A Journal for the healthcare professional with an interest in diabetes · 2017-04-18 · Globally 415 million people have diabetes, with more than 14 million people in the African

The Official Healthca e ProfessionalJournal of the CDE

A Journal for the healthcare professional with an interest in diabetes

EDITORIAL

ORIGINAL ARTICLES

• Chronic pain: Addressing the triad of

pain, sleep and depression/anxiety

• Achieving health objectives eating

the vegetarian way. A Case Study -

Sunjay Naidoo

• Recognising and Diagnosing

Cardiac Autonomic Neuropathy

in People with Diabetes

• Chronic diabetes and brain change

CPD ACCREDITED

DIABETES TRAINING

Volume 9 Number 3 • August 2016

To eat is a necessity,

but to eat intelligently

is an art.

~Francois de la Rochefoucauld

OPTISULIN, the clone of LANTUS

LANTUS and OPTISULIN are identical in all aspects except for the name and price and are therefore interchangeable 6,7,8

For full prescribing information, refer to current package insert.

SCHEDULING STATUS: S3 PROPRIETARY NAME AND DOSAGE FORM: LANTUS® solution for injection. COMPOSITION: Each ml of the solution for injection contains 3.64 mg of the active

ingredient insulin glargine, corresponding to 100 units (u) human insulin, 2.7 mg of the preservative metacresol and 0.0626 mg of zinc chloride as stabiliser. 10 ml vial contains 0.02 mg polysorbate 20

as additional stabiliser. REGISTRATION NUMBER: 34/21.1/0248.

SCHEDULING STATUS: S3 PROPRIETARY NAME AND DOSAGE FORM: OPTISULIN® solution for injection. COMPOSITION: Each ml of the solution for injection contains 3.64 mg of the active

ingredient insulin glargine, corresponding to 100 units (u) human insulin, 2.7 mg of the preservative metacresol and 0.0626 mg of zinc chloride as stabiliser. REGISTRATION NUMBER: 41/21.1/0363.

NAME AND BUSINESS ADDRESS OF THE APPLICANT: Sanofi-Aventis South Africa (Pty) ltd, 2 Bond Street, Midrand, 1685. Tel: 011 256 3700. Reg. No. 1996/10381/07.

SAZA.OPN.15.09.0155

References: 1. DeVries JH, Meneghini L, Barnett AH, et al. A Patient-level Analysis of Efficacy and Hypoglycaemia Outcomes Across Treat-to-target Trials with Insulin Glargine Added to Oral Antidiabetes

Agents in People with Type 2 Diabetes. Eur Endocrinol. 2014;10(1):23-30. 2. Gerstein HC, Bosch J, Dagenais GR, et al., and The ORIGIN Trial Investigators. Basal Insulin and Cardiovascular and Other

Outcomes in Dysglycemia. N Engl J Med. 2012;367:319-328. 3. South African Medicine Price Registry. Available from: http://www.mpr.gov.za/PublishedDocuments.aspx?DocCatId=34. Accessed:

3 September, 2015. 4. Mediscor Pharmaceutical Benefit Management (South Africa). Medicines Review 2014, table 12 of page 17. Mediscor PBM (Pty) Ltd. Accessed September 2015. 5. Discovery

Health, Medicine advisor accessed at www.discovery.co.za on the 28th September 2015. 6. Nissen L. Explainer: how do generic medicines compare with brand leaders? The Conversation [online].

Available from: http://theconversation.com/explainer-how-do-generic-medicines-compare-with-brand-leaders-1386. Accessed: 1 September, 2015. 7. Hollis A. How do Brands’ “Own Generics” Affect

Pharmaceutical Prices? Rev Indus Org. 2005;27:329-350. 8. Integrated Act 101 (2) of the Medicines and Related Substances Control Act 101 of 1965.

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EDITORIAL

Guest Editor - Dr Larry DistillerFCP (SA) FRCP FACESpecialist Physician / EndocrinologistPrincipal Physician & Executive Chairman, CDEHon Visiting Professor, Cardiff University School of Medicine, 2010-2015

Economic, political and social instability and chaosabounds. The Health Care community is notinsulated from this ever-changing landscape. The

incidence of Non-Communicable Disease is explodingworldwide, and in particular, diabetes and hypertensionare placing an ever-increasing burden on medical costs.

In the past decade, a number of new drugs andinsulins have been introduced - at present, over 200new products are in development for the treatment oftype 2 diabetes; some new molecules, others ‘me too’products. New drugs always come at an enhanced cost.In a country like South Africa, where we try to practice‘First World’ medicine in developing country economy,this creates very real problems, both in the private andpublic sectors. Notwithstanding the hype thataccompanies the launch of new drugs and new insulinsinto the market, the obvious questions are: What are theadvantages of these new products over the currentlyused classes, and, are these advantages worth theincreased cost? Or, to put it more simply, what is the“bang you get for the buck”?

When analysed unemotionally, the answer to thatquestion is unfortunately not exciting. Most of thenewer agents are either “as good as” currently availabletherapies, whilst others offer, at best, a minor advantage

Editor’s comment

at a massively enhanced cost. Even the so-calledcardioprotective advantages of liraglutide, whenanalysed in the light of economic practicality, becomeconcerning. The Liraglutide Effect and Action inDiabetes: Evaluation of Cardiovascular OutcomeResults (LEADER®) trial showed you would need totreat 66 patients with 1.8 mg of liraglutide daily, for 3years, to prevent one coronary event, and 98 patients toprevent one death. In real South African Rand terms,preventing one coronary event over 3 years would costabout R4, 400,000 and prevention of one death wouldcost around R6, 500,000. This is clearly not a viableoption that can be sold to healthcare funders.

So what is the alternative? With all the pressureplaced upon us by big Pharma with regard to their new‘wonder agents’, we tend to forget that type 2 diabetesis essentially a lifestyle condition - failure to placesufficient emphasis on lifestyle change is both a recipefor therapeutic failure and a major cause of risingtherapeutic costs in treating the condition. It is time forus to return to the basics. We need to be far moreproactive in promoting better eating habits, exerciseand lifestyle changes in our patients. Anypharmacological intervention should be in addition to,and not instead of, meaningful lifestyle improvements.

The world has gone mad!

The annual CDE Postgraduate Forum in Diabetes Management (now in its 18th year), has arich tradition of providing stimulating and vigorous debate on topical issues and challengesin diabetes care. We thank our Guest Editor for providing a thoughtful starting point fordebate for this Issue of the SAJD, which will arrive ‘hot-off-the-press’ on the opening day ofthe Forum. If you are attending as a Delegate, we welcome you to the Forum and we lookforward to spending the weekend with you, our colleagues and friends in diabetes.

Dr Stan LandauEditor

email: [email protected]

South African Journal of Diabetes - August 2016 | 1

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References: 1. Donnelly LA, Morris AD, et al. Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study. Diabetes, Obesity and Metabolism 2009;11:338-342. 2. Blonde L, Dailey GE, et al. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Research Opin 2004;20(4):565-572. 3. SEMDSA Guidelines 2012. Guideline for the Management of Type 2 Diabetes (Revised). Chapter 9.1. Journal of Endocrinology, Metabolism and Diabetes of South Africa. 2012;17(Suppl 1):523-531.

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Contents


CONTENTS

Volume 9 Number 3 • August 2016

EDITORDr Stan [email protected]

SUB-EDITORMichael [email protected]

EDITORIAL CONTRIBUTORSProf Brynne Ascott-Evans:[email protected] Catsicas:[email protected] Joel A Dave:[email protected] Larry Distiller:[email protected] Jocelyn Hellig:[email protected] Rakesh JainandDr David Webb:[email protected]

ADVERTISING ENQUIRIESAngela BellCell: 082 451 0193 Tel: 011 787 9366 Fax: 088 011 787 9366Email: [email protected]

PUBLISHERSouth African Journal of Diabetesis published by:Homestead Publishing (Pty) Ltd (Reg. No. 2011/128152/07).

Postnet Suite 354Private Bag X11Craighall2024

PRODUCTIONAdéle GouwsOutput Reproductions

PRINTINGBusiness Print Centre

COPYRIGHTMaterial appearing in this Journalbelongs to the South AfricanJournal of Diabetes and/or theindividual contributors. Thecontents of this publication maynot be reproduced in any partwithout the written consent of thepublisher. The views expressed bycontributors do not necessarilyreflect the views of the publisher,editors or advertisers. While everyeffort has been made to ensureaccuracy, the editors, contributorsand publisher do not acceptresponsibility for errors, emissionsor inaccuracies in the publication.

EDITORIAL 1

Dr Stan Landau with Guest Editor - Dr Larry Distiller

ORIGINAL ARTICLES

Chronic pain: Addressing the triad of pain, sleep and

depression/anxiety 7Prof Rakesh Jain, Dr David Webb

Achieving health objectives eating the vegetarian way.

A Case Study - Sunjay Naidoo 13Ria Catsicas

Recognising and Diagnosing Cardiac Autonomic Neuropathy

in People with Diabetes 18Dr Joel A Dave

Chronic diabetes and brain change 23Dr Jocelyn Hellig, Prof Brynne Ascott-Evans

PRESS RELEASE

Hypoglycaemia in type 2 diabetes increases the risk of

cardiovascular events 28

Specialists in human biosimilar insulins

The economic burden of diabetes is increasing worldwide, with the greatest demands and increases in developing countries.1

Globally 415 million people have diabetes, with more than 14 million people in the African Region; The International Diabetes Federation predicts that by 2040 these figures will more than double.2

Three-and-a-half million South Africans (about 6 % of the population) suffer from diabetes and there are many more who are undiagnosed. It is estimated that another five million South Africans have pre-diabetes, a condition where insulin resistance causes blood glucose levels to be higher than normal, but not high enough yet to be type 2 diabetes.3

The need for more cost-effective insulin therapy is critical in reducing the financial burden on patients and health care systems.1

Biosimilars are distinctly different from generic drugs, as they are protein compounds that rely on modification for efficacy and are therefore bioequivalent rather than bioidentical. Biosimilars must follow precise manufacturing, processing and purification procedures, and are regulated to pass stringent laboratory and clinical trials before approval.1

BIOSULIN insulins were approved for use in South Africa more than 10 years ago and are marketed by BIOSWISS, a wholly owned subsidiary of Ascendis Pharma.

Biosimilar insulins have the potential to dramatically lower healthcare costs by delivering insulin with similar anti-glycaemic effect and adverse reaction profile to standard, more expensive insulin preparations.1

In the BEST study (SAMJ July 2013) BIOSULIN 30/70 insulin was tested to confirm equivalence to other human premixed insulin preparations on the South African market.1 Seventy-seven subjects with type 1 (n = 18) and type 2 diabetes mellitus (n = 59) were switched from their existing human premix insulin to BIOSULIN 30/70. The change in HbA

1c from baseline to 6 months was considered the primary endpoint of the study.1

BIOSULIN 30/70 achieved at least equivalent glycaemic control with no reported new or severe adverse events. In addition there was no significant difference in body weight in the study subjects during the 6-month period on BIOSULIN 30/70.1

Despite the more complex production process and regulatory requirements for biosimilars, they offer a price reduction of between 21 % and 47 % of the parent insulin and analogue insulin.4

For more information regarding BIOSWISS and their products, please contact Laurett Correia on [email protected].

