Capita Selecta in Endocrinology and Metabolism-2007

8/10/2019 Capita Selecta in Endocrinology and Metabolism-2007

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1BAGIAN-S MF PENYAKIT DALAM FK. UNAIR R SU D r. S OETOMO S URABAYA

Capita Selecta in Endocrinology and Metabolism - 2007

(GLOBESITY, Formula G/O : P-39.5-120, ADMA, CMR, Anakinra)

Capita Selecta in Endocrinology and Metabolism - 2007(GLOBESITY, Formula G/O : P-39.5-120, ADMA, CMR, Anakinra)

Askandar T jok roprawi ro

SUMMARY

The th eme o f the 22nd Continuing Medical Education (CME) of Internal Medicine

(PKB-22) of the Department of Internal medicine, Airlangga University School of Medicine

Dr. So etom o Tea ch ing Hos pita l Su ra ba ya is , Upd a te in Interna l Med ic ine fromBasic to Clinical Relevancies. Based on the department, targets, this CME may present

ap proximately 50% clinica l experienc es, 25% biom olec ula r as pects, an d 25% rece ntad vanc es in internal medicine.

In this plenary lecture (Capita Selecta in Endocrinology 2007), 5 selected topicswill be presented such as:

I. G LOBES ITY : Time-B omb Diseas e in the Future?

1. Sta ging of Lifestyle Re lated Disea se (Sta ge 0-4): Obesity Rela ted Disea se2. Obesity and Its Serious Cons equences

3. ADMA in Obe sity an d in Diab etes Mellitus

4. G loba l Ca rdiometabolic Risk (CMR)

II. Five S ATAN-CYCLES in Diabetic Nephropa ty

III. Dia g nos is of C la s sica l Thy roid Sto rm with FO RMULA G /O: P-39.5-120

IV. Onc e-Wee kly EXENATIDE-LAR fo r T2DM?

V. ANAKINRA: the p romising drug for T2DM

In a dd itio n, S tan da rds of Medica l C a re in Diabete s (ADA-2007) on the targe ts o fglycemic control, blood pressure, and lipid profile will be also included in one of

TAB LES o f th is p a pe r.

On the basis of clinical experiences, thyroid storm (thyroid crisis) can be categorized

into 2 classe s: C la ssica l Thyroid Storm which can b e diag no sed by a uthor with FormulaG /O: P-39.5-120, a nd Non -C la ss ic a l Thyro id S torm with Burc h-Wa rto fsky S co re.

Abbreviations: ADMA = a s ym m e tr ic d im e thy la rg in ine ; AOPP = Adva nc e d Oxida t ion P ro te in P roduc t ; CMR =ca rdiom etabolic ris k; CVD = c a rd iova s c u la r d is e a s e ; DDAH= dimethylarginine dim enthylaminohyd rolas e; ESRD = e nd -

s tage rena l diseas e ; FDA= food an d drug adm inis tra t ion; GLP-1 = glucagons - l ike peptide-1; LAR= long- ac ting re leas e ;LRD= lifes tyle re la ted diseas e ; MetS = m e t a b o lic s y n d ro m e ; NOS = n it ric o x ide s yn tha s e ; PRMTs = prote ina rgininemethyltransfe rases ; RONS = reac tive oxida tive nitrogen s pec ies ; TC= thy ro id c r is is ; TS = t hy r o id s t o rm


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2 PENDIDIKAN KEDOKTERAN BERKELANJUTAN ILMU PENYAKIT DALAM XXII-2007

Askandar Tjokroprawiro

I . Glo besity : Time-Bom b Disease in the future?

The epidemic of obesity as release by WHO in 1998 now has become pandemic,defined as an epidemic occurring over a wide geographic area and affecting anextreme high proportion of the population. Roth et al (2004) reported that it seemsnow even happen in developing countries (including Indonesia?). First noted in adults,but now it has spread to adolescents and children (FIGURE-2). Studies in the US(Mokda d e t al 1999) have further shown the rapid spread and worsening of the pandemicthat has globally or it can be termed globesity.

Hence, globesity and also diabesity (FIGURE-1) will be most likely starting nowin year 2007. If no immediate programmed intervention in obesity (esp. in Indonesia),the Time-Bomb Diseases (obesity related diseases) will be emerging in the future(2020?).

