section: • WHO–Gestational Diabetes Mellitus, odds ratio 1.25, 95% CI 0.98–1.60 • NICE–Gestational Diabetes Mellitus 1.54, 95% CI 1.11–2.13 Macrosomia >4000 g: • WHO–Gestational Diabetes Mellitus, odds ratio 1.95, 95%CI 1.39–2.72 • NICE–Gestational Diabetes Mellitus 1.16, 95% CI 0.67–2.00

Patients who switch from sitagliptin to liraglutide experience better glycaemic control, weight loss, and reduced SBP and hypoglycaemic episodes By switching from sitagliptin liraglutide, patients insufficiently controlled on sitagliptin and metformin are more likely to improve in glycaemic control, lose weight, and reduce their systolic blood pressure and hypoglycaemia. T his conclusion, based on results of the randomised, parallel-group, double-blind, composite endpoints at week 26 were: • HaemoglobinA <7.0% (53 mmol/ mol) with no weight gain achieved each of the four composite end- points by switching

not achieving adequate glycaemic control with sitagliptin + metformin. Dr Bailey and colleagues com- pared the proportion of subjects meeting four composite endpoints at 26 weeks, relating to glycaemia, body weight, systolic blood pressure, and hypoglycaemia outcomes. Eligible subjects were at least 18 years of age, had haemoglobin A 7.5–9.5% (58–80 mmol/mol), body mass index ≥ 20 kg/m 2 , had been treated with stable doses of sitagliptin (100 mg daily) and met- formin ( ≥ 1500 mg daily or maximum tolerated dose ≥ 1000 mg daily) for ≥ 90 days, and were randomised 1:1 to switch to liraglutide 1.8 mg or continue sitagliptin 100 mg once daily, both + metformin. Predefined

Courtesy of EASD 2016

weight gain and no confirmed hy- poglycaemic episodes: 48.3% vs 24.2%, odds ratio 3.40, 95% CI 2.11; 5.49, P < 0.0001. Dr Bailey concluded that switch- ing from sitagliptin to liraglutide resulted in more subjects achieving each of the composite endpoints analysed, than those who continued sitagliptin. By switching from sitag- liptin to liraglutide, patients insuf- ficiently controlled on sitagliptin and metformin are more likely to meet clinically relevant goals relating to glycaemia, body weight, systolic blood pressure, and hypoglycaemia.

double-dummy, active-controlled LIRA-SWITCH trial, was presented at the meeting. T. S. Bailey, MD, of the AMCR Institute, Escondido, California, explained that limited clinical evidence is available to guide treat- ment choices beyond the addition of another drug to achieve glycaemic target when second-line therapy is inadequate for patients with type 2 diabetes. The LIRA-SWITCH trial com- pared the efficacy and safety of switching from sitagliptin to lira- glutide as an add-on to metformin in subjects with type 2 diabetes

from sitagliptin to liraglutide than those who continued sitagliptin: • Haemoglobin A <7.0% with no weight gain: 48.3% vs 24.2% (lira- glutide and sitagliptin, respectively), odds ratio 3.40, 95%CI 2.11; 5.49, P < 0.0001 • Haemoglobin A<7.0%, with no weight gain and systolic blood pressure <140 mmHg: 44.9% vs 19.2%, odds ratio 3.88, 95% CI 2.36; 6.39, P < 0.0001 • Haemoglobin A reduction ≥ 1.0% with no weight gain: 52.8% vs 29.1%, odds ratio 2.85, 95% CI 1.82; 4.47, P < 0.0001 • Haemoglobin A<7.0%, with no

• Haemoglobin A <7.0%, with no weight gain and systolic blood pressure <140 mmHg • Haemoglobin A reduction ≥ 1.0% with no weighwt gain. In addition, a post hoc analysis of haemoglobin A<7.0%, with no weight gain and no confirmed hypo- glycaemic episodes was conducted. A total of 407 subjects (male 60%, mean age 56 years, body mass index 32 kg/m 2 , haemoglobinA 8.3% [67 mmol/mol], type 2 diabetes dura- tion 8 years) were randomised (lira- glutide, n = 203; sitagliptin, n = 204). At week 26, more subjects