References: 1. Segal D, Tupy D, Distiller L. The Biosulin equivalence in standard therapy (BEST) study − a multicentre, open-label, non-randomised, interventional, observational study in subjects using Biosulin 30/70 for the treatment of insulin-dependent type 1 and type 2 diabetes mellitus. SAMJ 2013;103(7):458-460:1-4. 2. South Africa | International Diabetes Federation. Available from https://www.idf.org/membership/afr/south-africa Accessed 15 February 2016. 3. Prevalence of diabetes in South Africa | Health24. Available from http://www.health24.com/Medical/Diabetes/About-diabetes/Diabetes-tsunami-hits-South-Africa- Accessed 15 February 2016. 4. Database of Medicine Prices February 2016. Available from http://www.mpr.gov.za/ Accessed February 2016

S3 Biosulin R (solution for injection). Each Biosulin R solution for injection contains 100 I.U/ml biosynthetic human insulin. Reg. No: 37/21.1/0670 S3 Biosulin N (solution for injection). Each Biosulin N solution for injection contains 100 I.U/ml biosynthetic human insulin. Reg. No: 37/21.1/0671 S3 Biosulin L (solution for injection). Each Biosulin L solution for injection contains 100 I.U/ml biosynthetic human insulin. Reg. No: 37/21.1/0672 S3 Biosulin 30/70 (solution for injection). Each Biosulin 30/70 solution for injection contains 100 I.U/ml biosynthetic human insulin. Reg. No: 37/21.1/0673

Applicant: Dezzo Trading 392 (Pty) Ltd. Co. Reg No: 2002/001923/07 Cnr Birch Road and Bluegum Avenue, Anchorville, Lenasia, 1827. P. O. Box 725 Lawley 1824. Tel: 011 857 2090 Fax: 086 664 6223. Customer Careline: 086 111 4721 www.bioswiss-med.co.zaZA.BIOS.01 05/2016

Increased use of biosimilar insulins has the potential for significant cost savings with no loss in patients’ glycaemic outcomes.1

Biosimilar insulins, such as BIOSULIN, will play an ever increasing role in the management of diabetes.1

BIOSWISS offers a comprehensive range of human insulins in cartridge form, from the short acting BIOSULIN R, to the intermediate acting BIOSULIN N and BIOSULIN L, as well as the biphasic insulin BIOSULIN 30/70. They have 2 Biosulin insulin delivery devices, namely the YPSOMED BIOSULIN PEN, and GENSUPEN. In addition they provide blood glucose monitoring devices and strips, GLUCOPLUS® and newly launched GLUCOPLUS PRO®, as well as INSUPEN® NEEDLES and LORIS® SAFETY LANCETS.

HbA1c at baseline and after 6 months of therapy with BIOSULIN 30/70

Adapted from Segal D et al 1

Baseline

6 months

Overall Type 1 Type 2

Hb

A1c

(%

)

p=0.14

7.9

7.6

p=0.41

8.4

8.0p=0.19

7.7

7.4

03-2016 Bioswiss Best Study DPS Ad.indd 1 5/23/16 9:28 AM

S5 Yelate 30/60. Each capsule contains duloxetine hydrochloride equivalent to duloxetine 30/60 mg. Reg No’s 44/1.2/0114;0115. Dr. Reddy’s Laboratories (Pty) Ltd. Reg no. 2002/014163/07. North Wing, The Place, 1 Sandton Drive, Sandton 2196, South Africa. Tel: +27 11 324 2100, Fax: +27 11 388 1262, www.drreddys.co.za. ZA/01/2015/YEL/035.

YELATE (DULOXETINE)

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Yelate is indicated for the treatment of:• Depression as defined by

DSM-IV Criteria • Diabetic peripheral

neuropathic pain (DPNP)

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IntroductionEpidemiological studies indicate that the increasing worldwide prevalenceof chronic pain may be as high as 20-50 %. Furthermore, chronic pain isstrongly associated with psychiatric comorbidities, and in particular,anxiety, depression and insomnia. Accordingly, pain is associated withdecrements of many aspects of patient’s lives including physical andemotional functioning, affective symptoms and sleep problems. Thenegative impact is higher in patients with greater pain severity. However,there is a bidirectional relationship between chronic pain and thesesymptoms. Patients with somatisation, health-seeking behaviours andpoor sleep are at high risk of developing chronic widespread pain. Therisk increases in tandem with severity of anxiety, depression or sleepproblems, and those with multiple predisposing factors are at the highestrisk (Figure 1)

Therefore, clinically, it may be prudent to consider pain, sleepproblems and anxiety/depression as co-existent components of a triad,where the presence of symptoms of one component should promptinvestigation for the others.


ORIGINAL

Correspondence:Dr David Webb Email: [email protected]

Chronic pain: Addressingthe triad of pain, sleep and depression/anxiety

Prof Rakesh JainMD, MPH; Clinical Professor,Department of Psychiatry, Texas Tech University School ofMedicine, Midland Texas;Psychiatrist in Private Practice,Austin, Texas, USA

Dr David WebbPattacus Medical Consulting,Johannesburg

Figure 1: The Unholy Triad: chronic pain, sleep impairment andanxiety-depression. Common patient descriptors

Shared anatomy of sensation,emotion and cognitionPain perception due to injury orchronic pain states undergoessubstantial processing at supraspinallevels. Pain is both a sensory event ofthe peripheral and central nervoussystems and an experience thatarises from, and which, in turn,influences processes of higherconsciousness. The sensation ofchronic pain specifically engagesbrain regions critical in cognitive andemotional regulation (Figure 2).

Peripheral pain signals travelinitially from neospinothalamic andpaleospinothalmic tracts in thespinal cord to the amygdala andhypothalamus, and to the thalamusfrom where projections connect tothe anterior cingulate gyrus. Theseconnections mediate arousal andautonomic responses to pain andaffective dimensions of pain.Thalamocortical pathways project tothe primary and associativesomatosensory cortex to mediatesensory and discriminative aspectsof pain. These areas of the cortex

and cortical-insular-cingulatepathways also mediate cognitiveand emotional dimensions of pain,playing a role in pain sensation andpain-related behavioural responses.Projections from the cingulate tohypothalamic nuclei mediateneuroendocrine and autonomicresponses to pain, and projectionsto the caudate, putamen andnucleus accumbens mediate motorresponses to pain. Dopaminergicpathways from the ventraltegmental area and substantia nigrapars compacta are active in negativereinforcement emotional and motorconditioning effects to noxiousstimuli, whereas pathways from thehippocampus and related areasfurther mediate emotional, memoryand expectational domains of pain.Higher order cognitive dimensions,such as expectation and associativevalue of pain are mediated by thelateral dorsal thalamic nucleus andamygdala, together with efferentsfrom the lateral prefrontal,infero-medio-temporal and infero-parietal cortices.

Therefore complex hierarchicneural processing expands thesensation of painful stimuli intoconsciousness of internal state,external circumstance, memory andaffective factors that are subjectiveand individual to the personexperiencing the pain.

Chronic pain may be associatedwith atrophic changes in brainstructure, similar to, but occurringmore rapidly than those observedwith ageing. In patients with chronicback pain, grey matter density wasreduced bilaterally in thedorsolateral prefrontal cortex(DLPFC) and right thalamus. Thesechanges were strongly related topain characteristics, with distinctpatterns depending on whether painwas neuropathic or non-neuropathicin origin. The degree of atrophy alsocorrelated with duration of pain.However, treatment may reversethese changes and restore normalbrain function. Pain managementwith spine surgery or facet jointinjections was associated withincreased DLPFC thickness, whichcorrelated with the reduction of bothpain and physical disability.Furthermore, after treatment,DLPFC activity during an attention-demanding cognitive task that wasabnormal before treatment,returned to normal.

As already mentioned, areciprocal relationship existsbetween pain, sleep problems anddepression/anxiety. From aneurological point of view,depression is now recognised asmore than just a disorder of mood.It is characterised by a complexinterplay between commonpathways linking the brain,hypothalamic-pituitary-adrenal(HPA) axis, autonomic nervoussystem and inflammatorypathways. This explains howdepression may be associated withsignificant morbidity andmortality with primarymanifestations beyond thoserelated to disturbed affect.


ORIGINAL

Figure 2: Sensory, emotional and cognitive (SEC) interactions inchronic pain

Imaging studies havedemonstrated that in patients withinsomnia, there is an interactionbetween neural networks, includinga general arousal system (ascendingreticular formation andhypothalamus), an emotion-regulating system (hippocampus,amygdala, and anterior cingulatecortex), and a cognitive system(prefrontal cortex) that does not fullydeactivate from waking to sleep.Furthermore, these areas arecharacterised by reduced wakingmetabolism, suggesting that they arechronically sleep-deprived, andproviding an explanation for daytimefatigue and increased risk of mentaldisorders in patients with insomnia.Chronic sleep problems and poorsleep quality are associated with abilateral reduction in hippocampalvolume, impaired verbal and visualmemory and impaired frontal lobefunction. Chronic insomnia is alsoassociated with a significant risk ofall-cause dementia. In patients withchronic pain, there is a bidirectionalrelationship where sleep disturbanceoccurs consequent to pain, but sleepdisturbance is also associated withgreater severity of perceived pain,leading, in turn, to greaterimpairment of functional ability andincreased incidence of depression.

Clinical considerationsBecause of these shared centralpathways and theneurotransmitters common to painsensation, emotion and cognition(SEC), it is rational that effectivepain management should addresseach of the elements of this triad.Furthermore, each element mayrespond to both pharmacologicaland non-pharmacologicaltreatments and a combination ofthese management approaches isrecommended for each (Figure 3).

1. PharmacotherapyBenzodiazepines are notrecommended for routine treatmentof patients with pain and comorbid

anxiety or sleeping disorders. Theyare potentially addictive, cause gaitdisturbance and increase the risk offalls. They are also associated withan increased risk of accidents andmemory impairment. Furthermore,benzodiazepines suppress REMsleep, causing daytime fatigueconsequent to poor sleep quality.

Selective serotonin reuptakeinhibitors (SSRIs) are also notroutinely recommended for patientswith comorbid pain and depression,due to their relative lack of efficacyin this patient population.

Two classes of medications thatare recommended as first-lineagents for comorbid pain anddepression/anxiety and the efficacyof which has been demonstrated inclinical trials, are the serotoninnoradrenaline reuptake inhibitors(SNRIs) and α2δ ligands. Thenoradrenergic activity of the SNRIantidepressants is thought tomodulate inhibitory descendingpain pathways in the spinal cord andis also helpful in promotingmotivation, concentration and sleep.