HealthcareEconomic

Burden

RespiratoryProblem

StrokeOsteo-

arthritis

LiverDi se a se

CellB l a dde rDi se a se

HeartDi se a se

P s i c o -soc i a l

CertainCa nce r

G o u t

Repro-ductionProblem

Typ e 2Diabetes

GLOBESITYGLOBESITYTime Bomb Disea se Time Bomb Dise ase

1 2

3

4

5

678

9

10

11

12

Provided: 2007Provided: 2007Related Dise as esRelated Dise as es

FIGUREFIGURE--1 GLOBESITY and Its Related Diseases1 GLOBESITY and Its Related Diseases

I .1. Staging o f l i festyle related d isease (stage-4)

Based on clinical experiences (FIGURE-2), the evolution of lifestyle relateddisease (LRD) can be staged as follows: Stage-0 (healthy lifestyle), Stage-1(unhealthy lifestyle), Stage-2 (abdominal obesity), Stage-3 (the MetS, prediabetes,adolescent obesity), and Stage-4 (ASCVD, T2DM, Stroke, Etc).

The MetS, which affects about 40% of the population over 50 in the US andnearly 30% in Europe, is a significant public health issue worldwide and one of the


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3BAGIAN-S MF PENYAKIT DALAM FK. UNAIR R SU D r. S OETOMO S URABAYA



ma jor c a us es o f AS C VD. The prevalenc e of the MetS (ATP III criteria ) in ind ividua ls(over 40) who underwent medica l check up in Suraba ya wa s 32%, w hereas it wa s

reported 43.3% in trea ted T2DM a nd 59.0% in n a ve T2DM a s ob se rved in the private

clin ic; h ow ever, the p reva lenc e of the MetS (ATP III crite ria) in o b ese pa tien ts w ith

T 2 D M w a s 8 1 . 7 % (Tjokroprawiro 2005).

The MetS is a c ons tellation of interrela ted risk fac tors of me tab olic o rig in-meta bolic

risk factors that appear to directly promote the development of ASCVD, and

pa tients w ith the MetS a lso a re a t increase d ris k for developing T2DM.

The MetS (IDF 2005) :WC (INA) : > 90 cm () or > 80 cm ()Plus Any 2 of the Following 4 Factors

Waist Circumference = WC

> 90 cm > 80 cm

3 Blood Pressure

> 130/85 mmHg

4 Fasting Glucose

> 100 mg/dl

1 Triglyceride

> 150 mg/dl

2 HDL-Chol

< 40 mg/dl < 50 mg/dl

Healthy LifestylePreclinical Syndrome Clinical Dis eas esObesi ty

Unhealthy Lifestyle (Abdo minal Obes ity) ASCVD, T2DM, Stroke, etcPre DM, MetS,Adol. PreDM

STAGE 1 STAGE 2 STAGE 3 STAGE 4STAGE 0

Figure -2 Staging of Lifesty le Related Disease(Clinical Experiences : Tjokroprawi ro 2005-2007)

Figure -2 Staging of Lifesty le Related Disease(Clinical Experiences : Tjokroprawi ro 2005-2007)

IDF : International Diabetes Federation

WC : Waist Circumference

MetS : Metabolic SyndromeINA : Indonesia

I.2. Obesity and itS serious consequences

Obesity, a new pandemic, is a preclinical sign (Stage-2) of l i festyle related

disease and is associated with an increased cardiometabolic risk (CMR) factors dueto ab domina l obesi ty that a ppear to d irect ly (via the metab olic syndrome = the

MetS?) promote the development of cardiovascular disease (CVD).

Globally, there are more than 1 billion overweight adults, at least 300 million of

them o bes e (a B MI over 30 kg/m2; Ind one sian C riteria for ob ese is > 25 kg/m2). Such

fac ts po se a ma jor ris k for ch ron ic d isea se a s ma nifested in S ta ge -4, inc luding T2DM,CVD, hyper tens ion an d s t roke , a nd ce rta in form o f ca ncer (the Time-B omb

Disea se ). The ma in caus es o f such LRDs are increa sed c onsum ption o f energy-dens e


