role of the kidney in t2dm - physician · pea + viala,clin inf dis 2006, (42) : 1764-1771. sieving...
TRANSCRIPT
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ADRI KOK
NETCARE UNION AND CLINTON
HOSPITALS
ALBERTON
31st MAY 2015
THE TOP 10 MEDICATION ERRORS
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DISCLOSURES
ADVISORY BOARDS: AstraZeneca, Abbott , BMS, Pfizer,
Novartis, Janssen Pharmaceuticals, Boehringer-Ingelheim,
NovoNordisk, Sanofi, Merck, MSD, Lilly.
SPEAKER PANEL: Astrazeneca, Abbott, Boehringer-
Ingelheim, BMS, Janssen Pharmaceuticals, Lilly, Novartis,
NovoNordisk, Merck, MSD, Sanofi, Aspen-GSK,
Pharmaplan , Pfizer.
OPINION PAPERS: NovoNordisk, MSD, Astrazeneca.
RESEARCH INVOLVEMENT: Sanofi, NovoNordisk,
Novartis, MSD, Astrazeneca, Pfizer, Amgen. 2
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POSSIBLE CAUSES
• ELDERLY
• RENAL + HEPATIC IMPAIRMENT
• CO-MORBIDITIES : 133 interactions T2DM
89 Depression
111 Heart failure
( BMJ 2015: 350. p 949 )
DRUG INTERACTIONS
INAPPROPRIATE PRESCRIBING, DOSAGES
PHARMACY, NURSING, CLARITY
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Slide No. 4 • •
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CLARITHROMYCIN
• REDUCES ACTIVITY of P450 SYSTEM
• POTENTIATING EFFECT : SIMVASTATIN
GEMFIBROZIL
RISK of RHABDOMYOLYSIS
• POTENTIATING EFFECT : AMLODIPINE
RISK of HYPOTENSION
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STATIN TOXICITY
• FIBRATES Gemfibrozil 15x Fenofibrate
• AZOLE antifungals eg. Voriconazole, Fluc, etc
• AMIODARONE
• Erythromycin, Clarithromycin, NOT Azithromycin
• PROTEASE inhibitors eg. Ritonavir
• VERAPIMIL, DILTIAZEM
• Least with PRAVASTATIN
• Most with SIMVASTATIN, LEVOSTATIN
• Non-concurrent dosing can help
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STATINS
• NOT ALL MUSCLE PAINS ARE DUE TO STATINS
• CHECK CK, TSH, Vit D
• CHECK drug interactions
• Stop statin for a week, restart Rosuvastatin 2x/ week
or Atorvastatin alternate days
• Add Ezetimide , allows lower statin dosage
( IMPROVE-IT trial )
Rhabdomyolysis 0,01 %, Hepatic toxicity 0,0001%
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Myalgia with pravastatin
• Linked to low vit D level
• If < 35 give Vit D weekly
( Int J of Cardiol 2015: ( 178) 111-116 )
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LEVOFLOXACIN / QUINOLONES
• Quinolone related HYPERAESTHESIA
Neuropathy may develop within one week
• 81% prevalence hyperaesthesia
• May be permanent
• TENDONOPATHY
• Esp. Achilles
• Older patients
• Assoc. corticosteroids
• May affect shoulder, hand, Achilles = rupture
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QUINOLONES contd.
• ARRHYTHMIA
• Esp. risk with Moxy, less with Cipro
• INSOMNIA
• RETINAL DETACHMENTS
• PERIPHERAL NEUROPATHY
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TRAMADOL
• u opiod receptor binding, dependent on Cyt P 450
enzyme for activation ….. Active metabolite
• Large fluctuations possible/ individual pt
• Inhibits neuronal uptake of serotonin, epinephrine so
may precipitate SEROTONIN SYNDROME
• Esp with co-prescribed antidepressants
• Risk of HYPOGLYCEMIA even low doses, esp. elderly,
increased risk in pts DM
• FOUNIER et al JAMA 8 DEC 2014
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TRAMADOL ( TRAMACET, TRAMZAC Co, ULTRACET)
• HYPOGLYCAEMIA• (JAMA Dec 2014)
• SEIZURES
• SEROTONIN SYNDROME
• Esp. SSRI’S, higher dose
• Possibility of dependence
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WARFARIN ( COUMADIN )
• Most frequent admission : overwarfaranised
• Laboratory adjustment excessive
• Obese patients 84% increased risk major bleed
• Stepwise 3 levels of obesity : BMI > 30
• Require increased dose, longer to achieve Rx level
• ? WEIGHT RELATIONSHIP :Not proven with NOAC’s• ( Ogunsha Arteriosclerosis, Thrombosis, Vascular biology 2015 Scientific sessions)
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WARFARIN cont.