The α2δ ligands includegabapentin and pregabalin.Pregabalin improves pain in variouschronic pain states, includingfibromyalgia, diabetic peripheralneuropathic pain (DPNP), and alsopain-associated anxiety and sleepdisturbance. Pregabalin treatmentwas associated with a clinicallymeaningful improvement in sleepquantity and quality. Improving

sleep in patients with chronic painis also likely to improve associatedanxiety and depression.

2. Non-pharmacologicaltherapyWhen one considers the linkbetween brain and body, and thecommon areas of the brain andinteraction betweenneurotransmitters involved in pain,depression, regulation of mood andemotions, sleep and executivefunction, it becomes clear thatpharmacotherapy alone is notsufficient to manage the syndromespresenting in patients with chronicpain. Furthermore, the aim oftreatment is not only to managesymptoms, but to achieve recovery -to enable the patient to flourish, tolive a meaningful life. These greateraspects of ‘wellness’ - optimism,resilience, enthusiasm, happinessand wisdom - need to be addressedthrough teaching the patient to carefor him or herself, both physicallyand mentally. Therefore, in additionto pharmacotherapy, non-pharmacological management aimedat improving wellness is essential.

Five specific aspects of wellnessthat are important to consider, aremindfulness (purposefully drawingattention to the present), sleep,exercise, nutrition and socialisation.These interventions have beendemonstrated to improve quality oflife, health and wellness andimprove the likelihood of recovery.


ORIGINAL

Figure 3: The SEC model of pain management

Cognitive behavioural therapyCognitive behavioural therapy(CBT) improves clinical outcomesin chronic pain, with braincorrelates that have beenmeasured in imaging studies.

Chronic pain is associated withreduced cerebral grey mattervolume and density. A comparisonof anatomical MRI scans of patientswith chronic pain before and afteran 11-week CBT treatment showedincreased grey matter in bilateraldorsolateral prefrontal (DLPFC),posterior parietal (PPC), subgenualanterior cingulate(ACC)/orbitofrontal, andsensorimotor cortices, as well as thehippocampus. These brain changeswere associated with significantimprovements in clinical measuresand decreased pain catastrophizing.Brain correlates associated withdecreased pain catastrophizingwere left DLPFC and ventrolateralprefrontal cortex (VLPFC), rightPPC, somatosensory cortex, andpregenual ACC. It is proposed thatincreased grey matter in the PFCand PPC reflects greater top-downcontrol over pain and cognitivereappraisal of pain, and thatchanges in somatosensory corticesreflect alterations in the perceptionof noxious signals.

In a 3-week multidisciplinarytreatment programme consisting ofeducation, stretching, CBT,relaxation training and aerobicexercise, improved pain scores wereassociated with reduced salivarycortisol concentration. Thissuggests that one of the activemechanisms underlying the efficacyof this treatment approach, is animprovement in HPA axis function,with increased resiliency to stress.

MindfulnessMindfulness may be defined as “theawareness that emerges throughpaying attention on purpose, in thepresent moment, and non-judgmentally, to the unfolding ofexperience moment by moment.”

It involves a consciousness ofsensations, perceptions, emotionsand thoughts and is theattentional state that underlies allforms of meditation.

Mindfulness-based cognitivetherapy (MBCT) is believed towork by reducing cognitive andemotional reactivity to stressfulevents and promoting resilience. Ithas been shown to assist inrecovery from a variety of painfuland psychological conditions,especially depression and anxiety.

More than half of all people withdiabetes are estimated to sufferemotional distress relatedspecifically to the condition. One infour will, at some stage, experiencedepression. In comparison to usualcare, a mindfulness-based CBTprogramme has been shown toreduce stress, depressivesymptoms and anxiety andimprove quality of life (mental andphysical) in patients with type 1 andtype 2 diabetes.

ExerciseA substantial body of evidenceconfirms that exercise improvesmood and energy levels in patientswith depression, which itself isassociated with tiredness andfatigue, and reduced motivationand drive.

A large Cochrane meta-analysisof 39 studies concluded thatexercise improves symptoms ofdepression, but it needs to becontinued in the longer term for thebenefits to be maintained. Benefitsof sustained exercise were greaterthan control intervention, andcomparable to those achieved withpsychological and antidepressantpharmacological treatments.

The mechanisms behind theeffects of exercise on mood andwellbeing are complex andmultifactorial, involving directeffects on monoamine synthesisand availability in the centralnervous system, and regulation ofpro- and anti-inflammatory

pathways. Regular exercise hasbeen shown to reverse theneurodegeneration and atrophyobserved in various regions of thebrain associated with depression.Furthermore, in patients withdiabetes, clinical studies havedemonstrated that routineexercise can prevent or delaynerve damage and dysfunction,in turn delaying or preventingthe onset of symptomaticperipheral neuropathy.

Patients with diabeticperipheral neuropathy (DPN), whoparticipated in a programme ofregular aerobic and resistanceexercise, reported reduced painand neuropathic symptoms. Thiswas associated with increasedintraepidermal nerve fibrebranching observable in distal andproximal lower extremity skinbiopsies. In addition, aerobicexercise was associated withimprovements in general fatigue,physical fatigue, peak oxygenuptake; reduced total body fat andfat mass; and an improvement inperipheral blood flow.

WILD 5: A wellnessintervention programme forpatients with depressionand chronic painThe Wellness Interventions forLife’s Demands (WILD) 5 is atrackable, accountable, self-directed five-element wellnessprogramme that has been shownto significantly improve mood,function, measures of wellnessand quality of life in patients withdepression, anxiety and/orchronic pain. It encourages andsupports daily practice of the fiveelements of wellness - physicalexercise, mindfulness, optimizingsleep and nutrition, and improvingsocial connectedness.

A small pilot study of the WILD5 programme has demonstratedsignificant benefits of each of thefive wellness interventions in agroup of 47 patients with chronic


ORIGINAL

pain. The programme wasassociated with significantimprovements in mood, emotionaleating, sleep and pain scores(Table 1). Sleep duration increasedon average by 36 minutes per night(p<0.001). Results were similarregardless of whether or not thepatients were taking opioids.

Support materials to assist theclinician in teaching and guidingpatients through the wellnessinterventions are available onlineat: www.Wild5Resources.com(password: wellnessmatters).Resource materials are providedfor the initial 30 day inductionperiod, but patients should beencouraged to continue theprogramme thereafter for life.

ConclusionsThe mind is intimately involved inboth the perception of, andprotracted nature of chronic pain.Furthermore, the complex nature ofinterrelated pathways and chemicalmessengers within the centralnervous system that interlinkschronic pain with depression,anxiety and sleep disorders, meansthat it is impossible to separatethese pathologies into distinctclinical entities that can beaddressed in isolation. In addition,broader aspects of wellness, andspecifically resilience, happinessand optimism, must be addressed ifthe patient is to achieve a clinicaloutcome consistent with ameaningful quality of life.

Although still in its infancy,WILD 5 has demonstrated that, inaddition to usual care, patients canbe assisted to improve wellnessbehaviours. These changes areassociated with significantimprovements in pain and function,but also, and perhaps mostsignificantly, in overall wellbeing.

This article is based on apresentation by Prof Rakesh Jain,MD, MPH at the 6th Annual PfizerPforum held in Sandton,Johannesburg on Saturday 16April 2016. Prof Jain’s visit toSouth Africa was sponsored byPfizer, South Africa.

References on request


ORIGINAL

Table 1. Results before and after participation in the WILD 5 30-day induction programme in patients withchronic pain (N=47)

Parameter Rating scale Pre-study Post-study Percentagescore score change P value

(mean) (mean) (mean)

Depression PHQ-9 12.1 6.8 43 % <0.001

Anxiety GAD-7 10.4 6.3 39 % <0.001

Insomnia PSQI 11.8 8.4 28 % <0.001

Emotional (binge) eating DEBQ 35.5 30.0 15 % <0.001

Happiness NRS (0-10) 4.1 5.1 24 % <0.002

Optimism NRS (0-10) 3.8 5.3 39 % <0.001

Enthusiasm NRS (0-10) 3.2 4.6 43 % <0.001

Resilience NRS (0-10) 3.3 5.2 57 % <0.001

Worst pain BPI NRS (0-10) 5.9 4.8 18 % <0.001

Least pain BPI NRS (0-10) 2.8 2.2 21 % <0.02

Average pain BPI NRS (0-10) 4.4 3.6 18 % <0.001

Pain interference with activities BPI NRS (0-10) 4.3 3.6 16 % 0.05

PHQ-9: Patient Health Questionnaire 9-item version; GAD-7: Generalised Anxiety Disorder 7-item scale; PSQI: Pittsburgh Sleep Quality Index;

NRS (0-10): 11-point numeric rating scale; BPI: Brief Pain Inventory.

the SpikeIt’s time to

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References:1. International Diabetes Federation. 2011 Guideline for Management of PostMeal Glucose in Diabetes. Available from https://www.idf.org/sites/default/files/postmeal%20glucose%20guidelines.pdf. Accessed2/09/2015. 2. Schwartz SL, Ratner RE, Kim DD, et al. Effect of exenatide on 24-hour blood glucose profile compared with placebo in patients with type 2 diabetes: a randomized, double-blind, two-arm, parallel-group,placebo-controlled, 2-week study. Clin Ther 2008;30(5):858-867. 3. Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, cross-over noninferiority trial. Clin Ther 2007;29(11):2333-2348. 4. Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia 2007;50:259-267. 5. Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin 2008;24(1):275-286. 6. BYETTA® Approved Package Insert.

S3 BYETTA® 5 μg, solution for injection. Reg. No. 41/34/0068. Each dose contains 5 microgram (μg) exenatide in 20 microlitres (μl), (0,25 mg synthetic exenatide per ml). One pre-filled pen contains 60 doses of sterile, preserved solution (approximately 1,2 ml). S3 BYETTA® 10 μg, solution for injection. Reg. No. 41/34/0069. Each dose contains 10 microgram (μg) exenatide in 40 microlitres (μl), (0,25 mg synthetic exenatide per ml). One pre-filled pen contains 60 doses of sterile, preserved solution (approximately 2,4 ml). PHARMACOLOGICAL CLASSIFICATION: 32.16 Others. INDICATIONS: BYETTA® is indicated as add on therapy for patients with type 2 diabetes mellitus inadequately controlled by lifestyle modification and other oral antidiabetic therapy. For full prescribing information refer to the package insert approved by the Medicines Regulatory Authority. AstraZeneca Pharmaceuticals (Pty) Ltd. Reg. No. 1992/005854/07. Building 2, Northdowns Office Park, 17 Georgian Crescent West, Bryanston, 2191. Private Bag X23, Bryanston, 2021. Tel: 011 797-6000. Fax: 011 797-6001. www.astrazeneca.co.za. BYETTA® is a registered trademark of the AstraZeneca group of companies. Expiry Date: October 2017. Activity ID: 719524

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Sunjay Naidoo who is 30 years old, works as a strategy analyst for alarge accounting firm in Johannesburg. At the time of his firstconsultation, ten and a half years ago, he was diagnosed with type 2

diabetes. Sunjay’s work requires him to travel to African countries forapproximately one week every month. I requested his wife to join theconsultation as she was responsible for the shopping and cooking for thefamily. As many of our patients with a Hindu tradition do, the familyfollows a vegetarian way of eating. Specifically, Mrs Naidoo follows a vegandiet, while Sunjay follows a lacto-vegetarian diet and occasionally eats fishoutside his home.