VOL. 1 • No. 3 • 2016

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EASD 2016

6

Insulin degludec reduces severe or blood glucose-confirmed hypoglycaemia and is noninferior to insulin glargine in reducing HbA1c in types 1 and 2 diabetes

In the SWITCH 1 and 2 trials, despite similar reductions in haemoglobin A1c, insulin degludec reduced severe or blood glucose-confirmed symptomatic hypoglycaemia compared to insulin glargine in both type 1 and 2 diabetes. These outcomes of the randomised, double- blind, 2 x 32 week, treat-to-target, crossover SWITCH 1 and 2 trials, were reported at the EASD 2016 meeting. SWITCH 1, in type 1 diabetes

glucose-confirmed symptomatic overall and nocturnal hypoglycaemia versus insulin glargine. SWITCH 2, in type 2 diabetes Carol Wysham, MD, of the Rock- wood Center for Diabetes and En- docrinology, Spokane, Washington, explained that SWITCH 2 compared the same parameters as SWITCH 1. Aside from the patient population, SWITCH 2 differed from SWITCH 1 inasmuch as both insulin degludec U100 and insulin glargine U100 were given in combination with pretrial oral antidiabetic drugs. She said, “The study was per- formed to compare the relative risk of hypoglycaemia with insulin degludec versus insulin glargine in a population of patients with type 2 diabetes who were at high risk of hypoglycaemia. This is a popula- tion that would have been largely excluded from previous studies.” A total of 721 adults with type 2 diabetes and at least one factor associated with increased risk of hypoglycaemia received once-daily insulin degludec or insulin glargine followed by crossover to insulin degludec or insulin glargine for 32 weeks (a 16-week titration and a 16-week maintenance period). Pa- tients had been treated with basal insulin with or without oral antidia- betic drugs excluding sulphonylurea/ meglitinides. The primary endpoint was the number of severe or blood

glucose-confirmed (<3.1 mmoL/L) symptomatic hypoglycaemic episodes during the maintenance periods. Treatment with insulin degludec resulted in significantly lower rates of severe or blood glucose-confirmed symptomatic hypoglycaemia and severe or blood glucose-confirmed symptomatic nocturnal hypogly- caemia (00:01–05:59) than insulin glargine in the maintenance and total treatment periods. The proportion of patients experi- encing severe hypoglycaemia in the maintenance periods was 1.6% for insulin degludec vs 2.4% for insulin glargine (difference not significant). The rate of severe hypoglycaemia was significantly lower with insulin degludec than with insulin glargine in the total treatment period. Insulin degludec was noninferior to insulin glargine in haemoglobin A reduction. Adverse event rates were similar with the two agents. Dr Wysham concluded that, com- pared with insulin glargine, insulin degludec resulted in a consistent re- duction in hypoglycaemia in patients with type 2 diabetes at increased risk of hypoglycaemia and was shown to be noninferior to insulin glargine in haemoglobin A reduction. She added, “In clinical practice, the results give us direction in how to treat this population at high risk of morbidity and mortality from hy- poglycaemia”.

both with mealtime insulin aspart, for 32 weeks (a 16-week titration period and a 16-week maintenance period), followed by crossover to insulin degludec or insulin glargine. The primary objective was to con- firm noninferiority in terms of the number of severe or blood glucose- confirmed (<3.1 mmoL/L) symp- tomatic hypoglycaemic episodes during the maintenance periods. Treatment with insulin degludec resulted in an 11%, significantly lower rate of severe or blood glu- cose-confirmed symptomatic hy- poglycaemia than insulin glargine in the maintenance period. Severe

