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Highlights. Dr Mick Kumwenda MSc FRCP (London) Consultant Nephrologist and Clinical Director (Medicine) Glan Clwyd Hospital Rhyl Denbighshire UK Mick.kumwenda@wales.nhs.uk. PACD18 2014.

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highlights

Highlights

Dr Mick Kumwenda MSc FRCP (London)

Consultant Nephrologist and Clinical Director (Medicine)

Glan Clwyd Hospital

Rhyl

Denbighshire

UK

Mick.kumwenda@wales.nhs.uk

pacd18 2014
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 20141
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 Hafez

Vice chairs: Mohamed Fahmy Abdel-Aziz

Megahed Abou El-Magd

Assistant Secretary General: Gamela Nasr

Hyam Refaat Tantawi

type 2 diabetes
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

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
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
immune cells and modulation of energy balance
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
Cooperation between brain and islet in glucose homeostasis and diabetes

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

slide12

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
dual defect of type 2 diabetes treating a moving target

b-cell

Dysfunction

Insulin

Resistance

Type 2

Diabetes

Dual defect of type 2 diabetes: treating a moving target

Hyperglycaemia

Insulin Action

b-cell Failure

Insulin

Concentration

Insulin

Resistance

Euglycaemia

Diagnosis oftype 2 diabetes

Progression oftype 2 diabetes

Normal

IGT ± Obesity

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

guiding principles for nutrition education
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 education

Both structured education and one to one approach benefits patients.

trials to prevent delay progression from igt to type 2 diabetes
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.

slide19

ADA/EASD position statement 2012

Towardspersonalizedglycaemic targets

slide20

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

slide21

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

AGE (years)

15-40

40-70

>70

COMPLICATIONS

DURATION>10yrs

-

+

-

+

-

+

HbA1c(%)

<6

<6.5

<6.5

6.5-7

<7

7-8

HbA1c≥ 9%

Insulintreatment

HbA1c< 9%

METFORMIN

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 hba 1c
Insulin initiation is often delayed in type 2 diabetes despite high HbA1c

9.9%

10.0

9.7%

9.5%

9.5

9.2%

9.2%

9.1%

9.0

8.5

Baseline HbA1c (%)

8.0

7.5

7.0

6.5

A1chieve

Egypt

sub-group

0.0

INITIATEplus4

17075

EuroMix2

INITIATE1

IMPROVETM 3

8.6

- -

9.5

10.3

7.4

7.7

Diabetes duration (years)

  • Raskin et al. Diabetes Care 2005;28:260–5
  • Kann et al. Exp Clin Endo Diab 2006; 114:527–32
  • Valensi et al. Int J Clin Pract 2009;63:522–31
  • Oyer et al. Am J Med 2009;122:1043–9
  • Yang et al. Diabetes Care 2008;31:852–6
improvement of glycaemic control in combination therapy
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
Be aware of hypoglycemia
  • <3.5-4 mmol/L (<63-72 mg/dL)
  • Whipple’s triad:
    • Symptoms
    • Low blood glucose
    • Relief of symptoms when blood glucose raised
hypoglycemia unawareness
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
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;

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

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

slide30

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
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
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):951

Yang Z, et al. Diabetes Res Clin Pract. 2009 Jan;83(1):54-60.

14

incretin based therapies in early type 1 dm
Incretin-based Therapies in Early Type 1 DM

2

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

ramadan and glycaemic control
Ramadan and glycaemic control

Oral hypoglycemic agents

SUs

Unsuitable for use during fasting because of the inherent risk of

Hypoglycemia, use with caution. Consider dose adjustment.

TZDs

No treatment adjustment required 2–4 weeks to exert substantial antihyperglycemic effects

DPP4 inhibitors

The best tolerated drugs, Consider DPP4i as an alternative to SUs if the risk of hypoglycemia is high

Metformin

Modify timing of doses: Two thirds of dose at Iftar

• One third at suhur.