1. Assessment1.1 LifestyleSunjay reported that although he feels tired at night, he generallysleeps well. He goes to gym 3 to 4 times per week, doing a combinationof aerobic and resistance training for an hour. He was on insulintherapy using NovoMix 30 - 24 units in the morning and 16 units atnight. In addition to his insulin, he was taking 20 mg of Aspavor, 1000mg of Glucophage and 500 IU of Vitamin D daily. He tested his fastingblood glucose level approximately twice a week.

1.2 AnthropometryI measured Sunjay’s height at 1.69 m and his weight at 88 kg. His waistcircumference was 106 cm.

1.3 PathologyTable 1 displays the results of Sunjay’s laboratory results done justbefore his first consultation, as well as the tests done 3 months aftermedical and nutrition intervention. Of concern during the firstconsultation, was his HbA1c and his triglyceride level.


ORIGINAL

Achieving healthobjectives eating thevegetarian wayA Case Study - Sunjay Naidoo

Correspondence:R Catsicasemail: [email protected]

Ria CatsicasRegistered Dietitian,Nutritional Solutions

1.4 Nutrition HistoryMenu 1 in Table 2 displays thenutritional analysis ofSunjay’s representative foodchoices for one day in theweek. He would get up at 6:30and, after his gym session,enjoyed All-Bran® cereal withlow-fat milk and honey.Alternatively, he would pickup a smoothie from the gymconsisting of protein powderand fruit yoghurt. For lunch,he would select a tomato andlettuce bread roll or achickpea salad from thecafeteria. On arriving home inthe late afternoon, he wouldsnack on half a bag of potatocrisps, where after he endedthe day with a meal consistingof Aloo Gobi (cauliflower andpotato curry) and spaghetti.In terms of drinks, Sunjaywould enjoy two cups ofcoffee (without sugar orsweetener) and water daily.He took one alcoholic drink aweek. Sunjay would ratherchoose Marie biscuits, cerealbars, nuts, peanuts and potatocrisps than chocolates assnacks. On weekends, theywould order their favouritetake-out, a pizza margherita,and, when visiting friends andfamily, Sanjay would enjoy a

vegetable curry with naanbread or roti and sweets suchas carrot halva and coconutbarfi. On trips to Africancountries, Sunjay tried tomake the best choicesavailable, but found the high-calorie snacks in the barfridge in his hotel room,difficult to resist.

Sunjay’s typical mealpattern resulted in a highintake of calories, total fatand total carbohydrate and alow intake of protein and themajority of micronutrients.This pattern was supported bya low intake of whole grains,fresh fruit and vegetables.

2. Nutrition Intervention2.1 EducationExtensive nutrition educationfor the management of thehyperglycaemia anddyslipidaemia wasundertaken with specificfocus on the:

• physiology and benefits ofabdominal fat loss.

• concept of a calorie deficitto achieve fat loss, with theconsequent necessity ofcontrolling the quantitiesof carbohydrates, fats andproteins on a daily basis.

• consumption of anadequate amount of leanprotein to ensure optimalmuscle synthesis andoptimal appetite control,whilst creating a lowglycaemic load and a lowsaturated fat content forall three meals.

• concept of achievingoptimal blood glucosecontrol by theconsumption of highfibre, low glycaemic index(GI), whole-graincarbohydrates in controlledquantities, at the expenseof refined starches andsimple sugars.

• inclusion of foods rich innutrients considered ‘atrisk’ while following alacto-vegetarian diet(Vitamins B12 and D,calcium, iron and zinc).

• controlled intake of all fatscalculated to less than 35 %of total energy. An addedrestriction of saturated fatto less than <7 % wasadded. Preference wasgiven to the use ofunsaturated fats to helpimprove the dyslipidaemia.

• equal distribution ofcarbohydrates across threemeals and snacks.


ORIGINAL

Table 1: Comparison of metabolic markers pre- and post-medical andnutritional intervention

Metabolic marker Before intervention After intervention

HbA1c (%) 15.1 7.6

Total cholesterol (mmol/l) 6.6 4.8

LDL-cholesterol (mmol/l) 3.8 2.3

HDL-cholesterol (mmol/l) 1.5 1.23

Triglycerides (mmol/l) 3.1 2.7

Chol/HDL Ratio 4.4 3.9

Sunjay’s typical meal pattern resulted in a highintake of calories, total fat and totalcarbohydrate and a low intake of protein andthe majority of micronutrients

2.2 The nutritional planAn individualized, energycontrolled, nutritionally-balanced meal plan with a7-day cycle was negotiated.

Menus were formulated tomeet Sunjay’s lifestylerequirements. Recipes and ashopping list were alsoprovided to enable his wife toprepare the meals in a tastyand delicious way. Menu 2 inTable 2 reflects the choices ofdishes Sanjay could choosefrom for one day. Additionalchoices for breakfast wereoffered in the form of rolledoats and grapefruit. Drybeans, corn, soya andvegetables were introducedfor lunch and dinner toreduce the glycaemic load ofthe meals, and to improve thenutritional quality of theoverall meal plan. For snacks,peanuts and potato chips

were replaced with fresh fruit.Pleasure foods such as Indiansweets were reserved forweekends when attendingcelebrations with family andfriends.

On evaluation, thenutritional quality of Menu 2(the menu negotiated andthen prescribed) reflects ahigher nutritional qualitythan that provided by Menu 1(the way Sunjay was eating).Menu 2 provides a higherprotein and lower calorie,total fat, saturated fat andcarbohydrate content. The

addition of protein foods andwhole grains ensured thatSanjay met his requirementsfor the nutrients ‘at risk’ forthose following a vegetarianpattern of eating.

2.3 Progress - the follow-upmonitoring sessions

The purpose of the follow-upsessions was to provideadvice and support forSunjay to acquire thepractical skills to implementthe nutritional principlesby making daily healthyfood choices.


ORIGINAL

Table 2 – Comparison of food and nutrient intake pre- and post-medical and nutritional intervention

Food items – Menu 1 Food items – Menu 2

Breakfast Breakfast

• 60 g All-Bran® cereal served with • 200 g cooked rolled oats with

• 300 g low fat milk and • 125 g low fat milk,

• 20 g honey • cinnamon & sweetener

Lunch Lunch

• 80 g white bread rolls with Mexican bowl - salad with:

• 20 g margarine, • 140 g dry beans,

• 20 g mayonnaise, • 160 g corn kernels,

• tomato and • 60 g Guacamole and

• lettuce • onion salsa

Dinner Dinner

• 260 g Aloo Gobi and Tofu vegetable curry:

• 250 g Macaroni • 240 g Tofu served with

• 80 g wild / brown rice

• and a variety of vegetables)

Snacks Snacks

• 100 g Potato crisps • 120 g Apple

Nutritional analysis (day) Menu 1 Menu 2

Energy (kJ) 9475 6069

Protein (g) 47 53

Carbohydrate (g) 260 180

Total fat (g) 100 36

Saturated fat (g) 22 9

Unsaturated fat (g) 71 25

Fibre (g) 28 41

Calcium (mg) 543 739

Iron (mg) 15 24

Magnesium (mg) 350 590

Selenium (mcg) 10 40

Zinc (mg) 7 10.2

Folate (mcg) 259 279

Vitamin A (RE) 208 280

Vitamin C (mg) 86 142

Vitamin E (mg) 25 5

Vitamin B12 (mcg) 3.2 5

On evaluation, the nutritional quality of Menu 2(the menu negotiated and then prescribed)reflects a higher nutritional quality than thatprovided by Menu 1 (the way Sunjay was eating)

During his first follow-up visit, Sunjay weighed 90kg. He gained 2 kg in weightand 2 cm around his waist.Although he improved onthe quality of carbohydrateshe consumed, no attentionwas paid to portion control.During the consultation,practical advice wasprovided on:• Portion control using food

models as visual aids andusing measuring spoonsand cups as tools.

• How to include morevegetables in an appetizingway with lunch and dinnerto lower the glycaemicload of the daily meals.

• Improving the quantityand the quality of Sunjay’ssnack choices.

• Practical advice tofacilitate healthy choicesin restaurants whiletravelling, as well asmanaging the temptationof the bar fridges in hishotel rooms.

During Sanjay's secondfollow-up consultation, lossesof 2.5 kg in weight and 3 cmround his waist wererecorded. Both his A1C andfasting blood glucose levelshad improved dramatically.

To date, Sunjaymentioned that thanks to the

support of his wife, he foundfollowing the healthy eatingplan much easier. He finds heis less hungry and isexperiencing less cravings. Heweight has dropped to 80 kgand he has had a total loss of10 cm around his waist. Healso mentioned that he nowfinds following his gymregimen easier and moreenjoyable. It was agreed withhis doctor to reduce hisinsulin to 16 units in themorning and 8 units in theevening (a reduction of nearly50 % in total daily dose).

ConclusionAlthough Sanjay will benefit fromfurther weight loss, the healthyway of eating has finally becomepart of his lifestyle. He believesthe three most important qualitiesenabling him to implement thechanges were patience,perseverance and persistence, andthe sessions with the dietitianhelped him to practice these.


ORIGINAL

It was agreed with his doctor to reduce hisinsulin to 16 units in the morning and 8 unitsin the evening (a reduction of nearly 50 % intotal daily dose)

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ContourPlus AD_Diabetes Pub.indd 1 2015/04/14 10:40 AM

Recognising andDiagnosing CardiacAutonomic Neuropathyin People with Diabetes

IntroductionThe diabetes pandemic is spreading faster than any formulae or expert canpredict. Furthermore, only one third of patients with type 2 diabetesmellitus (T2DM) will achieve the recommended HbA1c target of < 7 %.Therefore, a dramatic increase in the prevalence of diabetes complicationsis also expected. Cardiovascular disease is the major cause of mortality inmale and female patients with either type 1 diabetes mellitus (T1DM) orT2DM. The risk of sudden cardiac death is also increased in patients withdiabetes mellitus (DM) (RR 2.18; 95 % CI, 1.89–2.98). It has been well-documented that patients with DM have accelerated atherosclerosis andthis is most likely to be the central cause for the increase in cardiovascularmorbidity and mortality. However, less clear, is the contribution of cardiacautonomic neuropathy (CAN) to the cardiovascular sequelae. Diabeticautonomic neuropathy (DAN) is one of the distinct clinical syndromes ofdiabetic neuropathy and CAN forms a part of the wide-spectrum ofabnormalities associated with DAN. Rather than focus on all theabnormalities associated with abnormal autonomic function in patientswith diabetes, this article will focus on recognising and diagnosing CANand will use recommendations from expert opinion to suggest who shouldbe screened.