• MOST SEVERE INTERACTION:
• TMP/ Sulfa
• Erythromycin
• Amiodarone: prolonged half life
• Propafenone
• Ketoconazole, Fluconazole
• Itraconazole
• metronidazole
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WARFARIN cont.
• MOST SEVERE
• TMP/ Sulfa
• Erythromycin
• Amiodarone : prolonged half-
life
• Propafenone
• Keto, Flu, Itraconazole
• Metronidazole
• POSSIBLE
• Quinolones
• Omeprazole
• Clarithromycin
• Azithromycin
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LINEZOLID ( ZYVOXID )
• MAO inhibitors within 2 weeks of such a product eg. phenelzine,
meclobemide
• Potential increased BP
• Avoid in uncontrolled HT eg. phaeo, thyrotoxicosis, vasopressors ,
dopaminergic agents
• Serotonin syndrome : avoid in carcinoid, SSRI’s, TCA’s
• Serotonon 5 HT1 R agonists, buspirone, meperidine (Pethidine)
• Reversible myelosuppression
• Lactic acidosis
• Peripheral + optic neuropathy > 28 days
• Risk of seizures
• C.diff, mild diarrhoea to fatal colitis
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SEROTONIN SYNDROME
• COGNITIVE DYSFUNCTION
• HYPERPYREXIA
• HYPEREFLEXIA
• INCOORDINATION
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LACTIC ACIDOSIS
• Recurrent nausea
• Vomiting
• Unexplained acidosis
• Low bicarb. level
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OEDEMA
• CCB’s : less with non-dihydropyridines Verapamil,
Diltiazem
• Pramipexole ( Pexola )
• Pioglitazones ( TZD’s )
• NSAID’s
• 7-8% gabapentin, pregabilin
• Omeprazole
• Estrogen
• Testosterone
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HYPERKALAEMIA
• TMP/SULFA:
• TRIMETHOPRIM acts like Amiloride
• K+ sparing with decreased excretion by 40%
• At risk: elderly
chronic renal failure
high dose steroids
ACE inhibitors/ ARB
sulphonylureas inhibit CYP2C9( J Geront Biol Sci 2015 ( 70 ) 247-54)
Odds ratio sudden death 1.38!
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PRAMIPEXOLE ( PEXOLA )
• Dose related
• Compulsive behaviour
• Also assoc dopaminergic drugs ( Levodopa, Sinemet )
• Gambling
• Aberrant sexual behaviour
• Binge eating
• Compulsive buying
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HYPONATREMIA
• Paroxetine and other SSRI’s
• esp. elderly
females
low BMI
concomitant diuretics esp. HCTZ
• HCTZ, Indapamide
• SNRI’s
• Carbamazepine ( Tegretol )
• Ecstasy
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CRITICAL ILLNESS
• SEVERE INFECTION SIRS VASODILATATION
INCREASED CO
• TRAUMA, BURNS FLUID EXTRAVASATION
MAJOR SURGERY FLUIDS, VASOACTIVE AGENTS
• Increased Vd HYDROPHILIC
• ORGAN FAILURE HEPATIC: Decrease clearance
LIPOPHILIC
AKI: decrease clearance/
HYDROPHILIC, NB. INCREASED RENAL CLEARANCE
HYPOALBUMINEMIA, PROTEIN BINDING
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KIDNEY AND HEPATIC FAILURE
ANTIBIOTIC USE AND
ADJUSTMENTS
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PLASMA PROTEIN BINDING
• HIGHLY PROTEIN BOUND > 80%
CLINDAMYCIN, TEICOPLANIN, CEFTRIAXONE
40-60%: AZTREONAM, VANCO,MOXIFLOXACIN,
LINEZOLID, CEFOTAXIME, LEVOFLOX, CIPROFLOX
< 20%: IMIPENEM, AMOXICLAV,CEFIPIME,
CEFTAZIDIME, METRONIDAZOLE, MEROPENEM
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AB PROPERTIES
HYDROPHILIC
BETA-LACTAMS:
PENICILLINS
CEPHALOSPORINS
CARBAPENEMS
MONOBACTAMS
GLYCOPEPTIDES
AMINOGLYCOSIDES
LOW VOLUME OF DISTRIBUTION
INABILITY TO DIFFUSE THRU
MEMBRANES
INACTIVE VS INTRACELLULAR
ORGANISMS
RENAL ELIMINATION UNCHANGED
LIPOPHILIC
MACROLIDES
FLUOROQUINOLONES
TETRACYCLINES
CHLORAMPHENICOL
