Dr Mick Kumwenda MSc FRCP (London)
Consultant Nephrologist and Clinical Director (Medicine)
Glan Clwyd Hospital
Rhyl
Denbighshire
UK
Mick.kumwenda@wales.nhs.uk
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.
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 (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 has been defined as heritable changes
in gene function that occur without a change in
the nucleotide sequence.
ie
Non -sequence dependent inheritance
• 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
 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
(Schwartz, M.W. et al., 2013)
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
Insulin
Resistance
Type 2
Diabetes
Insulin
Concentration
b-cell
Dysfunction
b-cell Failure
Insulin
Resistance
Euglycaemia
Normal
IGT ± Obesity
Diagnosis of
type 2 diabetes
Progression of
type 2 diabetes
DeFronzo et al. Diabetes Care 1992;15:318-68
Guiding principles for
nutrition education
Patients are responsible
Patients are therefore the final decisionmakers
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.
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.
Towards personalized glycaemic targets
ADA/EASD position statement 2012
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
The A1C and ABCDE of glycaemia management in type 2 diabetes: a
physician's personalized approach.
15-40
AGE (years)
40-70
>70
COMPLICATIONS
DURATION>10yrs
-
+
-
+
-
+
HbA1c (%)
<6
<6.5
<6.5
6.5-7
<7
7-8
HbA1c≥ 9%
Insulin treatment
HbA1c< 9%
METFORMIN
Physicia n should choose drug a ccording t o pa t ie nt 's risk
of w e ight ga in, hypoglyca e m ia , ca rdio-re na l com plica 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.
10.0
9.9%
9.7%
Baseline HbA1c (%)
9.5
9.5%
9.2%
9.0
9.1%
9.2%
8.5
8.0
7.5
7.0
6.5
0.0
9.5
10.3
7.4
--
Diabetes duration (years)
1.
2.
3.
4.
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
5. Yang et al. Diabetes Care 2008;31:852–6
7.7
8.6
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
•
•
<3.5-4 mmol/L (<63-72 mg/dL)
Whipple’s triad:
①Symptoms
②Low
blood glucose
③Relief of symptoms when blood glucose raised
COUNTER REGULATORY HORMONES: GLUCAGON, EPINEPHRINE, CORTISOL, GROWTH
HORMONE
• 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
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;
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


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


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
Hari Kumar KV, Shaikh A, Prusty P. Diabetes Res Clin Pract. 2013 May;100(2):e55-8
2
Oral hypoglycemic agents
SUs
Unsuitable for use during fasting because of the inherent
risk of
Hypoglycemia, use with caution. Consider dose
adjustment.
Metformin
Modify timing of doses: Two
thirds of dose at Iftar
• One third at suhur.
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
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.
Short acting
insulin SUs
Take twice daily at suhur and
iftar
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
Is
common causes of MODY are mutations in GCK, HNF1A and HNF4A.
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

HNF1A


GCK


No therapy except during pregnancy
HNF4A


Low-dose sulfonylurea (pills)
Low-dose sulfonylurea (pills)
HNF1B

Insulin?
OASIS Study Mortality by Diabetes and CVD Status
0.25
Event rate
0.2
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)
0.15
RR=1.71 (1.44-2.04)
0.1
RR=1.00
0.05
0
3
6
9
12
15
OASIS=Organization to Assess Strategies for Ischemic Syndromes
Malmberg K, et al. Circulation. 2000;102:1014-1019.
18
21
24
Months


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

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

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
GFR categories (ml/min/ 1.73
m²)
Description and range
Prognosis of CKD by GFR
and Albuminuria Categories:
KDIGO 2012
G1
Normal or high
≥90
G2
Mildly decreased
60-89
G3a
Mildly to moderately
decreased
45-59
G3b
Moderately to
severely decreased
30-44
G4
Severely decreased
15-29
G5
Kidney failure
<15
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
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
•
A cross-sectional survey of 301 outpatients attending a single tertiary referral
center using the plasma disappearance of isotopic 99mTc-diethylene-triaminepenta-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)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]
Intensive group n=80
Weight loss
Compared to usual
diabetic care
Exercise
Smoking cessation
BP & Lipid targets
Aspirin, Statin, ACEI
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: Number needed to treat
Number of microalbuminuric patients with type 2 diabetes needed to
treat for 13 years to prevent one …..
Death
Cardiovascular death
Major cardiovascular event
5 patients
8 patients
3 patients
Progression to nephropathy
5 patients
Dialysis
16 patients
Laser treatment
7 patients
Steno-2 Trial: multiple risk factor intervention in
T2DM

Aliskerin 300mg increased urinary albumin excretion

Dual caused reduction of e GFR

Stroke placebo 85 Aliskerin 112

Study discontinued
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
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




Glycaemic control
Control oedema
Debridement
Dressings

Incidence and prevalence is high worldwide

Effects up to 52% of men (40-70yrs)

Aetiology
- Organic
- Hormonal
- Anatomical
- Drugs
- Psychogenic
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



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.