CARDIAC AUTONOMIC FUNCTIONAnatomyThe internal physiologic homeostasis of our organs is maintained by asympathetic and parasympathetic nerve supply. Focusing on the heart,sympathetic innervation arises from the spinal cord at the level of the 1st tothe 4th thoracic vertebrae. It travels via sympathetic ganglia in thesympathetic chain and innervates the sinoatrial (SA) node, theatrioventricular (AV) node and the ventricular myocardium.Parasympathetic innervation of the heart arises in the medulla and travelsvia the vagus nerve to innervate the SA and AV nodes. For the heart andblood vessels, acetylcholine is the neurotransmitter at pre- and post-ganglionic parasympathetic nerve fibres, but only at pre-ganglionicsympathetic nerve fibres. Norepinephrine is the neurotransmitter at all post-ganglionic sympathetic nerve fibres going to the heart and blood vessels.


ORIGINAL

Correspondence:Dr Joel A Daveemail: [email protected]

Dr Joel A DaveMBChB (UCT) PhD (UCT) FCA (SA) Cert Endocrinology (SA)Kingsbury Hospital andKenilworth Diabetes Medical Centre

PhysiologySympathetic stimulation of theSA node increases the frequencyof action potentials, therebyincreasing heart rate (HR).Parasympathetic stimulationdecreases the frequency of actionpotentials, thereby decreasing theHR. Therefore, dual innervationof the SA and AV nodes byparasympathetic and sympatheticnerve fibres results in a push-and-pull control of the HR. Sincethe intrinsic rate of the SA nodeis about 100-110 beats per minuteand the average resting HR isabout 72 beats per minute, it isevident that under restingconditions, the parasympatheticsupply dominates.

Ventricular contractility isalmost entirely controlled by thesympathetic nervous system.Sympathetic stimulation resultsin the release of norepinephrine,which, after binding to β-1adrenergic receptors and therebyactivating adenylate cyclase,results in an increase in cyclicAMP. This has the effect ofopening calcium channels in theplasma membrane, increasingrelease of calcium from thesarcoplasmic reticulum,increasing myosin cross-bridgecycling and increasing calciumpump activity in thesarcoplasmic reticulum, all ofwhich favour enhancedcontractility.

CARDIAC AUTONOMICNEUROPATHY (CAN)IntroductionThe prevalence of CAN is difficultto assess, as variable diagnosticcriteria exist. It is alsoinfluenced by patient age and

Some of these abnormalitiesresult in distinct clinicalconsequences for patients:1. Exercise intolerance2. Abnormal blood pressure

regulation3. Orthostatic hypotension4. Resting tachycardia5. Hypoglycaemic unawareness6. Silent myocardial ischaemia7. Left ventricular dysfunction.

These abnormalities incardiovascular and peripheralvascular function translate into direclinical outcomes with reported5-year mortality rates up to 50 % inpatients with T1DM and T2DM,with a high proportion attributed tosudden cardiac death. In the Actionto Control Cardiovascular Risk inDiabetes (ACCORD) trial, CANstrongly predicted all-causemortality (HR 2.14; 95 % CI,1.37–3.37) and cardiovasculardisease (CVD) mortality (HR 2.62;95 % CI, 1.4–4.91), independent of


ORIGINAL

Table 1: Cardiac and peripheral vascular abnormalities associated with CAN *

Heart• Sympathovagal imbalance• Perioperative haemodynamic instability• Rhythm - resting tachycardia, loss of reflex heart rate variations, prolonged

QT interval• Blood pressure - hypertension, orthostatic hypertension, postprandial

hypotension, non-dipping, reverse dipping• Exercise intolerance• Impaired baroreflex sensitivity• Coronary arteries – silent myocardial ischaemia, increased arterial stiffness,

decreased sympathetically-mediated vasodilation of coronary vessels• Left ventricular dysfunction and hypertrophy

Peripheral blood vessels• Increased peripheral blood flow and warm skin• Increased venous pressure• Increased arteriovenous shunting and swollen veins• Leg and foot oedema• Loss of protective cutaneous vasomotor reflexes• Increased trans capillary leakage of macromolecules• Medial arterial calcification

*Adapted from Spallone, V, et al., Cardiovascular autonomic neuropathy in diabetes: clinical impact,

assessment, diagnosis, and management. Diabetes Metab Res Rev, 2011. 27(7): p. 639-53.

Sympathetic stimulation of the SA nodeincreases the frequency of action potentials,thereby increasing heart rate (HR)

duration of diabetes.Consequently, a wide spectrum ofprevalence is reported in thescientific literature ranging from1.6 to 90 %. Equally complex, isthe pathogenesis of CAN, whichis largely driven byhyperglycaemia, causing anincrease in inflammatorymediators (IL-6, TNF-α, TLR-2,TLR-4) and oxidative stressby activating the polyol,protein kinase C, hexosamineand AGE-RAGE pathways.

Clinical implicationsMultiple abnormalities incardiovascular and peripheralvascular function are associatedwith CAN (Table 1),

The symptoms ofCAN are non-specificand cannot be usedfor diagnosis

baseline CVD, diabetes duration, multiple traditional CVD riskfactors and medication. In theEURODIAB ProspectiveComplications Study, whichincluded a population of patientswith T1DM, CAN was thestrongest predictor for mortalityduring 7 years of follow-up,greater than traditional CVD riskfactors. Meta-analyses haveconfirmed the increased risk ofmortality in patients diagnosedwith CAN. CAN has also beenassociated with an increased riskof stroke, developing themetabolic syndrome, chronickidney disease andintraoperative/perioperativehaemodynamic instability.

Intensive management ofdiabetes can decrease thedevelopment or progression ofCAN in patients with T1DM,whereas multifactorialintervention is required inpatients with T2DM, asintensive diabetes control alonehas not been shown to alter thecourse of CAN.

Diagnosis and screeningThe symptoms of CAN are non-specific and cannot be used fordiagnosis. Rather, distinctcardiovascular tests are needed tomake the diagnosis. Multipletests have been used by variousresearchers to diagnose CAN, butthe tests that have becomeuniversally accepted are thosebased on the blood pressure (BP)response to standing (Table 2),the response of the heart rate(HR) to deep breathing (Table 3),standing up from a supine


ORIGINAL

Table 3: Heart rate (HR) response to deep breathing

Physiology• HR varies with respiratory cycles (sinus arrhythmia) - it increases during

inspiration and decreases during expiration• Under parasympathetic control. Thus, this test measures

parasympathetic function

Method• Continuous recording of heart rate (ECG)• Subject in supine or sitting position for at least 1 minute• Deep inspiration to the maximum total lung capacity for 5 seconds, followed by a

forced expiration down to the residual volume over 5 seconds• Repeat 6 times in 1 minute• Time to alternate the respiratory cycle is signalled directly to the patient by the

operator or, preferably, by a time-keeping instrument• Important that the subject does not change the respiratory phase before the 5

seconds have elapsed

Analysis• Expiration-inspiration ratio

(E/I ratio - average 3 longest RR intervals expiration/average 3 shortest RRintervals inspiration)

• Lowest normal values of E/I ratio by age:

• 20-24: 1.17 • 25-29: 1.15 • 30-34: 1.13 • 35-40: 1.12

• 40-44: 1.10 • 45-49: 1.08 • 50-54: 1.07 • 55-59: 1.06

• 60-64: 1.04 • 65-69: 1.03 • 70-75: 1.02

• Difference between maximum and minimum heart rate (HR)(Average of 3 highest HRs minus average 3 lowest HRs)o Normal, ≥ 15 beats; Borderline, 11-14 beats, Abnormal, ≤ 10 beats

Table 2: Blood pressure (BP) response to standing up from a supine position

Physiology• During standing, BP is maintained by an activation of the sympathetic nervous

system that increases both cardiac output and peripheral vascular resistance.This test therefore assesses sympathetic function.

Method• Patient lies supine for at least 5 minutes• BP is measured three or more times, 1 minute apart, until it stabilizes• Patient then stands up quickly• BP is measured twice, after 60 and 120 seconds, in the standing position• The arm in which the BP is measured should be placed horizontally at the level

of the right atrium, and supported to avoid any isometric physical exercise thatmight increase BP. Standing with the arm hanging alongside the body mayresult in an overestimation of BP values (up to 10 mmHg) and may thereforereduce the sensitivity of the manoeuvre in detecting orthostatic hypotension

Analysis• Postural drop in BP

(Supine systolic BP, minus lowest systolic BP, whilst standing)o Normal, 10 mmHg; Borderline, 11-29, Abnormal, ≥ 30)

position (Table 4) and theValsalva manoeuvre (Table 5).These tests should be performedafter an overnight fast or 2 hoursafter a light meal. Prior to thesetests, patients should not haveparticipated in any exercise forthe previous 24 hours and shouldavoid caffeine, alcohol andsmoking for at least 2 hoursbefore the tests. Furthermore,the tests should not beperformed during hypoglycaemiaor marked hyperglycaemia.Importantly, the Valsalvamanoeuvre test should not beperformed in any patient withproliferative retinopathy. Expertopinion suggests that to make thediagnosis of CAN, there must beat least two abnormal tests ofheart rate. The presence oforthostatic hypotension suggestssevere CAN.

Recommendations from expertopinion have suggested thatthe following patientcategories should be screenedfor CAN annually:• Patients with T2DM at diagnosis• Patients with T1DM, from 5

years after diagnosis• Patients with diabetes and

symptoms suggestingautonomic dysfunction

• Patients with diabetes beforeplanning a programme ofmoderate-to-high-intensityphysical exercise, especially inthe presence of highcardiovascular risk

• Patients with diabetes and ahistory of poor glycaemiccontrol, high cardiovascularrisk and microangiopathiccomplications

SUMMARYCAN is common and is a predictorof cardiovascular risk and suddendeath in patients with diabetes.Since there are simple bedsidetests to diagnose CAN, and thereare some treatment options that

may decrease progression of CANand improve symptoms, it isimperative that all ‘at risk’patients are screened annually.Knowing that a patient has CAN

helps with designing therapeuticstrategies and assessing riskand prognosis.