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5BAGIAN- SM F PENYAKIT DALA M FK. UNAIR RSU Dr. SOETOMO SURAB AYA



I.3. ADMA in obesity and in diabetes mellitus

Oxidative stress as occurs in severe obesi ty and uncontrol led DM (Eid et al 2004)

may increase the product ion of asymmetr ic d imethylarginine (ADMA), an endogenous

nitr ic ox ide synth ase (NO S) inhibi tor . Several l ines of eviden ce sug gest th at ADM A,be ing an endogenous NOS inh ib i to r , may not on ly be a marker o f severa l d isease

(end-stage renal disease = ESRD, liver failure, CVDs, hy pertension, diabetes, preeclamp sia)

but a lso as a n ac t ive p layer in the pro gression of atheroscleros is. ADMA is select ively

degraded by d imethy larg in ine d im enthy lam inohydro lase (DDAH) , and in hum ans there

are two major fo rms o f DDAH (DDAH-1 and DDAH-2) , w i th par t ly over lapp ing t issued i s t r i b u t i o n s i n k i d n e y , l i v e r a n d s m a l l i n t e s t i n e (Maas 2005) . Ox ida t i v e s t r es s

act ivates proteinarginine methyl transferases (PRMTs), and th is enzyme proteolyses

pro te in -1-arg in ine and leads to l ibera t ion o f ADMA. In k idney , ADMA is f i l t ra ted by

glomerul i whereas secret ion and re-uptake wi l l a lso happen in tubular cel ls .

Several studies reported that there is s trong relat ion ship foun d b etween BM I and

plasma levels o f ADMA and the Larg / A DM A rat io; th is indicates a l ink to end oth el ia l

dys func t ion in obese sub jec ts , and we ight loss may reduce c i rcu la t ing ADMA leve ls

in mor b id l y obes e women (Krzyanowska et al 2004) .

I.4. Global cardiometabo lic risk (CMR)

Car d iome tabo l i c r i s k i s bas ed on the c onc ep t o f r i s k c on t i nuum. G loba l CMR

represents the overa l l r i sk o f deve lop ing T2DM and / o r CVD ( inc lud ing myocard ia l

infarct ion an d strok e) , wh ich is due to a c luster of mo dif iable r isk factors / m arkers.

These factors / markers inc lude 9 com pon ents as seen in FIGURE-4.

1 . C lassica l r isk fac tors such as smo k ing, h igh LDL, hyper ten s ion , and e levatedb l o o d g l u c o s e

2 . E m e r g i n g r is k f a c t o rs s u c h a s ab d o m i n al o b e s i ty ( e sp . i n tr a- ab d o m i n a l

ad ipos i ty ) , insu l in res is tance, low HDL, h igh t r ig lycer ides , and in f lammatorymarkers


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6 PENDIDIKANKEDOKTERAN BERKELANJUTANILMUP ENYAKIT DALAMXXII- 2007


(Provided : 2007)

FIGURE-4 Global Cardiometabolic Risk (CMR)

CVDCVDType 2Type 2

DiabetesDiabetes LowLowHDLHDL--CC

IntraIntra--

abdominalabdominalAdiposityAdiposity

HighHigh

BloodBlood

PressurePressureHHighigh

LDLLDL--CC

InsulinInsulin

ResistanceResistance

ElevatedElevated

BloodBlood

GlucoseGlucose

InflammatoryInflammatory

MarkersMarkers

HighHigh TTGG

SmokingSmoking

II. Five Satan-Cycles in Diabetic Nephropaty

On slide presentation the five Satan Cycles will be much more easily understood.

On the basis of clinical experiences, 5 (five) Satan Vicious Cycles are summarized.

Thes e Vicious C yc les a re importantly well recog nized to unde rstand the p a thoge nes is,

and to perform rationa le trea tment of patients w ith diab etic neph ropa thy. Eac h S ata n

Cy cle is des c ribed b elo w. Recog nition of these S a tan Cy cles a re very importa nt tochose the appropriate drug for diabetic nephropathy.

The 1st Satan Cycle (especially in glomerular and tubular cells): from hypertension

proteinuria glomerular injury hy pertens ion). This C ycle s tarts from hypertension a nd

then be hypertension which is consecutively followed by proteinuria glomerular injury and back to hypertension again. Hence, hypertension and proteinuria are targets

of treatme nt. Ra tion ale tre a tment: AC E-1s, ARB s , Ins ulin a nd /or OAD.