RIFAMPICIN
LINEZOLID
HIGH VOLUME OF DISTRIBUTION
ABILITY TO DIFFUSE THRU
MEMBRANES
ACTIVE VS INTRACELLULAR
ORGANISMS
ELIMINATED AFTER LIVER
METABOLIZATIONPEA + VIALA,CLIN INF DIS 2006, (42) : 1764-1771
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SIEVING COEFFICIENT DURING CVVHD
Sc = Cuf/ Cp
• HIGHEST:CEFOTAXIME > 1
• 0,8 -1: AMIKACIN, TOBRAMYCIN, IMIPENEM,
CEFTAZIDIME, METRONIDAZOLE
• 0,6-0,8: PIPERACILLIN, GENTA, VANCO,AMPI,
PENICILLIN,CIPROFLOX
• < 0,4: CLINDA, CEFTRIAXONE,TEICOPLANIN,
OXACILLIN
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PK/PD RELATIONSHIPS
• BETA-LACTAMS,
GLYCOPEPTIDES,OXAZOLIDINONES
• TIME-DEPENDENT ANTI-BACTERIAL ACTIVITY
• TIME ABOVE MIC : Cmin > MIC
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PK/PD RELATIONSHIPS
• AMINOGLYCOSIDES
CONCENTRATION DEPENDENT ANTIBACTERIAL
ACTIVITY
OPTIMAL EXPOSURE: Cmax/ mic > 10
AUC / MIC > 40-50 vs G +ve
AUC / MIC > 125 vs G -ve
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DOSING ANTIFUNGALS + AB / CVVHD
• AMIKACIN
• MEROPENEM
• PIP/TAZ
• VANCO
• TEICOPLANIN
• LINEZOLID
• CIPROFLOXACIN
• TIGECYCLINE
• COLISTIN
• VORICONAZOLE
• FLUCONAZOLE
• CEFEPIME
• GENTAMYCIN
• BACTRIM
• CLINDAMYCIN
• 25mg/kg TDM
• 2g over 3hrs TDS
• 16g/2g by CI
• 35mg/kg over 4 hr, 14mg/kg
• TDM= 25-30mg/l
• 10mg/kg bd, 8mg/kg bd
• 600mg bd
• 800mg, 400mg tds
• 150mg, 100mg bd
• 9 MIU, 4,5 MIU tds
• 8mg/kg bd, 6mg/kg bd
• 600mg bd
• 2g tds
• 7mg/kg daily
• 1 200mg/240mg ( 3 amps), 2 amps
tds
• 900 mg qid
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THE CASE FOR AMIKACIN
• CONC- DEPENDENT ( PEAK ) BACTERICIDAL
ACTIVITY
• 1g AMIKACIN in AKI with CRRT?
• NEED AT LEAST 25mg/kg loading dose
• THEN DOSE / TDM
• REMOVAL of AMIKACIN during CRRT
• PEAK is linked to BACTERIAL KILLING
• TOXICITY more related to exposure time rather than
peak intensity
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THE CASE FOR BETALACTAMS
• PIP/TAZ not good tissue penetration esp alveolar space,
VAP
• TIME DEPENDENT
• REMOVAL during CRRT very effective
• LOADING DOSE most often neglected ( 4g)
• MAINTENANCE 16 – 20g / 24 hrs
• SEVERAL STUDIES ( including substudy from IVOIRE
trial) confirm underdosing of BETALACTAMS 80% of
patients when administered in bolus
BOSELLI et al, CRIT CARE MED 2008; 36: 1500-1506
BOYAN, HONORE et al, ICM 2013; 39: 1535-1546
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THE CASE FOR VANCOMYCIN
• POOR TISSUE PENETRATION esp ALVEOLAR
• NEW LOADING DOSE 35mg/kg in 4hrs
• MAINTENANCE DOSE 14mg/kg/ 24hrs
• EFFECTIVE ELIMINATION by CRRT
• ? USE in VAP on CRRT
Need higher trough 25-30mg/ l , MIC of 1-1,5 mg/l
Higher loading dose of 25mg/kg over 2 hrs for
intermittent HD
BEUMIER, J ANTIMICR THER 2013: 68: 2859-2865
KALIL et al BMJ 2013 OCT 14th
SPAPEN, HONORE et al ANN INT CARE 2011 : 1-21
CLIN INF DIS 2011 ; 53: 124-129
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WHAT ABOUT COLISTIN
• EASILY ELIMINATED by CRRT, 80% by adsorption
• LOADING DOSE of 9 MIU
• MAINTENANCE DOSE of 4,5 MIU 3x / day on CRRT
• NO toxicity found
• Change filter every 3 days
• Regimen has been infused for 15 days without toxicity
• No greater incidence of CKD
HONORE al Int J Nephr Renovasc dis 2013;6:107-111
HONORE et al BLOOD Purif 2014; 37: 291-295
HONORE et al INDIAN J Crit Care 2014; 7: 415-417
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CONCLUSIONS and PERSPECTIVES
• DOSE derived from IHD cannot be simply used / CRRT
• 80% b- LACTAMS underdose in CRRT