ORIGINAL

Table 4: Heart rate (HR) response to standing up from a supine position

Physiology• Initially, on standing, baroreflex-mediated vagal inhibition and sympathetic

stimulation results in an increased HR to maintain stroke volume (maximumincrease of HR is between the 10th and 20th beat). This is then followed bybaroreflex-mediated vagal enhancement that results in a decrease in HR (occursbetween the 25th and 35th beat)

• Most of the heart rate changes are due to changes in parasympatheticstimulation; therefore, this test is a measure of parasympathetic function

Method• Patient lies in supine position for at least 5 minutes• Continuous ECG recording, also blood pressure monitoring• Ask the patient to stand up quickly, but remain relaxed, with their arms at rest

alongside the body, without speaking or moving until the end of the test• The test usually ends 30-45 seconds after standing up

Analysis• 30:15 ratio

(Longest RR interval 25th to 35th beat/shortest RR interval 10th to 20th beat)o Normal, ≥ 1.04; Borderline, 1.01-1.03, Abnormal, ≤ 1.00

Table 5: Heart rate (HR) response to the Valsalva manoeuvre

Physiology• During straining, the rise in intrathoracic pressure causes a decrease in venous

return with a consequent drop in BP and a reflex tachycardia. When the strainingis released, the drop in intrathoracic pressure causes an abrupt increase invenous return with a consequent increase in BP. This often overshoots, resultingin baroreflex-mediated parasympathetic stimulation, causing a bradycardia

• This is therefore a test of parasympathetic function

Method• Patient in sitting position• Continuous ECG monitoring• Blows with an open glottis into a mouthpiece connected to a manometer, without

taking a deep breath beforehand. To maintain a constant expiratory effortequivalent to an intraoral pressure of 40 mmHg, for 15 seconds.

• After this period, the expiratory straining is suddenly released. The subject shouldbreathe regularly and remain silent and motionless until the end of the test

• The occurring of facial flushing and plethora, and neck vein engorgement testifyto the correctness of the manoeuvre

Analysis• Valsalva ratio

(Longest RR interval after expiratory straining/shortest RR interval duringexpiratory straining)o Normal, ≥1.21; Borderline, 1.11-1.20, Abnormal, ≤ 1.10

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DiversionsPublication_Accord Metformin.pdf 1 2015/02/26 8:14 AM

Our understanding of the impact of diabetes on organ function hasbeen evolving since the discovery of insulin in the 1920s. Giddywith the joy of discovery, insulin was thought to be a miracle drug

that appeared to cure childhood diabetes. However, it soon became clearthat although insulin prevented an early metabolic death, latecomplications of this progressive condition affected the eyes, kidneys,peripheral nerves, heart and vasculature, leading to serious disability andincreased mortality.

The brain has been described as the final frontier of diabetes-relatedcomplications but, until two decades ago, it was largely ignored as a sitefor diabetes-associated end-organ-damage. However, much has changedsince then.

Diabetes is a complex disorder, and several factors related either to thecondition itself, treatment effects, long-term complications andcomorbidities can affect the brain. Moreover, intrauterine and childhoodfactors, as well as socio-economic circumstances, muddy the landscapeeven further. Poor socio-economic status has been linked to both thedevelopment of type 2 diabetes and cognitive dysfunction (even in thosewithout diabetes) later in life.

The relationship between diabetes and mild forms of cognitivedysfunction is quite well established (see Table 1).

For the purposes of this article, we are on fairly firm ice regardingdiabetes and mild cognitive dysfunction, but we need to tread morecarefully when linking diabetes and major types of dementia. The current


ORIGINAL

Chronic diabetes andbrain change“Is this the promised end?” - Kent, King Lear

Correspondence:Dr Jocelyn Hellig Email: [email protected]

Dr Jocelyn Hellig (FCP SA)Division of Endocrinology,Department of Medicine,Stellenbosch University,Tygerberg Hospital

Prof Brynne Ascott-Evans (FCP SA)Division of Endocrinology,Department of Medicine,Stellenbosch University,Tygerberg Hospital

Table 1: The relationship between diabetes and mild forms of cognitivedysfunction

What we know about diabetes and the brain:• Diabetes is bad for your brain, but mostly it is associated with mild to

moderate changes in cognition such as changes in mental speed, mentalflexibility and learning

What we are unsure about:• The exact link between diabetes and the major types of dementia• Many mechanistic studies make pathophysiological sense, but…• It is difficult to tease out the exact role of diabetes in dementia, as it may be

judged by the company it keeps (such as hypertension and dyslipidaemia)• Diabetes does not seemed to be linked to subjective memory complaints

literature is awash with possiblepathophysiological mechanismslinking the two conditions, but theclinical relevance is still uncertainand controversial. The role ofhyperglycaemic emergencies(specifically diabetic ketoacidosis)on cognitive decline, will not bediscussed here.

Diabetes and cognition: thesubtle diseaseDiabetes mellitus is associatedwith changes in cognition. Age,genetics, the type of diabetes, andrelated comorbidities are crucialfactors in the variation seenbetween individuals with diabetes.In people with type 1 diabetes,this association is characterisedby a mild to moderate slowing ofmental speed and a diminishedmental flexibility. However, intype 2 diabetes, cognitive changesmainly affect learning andmemory, but also mental speedand flexibility. Several largelongitudinal population-basedstudies have shown that the rateof cognitive decline is acceleratedin the elderly with type 2 diabetes.Effect sizes (see Table 2) aremoderate to large in patientsolder than 65 years and rangefrom 0.4 - 1.0. Smaller effect sizes(<0.5) are found in relatively

younger adults (<60 years old)with type 2 diabetes. By contrast,a study on the effect of cognitionin the oldest old (age at studyentry 85 years) did not find anassociation between diabetes andaccelerated cognitive decline.Whether this is a form ofsurvivor effect or anotherphenomenon is unknown.

The determinants of thisaccelerated cognitive decline,however, are less clear; someresearchers suggest thathypertension could be animportant mediator, whereasothers have found it associatedwith glycaemic control.

Crucial periodsClinically relevant cognitivedecrements in relation to thecourse of diabetes mainly occurduring two crucial periods in life;the period of brain development inchildhood, and the period when thebrain undergoes neurodegenerative

changes associated with ageing.Outside of these periods, cognitivedecrements mainly occur inpatients with substantialdiabetes-related comorbidity,particularly micro- andmacrovascular complications.

Early childhoodMany neuropsychological studieshave shown that children withtype 1 diabetes perform worsethan children without thecondition on measures ofintelligence, processing speed,memory, and executive skills,although the magnitude of thereported effects varies. Themethodological limitations ofmany of the early studies are apotential source of this variation.However, more recently, severalwell-designed longitudinal studieshave found consistent evidence oflower intelligence quotient (IQ)scores, reduced mental efficiencyand poorer school performance inchildren with type 1 diabetes.

Early onset of diabetes is knownto be a potent predictor of worsecognitive outcomes in children;here, repeated episodes of severehypoglycaemia might be a culprit.Interestingly, the role of poorglycaemic control on cognition inthis age group, is less clear.

Late adulthoodAdults who develop type 2diabetes later in life also havecognitive decrements comparedwith adults without type 2diabetes; psychomotorefficiency, executive function,and learning and memory skillsare often most affected.


ORIGINAL

Table 2: The approach to assessing effect sizes of cognitive decline inexperimental vs. control groups

• A neuropsychological examination generally uses multiple tests on eachcognitive domain. The results of individual tests are converted to z-scores andsummed per domain. If the performance on a test is one standard deviationbelow the mean of the reference group, the z-score is -1.

• In a research setting, the performance of one group relative to another is oftenreported as effect sizes, which show between-group differences in standarddeviation units. Effect sizes are calculated by dividing the mean differencebetween the group by the standard deviation of the control group or by thepooled standard deviation of the two groups, taking in account sample sizes.

• In both cases, reduced performance, with an effect size of 1, places the meanperformance of the experimental group around the 15th percentile of the controlgroup, and an effect size of 0.5 translates into the 30th percentile.

• By convention, most neuropsychological studies consider an effect size of0.2 as small, 0.5 as medium, and 0.8 as large.

Several large longitudinal population-basedstudies have shown that the rate ofcognitive decline is accelerated in theelderly with type 2 diabetes

Studies with cognitive screeninginstruments, or batteries of morecomprehensive neuropsychologicaltests, show that the rate ofcognitive decline due to ageing isincreased 1.5- to 2.0-fold inindividuals with type 2 diabetes.

Structural brain imaging studiesin older adults (60 - 65 years) withtype 2 diabetes, show that cerebralatrophy is more pronounced andlacunar infarctions are morecommon (OR 1.3 - 2.2), suggestingthe role of hypertension to be asignificant one. The associationbetween type 2 diabetes andhyper-intense regions of whitematter is a controversial topic.However, analyses done withsensitive volumetric techniques doindicate a modest increase in thislesion load in people with diabetes.In a large 2010 BMJ meta-analysis,white matter hyper-intensitieswere found to be a predictor ofstroke, dementia and death,thereby implicating them assomething more than merely aradiological abnormality.

The risk factors for cognitivedecline and brain imagingabnormalities in older individualswith type 2 diabetes are stilluncertain. Thus far, most of theavailable studies are cross-sectionaland relate cognition and imagingfindings to concurrent vascular andmetabolic risk factors.

Work by Keokuk and colleagues(2015) interprets the results ofcognitive function testing in adultswith and without diabetes, toindicate that cognitive decrementsoccur secondary to diabetes itself,but other explanations are possible.Childhood factors strongly affect

adult cognitive ability, and adversesocioeconomic circumstances earlyin life increase the risk of bothtype 2 diabetes and late-lifecognitive disorders. Hence,cognitive decline in patients withdiabetes might be a result of thesame premorbid circumstances thatpredisposed them to diabetes.

Crucial conditionsThe presence or development ofmicrovascular complications isclearly linked to neurocognitivedysfunction. This is particularlyseen in adult patients with type 1diabetes, where the occurrence ofmicrovascular complications isassociated with reduced cognitiveperformance and cognitive decline.The mechanisms that underlie thisassociation remain to bedetermined. The co-occurrence ofthese complications may be anindex of chronic exposure tohyperglycaemia and thus, indicativeof disease severity. On the otherhand, it could reflect thesusceptibility of an individual tohyperglycaemia-mediated damage.Alternatively, as noted in the retina,microvascular disease might be anindirect marker of changes in themicrocirculation in the brain.

A much-feared factor amongstpeople with diabetes (and theirrelatives) is the occurrence of severehypoglycaemic episodes. Thus far,the largest available prospectivestudies did not find long termadverse effects of severehypoglycaemic events on cognition;however, in selected patient groups,repeated episodes of severehypoglycaemia may have permanentadverse cognitive sequelae.

The relationship betweenglycaemic control, as assessed byglycated haemoglobin, andcognition, is still murky, althoughfollow-up of the Diabetes Controland Complications Trial (DCCT) inpeople with type 1 diabetes, showsthat poor glycaemic control isassociated with an accelerateddecline in the psychomotorefficiency and motor speeddomains. Relatively less is knownabout the risk factor profile that isassociated with more pronouncedcognitive decrements in patientswith type 2 diabetes, buthypertension, microvascular andmacrovascular disease have allbeen implicated.

ACCORD MIND resultsThe results of the Action toControl Cardiovascular Risk inDiabetes (ACCORD) Memory inDiabetes (MIND) study addfurther controversy to what isalready a contentious field.ACCORD MIND is the firstrandomized study in olderpeople with type 2 diabetes totest the effect of intensive (targetHbA1c of less than 6.0 %)compared with standardglycaemic lowering strategies oncognitive domains and onstructural changes in the brain.Both groups had longstandingtype 2 diabetes, a high risk ofcardiovascular disease, and amean age of 62 years. Overall,the 4-year study showed nocognitive benefit in the intensivetreatment group. There was asmall but significant differencein total brain volume (TBV).However, this difference doesnot support the use of intensivetreatment to reduce brainatrophy, in view of the effects ofthis intervention in the mainACCORD trial: raised mortality,no overall benefit oncardiovascular disease events, anincrease in hypoglycaemicevents, and weight gain.