or blood glucose-confirmed symp- tomatic nocturnal hypoglycaemia (00:01–05:59) was also significantly reduced by 36% for insulin degludec versus insulin glargine. Severe hypoglycaemia was signifi- cantly reduced, by 35%more with in- sulin degludec versus insulin glargine. Significant reductions for all three hypoglycaemia categories were also seen for the total treatment periods. In addition, a significantly lower proportion of patients taking insulin degludec experienced severe hypo- glycaemia during both the mainte- nance and total treatment periods than those taking insulin glargine (P = 0.0016). Noninferior reduction in hae- moglobin A1c between insulin de- gludec versus insulin glargine was confirmed in both treatment periods (week 32: 6.95 vs 6.92%; week 64: 6.95 vs 6.97%). The rates of adverse events were similar for insulin deglu- dec and insulin glargine. Dr Lane concluded that in patients with type 1 diabetes at increased risk of experiencing severe hypoglycae- mia, insulin degludec was noninferior in terms of haemoglobinA reduction and significantly reduced the rates and proportions of severe hypogly- caemia and rates of severe or blood

Wendy Lane, MD, of Mountain Diabetes and Endocrine Center, Asheville, North Carolina, explained that SWITCH 1 compared the num- ber of severe or blood glucose-con- firmed, symptomatic hypoglycaemic episodes in patients with type 1 dia- betes treated with insulin degludec U100 versus insulin glargine U100, both in combination with mealtime insulin aspart. Five-hundred one adults with type 1 diabetes and at least one fac- tor associated with increased risk of hypoglycaemia received once-daily insulin degludec or insulin glargine,

Courtesy of EASD 2016

Even in a clinical trial setting, keeping HbA1c at goal for 3 years is difficult Maintaining haemoglobin A1c to goal over 3 years in patients with type 2 diabetes has been shown to be a challenge, even in a clinical trial setting. Reduced haemoglobin A1c and fasting glucose values after 26 weeks of treatment increases a patient’s likelihood of sustaining a haemoglobin A1c <53 mmol/mol (<7%) over 3 years

antibodies, and sulfonylurea use, were not related to sustained response. Dr Trautmann concluded that the analysis demonstrated the difficulty of maintaining haemoglobin A1c to goal over 3 years, even in a clinical trial setting, and suggested that lower haemoglobin A1c and fasting glucose values after 26 weeks of treatment raise a patient’s likelihood of sustaining haemoglobin A1c <53 mmol/mol (<7%) over 3 years with minimal medication changes. Weekly fixed-dose exenatide supported long-term glycaemic control to a greater extent than titrated insulin glargine, though sustained success was achieved with both therapies. Greater response to weekly ex- enatide treatment after 26 weeks raises the likelihood of sustaining glycaemic control over 3 years.

with minimal medication changes. T his conclusion, based on a retrospec- tive analysis of DURATION-3, a 3-year, randomised, open-label trial of exena- tide versus insulin glargine in type 2 diabetes, was presented at the EASD 2016 meeting. M.E. Trautmann, MD, of Diabetes Re- search, Hamburg, Germany, explained that long-term haemoglobin A1c control with minimal medication change is a reasonable goal for patients with type 2 diabetes. Dr Trau- tmann and colleagues analysed 3-year data from the DURATION-3 study retrospectively to characterise patients who sustained a hae- moglobin A1c response to goal (<53 mmol/ mol [7%]) over 3 years. Type 2 diabetic patients taking metformin ± sulfonylurea were randomised to 2 mg sub- cutaneous exenatide once weekly or insulin glargine titrated to a fasting glucose level of 4.0–5.5 mmoL/L). Patients with a sustained response to ther- apy were defined as achieving haemoglobin A1c <53 mmol/mol (<7%) at 26 weeks and maintaining haemoglobinA1c <53 mmol/mol (<7%) for 80% of remaining visits, includ- ing one of two visits in the last 6 months.