The 2nd Sa tan Cy cle (from G LUT-1 a nd the n b e ba c k ag ain to G LUT-1). ThisCy cle occ urs esp ecially in the me sa ng ial c ells, a nd s tarts from G LUT-1 tha t permits

g lucose to en ter the ce l l , and subsequent ly to increase DAG produc t ion to

increa se a c t iva ted PKC increase s TG Fb tha t inh ib it s NOS , s t imula tes ECM

pro duction, a nd a lso a ctivates G LUT-1. The inc rea se d produ ction o f ECM ma y promote


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the progression of diabetic nephropathy. Rationale treatment: excellent glycemiccontrol, ACE-1s, and/or ARBs, TGFb inhibitors.

The 3rd Satan Cycle (in mesangial cells): from A-II and back to A-II. This Satan

Cycle starts from A-II (increased production is due to hyperglycemia) stimulatesTGF-formation stimulates PAI-1 and then back to stimulate A-II formation. PAI-1 also

decreases the activity of plasmin (which causes decreased matrix degradation, and

diabetic nephropathy may pursue). Rationale treatment; excellent glycemic control,

ARBs, TGF-b inhibitors, PAI-1 inhibitors.

The 4thSatan Cycle (in mesangial cells): from A-II PKC A-I and then back to

A-II. This Satan Cycle starts from A-II (due to hyperglycemia) which activates PKC

and this PKC may stimulate A-I and back to increase A-II production. Rationale

treatment: excellent glycemic control, ACE-1s, ARBs, and PKC-antagonists.The 5th Satan Cycle (from cytokines: IL-1, IL-8, TNF, PAF, VCAM-1, and MCP-1

increased ROS, and then back to these cytokines again). This Deadly Satan Cycle

most frequently occurs on hemodialyzed patients with diabetic nephropathy. The

cytokines of this Satan Cycle are generated by the 3 components (dialysate, mem-brane of the coil, and uremia or AOPP (Advanced Oxidation Protein Product) in which

all of them all present in hemodialyzed patients. These cytokines activate NADPH

oxidase, p47, p67, p21, rec stimulate ROS and RONS (reactive oxidative nitrogen

species) which then to increase the production of MMP9 (which may cause acute

thrombosis and vascular sudden death) and activated MAPK, NFkB/AP-1, and all ofthese may stimulate the production of the previous cytokines of this Cycle. Rationale

treatment: excellent glycemic control, low protein diet to suppress the increased

AOPP, or strong antioxidants, etc.

III. DIAGNOSIS OF Classical Thyroid Storm WITH Formula G/O: P-39.5-120

Based on clinical experiences and for practical point of view, thyroid storm(thyroid crisis) can be classified into 2 classes. 1. Classical Thyroid Storm and 2.

Non-Classical Thyroid Storm.

List of precipitant (TABLE-1) should be known before collecting the clinical score

of thyroid storm for diagnosis.


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8 PEN DIDIKAN KEDOKTE RAN BER KELANJUTAN ILMU PENYAKIT DAL AM XXII-2007

Askandar T j okro p ra wir o

Burch et al 1993, Tietgenset al 1995, Hall et al 1999,Turner et al 2003, Greenspan et al 2004(Summarized : Tjokroprawiro 2002 - 2007)

TABLE 1 24 Known Precipitants of Thyroid Storm

No 1No 1 -- 13 are Known Precipitants presented by Burch and Wartofsky13 are Known Precipitants presented by Burch and Wartofsky--19931993

1 Infection

2 Thyroid Surgery

3 Non-Thyroid Surgery

4 Iodinated Contrast Dyes

5

6 Radioiodine Therapy

7 Diabetic Ketoacidosis

8

9

10 Pulmonary Embolism

11 Cerebral Vascular Accident

12 Trauma : Fracture, etc.

13

Withdrawal of Antithyroid Drug Therapy

Severe Emotional Stress

Vigorous Thyroid Palpation

Parturition

14 Hypoglycemia

15

16 "Healthy Food" Preparation Containing

Sea weed or Kelp

17 Congestive Heart Failure18

19 Bowel Infarction

20 Tooth Extraction

21 TH Ingestion

22 Burn Injury

23 Sepsis

24 Childbirth

Sympathomimetic Drugs :

