leading article inlacin therapy in patients with type-2 diabetes mellitus

7/23/2019 LEADING ARTICLE Inlacin Therapy in Patients With Type-2 Diabetes Mellitus

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ABSTRACT

Prospective study on DLBS (Inlacin) which is called Surabaya-Inlacin Study (SIS) has been per-formed (-) by SURABAYA DIABETES and NUTRITION CENTER (SDNC) by using modified rocket

system design (Tjokroprawiro ). As seen in the map of OAD (Oral Anti Diabetes) which has beenillustrated TABLE-, Inlacin (DLBS) is catagorized in a class of insulin sensitizer. Surabaya Diabatesand Nutrition Centre investigated this novel insulin sensitizer (-) through a study titled: The Ef-fect of add-on therapy with DLBS on glycemic control, lipid profile and adiponectin in patients withtype--diabetes mellitus). A sample size of type--diabetes mellitus (TDM) patients with AC levelof . after at least a -month therapy with a combination of metformin plus one or more oral OADswere enrolled in a -week study period. The study has currently been finished. The complete results andconclusions are presented in this paper, under Section IV.

Interestingly, after weeks of treatment with Inlacin on top of the other OADs previously taken bythe subjects, a significant metabolic improvement consisting of: reduced -hour post prandial glucose

(p


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C. Biguanide: Metformin XR (Glucophage XR), -Guanidinopropionic-Acid D. DLBS (Inlacin). Intestinal Enzyme Inhibitors: a-Glucosidase Inhibitor (AGI), a-Amylase Inhibitor (AMI). Incretin-Enhancers DPP- Inhibitors: (Sitagliptin, Vildagliptin, Saxagliptin, Alo gliptin, Denagliptin, Du-

togliptin, Linagliptin, Melogliptin, Teneligliptin, SYR-, TA-)

. Fixed Dose Combination (FDC) Types: Glucovance, Amaryl-M, Galvusmet, Janumet, KombiglyzeXR,TrajentaDuo, ACTOSmet, Duet act

. Other Specific Types: Sodium GLucose co Transporter- (SGLT)-Inhibitors: ASP, BI , Cana-gliflozin, Dapagliflozin, Seragliflozin, Remogliflozin, AVE-, KGT-, LX-, TS-, YM-; Glu-cokinase Activator (GKA): MTBL, MK-; OXPHOS-blocker; FBPase-Inhibitor, INCB (HSD-inhibitor); Berberine.

Berberine (Shan et al ), a natural plant alkaloid isolated from Chinese herb Coptis chinensis (Huan-glian), stimulates GLP- secretion (co-secreted with GLP-) from intestinal L-cells. Berberine treatment isefficient in repairing the damaged intestinal mucosa, restoring intestinal permeability and improvingendotoxemia, all simultaneously while showing antidiabetic effects and a modulation of GLP- release

in the ileum. Berberine may improve hyperinsulinemia and insulin resistance. On the basis of clinicalexperiences in daily practice, the map of OADs can be illustrated below (TABLE-).

Thiazolidinediones (TZDs) such as pioglitazone and biguanide (metformin) as previous insulin sensiti-zers have been available in Indonesia for years. However, Inlacin (DBLS), the novel sensitizer (see theInsulin Sensitizer Group in TABLE ), has been recently launched and available in the first monthsof the year

The aim of this article is to introduce the novel insulin sensitizer, Inlacin (DLBS) with its (seven)unique possible mechanisms of action underlying several metabolic improvements demonstrated inour Inlacin-study performed in Surabaya), to the residents of internal medicine and their associates,internists, and associated spesialists.

(Summarized : Tjokroprawiro1996-2013)

TABLE-1. Map of Oral Anti Diabetes (OAD) in Daily Practice

III INTESTINAL ENZYME INHIBITOR -Glucosidase Inhibitor (AGI): Acarbose

-Amylase Inhibitor (AMI): Tendamistase

1

2

I INSULIN SECRETAGOGUE

V FIXED DOSE COMBINATION (FDC) TYPE

Glucovance, Amaryl-M, Galvusmet, Janumet, KombiglyzeXR, TrajentaDuo,ACTOplusmet, Duet act

IV INCRETIN-ENHANCER(Sita-, Vilda-**) , Saxa-, Lina-Alo-, Dena-, Duto-,Melo-, Teneli-gliptin, SYR-322, TA-666)

