Dr Mick Kumwenda MSc FRCP (London) Consultant Nephrologist and Clinical Director (Medicine) Glan Clwyd Hospital Rhyl Denbighshire UK [email protected].

HIGHLIGHTSDr Mick Kumwenda MSc FRCP (London)

Consultant Nephrologist and Clinical Director (Medicine)Glan Clwyd Hospital

RhylDenbighshire

[email protected]

PACD18 2014

We are delighted to present you with the highlights this year from yet again a very successful congress attended by 2003 multidisciplinary delegates from around the globe.We wish to thank all those who attended and hope you left the congress full of knowledge that made a difference when you returned back to your home base.We also thank all the speakers that contributed, the quality of all the papers was exceptional and we have selected a few slides with the kind permission of the presenters to summarise key messages from the congress.

PACD18 2014

The PACD continues to serve the diabetes health care providers in the Middle East as an academic forum for the exchange of knowledge, training and experience.Conference chair : Sherif HafezVice chairs: Mohamed Fahmy Abdel-Aziz Megahed Abou El-MagdAssistant Secretary General: Gamela Nasr Hyam Refaat Tantawi

Message from molecular metabolism workshops

Type 2 diabetes

Type 2 diabetes (T2D) is a complex disorder

that is affected by multiple genetic and environmental

factors.

Existing genetic markers explain only a

modest (15%) part of the heritability of T2D.

Epigenetics

Epigenetics has been defined as heritable

changes in gene function that occur without

a change in the nucleotide sequence.

i e

Non -sequence dependent inheritance

Key Enzymes in epigenetics

• It has recently been suggested that glucose

availability can affect histone acetylation in an ATP-

citrate lyase-dependent manner, further linking

energy metabolism to epigenetic regulation

Mitochondrial disease and diabetes

Immune cells and Modulation of Energy Balance

The effectors of innate and adaptive immune cells implicated in maintaining energy balance include:

- Macrophages(MQ) - T cells - Neutrophils - Dendritic cells(DCs) - Mast cells (MCs) - Eosinophil's - Natural Killer (NK ) cells - Natural killer T(NKT) cells

Cooperation between brain and islet in glucose homeostasis and diabetes

(Schwartz, M.W. et al., 2013)

Message from obesity workshop

Obesity and life expectancy

● January 2003 Life Table analysis of Framingham Data

● Obese at 40 live 6 to 7 years less than normal

● Overweight at 40 live 3 years less than normal

● Obese smoker live 14 years less than normal

HEALTHY DIET RECOMMENDATIONS

Understanding natural history of type 2 diabetes and targeted therapies

InsulinResistance

Type 2 Diabetes

b-cellDysfunction

InsulinResistance

Hyperglycaem

ia

InsulinConcentration

Insulin Action

Euglycaemia

b-cell Failure

Normal IGT ± Obesity Diagnosis oftype 2 diabetes

Progression oftype 2 diabetes

Dual defect of type 2 diabetes: treating a moving target

DeFronzo et al. Diabetes Care 1992;15:318-68

Guiding principles for nutrition education Patients are responsible

Patients are therefore the final decision-makers Knowing what is best for diabetes, is not the same as knowing what is best for that patient These principles have re-defined how we provide educationBoth structured education and one to one approach benefits patients.

Trials to Prevent / Delay Progression From IGT to Type 2 Diabetes

Lifestyle Changes Malmo Study Da Qing Study Finnish Diabetes Prevention

Study Diabetes Prevention Program

Medications Diabetes Prevention Program: metformin TRIPOD: troglitazone PIPOD: pioglitazone STOP-NIDDM: acarbose NAVIGATOR: nateglinide and valsartan DREAM: rosiglitazone and ramipril XENDOS: orlistat ORIGIN: glargine insulin ACT NOW: pioglitazone

TRIPOD=Troglitazone in Prevention of Diabetes Study; PIPOD= Pioglitazone in Prevention of Diabetes Study; STOP-NIDDM=Study to Prevent Non–Insulin-Dependent Diabetes Mellitus; NAVIGATOR=Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; DREAM=Diabetes Reduction Approaches with Ramipril and Rosiglitazone; XENDOS=Xenical in the Prevention of Diabetes in Obese Subjects; ORIGIN=Outcomes Reduction with Initial Glargine Introduction.

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ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S27. Figure 2;adapted with permission from Inzucchi SE, et al. Diabetes Care 2012;35:1364–1369

METFORMIN

The A1C and ABCDE of glycaemia management in type 2 diabetes: a physician's personalized approach.