Toxemia of Pregnancy

Pseudoephedrine , Amiodarone , etc

1. Classical Thyroid StormCharac ter is t ics o f th is c lass are : the presence o f go i te r (G) and /o r o rb i ta l (O)

s i g n s , o n e o r m o r e p r e c i p i t a n t ( P ) , b o d y t e m p e r a t u r e> 39 .5 C, and pu lse ra te >

120 per minute. Hence, formula G/O: P-39.5-120 can be used for diagnosis of classicalthyroid storm. I f the case meets the character is t ics of th is formula, the total number of

Burch-Wartofsky Score (BW-Score) wi l l be > 50, wi th the calculat ion as fo l lows: P =

10, tempera ture > 39 .5 = 25 , pu l s e r ate ( tac hy c a r d ia ) > 1 2 0 = 1 5 , a n d t h e to t a l

score = 50. List o f p rec ip itan t can be fo und in TABLE-2.


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9BAGIAN-SMF PENYAKIT DALAM FK. UNAIR RSU Dr. SOETOMO SURABAYA

Capita Selecta inEndocrinology andMetabolism- 2007


(Clinical Experiences: Tjokroprawiro 2005-2007)

TABLE-2 Dx with ASK-SCORE >50 for Classical Thyroid Storm

Should this Tetralogy (TTS) is Met, the SCORE will be > 50

1 T w o o f th e F oll ow in g :

2

3

4

a Goiter, b Orbital Signs, c And /Or : TSHs, FT3, FT4

Tempera tu re > 39 .5 0C : S co re > 2 5

T a ch yc a rd ia > 1 2 0/m i n : S co re > 1 5

Precipi tant (+) : Score 10 , or CNS E ffects (+) : Score 10-30

FORMULA G/O : P 39.5 120

Diagnosis of CLASSICAL TS with FORMULA G/O : P 39.5 - 120

G /O = G o i t er , O r b i t al S i g n s : P 3 9.5 1 20

2. Non-Classical thyroid Storm

If the temperature of patients is less than 39.5 and tachycardia is less than 120,the calculation with the table of BW-Score should be used for diagnosis of Non-

Classical Thyroid Storm. TABLE-1, TABLE-2 and TABLE -3 can be used for score

calculation of BW-Score.


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10 PENDIDIKAN KEDOKTERAN BERKELANJUTAN ILMU PENYAKIT DALAM XXII-2 007


A score of 45 or greater is highly suggestive of thyroid crisis

A score of 25-44 is suggestive of impending thyroid crisis

A score below 25 is unlikely to represent thyroid crisis

IV. Once-Week ly EXENATIDE-LAR for the treatment of T2DM?

Incretins are hormones produced from the gastrointestinal track that act to

enhance the normal release of insulin after the oral ingestion of carbohydrates. Theirp l e i o t r o p i c e f f e c t s a r e (Gautier et al 2005, DeFronzo et al 2005):

1. to decrease gastric emptying

2. to promote a feeling of satiety that can lead to weight loss in overweightpatients (an increased sense of satiety)

3. to reduce post prandial glucagons levels

4. to increase islet cell mass (?)


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The most well-characterized incretin is GLP-1.Extenatide is the currently available incretin mimetic. On April 28, 2005, the Food

and Drug Administration (FDA) approved twice daily extenatide sc injection under

the trade name Byetta. This drug is the first in a new class of drugs for the treatment

of T2DM called incretin mimetic and exhibits many of the same effects as the human

incretin hormone glucagons-like peptide-1 (GLP-1). GLP-1, secreted in response tofood intake, has multiple effects on the intestine, liver, pancreas and brain that work

in concert to improve blood sugar.

Indications of Byetta injection (Buse et al 2004, Kendal l et al 2005 ):

1. Patients with T2DM who are unsuccessful at controlling their blood sugar levels

despite using commonly prescribed oral medications metformin, a sulfonylurea,

or both.2. Patients with T1DM who are undergoing islet cell transplantation; exenatide haspotential effects to help with islet function.

Amylin Parm., Inc., Eli Lilly and company and Alkermes, Inc. announced in 2006

the results from the ongoing Phase-2 multi-dose study of a long-acting release (LAR)formulation of Once-Weekly Extenatide-LAR clinical study in patients with T2DM (http:/

/ww w.diabetesincontrol.co m/results_print.php?storyarticle= 3060).