Thirty-two potential model parameters were tested iteratively and included if related to sustained success (P < 0.05). The intent-to-treat population was com- posed of 456 patients, of whom 287 (63%) completed 3 years. Of the 287 completers, 175 (61%) had a haemoglobin A1c level <53 mmol/mol (<7%) at 26 weeks. Of completers who reached the haemoglobin A1c goal, 84 (48%) demon- strated sustained control for ≥ 80% of visits over 3 years. Responders with a sustained haemoglobin A1c response were a mean age of 57.7 years, baseline body mass index was 32.2 kg/m 2 . Fifty-percent were males and 81% were white. Their mean baseline and week 26 haemoglo- bin A1c levels were 62 mmol/mol (7.8%) and 44 mmol/mol (6.2%), respectively. Patients unable to sustain goal response were a mean age of 58.6 years and had a baseline body mass index of 32.3 kg/m 2 . Fifty-three percent were male and 92% were white. Their mean baseline and week 26 haemoglobin A1c were 65 mmol/mol (8.1%) and 48 mmol/mol (6.5%), respectively. Among

patients achieving haemoglobinA1c goal con- sistently, significantly more were treated with weekly exenatide (n = 53) than with insulin glargine (n = 31; P = 0.03). Other factors related to sustained treat- ment success included haemoglobin A1c and fasting glucose at 26 weeks. The major- ity of evaluated factors, including age, weight loss, waist-to-hip ratio, titre of anti-exenatide

Courtesy of EASD 2016

PRACTICEUPDATE ENDOCRINOLOGY

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 dosing may lead to hyperglycaemia and DKA. Hypoglycaemia may occur if dose too high in relation to requirements (see full PI). For subcutaneous administration only. 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/0616/0119d. INK2592-02_CEN. June 2016.

CONFERENCE COVERAGE

8

Patients with diabetes are more likely to overuse than to underuse acetylsalicylic acid In large primary care settings, patients with diabetes are more likely to overuse

Prediabetes is associated with white matter atrophy in the MAASTRICHT study Prediabetes and type 2 diabetes have been associated with white matter hyperintensities and white matter atrophy, and type 2 diabetes with brain atrophy, as indicated by smaller white matter volumes. T his finding of a cross-sectional, comparative study of magnetic resonance and fluid-attenuated inversion recovery weighted images was reported at the EASD 2016 meeting. Marnix.J.M. van Agtmaal, MD, of Maastricht University Medical Center, The Nether- lands, explained that type 2 diabetes mellitus associated with brain atrophy and cerebral small vessel disease is believed to involve cerebral microvascular dysfunction. He said, “The epidemic of type 2 diabetes is a major health problem, and prevention of its complications is important. The brain is a major target for the effects of type 2 diabetes. Patients with type 2 diabetes are at increased risk of stroke, cognitive impair- ment, dementia, and depression.” “Moreover, age-related structural brain changes on MRI, such as markers of cerebral small vessel disease and brain atrophy, are more common in patients with type 2 diabetes. Little is known, however, about the pathophysiology of these structural brain changes.” “In light of the growing diabetes epidemic, the identification of factors contributing to structural brain changes is paramount. Microvascular dysfunction has been implicated in the aetiology of cerebral small vessel disease and brain atrophy in type 2 diabetes. Little is known about structural brain changes before the onset of type 2 diabetes, so preventing these changes is problematic.” “Since it has not been determined whether individuals with prediabetes harbour struc- tural brain changes,” Dr vanAgtmaal asserted, “we hypothesised that cerebral small vessel disease and brain atrophy are present in prediabetes. Answering this question is important because cerebral small vessel disease and brain atrophy are preventable. After the brain has undergone structural damage, however, the consequences are irreversible.” Dr van Agtmaal and colleagues set out to determine whether prediabetes and type 2 diabetes are associated with white matter hyperintensities, a proxy of cerebral small vessel disease, and brain atrophy in a general population age 40–75 years. The Maastricht Study is a population-based cohort study with an oversampling of participants with type 2 diabetes (the present analysis, n = 2243; mean age 59.2 ± 8.2 years; 45.6% females). A total of 1372 subjects had normal glucose metabolism, 347 had prediabetes, and 524 had type 2 diabetes. White matter hyperintensity, white matter, grey matter, and cerebrospinal fluid volumes were determined relative to intracranial volume using automated segmentation of T1, T2, and fluid-attenuated inversion recovery weighted magnetic resonance images. The association between glucose metabolism status and tissue volumes was assessed by linear regression analysis and adjusted for age, sex, body mass index, systolic blood pressure, total-to-high-density lipoprotein-cholesterol ratio, triglyceride levels, and edu- cational level. Prediabetes and type 2 diabetes were associated with a smaller white matter volume after full adjustment. The regression coefficient ( β ) of white matter volume was –0.305 (–0.569; –0.041), P < 0.001 and –0.628 (–0.876; –0.380(, P < 0.001. No association was found between prediabetes and type 2 diabetes grey matter volume. Type 2 diabetes was associated with a larger cerebrospinal fluid volume (0.723 [0.450; 0.995], P < 0.001), while prediabetes was not. Prediabetes and type 2 diabetes were associated with a larger white matter hyperin- tensity volume ( β 0.122 [0.15– 0.228], P = 0.05 and 0.228 [0.127; 0.328], P < 0.001). Dr vanAgtmaal concluded that prediabetes and type 2 diabetes are associated with larger white matter hyperintensity volumes. In addition, while type 2 diabetes is associated with a smaller white matter volume, while type 2 diabetes is associated with a smaller white matter volume and a larger cerebrospinal fluid volume. These data may indicate that, in