II

- Metformin , Metformin XR (Glucophage XR), 3-Guanidinopropionic-Acid

1

3 BIGUANIDE :

a

b

Glitazar Class (Mura-*), Raga-, Ima-, Tesaglitazar) : MRIT

Non-Glitazar Class (Metaglidasen : Non Edema and Non Weight Gain)

2 NON-TZDs :THIAZOLIDINEDIONES (TZDs): Glitazone Class

*) Withdrawn

INSULIN SENSITIZER(Rosi-*), Pio-, Neto-, Dar-glitazone)

4 DLBS-3233 (INLACIN)

VI OTHER SPECIFIC (OS) TYPEASP1941, BI 10773 , Canagliflozin, Dapagliflozin, Seragliflozin, Remogliflozin, AVE-2268,KGT-1681, LX-4211, TS-033, YM-543

1

3 Oxphos-Blocker FBPase Inhibitor4 INCB13739 (11 HSD1inhibitor)5

Sodium GLucose co Transporter-2 (SGLT2)-Inhibitors:1

2 Glucokinase Activator (GKA): MTBL1, MK-0941.

DPP-4 Inhibitors

GLP-1 Enhancers

NON-SUs (Metaglinides : Nateglinide,REPAGLINIDE)

SUs : Gliquidone, Glipizide, Gliclazide, Glibenclamide, Glimepiride

GPR40 Agonist (TAK-875) : 50-200 mg once/day. Long-chain FAs amplify glucose-stimulated insulin secretion, GLP-1

GLIMIN (new tetrahydrotriazine-containing class) : IMEGLIMIN (1500 mg twice/day) : Insulin, Muscle glucose uptake, HGP

1

2

3

4

Berberine6



This article comprises (five) subtopics men-tioned below.

I. RECENT INFORMATION ABOUT DIABETESMEL LITUS IN -II. INLACIN (DLBS-), THE NOVEL INSULINSENSITIZER: AN OVERVIEWIII. SUMMARY AND CONCLUSIONS OF THE RE-VIEWIV. PROSPECTIVE OPEN STUDY ONINLACIN(SURABAYA-INLACIN STUDY)V. THE RESULTS OF THE SURABAYA-INLACINSTUDY (SIS)VI. CONCLUSIONS OF THE SURABAYA-INLACINSTUDY

I. RECENT INFORMATION ABOUT DIABETESMELLITUS IN -

Based on the report of Clinical Practice Recom-mendation of the American Diabetes Asso-ciation (ADA) published in Diabetes Care Janu-

ASK-SDNC

TABLE-2 CURRENT CRITERIA FOR THE DIAGNOSIS OF DIABETES-ADA 2013

STANDARDS of MEDICAL CARE in DIABETES-2013Diabetes Care 36 (Suppl 1), S12, January 2013, Summarized : Tjokroprawiro 2013

In a PATIENT with CLASSIC SYMPTOMS of HYPERGLYCEMIA or

HYPERGLYCEMIC CRISIS, a RANDOM PLASMA GLUCOSE >200 mg/dL

(11.1 mmol/L)

4

In the ABSENCE of UNEQUIVOCAL HYPERGLYCEMIA, RESULT SHOULD

BE CONFIRMED BY REPEAT TESTING.

or

or

A1C >6.5%. The test should be performed in a laboratory using amethod that in NGSP certified and standardized to the DCCT assay.

1*)

or2 FPG >126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at

least 8 h.*)

3 2-h PLASMA GLUCOSE >200 mg/dL (11.1 mmol/L) during an OGTT. The test should beperformed as described by the WHO, using a glucose load containing the equivalent of 75 g

anhydrous glucose dissolved in water. *)

*)

NORMAL : A1C < 5.7 % Pre-Diabetes: A1C 5.7 6.4%

ary (Vol. , Supplement ), categories ofincreased risk for diabetes (IRDM) or prediabetes(PreDM) can be listed below.. FPG mg/dL to mg/dL: IFGprediabetes

. -h PG mg/dL to mg/dL in the gOGTT: IGTprediabetes. AC . .: IRDM or prediabetes. The termPre DM may be applied if desired. Patients with any of the abovementioned cri-teria: , , or its combination of each with other.

The summarized criteria for the diagnosis of dia-betes of ADA- can be seen in TABLE-.

In , an International Expert Committee thatincluded representatives of the ADA, the Inter-national Diabetes Federation (IDF), and the Euro-pean Association for the Study of Diabetes (EASD)recommended the use of the AC test to diagnosediabetes, with a threshold of > ., and ADAadopted this criterion in . The diagnostic testshould be performed using a method that is certi-fied by the National Glycohemoglobin Standardi-zation Program (NGSP) and standardized or trace-able to the Diabetes Control and ComplicationsTrial (DCCT) reference assay.