AGE (years)

COMPLICATIONSDURATION>10yrs

HbA1c (%)

HbA1c≥ 9%

HbA1c< 9%

Insulin treatment

15-40 40-70 >70

- - -+ + +

<6 <6.5 <7<6.5 6.5-7 7-8

Physicia n should choose drug a ccording to pa t ie nt 's riskof w e ight ga in, hypoglyca e mia , ca rdio-re na l complica t ions

Pozzilli P, Leslie RD, Chan J, De Fronzo R, Monnier L, Raz I, Del Prato S. The A1C and ABCD of glycaemia management in type 2 diabetes: a physician's personalized approach. Diabetes Metab Res Rev.

2010 May;26(4):239-44.

Insulin initiation is often delayed in type 2 diabetes despite high HbA1c

Diabetes duration (years)

1. Raskin et al. Diabetes Care 2005;28:260–52. Kann et al. Exp Clin Endo Diab 2006; 114:527–323. Valensi et al. Int J Clin Pract 2009;63:522–314. Oyer et al. Am J Med 2009;122:1043–9

5. Yang et al. Diabetes Care 2008;31:852–6

INIT

IATE

plus

40.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10.0

Base

line H

bA

1c (%

)

INIT

IATE

1

Euro

Mix

2

9.2%

IMPR

OVETM

3

9.7%

9.2%

9.9%

1707

5

9.5%

9.5 10.3 7.4 7.7- -

9.1%

8.6

A1chi

eve

Egyp

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sub-

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Improvement of glycaemic control in combination therapy

Regime

Insulin and SU – 7 studies

Insulin and metformin – 4 studies

Insulin and TZD – 2 studies

Glycated Hb reduction vs insulin alone

- 0.4%

- 1.3%

- 1.3%

Yki Jarvinen H Diabetes Care 2001 24 : 738-67

Be aware of hypoglycemia

• <3.5-4 mmol/L (<63-72 mg/dL) • Whipple’s triad:

① Symptoms② Low blood glucose③ Relief of symptoms when blood glucose raised

COUNTER REGULATORY HORMONES: GLUCAGON, EPINEPHRINE, CORTISOL, GROWTH HORMONE

Hypoglycemia unawareness

• Glucagon response often lost after five years with type 1 diabetes

• Epinephrine response may be blunted and delayed

• Adrenergic symptoms blunted

• Reliance on recognizing neuroglycopenic symptoms

Metformin: multiple mechanisms for vascular protection

Improved Reduced

All refs Diabetes Metab (2003): 1Gianarelli R vol. 29:6S28-35; 2Després JP 29:6S53-61;3Grant PJ ;29:6S44-52; 4Wiernsperger N 29:6S77-8; 5Schäfers RF 29:6S62-70;6Beisswenger 29:6S95-103; 7Leverve XM 29:6S88-94; 8Mamputu JC 29:6S71-6;

The proposed pathways by which GLP-1 may exert its cardiovascular Effects .

Cardio protective potentials of DPP-4 inhibitors beyond their glucose-lowering

action

Balakumar P, et al. Cell Signal. 2013 Sep;25(9):1799-803

197 studies identified

Metformin was well tolerated, albeit with a trend towards increased hypoglycaemia. Formal estimates of combined effects from the five trials which reported appropriate data indicated a significant reduction in insulin dose (6.6 U/day, p<0.001) but no significant reduction in HbA1c (absolute reduction 0.11%, p=0.42). No reported trials included cardiovascular outcomes

12

Alpha Glucosidase Inhibitors in Type 1 DM

Prevention of nocturnal hypoglycemia? Reduce postprandial hyperglycemia

Raju B, et al. J Clin Endocrinol Metab. 2006 Jun;91(6):2087-92. Riccardi G, et al. Diabet Med. 1999 Mar;16(3):228-32.

13

Thiazolidinediones in Type 1 DM

Potential insulin sparing role in overweight patients with type 1 diabetes.

Mixed effects on progression of diabetes reported

Strowig SM, Raskin P. Diabetes Care. 2005 Jul;28(7):1562-7.Shimada A, et al. Diabetes Metab Res Rev. 2011 Nov;27(8):951Yang Z, et al. Diabetes Res Clin Pract. 2009 Jan;83(1):54-60.

14

Incretin-based Therapies in Early Type 1 DM

Hari Kumar KV, Shaikh A, Prusty P. Diabetes Res Clin Pract. 2013 May;100(2):e55-8 2

Oral hypoglycemic agents

Short acting insulin SUs

Take twice daily at suhur and iftar

TZDsNo treatment adjustment required 2–4 weeks to exert substantial antihyperglycemic effects

DPP4 inhibitorsThe best tolerated drugs,

Consider DPP4i as an alternative to SUs if the risk

of hypoglycemia is high

SUsUnsuitable for use during fasting because of

the inherent risk ofHypoglycemia, use with caution. Consider dose

adjustment.