than to underuse acetylsalicylic acid. T his conclusion, based on results of an analysis conducted as part of a primary prevention effort to lower the risk of ath- erosclerotic vascular disease was presented at the EASD 2016 meeting. Lauren Crain, PhD, of HealthPartners Insti- tute, Minneapolis, Minnesota, explained that acetylsalicylic acid is recommended for primary prevention of cardiovascular disease for people with and without diabetes when the risk re- duction outweighs the risk of gastrointestinal haemorrhage. In a primary care setting, the complexity and time required to assess acetylsalicylic acid benefits and risks can result in inappropriate acetylsalicylic acid use through either overuse or underuse. Dr Crain and colleagues set out to assess the appropriateness of acetylsalicylic acid use for primary prevention in diabetes and other patients at high risk of cardiovascular disease in a large primary care setting. As part of a study funded by the US National Institutes of Health to lower the risk of athero- sclerotic cardiovascular disease, Dr Crain’s team implemented electronic clinical decision support algorithms to encourage appropriate acetylsali- cylic acid use. The algorithms recommend acetylsalicylic acid if risk scores for atherosclerotic cardiovascular disease are high and consistent with benefit greater than gastrointestinal bleed risk using criteria from the US Preventive Services Task Force. Coinvestigator JoAnn Sperl-Hillen, MD, speaking from a clinician perspective, said, “The latest aspirin guidelines highlight the need for an individualised approach to aspirin recommenda- tions for primary cardiovascular prevention that balances a person’s benefits and risks.” In the study, acetylsalicylic acid was not rec- ommended if risk reduction was low or if major contraindications were identified (anticoagulant use or a history of intracerebral haemorrhage). Providers were also alerted to the presence of other potential acetylsalicylic acid risks including allergy or intolerance, history of conditions indica- tive of gastrointestinal bleed risk, and concomitant use of nonsteroidal anti-inflammatory drugs. Baseline study data was collected for whether

risk, clinical decision support algorithms recom- mended acetylsalicylic acid for 2484 (62.7%) patients with diabetes and 5341 (76.3%) without diabetes. Among patients for whom acetylsalicylic acid was recommended, the agent was underused in 5171(20.8%) with diabetes and 5638 (74.4%) without diabetes. Among patients for whom the algorithms did not recommend acetylsalicylic acid, the agent was overused in 840 (57.0%) with diabetes and 559 (33.7%) without diabetes. Dr Crain concluded that in this large primary care setting, acetylsalicylic acid was more likely to be overused than underused in patients with diabetes. Those with diabetes who were likely to benefit from acetylsalicylic acid use had higher use rates than similar high cardiovascular-risk patients without diabetes. Those with diabetes who were unlikely to ben- efit from acetylsalicylic acid (risks greater than benefit), however, had higher rates of acetylsali- cylic acid overuse than those without diabetes. Dr Sperl-Hillen said, “Our study suggests that in primary care practice, aspirin use is often not concordant with an individual’s assessed risk and benefit. This is due in part to the lack of available practical assessment tools that can be used in the context of busy clinician practices.” She continued, “Care can be improved through shared decision making facilitated by risk/benefit assessment tools integrated with the electronic health record. We successfully implemented a Web-base, electronic health record – integrated tool to help patients and clinicians quickly as- sess and prioritise cardiovascular risk factors and risk-lowering treatment opportunities. We achieved high use rates for appropriate patients in a primary care setting.” When asked about the team’s further research, Dr Sperl-Hillen replied, “We are studying how well these electronic health record – integrated tools work to improve patient outcomes. Risk information that may be impacted by patient characteristics, such as educational level, health literacy, and numeracy, can be presented in nu- merous ways. A major focus of our work will be to evaluate how different formats of risk assessment information presented to patients and clinicians can influence clinical decisions and patient be- haviours.”