The advantages and disadvantages of AC meas-urements are summarized below.Advantages of AC measurement:. AC, a picture of the average of BG level over thepreceding - months. Its values vary less than FPG (Fasting PlasmaGlucose)

. More stable chemical moiety. More convenient. No fasting; thus, AC measurement can be per-formed anytime

. Correlated tightly with the risk of retinopathy. Sufficiently sensitive and specific.

Disadvantages of AC Measurement:. More expensive (Costly). Inaccurate in case of severely low Hb levels (se-

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vere chronic anemia, hemolytic anemia, etc).Based on AACE Diabetes Care Plan Guidelines, there are interpretations :AC < . : NormalAC ..: High risk/prediabetes; requiresscreening by glucose criteriaAC > .: Diabetes, confirmed by repeating thetest on a different day.

II. INLACIN (DLBS-), THE NOVEL INSULINSENSITIZER : AN OVERVIEW

Inlacin (DLBS) is extracted from Lagerstro-emin speciosa and Cinnamomum burmanii. Thebioactive fraction DLBS is standardized by itscontent of lagerstroemin, an ellagitannin.

The summarized unique mechanisms of action

of Inlacin (DLBS) are listed in TABLE- and il-lustrated in FIGURE-.

Inlacin (DLBS) has (seven) unique mecha-nisms of action briefly illustrated in the followings(FIGURE-).. To stimulate insulin insulin receptor binding. To increase phosphorylation of tyrosine re-

sulting in an increased insulin sensitivity. Thus,Inlacin decreases insulin resistance. Inlacin(DLBS) increases phosphorylation of tyros-ine IRS (IRS-Ptyr) improve cellular responses increased insulin sensitivity decreased insulin

resistance.. Inlacin (DLBS) increases genes expressionof PPAR and PPAR which results in increasedGLUT- synthesis, increased PPAR number, sti-mulated GLUT- activities (translocation, etc).. Inlacin stimulates GLUT- translocation fromcytoplasm to membrane.. Inlacin decreases TNF leading to a decreasedFFA decreased translocation of PKC and de-creased PKC decreased serine phosphoryla-tion and finally resulting in a decreased insulinresistance. Inlacin also directly decreases trans-location of PKC and decreases PKC and thensuppresses serine phosphorylation; and on theother hand, it stimulates phosphorylation of ty-rosine, and hence, decreased insulin resistancecan be pursued.. Inlacin increases adiponectin level

. Inlacin may lower resistin level.

Based on the available data of DLBS (ReleaseDate: December ) and recent publications ofTjandrawinata et al , Nailufar et al , andTandrasasmita et al , Inlacin (DLBS) canbe regarded as the novel insulin sensitizer withmetabolic-cardiovascular (MECAR) properties.

The eighteen () supporting findings for MECARproperties of Inlacin are listed below (FIGURE-).. Decreased fasting plasma glucose (FPG): .. Decreased prandial plasma glucose (PPG):.. Lowered AC after weeks of treatment: .

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. Decreased random plasma glucose: .. Enhanced PPAR expression: . Enhanced PPAR expression: . Stimulated PI kinase:

. Stimulated Akt Expression (esp. Akt): . Enhanced GLUT- expression: . Stimulated glucose uptake: . Lowered insulin plasma levels: .. Decreased HOMA-R after weeks of treat-ment: .. Increased adiponectin expression: . Decreased resistin expression: comparedto control. Lowered total cholesterol plasma level: .. Lowered LDL-cholesterol plasma level: .

. Lowered triglyceride plasma level: .. Increased HDL cholesterol level: .

For practical point of view, such supportingproperties of Inlacin (DLBS) with its uniquemechanisms of action can be illustrated in FIG-URE-.

III. SUMMARY AND CONCLUSIONS OF THE RE-VIEW

. Inlacin (DLBS) is the novel OAD and thisdrug can be included in insulin sensitizer ca-tegory in the map of OAD (TABLE-)

. Inlacin (DLBS) has unique mechanisms ofaction which results in possible therapeutic

benefits (TABLE- and FIGURE-). Inlacin (DLBS) is more than just an OAD-

since this novel OAD also shows metabolic car-diovascular (MECAR) properties (FIGURE-)

. In conclusion, Inlacin can be used either asmonotherapy or as an add-on-therapy for pa-tients with type diabetes mellitus. On the ba-sis of its metabolic-cardiovascular properties,this novel insulin sensitizer can be assumed asthe promising drug for diabetic patients withprominant insulin resistance and vascular com-plications (FIGURE-)

. In clinical experiences with Inlacin as an add-ontherapy in more than patients with TDM,improved glycemic control was demonstrated

and promising, and no significant adverse reac-tion was observed.