Short acting

insulin SUs

Take twice daily at suhur and iftar

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.

don t miss mody genetic testing for mody
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
MODY – Treatment Decisions
  • HNF1A
    • Low-dose sulfonylurea (pills)
  • GCK
    • No therapy except during pregnancy
  • HNF4A
    • Low-dose sulfonylurea (pills)
  • HNF1B
    • Insulin?
slide38

OASIS Study Mortality by Diabetes and CVD Status

Diabetes/CVD (n=1,148)

RR=2.88 (2.37-3.49)

No Diabetes/CVD (n=3,503)

Diabetes/No CVD (n=569)

No Diabetes/No CVD (n=2,796)

RR=1.99 (1.52-2.60)

Event rate

RR=1.71 (1.44-2.04)

RR=1.00

6

12

15

3

9

18

21

24

Months

OASIS=Organization to Assess Strategies for Ischemic Syndromes

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

slide39
State of the art lecture in memory of Prof Zakarya El BAZ Diabetic Nephropathyby Prof Sherif HafezDr Mick Kumwenda
definitions based on quantification
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
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

current chronic kidney disease ckd nomenclature used by kdigo
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).

Persistent albuminuria categories

Description and range

Prognosis of CKD by GFR

and Albuminuria Categories:

KDIGO 2012

Previously micro-albuminuria

Previously macro-albuminuria

GFR categories (ml/min/ 1.73 m²)

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.

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

slide43

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
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

blood pressure target goals in ckd patients
Blood Pressure Target Goals in CKD patients
  • CHEP 2014 (BP target)¹
  • Target Blood pressure Should be less than 140/90 mmHg in most patients, including those with chronic kidney disease.
  • ESC 2013 (BP target)²
  • Target Blood pressure <140/90 mmHg should be considered in patients with diabetic or non-diabetic CKD.
  • JNC IV (BP target)³
  • In patients with CKD, initiate treatment at SBP ≥140 mmHg or DBP ≥90 mmHg, and treat to achieve SBP <140 mmHg and DBP <90 mmHg.

1: Canadian Hypertension Education Program (CHEP) 2014 Recommendation, adopted from: https://www.hypertension.ca/chep. Accessed at 5/2/2014

2: Mancia G, et al. J Hypertens. 2013 Jul;31(7):1281-357

3: James PA, et al. JAMA. 2013 Dec 18. [Epub ahead of print]

slide47

Intensive group n=80

Weight loss

Exercise

Smoking cessation

BP & Lipid targets

Aspirin, Statin, ACEI

CV morbidity & mortality -50%

Compared to usual diabetic care

8 years follow up

Progression to proteinuria -60%

Progression to Retinopathy -60%

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

slide48

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 patients

Cardiovascular death 8 patients

Major cardiovascular event 3 patients

Progression to nephropathy 5 patients

Dialysis 16 patients

Laser treatment 7 patients

Steno-2 Trial: multiple risk factor intervention in T2DM

slide51
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
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
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

-oocytes

Adipocytokinine Zinc alpha 2 glyco protein (ZAG) in non-albuminurics

slide56

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 failure current knowledge
Diabetes and heart failureCurrent knowledge

Piccini JP et al,Am J Med 2004: 116: 64s-75s

Trost S, LeWinter M. Curr Treat Options Cardiovasc med. 2001: 3: 481-492

evidence based management of diabetic foot
Evidence based management of diabetic foot
  • Glycaemic control
  • Control oedema
  • Debridement
  • Dressings
erectile dysfunctiom
Erectile dysfunctiom
  • Incidence and prevalence is high worldwide
  • Effects up to 52% of men (40-70yrs)
  • Aetiology

- Organic

- Hormonal

- Anatomical

- Drugs

- Psychogenic

treatment
Treatment

Oral therapy

PDE-5 inhibitors improve relaxation of smooth muscle. Contraindicated in patients receiving nitrates, recent stroke/MI, unstable angina

Intracavernosal injection

Papaverine

Phentolamin

PGE1

Atropine

Vacuum devices

Penile prosthesis

pacd18 20142
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.