• Amikacin at least 25mg/kg loading / CRRT
• Vanco 35mg/kg over 4 hrs loading , 14 mg/kg over
remaing 24hrs on CRRT
• Aim in particular MRSA VAP MIC of 1-1,5 mg/l, trough
value of 25- 30 mg/ l
• Colistin mainly adsorbed during CRRT , loading dose
9miu, then 4,5 miu tds , change filters every 3 days
• Adsorption of Antibiotics onto membrane NOT negligible
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PROPOFOL
• If used for induction : decreased CO
• 1mg/kg ASA II –III
• > 55 years
• Maintenance ICU sedation: 0,3mg/kg body wt/hour
• max 4mg/kg
• not > 7 days, monitor lipids
• esp. TG every 2 days
• Infuse saline or 5% D/W
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PROPOFOL
• CONTRA-INDICATIONS:
hypersens to Propofol
allergies to soya, peanuts
not < 16 yrs of age
PROPOFOL INFUSION SYNDROME
Metabolic acidosis
Hyperlipidemia
ARF, rhabdomyolysis
acute CCF
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PROPOFOL
• DRUG INTERACTIONS: ANAESTHETIC DRUGS
• Synergism, increased sedation
• Prolonged anaesth benzo, inhalational anaesth.
• OPIOIDS
• FENTANYL increased blood levels of Prop, apnoea
• Suxamethonium/ Neostigmine brady, cardiac arrest
• INCOMPATIBLE: aminoglycosides, diazepam, digitalis,
theophylline, phenytoin, pentobarbital, sodabic,
chlordiazepoxide
• LIMITED COMPATIBILITY : dopamine, dobutamine,
epinephrine, norepinephrine, Na nitroprusside
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PERFALGAN
• Not extensively protein bound
• Present in CSF within 20 min of 1g infusion.
• 2 hepatic pathways: glucoronic acid conjugation
• sulphuric acid conjugation
• < 4% via Cyt P 450 normally
• With paracetamol poisoning glutathione pathway
swamped = toxic metabolites produced
• 90% excreted urine within 24 hrs
• < 5 % unchanged
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PERFALGAN
• RENAL INSUFFICIENCY:
Creat cl < 30 ml/min delayed elimination
Allow 6 hrs between doses
HEPATIC INSUFFICIENCY:
Use with caution mild to moderate liver impairment
Contra-indicated active disease, alcoholic hepatitis
due to CYP 2E1 induction
ELDERLY:
no dosage adjustments needed
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PreceDEX
• Alpha-2 adrenergic receptor agonist, 6-8x affinity vs
Clonidine
• Sedative and analgesic after cardiac surgery
• 94% protein bound, liver metabolism
• 95% elimination via kidneys
• C/I : sepsis, unstable trauma, hypovolaemia, heart block,
uncontrolled cardiac failure
• CAUTION: LV dysfunction, hepatic impairment
• ELDERLY: consider dose reduction, may cause
hypotension, bradycardia
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PreceDEX ( Dexmedetomidine)
• DRUG INTERACTIONS:
anaesthetics
sedatives, hypnotics
opioids
SA package insert: not to exceed infusion > 24 hrs
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ULTIVA (REMIFENTANIL)
• Potent ultra short-acting opiod analgesic
• Rapid metabolism tissue and red blood cell esterases
• 70% protein bound
• Supplemental to GA / induction, maintenance
• With OD = muscle rigidity, apnoea, bradycardia
• Not a substrate for plasma cholinesterase
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ULTIVA ( REMIFENTANIL)
• RENAL IMPAIRMENT:
no change up to 3 days infusion
clearance of carboxylic acid metabolite reduced
NO clinically relevant u-opiod effects
not extracted during IHD / CRRT but carboxylic acid
metabolite will be by 30% HD
HEPATIC IMPAIRMENT:
No need to reduce in hepatic impairment
severe liver failure may cause resp. depression,