Inlacin at a dose of mg and mg daily canbe prescribed, depending on the previous level ofthe blood sugar. For practical point of view andbased on clinical experiences, FIGURE- and FIG-URE- can be used as daily guideline to prescribeInlacin. In general, there are (four) possible clin-ical indications of Inlacin as listed below.A. TYPE DIABETES MELLITUS :

METFORMIN-, GLITAZONE-, ACARBOSE-, Sus-, IN-SULIN- TREATED, ELDERLY, OBESITYB. PREDIABETESC. MODY (MONOGENIC DM AACE )D.TYPE-X DM (Tjokroprawiro, ). Type-X DM is

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insulin dependent (partially: X and X, or totallyX) DM, derived from TDM. Most patients are thoseTDM tho are suffering from poorly controlledTDM who have been long time. Mostly, they are ofmore than years old.

IV. PROSPECTIVE OPEN STUDY ON INLACIN

(SURABAYA-INLACIN STUDY)

Study title: Effect of add-on therapy with DLBS- on glycemic control, lipid profile and adi-ponectin in patients with type--diabetes mel-litus.Investigators and Study Site Principal Investigator: Prof. Dr. dr. AskandarTjokroprawiro, Sp.PD-KEMD, FINASIMCo-Investigators :

- dr. Sri Murtiwi, Sp.PD-KEMD, FINASIM- dr. Jongky Hendro Prayitno, Sp.PD- dr. Hermina Novida, Sp.PD- dr. Hermawan, Sp.PD- dr. Musofa Rusli, Sp.PD- dr. M. Miftahussurur, Sp.PDStudy Site : Surabaya Diabetes and Nutrition Centre,

Dr. Soetomo Teaching Hospital Faculty of MedicineAirlangga University SurabayaStudy population- TDM patients with AC level of . after at leasta -month therapy with a combination of metforminplus one or more oral anti-diabetic agents (uncon-trolled / persistent hyperglycemia), sample size : Study treatment : DLBS on top of current OHAsused by each subject.Study Design (FIGURE-)

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Study Objectives. To investigate clinical efficacy of add-on therapy with DLBS in improving blood glucose control,lipid profile and adiponectin in subjects with type--diabetes mellitus.. To investigate the safety of add-on therapy with DLBS in subjects with type--diabetes mellitus.

V. THE RESULTS OF THE SURABAYA-INLACIN STUDY (SIS)

The results of the Surabaya-Inlacin Study (SIS) canbe described shortly in several points mentionedbelow.. FASTING PLASMA GLUCOSE : . mg/dL (W :.) p = .; . mg/dL (W :.) p = . (NS).For routine exercise subgroup of patients (n=):

. mg/dL (W:.) p=.. W = weeks. -h PRANDIAL PLASMA GLUCOSE: . mg/dL (W : .) p = .; . mg/dL (W : .) p = .. AC (TABLE-B) : . mg/dL (W :.) p = .; . mg/dL (W :.) p = .. LDL CHOLESTEROL (TABLE-C): . mg/dL (W : .) p = .; . mg/dL (W : .) p = .. TOTAL CHOLESTEROL (TABLE-D):

. mg/dL (W : .) p = .; . mg/dL (W : .) p = .. TRIGLYCERIDE (TG): . mg/dL (p = .); , mg/dL (p = .).For Routine Exercise subgroup, the reduction in TG

is much better.. ADIPONECTIN (Apn, TABLE-E) :+.mg/mL (W : .) p = . (not signifi-cant),+.mg/mL (W : .) p = ..But for Routine Exercise subgroup:+.mg/mL (W : .) p=..+.mg/mL (W : .) p = .