ORIGINAL

Childhood factors strongly affect adult cognitiveability, and adverse socioeconomic circumstancesearly in life increase the risk of both type 2diabetes and late-life cognitive disorders.

In a 2011 editorial, Biesselsbroke down ACCORD MIND intodigestible pieces. A number ofproblems were encountered in thestudy but, despite this and thelargely negative results, ACCORDMIND was an important study. Itwas the first large randomizedtrial to target cognition andabnormalities on brain MRI inpeople older than 55 years withtype 2 diabetes. Recording ofcognitive and MRI outcome wasmeticulous and loss to follow-upwas low. The study does, however,raise important questions. What isthe clinical significance of theoutcomes measures? Can we nowdiscard dysglycaemia as atreatment target to preventcognitive decline?

Diabetes and dementia:reasonable bedfellows?Although the association betweendiabetes and modest cognitivechanges is now well established,the relationship between diabetesand dementia is an area ofcontroversy. A causal associationbetween type 2 diabetes anddementia is difficult to establish,owing to the number andcomplexity of possible risk factorsand pathways.

Culprit risk factors fordementia in patients with type 2diabetes include those that lead tothe condition itself (poor lifestylechoices resulting in insulinresistance), diabetes-specificvariables (hyperglycaemia,hypoglycaemia, endothelialdysfunction, inflammation,microvascular complications, andmacrovascular disease), andcardiovascular risk factors(metabolic syndrome andsmoking) that are associated withtype 2 diabetes.

A large systemic review ofpopulation-based studiesinvestigating the risk of dementiain diabetes mellitus (Biessels et al,2008) concluded that in general,

there is in an increased risk ofdementia in patients withdiabetes. The increased riskincludes both Alzheimer’s diseaseand vascular dementia, althoughthe limitations of clinicaldiagnostic criteria in theclassification of dementia bypathological subtype should benoted. Unfortunately, the availableepidemiological data lacksufficient detail to reliably teaseout specific risk factors linkingdiabetes to dementia.

Underlying mechanismsStudies of the pathophysiologicalmechanisms that might suggesthow diabetes-related factors andcomorbid conditions can affect thebrain, greatly outnumber thosestudies that address clinicalproblems. However, these studiesfail to show whichpathophysiological mechanism isthe main driver of the associationbetween diabetes and dementia, ina clinical setting.

In a nutshell: diabetes and itscomorbidities are associated withan increased risk ofatherosclerosis and strokeleading to vascular pathology inthe brain. Glucose-mediatedtoxicity can lead to microvascularabnormalities and advancedprotein glycation with oxidativestress resulting in morewidespread changes in cognitionand brain structure, referred toas “accelerated brain ageing”.Additionally diabetes mightinterfere with amyloidmetabolism, giving rise to anAlzheimer’s-type pathology.

Future research: what doour patients need?Cognitive dysfunction affects theability of patients to followcomplex disease managementprotocols, and impairedcognition also predictscardiovascular disease and severehypoglycaemic events.

The available trials ofglycaemic control have notshown a benefit for cognitivehealth with tight glycaemiccontrol, but they might have beentoo short to detect benefit. Evenless information is available onhow to manage people who havediabetes with cognitiveimpairment and dementia.Studies of how or when to modifycomplex diabetes managementregimens appropriately incognitively impaired patientswould be useful, given the risk ofsevere hypoglycaemia.

The symptoms of dementiaassociated with diabetes coulddiffer from dementia not associatedwith diabetes, and studies of theeffects on carers coping with thecombined burden of these twodiseases would be helpful.

Summary: Much adoabout everything?We know that diabetes isassociated with milder forms ofcognitive dysfunction and thatsome evidence shows an increasedrisk of dementia in people withdiabetes. But, there are fewdetailed epidemiological data forrisk factors. Some studies providepathophysiological leads, but theydo not indicate which of theseleads are clinically relevant. Thisgap in evidence betweenepidemiological and mechanisticstudies needs to be closed. Therisk factors and mechanisms thatdrive the association betweendiabetes and accelerated cognitivedecline and dementia need to beidentified, before we are able tooffer our patients optimumtherapeutic targets and regimens.The catastrophic effect of cognitivedecline and dementia on not onlythe health care system and workforce, but on our patients andtheir families, should be ignored atour own peril.



ORIGINAL

NEW

Proprietary Name: Ryzodeg® Scheduling Status: S3 Composition: Each ml contains insulin degludec/insulin aspart (70 % soluble insulin degludec and 30 % soluble insulin aspart) 100 units/ml. Indications: Treatment of adult diabetes mellitus patients, as basal add on to co-medication in patients who are inadequately controlled: - In type 1 diabetes mellitus, Ryzodeg® should be used with short-acting soluble insulin for use at the meal times when Ryzodeg® is not used. - In type 2 diabetes mellitus, Ryzodeg® should be used as an add on to oral antidiabetic medicines. Contra-Indications: Hypersensitivity to the active substances or to any of the excipients, pregnancy. Warnings & Special Precautions: Too high insulin dose, omission of a meal or unplanned strenuous physical exercise may lead to hypoglycaemia. Patients whose blood-glucose control is greatly improved may experience a change in their usual warning symptoms of hypoglycaemia and must be advised accordingly. Usual warning symptoms may disappear in patients with long-standing diabetes. Inadequate dosing and/or discontinuation of treatment in patients requiring insulin may lead to hyperglycaemia and potentially to diabetic ketoacidosis. Concomitant illness, especially infections, may lead to hyperglycaemia and thereby cause an increased insulin requirement. Transferring to a new type, brand, or manufacturer of insulin must be done under strict medical supervision. When using Ryzodeg® in combination with pioglitazone, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Thiazolidinediones should be discontinued if any deterioration in cardiac function occurs. Hypoglycaemia may constitute a risk when driving or operating machinery. Pregnancy and lactation: Safety has not been established in pregnancy and lactation and Ryzodeg® should not be recommended for use during pregnancy. Dosage and Directions for Use: Ryzodeg® can be administered once- or twice-daily with the main meal(s). When needed, the patient can change the time of administra-tion as long as Ryzodeg® is dosed with a main meal. The potency of insulin analogues, including Ryzodeg®, is expressed in units (U), 1 unit (U) Ryzodeg® corresponds to 1 international unit (IU) of human insulin and one unit of all other insulin analogues. In patients with type 2 diabetes mellitus, Ryzodeg® can be combined with oral anti-diabetic products approved for use with insulin, with or without bolus insulin. In type 1 diabetes mellitus, Ryzodeg® is combined with short-/rapid-acting insulin at the remaining meals. Ryzodeg® is to be dosed in accordance with individual patients’ needs. Dose-adjustments are recommended to be primarily based on pre-breakfast glucose measurements. An adjustment of dose may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.Initiation: For patients with type 2 diabetes mellitus, the recommended total daily starting dose of Ryzodeg® is 10 units once daily with meal followed by individual dosage adjustments. For patients with type 1 diabetes mellitus, Ryzodeg® is to be used once-daily at mealtime and a short-/rapid-acting insulin should be used at the remaining meals with individual dosage adjustments. The recommended starting dose of Ryzodeg® is 60 − 70 % of the total daily insulin requirements. Transfer from other insulin medicinal products: Close glucose monitoring is recommended during transfer and in the following weeks. Patients with type 2 diabetes: Patients switching from once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily Ryzodeg® at the same total insulin dose as the patient’s previous total daily insulin dose. Patients switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to twice-daily Ryzodeg® at the same total insulin dose as the patient’s previous total daily insulin dose. Patients switching from basal/bolus insulin therapy to Ryzodeg® will need to convert their dose based on individual needs. In general, patients are initiated on the same number of basal units. Doses and timing of concomitant antidiabetic treatment may need to be adjusted. Patients with type 1 diabetes: For patients with type 1 diabetes mellitus, the recommended starting dose of Ryzodeg® is 60 − 70 % of the total daily insulin requirements in combination with short-/rapid-acting insulin at the remaining meals followed by individual dosage adjustments. Doses and timing of concurrent short-/rapid-acting insulin products may need to be adjusted. Flexibility: Ryzodeg® allows for flexibility in the timing of insulin administration as long as it is dosed with the main meal(s). If a dose of Ryzodeg® is missed, the patient can take the next dose with the next main meal of that day and thereafter resume the usual dosing schedule. Patients should not take an extra dose to make up for a missed dose. Ryzodeg® should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Side Effects: Very common (≥1/10); common (≥1/100 to < 1/10); uncommon (≥1/1.000 to < 1/100); rare (≥ 1/10.000 to < 1/1.000); very rare (< 1/10.000); not known (cannot be estimated from the available data). Very common: Hypoglycaemia. Common: Injection site reactions. Uncommon: Peripheral oedema and rare: Hypersensitivity and urticaria. Pharmacological classification: A 21.1 Insulin Preparations Reg. No.: 47/21.1/0165

References: 1. Ryzodeg® [summary of product characteristics]. Bagsværd, Denmark: Novo Nordisk A/S; 2013. 2. Fulcher G, Christiansen JS, Bantwal G, Polaszewska-Muszynska M, Mersebach H, Andersen TH, Niskanen LK; on behalf of the BOOST: Intensify Premix I Investigators. Comparison of insulin degludec/insulin aspart and biphasic insulin aspart 30 in uncontrolled, insulin-treated type 2 diabetes: a phase 3a, randomized, treat-to-target trial. Diabetes Care. In press. 3. De Rycke A, Mathieu C. Degludec – first of a new generation of insulins. European Endocrinology. 2011;7(2):84–87.

Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. 150 Rivonia Road, 10 Marion Street Office Park, Building C1, Sandton, Johannesburg, 2196. Tel: (011) 202 0500 Fax: (011) 807 7989 www.novonordisk.co.za RYZ11/05/2016

At Novo Nordisk, we are changing diabetes.In our approach to developing treatments,in our commitment to operate profitably andethically and in our search for a cure.

RYZ A4 web adv.indd 1 2016/07/22 2:00 PM

In type 2 diabetes, careful control of blood glucosecan help prevent or delay micro- andmacrovascular complications. Initially, this may be

adequately achieved with lifestyle change and oralmedication, but because of the progressive nature ofdiabetes, characterised by gradual decline in β-cellfunction and density, most patients will eventuallyrequire insulin to achieve glycaemic goals.1 p72a

The benefits of control achievedearly in the condition remain formany years, despite it becomingmore difficult to maintain targetglucose levels.2 p1577a

Hypoglycaemia limits effective diabetesmanagementA common limitation in achieving glucose targetshowever, both with oral therapies and especially as oneintensifies insulin therapy, is hypoglycaemia.3 p155a

Hypoglycaemia not only has anegative impact on the wellbeing ofthe patient in the short- and long-term, it is also an important factorunderlying clinical inertia.