titrate
ELDERLY:
reduce initial dose by 50% as more intense response
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The diabetes epidemic: global projections, 2011–2030
IDF. Diabetes Atlas 5th Ed. 2011
World 2011 = 366 million2030 = 552 millionIncrease = 51%
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Leads to
Diabetes
Epidemic
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Visceral Fat Distribution:Normal vs Type 2 Diabetes
Normal Type 2 Diabetes
2-11
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DIABESITY
• Obesity
• Type 2 Diabetes
• Hypertension
• Dyslipidemia
The Deadly Quartet
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THE OMINOUS OCTET
Islet b-cell
Impaired
Insulin Secretion
Neurotransmitter
Dysfunction
Decreased Glucose
Uptake
Islet a-cell
Increased
Glucagon Secretion
IncreasedLipolysis
Increased Glucose
Reabsorption
Increased
HGP
DecreasedIncretin Effect
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Blood Glucose Lowering Therapies
Glucose dependent
GLP-1 RA
a-Glucosidase
InhibitorsDPP-4 Inhibitors
Glucose independent
Exogenous Insulin
Glinides
Sulfonylurea
Metformin
TZDs
Inhibition of Glucose
Absorption
Insulin Resistance Insulin Secretion
SGLT2
inhibitors
Insulin independent
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Metformin is eliminated unchanged by kidney
Accumulates in chronic kidney disease
Concern about the increased risk of lactic acidosis
Risk increased in the elderly and in the presence of other co-morbidities
Metformin in CKD
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Recommendations for the use of metformin in different stages of chronic kidney disease
Avogaro A & Schernthaner G (2012)
ESRD Haemodialysis
505560 40 35 30 2545
<30>60eGFR
mL/min 1.73 m²
SmPC/
NICE
Australian
Canadian
Lipska et al.
Use with caution
Review and reduce dosage use with caution
Review use
Use with caution
SmPC: Summary of product characteristics
No problem with eGFR > 45
Reduce dose with eGFR 30-45
Do not use with eGFR <30
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“Second generation”
Glibenclamide
Gliclazide – “standard” and modified release
Glimeperide
Glipizide
Sulfonylureas
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Indicator Comment
Glycaemia +++
Outcomes-Microvascular-Macrovascular
Reduction (UKPDS; ADVANCE)Reduction (UKPDS long term); ADVANCE no effect
Hypoglycaemia Increased
Weight change Increase
Side effects / precautions Renal impairment (some agents)
Patient Acceptability High
Cost Low
Other
Therapeutic Options - SU
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Sulfonylureas: hypoglycemia risk
*<50 mg/dL.
Tayek J. Diabetes Obes Metab. 2008; 10: 1128–1130.
0
5
10
15
20
25
30
Gliclazide
0.85
Glipizide
8.70
Glimepiride
0.86
Tolbutamide
3.50
Chlorpropamide
16.00Glyburide
16.00
Severe hypoglycemia*
n/1000 person years
Rela
tive R
isk (
%)
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Inhibition of DPP-4 Increases Active GLP-1
GLP-1inactive
(>80% of pool)
ActiveGLP-1
Meal
DPP-4
IntestinalGLP-1 release
GLP-1 t½=1–2 min
Adapted from Rothenberg P, et al. Diabetes 2000; 49 (suppl 1): A39. Abstract 160-OR.
Adapted from Deacon CF, et al. Diabetes 1995; 44: 1126-1131.
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PLEIOTROPIC ACTIONS of GLP-I
Insulin Secretion
β-Cell Neogenesis
β-Cell Apoptosis
Glucagon Secretion
Glucose
Production
Heart
GI TractLiver
MuscleDrucker DJ. Cell Metab. 2006;3:153-165.