. HOMA-R: . (W :.) p = .; .(W : .) p = . (NS).For Routine Exercise subgroup (n=): . (W :.) p=.. IMPROVEMENT IN HOMA-B (overall) was notsignificant, but improvement in routine ExerciseGroup is much better than that in Non-routineExercise subgroup.. NO EFFECT ON BODY WEIGHT : +. kg (W )p = .; +. kg (W ) p = .. NO SIGNIFICANT CHANGE IN HEART RATE AND

DIASTOLIC BLOOD PRESSURE (BP), HOWEVERTHERE IS A SIGNIFICANT REDUCTION IN SYSTOL-IC BP FROM BASELINE AT WEEK- (from , to, mmHg, p=.), AND AT WEEK- (from, to , mmHg, p=.). NO CLINICALLY SIGNIFICANT ADVERSE EVENTS

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(AEs). Most AEs were mild and resolved at the endof study. The most observed AEs are dizziness andfeeling general weekness.. TAKEN TOGETHER, COMBINING WITH PHYSI-CAL ACTIVITY, THE EFFICACY OF DLBS WILL

RESULT IN A MORE POWERFULL EFFECT.

For practical point of view, six tables on -h postprandial glucose (TABLE-A), Reduction in AC(TABLE-B), Reduction in LDL (TABLE-C), Reduc-tion in total cholesterol (TABLE-D), Elevation ofAdiponectin (TABLE-E), and Reduction in HOMA-R in Routine Exercise Group of Patients, either atWeek- or at Week- (TABLE-F) will be illustratedin the following TABLES.

A. REDUCTION IN -h POST PRANDIAL GLUCOSE(TABLE-A)

TABLE-A shows a significant reduction on onehour-plasma glucose (-h PG) after weeks and weeks of treatment with DLBS from baselinewith p = . and p = ., respectively. This re-sult showed that DLBS was effective in reduc-ing -h PG.

B. REDUCTION IN A1C (TABLE-B)

TABLE-B shows a marked reduction in A1C frombaseline, after 6 and 12 weeks of treatment withDLBS-3233 with p = 0.009 and p = 0.001, respec-tively. These results showed that DLBS3233 was ef-fective in reducing A1C.

At WEEK 12, about 12.0% of subjects reached the tar-get A1C level of less than 7.0%

C. REDUCTION IN LDL (TABLE-C)

TABLE-C shows a significant reduction from base-

line in LDL cholesterol level, after 6 weeks and 12weeks of treatment with DLBS3233 with p = 0.006,and p = 0.020, respectively. This result showed thatDLBS3233 was effective in reducing LDL cholesterol.Of the total of 50 evaluable study subjects, only onesubject took statin (i.e. simvastatin) during the studyperiod.

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D. REDUCTION IN TOTAL CHOLESTEROL (TABLE-D)

TABLE-D shows that treatment with DLBS-3233 sig-nificantly reduced total cholesterol level after 6 and 12weeks with p = 0.002 and p = 0.013, respectively. These

results showed that DLBS3233 was effective in reducingtotal cholesterol. Of the total of 50 evaluable study sub-

jects, only one subject took statin (i.e. simvastatin) du-

ring the study period.

E. INCREASE IN ADIPONECTIN (TABLE-E)

TABLE-E shows a marked elevation from baseline ofadiponectin (Apn), after 12 weeks of treatment withDLBS3233 (p = 0.001). This result showed that DLBS3233was effective in elevating adiponectin level. No signifi-cant increase in Apn at week-6, however for Routine Exer-cise Group showed significant increase in Apn (p=0.028)

F. REDUCTION IN HOMA-R IN PATIENTS WITH ROUTINE

EXERCISE, EITHER AT WEEK-6 OR AT WEEK-12 (TABLE-F)

TABLE-F shows that DLBS3233 regardless of exercise(overall analysis) resulted in a significant reduction onHOMA-R, after 6 weeks of treatment ( 0.77, p =0.043).Interestingly, if we subset the analysis, the result indi-cates that DLBS3233 altogether with routine exercisedemonstrated a more powerful effect on HOMA-R re-duction (1.12, p=0.05). This is especially true becauseexercise and DLBS3233 act in synergy in inducing insu-lin-signaling pathway.In Week 12, Non-Routine Exercise Group showed betterHOMA-R reduction than that of the Routine Exercise sub-group (0.63 vs 0.37). This also indicates that the effect

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of DLBS3233 was continuing while the more modesteffect in the Routine Exercise subgroup might be as-sociated to non-compliance of subjects to lifestyle.

VI. CONCLUSIONS OF THE SURABAYA-INLACINSTUDY (SIS)

Inlacin (DLBS3233), the novel insulin sensitizeris able to demonstrate several significant benefitswhich are important for the management of patientswith diabetes mellitus and also for the preventionand treatment of its cardiovascular complications.Such beneficial effects of DLBS3233 are listed below.

A. reduced 1 hour post prandial glucose p

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