acetylsalicylic acid was algo- rithmically recommended for all patients at their first eligible primary care encounter in 20 clinics from 2012 to 2014. The analysis excluded pa- tients with coronary heart disease and included 3958 adults with diabetes (mean age 54.6 years, mean 10-year risk of cardiovascular disease risk 29.2%) and 7000 adults meeting prespecified criteria for high risk of cardiovascular disease risk without diabetes (mean age 58.5 years, mean 10-year risk of cardiovascular disease 25.6%). Over- and underuse were determined by comparing con- cordance with acetylsalicylic acid algorithm recommenda- tions and documented acetyl- salicylic acid use. For the targeted population at high cardiovascular disease

a middle-aged population, changes in cerebral white matter occur before onset of type 2 diabetes. “We showed in a population-based study, that both prediabetes and type 2 diabetes are associated with cerebral small vessel disease and brain atrophy, independent of major cardiovascular risk factors,” Dr van Agtmaal said. He continued, “The findings sup- port the concept that (micro)vascular structural brain damage precedes the clinical diagnosis of type 2 diabetes and may contribute to the cerebral complications of prediabetes and type 2 diabetes, such as stroke, cognitive decline, and depression.” He added, “We will explore the association of structural brain dam- age with stroke, cognitive decline, and depression. And we will follow up on the participants after 5 years to measure the effects of structural brain damage on mortality and co- morbidity.

Courtesy of EASD 2016

PRACTICEUPDATE ENDOCRINOLOGY

EASD 2016

9

Platelets from poorly controlled type 2 diabetes patients show impaired ability to protect against cardiac ischaemia/reperfusion injury Platelets from poorly controlled type 2 diabetic patients have been shown to have lost their ability to protect against ischaemia/reperfusion injury, but also induced an increase of infarct size and of lactate dehydrogenase release, a marker of necrosis. T his outcome of an investiga- tion of the direct role of plate- lets to influence infarct size in

Ischaemia and reperfusion are implicated in a variety of clinical conditions including thrombolytic therapy for myocardial infarction. Reperfusion of previously ischae- mic tissue, while essential to prevent irreversible tissue injury, elicits inflammatory responses with increased production of reactive oxy- gen species and soluble mediators, leading to impaired organ function. Dr Russo and colleagues perfused hearts from male Wistar rats in

Langendorff mode with an oxygen- ated Krebs solution at constant flow (9 –10 mL/min/g). After 20 minutes of stabilisation, hearts were divided into three groups: 1.Controls received 20 minutes of oxygenated buffer perfusion 2. A group received 20 minutes of oxygenated buffer containing 30 x 10 6 /mL platelets from healthy subjects (n=6, four males, two females, age 49 ± 3 years) 3. A group received 20 minutes of

oxygenated buffer containing 30 x 10 6 /mL platelets from pa- tients with type 2 diabetes (n=5, four males/one females, age 55 ± 3 years, haemoglobin A1c 14 ± 1%) At the end of platelet-perfusion, the hearts underwent 30 minutes of normothermic global ischaemia fol- lowed by 60 minutes of reperfusion. Lactate dehydrogenase release and infarct size were assessed. In plate- let samples from each subject, the following were also evaluated:

• platelet aggregation to adenosine diphosphate 10 µmoL/L, col- lagen 4 mg/L, arachidonic acid 0.5 mmoL/L (Born’s method) • activation of PI-3 kinase/Akt and MAPK/Erk-1/2 pathways • intraplatelet reactive oxygen spe- cies production • cyclooxygenase-1 expression. In type 2 diabetes, platelet hyperreactivity could hold predictive value of myocardial dysfunction after ischaemia/reperfusion injury. Infarct size was 59 ± 2% of risk area in control hearts and was small- er in hearts pretreated with platelets from healthy subjects (49 ± 3% of risk area; P < 0.05), but higher in hearts pretreated with platelets from type 2 diabetic patients (63 ± 4% of risk area; P < 0.05) than in those pretreated with platelets-from healthy subjects. Lactate dehydrogenase release corroborated the data on infarct size. Perfusion pressure was not affected by any of the treatments. Interest- ingly, platelets from type 2 diabetic patients, in comparison with those from healthy subjects, showed: • A higher trend to aggregate in re- sponse to arachidonic acid (76 ± 11 vs 51 ± 3, P < 0.05); adenosine diphosphate (78 ± 14 vs 63 ± 2, difference not significant); and collagen (89 ± 13 vs 65 ± 2, dif- ference not significant) • A greater increase in basal values of phosphorylated Akt and Erk-2 in response to collagen (2.9 ± 0.2 vs 1.5 ± 0.6, P = 0.07; and 15.6 ± 3.3 vs 5.5 ± 1.2, P < 01.03, re- spectively) and arachidonic acid (2 ± 0.3 vs 1.4 ± 0.6, difference not significant; and 22 ± 4.9 vs 5.4 ± 1.5, P < 0.007) • Greater reactive oxygen species production (mean fluorescence intensity per minute) stimulated by arachidonic acid (73,708 ± 560 vs 35, 350 ± 720, P < 0.0001) • Higher expression of cyclooxyge- nase-1 (arbitrary units 26,643 ± 210 vs 13,200 ± 350, P < 0.0001). Dr Russo concluded that platelets from poorly controlled type 2 diabetic patients lost not only their ability to protect against ischaemia/reperfusion injury but also induced an increase of infarct size and lactate dehydro- genase release, a marker of necrosis. These effects were associated with an increased tendency of plate- lets to aggregate in response to the main physiological proaggregating agents, as well as increased produc- tion of reactive oxygen species and cyclooxygenase-1 expression. These findings suggest that, in type 2 dia- betes, platelet hyperreactivity could hold predictive value of myocardial dysfunction after ischaemia/reperfu- sion injury.

a rat model of ischaemia/reperfusion after infusion of human platelets from type 2 diabetic or healthy sub- jects was reported at the meeting. Isabella Russo, PhD, of the Uni- versity of Turin, Italy, explained that in type 2 diabetes, platelet hyper- reactivity is partially responsible for a switch of the coagulation system toward a prothrombotic state.

1

1

Dual Action NovoMix ® 30 2,3

PBS Information: This product is listed on the PBS for the treatment of diabetes mellitus.

Please review Product Information before prescribing. The Product Information can be accessed at www.novonordisk.com.au

Minimum Product Information. NovoMix ® 30 (insulin aspart (rys)). Indication: Treatment of diabetes mellitus. Contraindications: Hypoglycaemia. Hypersensitivity to insulin aspart or excipients. Precautions: Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, 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. Do not use in insulin infusion pumps. No studies in children and adolescents under the age of 18. No clinical experience in pregnancy. 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. 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. NovoMix ® 30 should be administered immediately before a meal, or when necessary after the start of a meal. Resuspend immediately before use. Discard the needle after each injection. Subcutaneous injection only. NovoMix ® 30 must not be administered intravenously. (July 2014). References: 1. Liebl A et al. Drugs 2012; 72(11): 1495–520. 2. Wu T et al. Diabetes Ther 2015; 6(3): 273–87. 3. NovoMix ® 30 Approved Product Information (Jul 2014). 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/NM/0116/0004. January 2016.

insulin aspart (rys)

NOVMIX0065/CEN/A4

VOL. 1 • No. 3 • 2016

NOVMIX0065/CEN/A4.indd 1

16/03/2016 12:01 pm