Brain
Appetite
Cardioprotection
Cardiac OutputGLP-1
Stomach
Gastric
Emptying
Neuroprotection
Glucose
Uptake
_
+
Pleiotropic Actions of GLP-1
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1. DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-29522. Drucker DJ and Nauck MA. Lancet. 2006;368:1696-1705
Properties/Effect
GLP-1 Receptor
Agonists1,2
DPP-4
Inhibitors1,2
Insulin production +++ ++
First-phase insulin
response +++ ++
Glucagon;
glucose output+++ +
Gastric emptying Delayed No effect
Food intake No effect
Body Weight No effect
Hypoglycemia No No
Side effects Nausea, vomiting Minimal
Incretin Therapies: Major Differences
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Hypoglycaemia results in ECG abnormalities
• Abnormalities in:
• atrioventricular conduction
• ventricular depolarisation
• ventricular repolarisation
• R-wave amplification associated with norepinephrine counter-regulatory response
• T-wave flattening associated with epinephrine counter-regulatory response
Laitinen et al. Ann Noninvasive Electrocardiol 2008;13:97–105
ECG, electrocardiogram
Amplification of R-wave
Flattening of T-wave
Decrease in ST segment
P
R
S
T
Q
Prolongation of QT interval
ECG
(m
V)
Time (seconds)
Baseline
Euglycaemic hyperinsulinaemia
Hypoglycaemic hyperinsulinaemia
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Cardiac ischaemia associated with hypoglycaemia episodes
• Increased episodes of chest pain and ECG abnormalities
• CGMS and Holter monitoring abnormalities
Study included patients (n=19, mean age, 58±16 years) with type 2 diabetes, a history of frequent hypoglycaemia, an HbA1c of <8% and coronary
artery disease (defined as a history of myocardial infarction, coronary bypass surgery or angioplasty)
*p<0.01 vs. episodes during hyperglycaemia and normoglycaemia
Desouza et al. Diabetes Care 2003;26:1485–9
Total episodes
Episodes with
chest pain/angina
Episodes with ECG
abnormalities
Hypoglycaemia 54 10* 6*
Symptomatic 26 10* 4*
Asymptomatic 28 – 2
Normoglycaemia without rapid changes N/A 0 0
Hyperglycaemia 59 1 0
Rapid changes in glucose (>100 mg/dL-1/h-1) 50 9* 2
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Link between hypoglycaemia and acute cardiovascular events in type 2 diabetes
• Retrospective, observational study (n=860,845) assessing association between hypoglycaemic events and acute cardiovascular events
• 3.1% patients had a hypoglycaemic event during the evaluation period (1 year)
• Patients with hypoglycaemic events had 79% higher odds of acute cardiovascular events than patients without hypoglycaemic events
Johnston et al. Diabetes Care 2011;34:1164–70
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SGLT2 Inhibition
A Novel Treatment Strategy for
Type 2 Diabetes
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Renal Glucose Reabsorption
in Type 2 Diabetes
• Sodium-glucose cotransporter 2 (SGLT2) plays a role in
renal glucose reabsorption in proximal tubule
• Renal glucose reabsorption is increased in type 2
diabetes
• Selective inhibition of SGLT2 increases urinary glucose
excretion, reducing blood glucose
Wright EM, et al. J Intern Med. 2007;261:32-43.
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SGLT1
(180 L/day) (900 mg/L)=162 g/day
10%
Glucose
No Glucose
S1
S3
Renal Handling of Glucose
SGLT2
90%
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Gerich JE. Diabet Med. 2010;27:136–142.
Renal glucose re-absorption in patients with hyperglycaemia
SGLT1
SGLT2
~10%
~90%
When blood
glucose
increases above
the renal
threshold
(~10 mmol/L or
180 mg/dL), the
capacity of the
transporters is
exceeded,
resulting in
urinary glucose
excretion
Filtered glucose
load 180 g/day
69
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Rationale for SGLT2 Inhibitors
• Inhibit glucose reabsorption in the renal proximal tubule
• Resultant glucosuria leads to a decline in plasma
glucose and reversal of glucotoxicity
• This therapy is simple and nonspecific
• Even patients with refractory type 2 diabetes are likely to
respond
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In a challenging obese population of uncontrolled Type 2 DM
on MDI and high Insulin Requirements, add-on Empagliflozin
resulted in:
Significant improvements in HbA1c level closer to 7%
Lower Insulin requirements
Weight loss
No increased Hypoglycemia Risk
Increased Genitourinary infections
Trends of BP reductions
Conclusions
Empagliflozin as Add-On to MDI Insulin Study
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THYROID DISEASE IN THE ELDERLY
HYPOTHYROIDISM
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THYROID DISEASE IN THE ELDERLY
HYPOTHYROIDISM
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Case Presentation
• During her routine visit to doctor, Ayesha, an apparently healthy 70-year-old woman complained of mild fatigue, dry skin, and difficulty in losing weight since last 2 years.
• The past medical and surgical history were uneventful.
• There was no reported family history of DM/HTN/IHD.
• Physical examination results were normal including a non- palpable thyroid gland.
• ECG was normal. Fasting and postprandial blood sugar and CBC were within normal limits.