This describes both a reluctance by clinicians tointensify therapy in patients who are insufficientlycontrolled on current therapies, and decreasedmotivation of patients to adhere to prescribedtherapies.3 p155b,c; p156d

Hypoglycaemia becomes more commonwith duration of therapyAlthough hypoglycaemia is infrequent in early type 2diabetes (T2DM), with longer durations of diabetes(and loss of the glucagon response to hypoglycaemia),and of insulin therapy, the incidence begins toincrease, approaching that of hypoglycaemia intype 1 diabetes.

Mild hypoglycaemic events areeven more common, but lessreported. One prospective studyreported that patients with type 2diabetes were experiencing morethan 16 mild hypoglycaemicepisodes per year.4 p1389a, 1390b,c

Nocturnal hypoglycaemia is especially common.Asymptomatic hypoglycaemia may be identified withcontinuous glucose monitoring in around 50% ofpatients with T2DM - the majority of episodes (74%)occur at night.5 p1153a Nocturnal hypoglycaemia may besuspected in patients who report morning headache,poor quality of sleep, vivid dreams or nightmares andprofuse sweating in bed. Restlessness during sleep maydisturb the partner.6 p89a

Hypoglycaemia worsens an alreadyincreased risk of CVDPatients with type 2 diabetes are at increased risk ofcardiovascular disease (CVD). However, results oflong-term studies of intensive glucose-lowering forCVD prevention have been disappointing. Tighter


PRESS RELEASE

Hypoglycaemia in type 2 diabetesincreases the risk ofcardiovascular events

glycaemic control appears to be no more effective thanstandard glucose reductions in reducing the risk ofCVD mortality among high-risk individuals.

One hypothesis that might help toexplain these observations, is theoccurrence of severe hypoglycaemicepisodes with intensive therapy. Ithas been suggested that severehypoglycaemia is associated with asignificantly increased risk ofadverse vascular events and CVDmortality.7 p33a-e

Various mechanisms link hypoglycaemia to increasedrisk of myocardial ischaemia, acute thrombotic eventsand accelerated atherosclerosis, especially in anindividual who is already at high risk of CVD.Hypoglycaemia induces number of adverse acutehaemodynamic changes, including tachycardia,systolic hypertension, elevated cardiac output andmyocardial oxygen demand, and increases the risk ofpotentially fatal cardiac arrhythmias. It is alsoassociated with pro-thrombotic and pro-inflammatoryeffects, such as increased neutrophil and plateletactivation, increased factor VII, increased C-reactiveprotein, vascular endothelial growth factor (VEGF) andinflammatory mediators, and reduced vasodilatationconsequent to endothelial dysfunction.7 p34f,g

Clinical implications of treatment-relatedhypoglycaemiaFrom a clinical perspective, whilst it is important toachieve adequate glycaemic control, it is also desirableto avoid hypoglycaemia, especially in patients who areat high risk for CVD.7 p34h

Patients and relatives require education on thesymptoms of and risk factors for hypoglycaemia, andappropriate management, should it occur.3 p159 a Where

appropriate, it would be prudent to consider therapieswith lower propensity to hypoglycaemia. Where insulinis required, it needs to be titrated carefully.

New insulins provide solutions to betterdiabetes managementModern insulins carry a lower risk of hypoglycaemiathan do older insulins.3 p160a Furthermore, progress ininsulin therapy continues, allowing improvedglycaemic control with fewer injections and less chanceof hypoglycaemia, especially at night.8

Leading these developments, NovoNordisk aims to make betterdiabetes outcomes available to allpeople with diabetes. Achievingtarget glycaemic control should notbe at the expense of adverseoutcomes which can be a directresult of therapy.


PRESS RELEASE

Patients who are especially at risk include thosewith3 p157a

• Older age• Longer duration of diabetes• Concomitant medication• Renal dysfunction• Hypoglycaemia unawareness• Cognitive dysfunction• Peripheral neuropathy• Intense glucose-lowering treatment strategies

References1. Henske JA, Griffith ML, Fowler MJ. Initiating and

titrating insulin in patients with type 2 diabetes.Clin Diab 2009; 27(2): 72-76.

2. Holman RR, Paul SK, Bethel MA, et al. 10-yearfollow-up of intensive glucose control in type 2diabetes. N Engl J Med 2008; 359: 1577-1589.

3. Ahren B. Avoiding hypoglycaemia: a key to successfor glucose-lowering therapy in type 2 diabetes.Vasc Health Risk Manag 2013; 9: 155-163.

4. Desouza CV, Bolli GB, Fonseca V. Hypoglycemia,diabetes, and cardiovascular events. Diab Care2010; 33(6): 1389-1394.

5. Chico A, Vidal-Ríos P, Subirá M, Novials A.The continuous glucose monitoring system is usefulfor detecting unrecognized hypoglycemias inpatients with type 1 and type 2 diabetes but is notbetter than frequent capillary glucose measurementsfor improving metabolic control. Diabetes Care2003; 26(4): 1153-1157.

6. Frier BM. How hypoglycaemia can affect the lifeof a person with diabetes. Diab Metab Res Rev2008; 24: 87-92.

7. Kilov G. Hypoglycaemia and cardiovascular risk inpeople with type 2 diabetes. Diabetes Prim CareAustralia 2016; 1: 33-35.

8. Cooper JG, Pieber TR, Cariou B, et al. Treatmentintensification with IDegAsp BID vs IDeg OD plusIAsp in insulin-treated patients with type 2 diabetes:a randomised, controlled phase 3 trial.Diabetologia 2014; 57(Suppl 1): S69.


Presents a Five-Day Advanced Course in Diabetes Care for Health Professionals

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WHO SHOULD ATTEND THE COURSE? This is an Advanced Course, and is aimed at Health Care Professionals who have a basic knowledge and understanding ofdiabetes mellitus. It is designed to give an extensive overview of the core principles of modern team diabetes management,so enabling the participants to understand the condition in sufficient depth, to make a real difference in the lives of peoplewith diabetes. Pre and Post Course multiple-choice knowledge evaluation tests are administered, to allow for evaluation ofthe learning experience.

Attendance is also part of the contractual requirements for Practitioners wanting to open CDE affiliated “Centre forDiabetes Excellence” Branches.

DIABETES ~ THE BURDEN, THE RELIEF Latest estimates place the age-adjusted (20-79) comparative prevalence of Diabetes Mellitus in South Africa at 7.6 %(International Diabetes Federation, 2015) and this is increasing. Up to 62 % of persons with the condition are undiagnosedand at risk from disabling and life threatening complications. Diabetes, together with its associated cardiovascular risk factorsis one of the leading causes of death, either directly or indirectly, in our population.

Over the past three decades, it has become evident that good control of diabetes, as well as the common co-morbiditiesof hypertension and the dyslipidaemias, is vital to prevent or delay the devastating long-term complications of diabetes.To achieve this, people with diabetes need to understand their largely silent condition and the correct principles of self-care.

Health professionals often do not have access to updated approaches to a chronic, mostly self-managed condition such asdiabetes ~ vital opportunities for therapeutic interaction and patient education are lost. Additionally, insight is needed intothe ever-widening range of available medications and treatment strategies as well as the relationships betweencardiovascular and other risk factors and diabetes.

As health services evolve, there is a move towards Team Management of Chronic Conditions. This has resulted in the restof the Health Care Team (Nurses, Pharmacists, Dieticians, Podiatrists, Biokineticists and others) playing an ever-increasingrole in diabetes care.

COMMENTS FROM DELEGATES TO PREVIOUS 5-DAY COURSES: I realise that I had been blundering around in the dark in treating my patients with diabetes and now someone has turned onthe light! This a life changing Course. You have reformed my medical practice forever - General Practitioner

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CPD ACCREDITED DIABETES TRAINING

CPD ACCREDITEDThe Course offers 34 contact hours. The Course is accredited to provide 30 CPD points for Medical Practitioners and otherHealthcare Practitioners registered with the Health Professions Council of South Africa.

Pre-Course readings will be supplied by e-mail to all delegates and an electronic manual of all speaker notes will beprovided on the first day of each Course.

Official completion certificates will be provided to delegates who achieve a mark of at least 60 % in the final Post-CourseKnowledge Evaluation.

ANSWERS TO FREQUENTLY ASKED QUESTIONS Presented at: Glenhove Conference Centre, 52 Glenhove Road, Melrose Estate, Johannesburg. Dates & Fees: Available at www.cdediabetes.co.za (Click on Diabetes Courses). Early bookings are advised. Course Hours: Five days of lectures, workshops and discussion (08h00 – 17h00). Dress: Comfortable, smart-casual Language Medium: English Course Information: The Course Coordinator Tel: +27 11 053-4400 / Fax: +27 (0)86 247-0674Email: [email protected]

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TOPICS INCLUDE: • Holistic Team Care Philosophy & Educational Approaches • Diagnosis, Classification, Pathophysiology & Prevention of Type 1 & Type 2 Diabetes Mellitus • Other types of diabetes including Gestational Diabetes • Treatment of Type 1 & Type 2 Diabetes • Psychological Adjustment to Diabetes • Meal Planning & Nutrition in Diabetes • The Importance of Exercise in Diabetes • The Medical Management of Diabetic Ketoacidosis • The Foot of the Person with Diabetes • Acute Complications of Diabetes • Diabetes as a Micro- & Macro-vascular Disease & Risk Factor Control • Managed care in diabetes • Interactive Team-facilitated Case Study Sessions • Practical Workshop on Self Care Devices & Equipment

OUR INTERDISCIPLINARY TEAM OF COURSE LECTURERS AND FACILITATORSLarry A. Distiller BSc MBBCh (Rand) FCP (SA) FRCP (London) FACE Specialist Physician, Endocrinologist Brian D. Kramer MBBCh (Rand) DMRD (London) FCP (SA) DTM&H (Wits) Specialist Physician, Endocrinologist Barry I. Joffe MB FRCP FCP (SA) DSc Specialist Physician, Endocrinologist David Segal MBBCh (Wits) FAAP (USA) Paediatric Endocrinologist Laura Blacking MBBCh (Wits) FCP (SA) Specialist Physician, Endocrinologist Stan Landau MBChB (Stell) FCP (SA) Specialist Physician Andrew Heilbrunn B PHYS ED (Wits) BA (Hons) Biokinetics Biokineticist Michelle Daniels BSc Dietetics (Natal) Dip. Hosp. Dietetics (Pretoria) Registered Dietician Gerda Janse van Rensburg ND Pod SA IIWCC (Toronto, US) PgDipDM (Glamorgan) Podiatrist Michael Brown B. Nursing (Wits) ACDM (Wits) Diabetes Specialist Nurse Rosemary Flynn MSc (Clinical Psychology) Clinical Psychologist

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