MetforminModify timing of doses:

Two thirds of dose at Iftar

• One third at suhur.

E Hui et al , BMJ, 26 june 2010 , Volume 340; Al-Arouj M. et al, Recommendations for management of diabetes during Ramadan. Diabetes Care. 2010;33: 1895-1902.

Ramadan and glycaemic control

Don’t miss MODY!Genetic Testing for MODY

Who should be tested?MODY misdiagnosed as type 2 diabetes and sometimes type 1

diabetes.Mutations can be inherited (commonly) or de novo (rarely).

What genes should be tested?Most common causes of MODY are mutations in GCK, HNF1A and

HNF4A.

Is genetic testing good healthcare policy?Change from expensive therapy to cheaper therapy – saves money.If you have a GCK mutation, you DO NOT have type 2 diabetes and

you do not need any drugs or a diabetes doctor!MonogenicDiabetes.org

MODY – Treatment Decisions

HNF1A Low-dose sulfonylurea (pills)

GCK No therapy except during pregnancy

HNF4A Low-dose sulfonylurea (pills)

HNF1B Insulin?

MANAGING DIABETES RELATED COMPLICATIONS

0

0.05

0.1

0.15

0.2

0.25

Even

t ra

te

Months6 9 153 18 2112

RR=2.88 (2.37-3.49)

24

RR=1.99 (1.52-2.60)

RR=1.71 (1.44-2.04)

RR=1.00

Diabetes/CVD (n=1,148)

No Diabetes/CVD (n=3,503)Diabetes/No CVD (n=569)No Diabetes/No CVD (n=2,796)

OASIS Study Mortality by Diabetes and CVD Status

Malmberg K, et al. Circulation. 2000;102:1014-1019.

OASIS=Organization to Assess Strategies for Ischemic Syndromes

State of the art lecture in memory of Prof Zakarya El BAZ

Diabetic Nephropathy

by Prof Sherif HafezDr Mick Kumwenda

Definitions – based on quantification

Micro albuminuria - dipstick negative > 2.5 mg/mmol males > 3.5 mg/mmol females 30 - 300mg/day

Macrolbuminuria – dipstick positive > 25 mg/mmol both males and females > 300mg/day – diabetic nephropathy (low serum albumin = nephrotic syndrome

Can be proteinuria negative in type 2

+/- e GFR < 60ml/min

Diabetic Nephropathy: pathological classification

Class 1 – EM proven GBM thickening

Class 2a – Mild mesangial expansion

Class 2b – Severe mesangial expansion

Class 3 - Nodular sclerosis ( KW lesions)

Class 4 - Advanced sclerosis ( > 50% glomeruli)

Tervaert TC et al J Am Soc Nephrol 2010 online

A1 A2 A3

Normal to mildly

increased

Moderately increased

Severely increased

<30 mg/g <3 mg/mmol

30-300 mg/g 3-30 mg/mmol

>300 mg/g >30 mg/mmol

CURRENT CHRONIC KIDNEY DISEASE (CKD) NOMENCLATURE USED BY KDIGO

CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health and CKD is classified based on cause, GFR category, and albuminuria category (CGA).

KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3:136-150. http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf Accessed February 26, 2013

Previously

micro-

albuminur

ia

Previously

macro-

albuminur

ia

G1 Normal or high ≥90

G2 Mildly decreased 60-89

G3aMildly to moderately

decreased 45-59

G3bModerately to

severely decreased 30-44

G4 Severely decreased 15-29

G5 Kidney failure <15

GFR

cate

gori

es

(ml/

min

/ 1

.73

m²)

Descri

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Persistent albuminuria categories Description and range

Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk; Orange: high risk; Red, very high risk.

Prognosis of CKD by GFR and Albuminuria Categories:

KDIGO 2012

Although we understand the natural history of diabetic kidney disease some patients with type 2

diabetes progress to end stage kidney disease without developing proteinuria

Nonalbuminuric Renal Insufficiency in Type 2 Diabetes, MacIsaac 2004

• A cross-sectional survey of 301 outpatients attending a single tertiary referral center using the plasma disappearance of isotopic 99mTc-diethylene-triamine-penta-acetic acid to measure GFR and at least two measurements of urinary albumin excretion rate (AER) over 24 h to determine albuminuria.