• Serum TSH and FT4 tests were repeated 2 weeks after the first visit and were found to be 8.1 mIU/L and 1.4 ng/dL, respectively.
• Diagnosis: Subclinical hypothyroidism (Hashimoto’s thyroiditis)
Serum TSH 8.0 mlU/L
Serum free T4 1.3 ng/dL
Serum total cholesterol 220 mg/dL
Serum HDL cholesterol 46 mg/dL
Serum LDL cholesterol 150 mg/dl
Serum triglycerides 80 mg/dL
Thyroperoxidase antibodies Positive
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Clinical Manifestations: Symptoms
• Symptoms1,2
• Tiredness/ weakness
• Dry skin
• Cold sensation
• Hair loss
• Poor concentration/memory loss
• Constipation
• Weight gain with poor appetite
• Dyspnea
• Hoarseness of voice
• Menorrhagia
• Paresthesia
• Hearing impairment
1. Ladenson P and Kim M. Cecil Medicine. 2008:1698-1713.
2. Jameson JL, et al. Harrison's Principles of Internal Medicine. 2008: 2224-2247.
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Clinical Manifestations: Signs
• Signs1,2
• Cold peripheral extremities
• Dry, coarse and yellow skin
• Puffiness of face, hands and feet
• Hair loss and brittle nails
• Bradycardia/ diastolic hypertension
• Delayed tendon reflex relaxation
• Peripheral edema
• Serous cavity effusions
• Normal/enlarged/atrophied thyroid gland
• Hypothyroidism in children
• Delayed linear growth in children
• Delayed or precocious puberty
• Pseudohypertrophy of muscles1. Ladenson P and Kim M. Cecil Medicine. 2008:1698-1713.
2. Jameson JL et al. Harrison's Principles of Internal Medicine. 2008: 2224-2247.
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Levothyroxine: Important Facts
• Levothyroxine sodium has a narrow therapeutic range
• Regardless of indication of use, careful dose titration is necessary to avoid consequences of over- or under-treatment
• Even small changes in the dose of LT4 can shift a patient from a euthyroid to a hyperthyroid or hypothyroid state.
• The AACE recommends the use of a high-quality brand preparation of levothyroxine
• Same brand of LT4 should be received throughout treatment
AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13
http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf.
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Mild Thyroid Failure and
Aortic Atherosclerosis in Women
0
50
100
Pa
tie
nts
, %
Condition Present
Condition Absent
Presence of Aortic Atherosclerosis
Hak AE, et al. Ann Intern Med. 2000;132:270-278.
Women With
Mild Thyroid
Failure
Euthyroid
Women
Women
With Mild
Thyroid
Failure and
Antibodies
to Thyroid
Peroxidase
Euthyroid
Women
Without
Antibodies to
Thyroid
Peroxidase
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Learning Objectives
Define and classify hypothyroidism
Explain the etiology of hypothyroidism
List the clinical manifestations of hypothyroidism
Explain the defining criteria and associated risks of
subclinical hypothyroidism
Discuss the treatment of overt and subclinical
hypothyroidism with levothyroxine
Describe the special conditions associated with
hypothyroidism and their management
Algorithm for Diagnosis of Thyroid Dysfunction
TSH
High Normal Low
Free T4
Low Normal
HypothyroidismSubclinical
Hypothyroidism
Normal
Free T4
High
Subclinical
HyperthyroidismHyperthyroidism
Joshi S. Journal of The Association of Physicians of India; 2011:14-20.