Results of Once-Weekly Extenatide-LAR (2.0 mg subcutaneous injection weekly),

after 15 weeks with Phase-2, randomized, placebo-controlled, double-blind studyincluding 45 patients with T2DM are:

1. AIC, improved approximately 2 (two) %

2. Fasting blood glucose dropped 50 mg/dl

3. Average weight loss was 9 poundsHowever, the most common adverse event was mild nausea which occurred in

approximately 20% of subjects in the high dose (2.0 mg) group compared to

approximately 7% in the placebo group.

These studies assessed the potential for exenatide to help improve beta-cell

survival in patients receiving islet cell transplants. In animal studies, this drug is

suggested can help increase islet cell mass. There are very small studies, but they

are encouraging, both for patients who are undergoing islet cell transplants and for

the potential of exenatide to help restore the abnormal beta-cell function in patientswith type 2 diabetes mellitus.

Excenatide_LAR has not been approved by the FDA for marketing in the United

States.

V. ANAKINRA: the promising drug for the treatment of T2DM

Anakinra is a recombinant version of the naturally occurring human interleukin-1

receptor antagon ist that blocks the effects of interleukin-1 and (Perr ier e t a l

2 0 0 6 ). Interleukin-1 , a proinflammatory cytokines, impiclated as an effector

molecule of inflammatory beta-cell destruction leading to T1DM, inhibits the functionand promotes the apoptosis of beta-cells (Dinare l lo 1996, Mandrup-Poulsen 1996,

Bend t zen e t a l 1986 ). Beta-cell producing interleukin-1 have been observed in

pancreatic sections obtained from patients with T2DM, leading to impaired insulin


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secretion, decreased cell proliferation, and apoptosis (Maed le r 2002 , La rsen e t a l2007). The expression of interleukin-1 receptor antagonist is reduced in pancreatic

islet of patients with T2DM, and high glucose levels induce the production of

interleukin-1(Larsen et al 2007).

Anakinra (a recombinant of human interleukin-1 receptor antagonist), a naturally

occurring competitive inhibitor of interleukin-1 binding to the type 1 receptor, protects

human beta-cells from glucose-induced functional impairment and apoptosis (Dinarello

1996, 2000; Maed ler 2002).

Hypothetically, intervention in the islet balance between interleukin-1 receptor

antagonist and interleukin-1 might improve beta-cell function and glycemic control

in patients with T2DM.

Most recently, Larsen et al (2007) in double-blind, parallel-group trial involving70 patients with T2DM, randomly assigned 34 patients to receive 100mg of anakinra

subcutaneously, once daily for 13 weeks and 36 patients to receive placebo

concluded: that blockade of interleukin-1 with anakinra improve glycemia and beta-cell

secretory function and reduce markers of inflammation (C-reactive protein, interleukin-6).

In conclusion, ankinra is most likely to be promising therapeutic potential in the

treatment of patients with T2DM. However, further investigation is needed to evaluate

its long-term use and adverse reaction, and its detailed potential effects in preventing

beta-cell destruction and promoting beta-cell regeneration in T2DM.

As a supplement of this paper, Standard of Medical Care in Diabetes recommended

by ADA-2007 can be seen in TABLE-4.


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13BAGIAN-SMF PENYAKIT DALAM FK. UNAIR RSU Dr. SOETOMO SURABAYA

Capita Selecta inEndocrinology andMetabolism- 2007


TABLE-4 Standards of Medical Care in Diabetes of ADA : 2007

(Summ a rized : Tjokrop rawiro 2007)

Glycemic Control (D) :

AIC (Primary Target for Glycemic Control)

Pre Prandial Capillary Plasma Glucose

Peak Prandial Capillary Plasma Glucose

Blood Pressure (H) :

Lipids (L) :

LDL

TG*)

HDL

Target :

< 7%

90-130 mg/dl

< 180 mg/dl

< 130/80 mmHg

Target :

< 100 mg/dl

< 150 mg/dl

> 40 mg/dl **)

A normal AIC , < 6 % ; P ost P ra ndial G lucose ma y be ta rgete d if A IC G oals

Non-HDL = Total Chol. minus HDL Chol.

**) For W omen : I t has been suggested that HDL goal be increased by 10 mg/dl

are not met (despite normal prepra ndial glucose go als)*)CURRENT NCEP/ATPIII: If TG >200 mg/dl, Non-HDL Chol. should be < 130 mg/dl

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