Conclusion: patients with type 2 diabetes can commonly progress to a significant degree of renal

impairment while remaining normoalbuminuric. MacIsaac et al, Diabetes Care. 2004 Jan;27(1):195-200

CHEP 2014 (BP target)¹Target Blood pressure Should be less than 140/90 mmHg in most patients, including those with chronic kidney disease.

ESC 2013 (BP target)²Target Blood pressure <140/90 mmHg should be considered in patients with diabetic or non-diabetic CKD.

JNC IV (BP target)³In patients with CKD, initiate treatment at SBP ≥140 mmHg or DBP ≥90 mmHg, and treat to achieve SBP <140 mmHg and DBP <90 mmHg.

Blood Pressure Target Goals in CKD patients

1: Canadian Hypertension Education Program (CHEP) 2014 Recommendation, adopted from: https://www.hypertension.ca/chep. Accessed at 5/2/20142: Mancia G, et al. J Hypertens. 2013 Jul;31(7):1281-3573: James PA, et al. JAMA. 2013 Dec 18. [Epub ahead of print]

ACE inhibitors in Hypertensive diabetic patients

Intensive group n=80

Weight loss

Exercise

Smoking cessation

BP & Lipid targets

Aspirin, Statin, ACEI

Compared to usual diabetic care

8 years follow up

CV morbidity & mortality -50%

Progression to proteinuria -60%

Progression to Retinopathy -60%

Gaede P et al. Multifactorial intervention , N Engl J Med 2003; 348: 383 -93

Steno-2 Trial: multiple risk factor intervention in T2DM

Steno-2: Number needed to treat

Number of microalbuminuric patients with type 2 diabetes needed to treat for 13 years to prevent one …..

Death 5 patientsCardiovascular death 8 patientsMajor cardiovascular event 3 patients

Progression to nephropathy 5 patients

Dialysis 16 patients

Laser treatment 7 patients

RAS MANAGEMENT CAUTION: avoid combined therapies

Caution : ACEi or ARB in combination with RENIN inhibitor

ALTITUDE – Murray JJ Eur J Heart Fail 2012 14(4) 341-3

Aliskerin 300mg increased urinary albumin excretion

Dual caused reduction of e GFR

Stroke placebo 85 Aliskerin 112

Study discontinued

Diabetic Kidney disease guidelines

CKD 1-2 CKD 3-4

Life style modification

Protein intake 0.8g/kg

Treat all risk factors

HbA1C <7% BP < 140/80 Refer to Nephrologist : -rapid progressors - nephrotic syndrome - haematuria - e GFR < 40ml/min

Same as CKD1-2

CKD group education: -Bone mineral disease - phosphorus 800-1000mg/day - salt intake <6g/day - anaemia Hb 10-12g/dl - ferritin >100ng/ml

Preparation for renal replacement therapy including transplantation

Can we identify patients at risk using biomarkers?

Microalbuminuria remains the gold standard

Other candidate markers associated with microalbuminuria or low e GFR: - Neutrophil gelatinase associated lipocalin (NGAL) - Kidney Injury Molecule 1(KIM 1), -Transforming Growth Factor Beta -Cystitis C -Tumour Necrosis Factor -oocytesAdipocytokinine Zinc alpha 2 glyco protein (ZAG) in non-albuminurics

Meta-analysis in primary prevention 2009ASA and diabetes

Meta-analysis in primary prevention 2009ASA and diabetes: Total mortality

Efficacy of Antiplatelet Therapies in ACSResults in the Diabetes Mellitus Subgroups (Adapted from

Ferreiro JL et al. Circulation 2011; 123: 798-813)

Diabetes and heart failureCurrent knowledge

Piccini JP et al,Am J Med 2004: 116: 64s-75sTrost S, LeWinter M. Curr Treat Options Cardiovasc med. 2001: 3: 481-492

Glucose management strategy

Clinical management of diabetic foot

Clinical management of diabetic foot

Evidence based management of diabetic foot

Glycaemic control Control oedema Debridement Dressings

Erectile dysfunctiom

Incidence and prevalence is high worldwide

Effects up to 52% of men (40-70yrs)

Aetiology - Organic - Hormonal - Anatomical - Drugs - Psychogenic

Treatment

Oral therapyPDE-5 inhibitors improve relaxation of smooth muscle.

Contraindicated in patients receiving nitrates, recent stroke/MI, unstable angina

Intracavernosal injection Papaverine Phentolamin PGE1 AtropineVacuum devicesPenile prosthesis

PACD18 2014

Diabetes continues to be a global epidemic particularly effecting the Middle East

The ultimate goal of the congress is to support thaw commitment of health professionals to fight against diabetes.

We hope you have gained more knowledge yet again this year and see you again at PACD19 2015 in Cairo.