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Cardiovascular Effects of Hypothyroidism
• Haemodynamic changes
– Increase in vascular resistance
• Decreased vasodilator action of T3 and NO
– Impaired ventricular performance
• Changes in the expression of myocyte-specific regulatory
proteins
• Increased cardiovascular risk
– Increased risk for functional cardiovascular
abnormalities
– Increased risk for atherosclerosis
Klein I.L. The Thyroid, 9 ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:774780
Biondi B, et alI. Endocrine 2004;24:1–13
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Changes in Renal Function
in Hypothyroidism
Adapted from Kaptein EM. The Thyroid, 9 ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:789–795
Hypothyroidism
Changes in renal function
Renal blood flow
Glomerular filtration
Sodium conservation during sodium restriction
Potassium excretion
Free water and osmolar clearance
Oedema
Total body sodium and water
Capillary permeability
Endocrine-metabolic changes
Plasma catecholamines
Plasma renin activity
Serum aldosterone
Serum atrial natriuretic peptide
Hypertension
Plasma catecholamines
α-adrenergic response
Salt sensitivity
Hyponatraemia
Glomerular filtration
Free water delivery to distal tubule
Hyperuricaemia/gout
Cardiovascular changes
Cardiac output
Peripheral vascular resistance
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Changes in Renal Function
in Hypothyroidism
Adapted from Kaptein EM. The Thyroid, 9 ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:789–795
Hypothyroidism
Changes in renal function
Renal blood flow
Glomerular filtration
Sodium conservation during sodium restriction
Potassium excretion
Free water and osmolar clearance
Oedema
Total body sodium and water
Capillary permeability
Endocrine-metabolic changes
Plasma catecholamines
Plasma renin activity
Serum aldosterone
Serum atrial natriuretic peptide
Hypertension
Plasma catecholamines
α-adrenergic response
Salt sensitivity
Hyponatraemia
Glomerular filtration
Free water delivery to distal tubule
Hyperuricaemia/gout
Cardiovascular changes
Cardiac output
Peripheral vascular resistance
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Effects of Hypothyroidism on the Skeletal
System
• Decreased recruitment, maturation and activity
of bone cells
• Decreased bone turnover (bone resorption
and bone formation)
• Increased fracture risk in elderly patients– Decreased trabecular bone turnover
– Reduced renewal of bone
– Accumulation of stress fractures
– Increased risk for falling (poor muscular function)
Gittoes NJL, et al. The Thyroid, 9 ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:830–835
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Hypothyroid Patient – Case
Study• 75-year-old lady with cold intolerance
– Chronic use of electric blanket with burning of the skin
• Weakness, fatigue, weight gain
• Global heart failure, bradycardia
Chronic use of electric blanket75-year-old lady with hypothyroidism
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Hypothyroid Patient Case Study – Treatment
• Treatment with levothyroxine 50 µg/d for 2 weeks,
increasing the dosage to 100 µg/day for another 2 weeks
• Clinical signs of hypothyroidism already improved
Before T4 4 weeks after T4
Before T4
4 wks after T4
Achilles tendon reflex relaxation time
• Maintenance dose: 125 µg/day (1.2 µg/kg BW)
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Hypothyroid Patient Case Study – Treatment
• Treatment with levothyroxine 50 µg/d for 2 weeks,
increasing the dosage to 100 µg/day for another 2 weeks
• Clinical signs of hypothyroidism already improved
Before T4 4 weeks after T4
Before T4
4 wks after T4
Achilles tendon reflex relaxation time
• Maintenance dose: 125 µg/day (1.2 µg/kg BW)
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NOT ALL PEOPLE ARE THE SAME!
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Always look your patient in the eyes and LISTEN to them! THEN ACT!
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THE ELDERLY PATIENT with
ENDOCRINE DISEASE
WCIM 2014
ADRI KOK
SPECIALIST PHYSICIAN
NETCARE UNION HOSPITAL
SOUTH AFRICA
27TH OCTOBER 2014
SEOUL, SOUTH KOREA
91
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ELDERLY?
• DIFFICULT TO DEFINE “ELDERLY” / “OLDER
PEOPLE”
• > 65 YRS?
• 2026 anticipated that > 20% > 65 yrs of age
• MANY COUNTRIES > 85 INCREASING
• WOMEN LIVE ON AVERAGE 5 YEARS LONGER
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CLINICAL CLUES TO ENDOCRINE DISEASE
• ANXIETY, TREMOR
• LOSS OF TASTE
• VOICE CHANGES
• CONSTIPATION
• POLYURIA
• FALLS, BRADYCARDIA
• HYPERTHYROIDISM
• ADRENAL INSUFFICIENCY
• HYPOTHYROIDISM
• HYPOTHYROIDISM,
HYPERCALCEMIA, PTH
• DIABETES MELLITUS,
DIABETES INSIPIDUS ( ADH
action decreased)
• HYPOTHYROIDISM
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ENDOCRINE CHANGES WITH AGEING
PHYSIOLOGICAL CHANGE
• MENOPAUSE: decreased
oestrogen, progesterone
• TESTOSTERONE decreased
• GROWTH HORMONE
secretion decreased
• VITAMIN D : decreased
absorption, activation
• THYROID: increased risk, esp
• Hypothyroidism
• DIABETES: increased risk,
increased insulin resistance,
decreased insulin sens.
• ADH: increased secretion
response to osmolar stimuli
CLINICAL MANIFESTATIONS
• Decreased bone mass,
• Decreased muscle mass
• Fracture risk increased
• Vaginal dryness
• Skin changes, dry, easy
bruising
• Tendency towards water
intoxication