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HIGHLIGHTSDr Mick Kumwenda MSc FRCP (London)
Consultant Nephrologist and Clinical Director (Medicine)Glan Clwyd Hospital
RhylDenbighshire
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
t
sub-
grou
p
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
pti
on
an
d
ran
ge
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.