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Inlacin® Therapy in Patients with Type-2 Diabetes
Mellitus (The Prospective Surabaya-Inlacin® Study)
Askandar Tjokroprawiro
Sri Murtiwi
Surabaya Diabetes and Nutrition Center – Dr. Soetomo Teaching Hospital Faculty of Medicine Airlangga University, Surabaya Prospective study on DLBS3233 (Inlacin®) which is called Surabaya-Inlacin® Study (SIS) has been per- formed (2012-2013) by SURABAYA DIABETES and NUTRITION CENTER (SDNC) by using modified rocket system design (Tjokroprawiro 1978). As seen in the map of OAD (Oral Anti Diabetes) which has been illustrated TABLE-1, Inlacin® (DLBS3233) is catagorized in a class of insulin sensitizer. Surabaya Diabates and Nutrition Centre investigated this novel insulin sensitizer (2012-2013) through a study titled: The "Ef- fect of add-on therapy with DLBS3233 on glycemic control, lipid profile and adiponectin in patients with type-2-diabetes mellitus"). A sample size of 50 type-2-diabetes mellitus (T2DM) patients with A1C level of ≥ 7.0 % after at least a 3-month therapy with a combination of metformin plus one or more oral OADs were enrolled in a 12-week study period. The study has currently been finished. The complete results and conclusions are presented in this paper, under Section IV. Interestingly, after 12 weeks of treatment with Inlacin® on top of the other OADs previously taken by the subjects, a significant metabolic improvement consisting of: reduced 1-hour post prandial glucose (p<0.021), reduced A1C (p<0.001), reduced LDL Chol (p<0.020), reduced total Chol. (p<0.013), and in- creased adiponectin (p<0.001), was demonstrated. While regarding HOMA-R, we found an insignificant reduction at week-12 (p<0.281); however, it was significant at week-6 (p<0.043). In addition, particular- ly for the subgroup of subjects with routine exercise, the effect of Inlacin® treatment on HOMA-R was found more powerful than that in non-exercise subgroup, and significant reduction of HOMA-R at week- 6 (p=0.05) was obtained (TABLE-F).
Conclusion: The study concluded that add-on therapy with Inlacin® (DLBS3233) in T2DM patients was effective and safe in improving glycemic control and lipid profile, as well as increasing adiponectin level. It was also indicated in this study that implementing routine physical activity plus this novel insulin sen- sitizer may result in a more powerful effect. Based on clinical experiences in daily practice, OAD can be categorized into 6 groups briefly described 1. Insulin Secretagogues: SUs : Gliquidone, Glipizide, Gliclazide, Glibenclamide, Glimepiride; Non-Sulpho- nylureas (Metaglinides) : Nateglinide, Repaglinide (Dexanorm®); GPR40 Agonist (TAK-875) : 50-200 mg once/day. Long-chain fatty acids amplify glucose-stimulated insulin secretion, and increases GLP-1 level; GLIMIN (new tetrahydrotriazine-containing class) : IMEGLIMIN (1500 mg twice/day): increases insulin secretion, increases muscle glucose uptake, and decreases hepatic glucose production. 2. Insulin Sensitizers: A. Thiazolidinediones (TZDs): Glitazone Class (Pioglitazone, Neoglitazone, Darglitazone). i. Glitazar Class (Muraglitazar, Ragaglitazar, Imaglitazar, Tesaglitazar = MRIT); Muraglitazar has been ii. Non-Glitazar Class (Metaglidasen: Non Edema and Non Weight Gain) Vol. 27, No. 1 April 2014 C. Biguanide: Metformin XR (Glucophage® XR), 3-Guanidinopropionic-Acid D. DLBS3233 (Inlacin®) 3. Intestinal Enzyme Inhibitors: a-Glucosidase Inhibitor (AGI), a-Amylase Inhibitor (AMI) 4. Incretin-Enhancers DPP-4 Inhibitors: (Sitagliptin, Vildagliptin, Saxagliptin, Alo gliptin, Denagliptin, Du- togliptin, Linagliptin, Melogliptin, Teneligliptin, SYR-322, TA-666) 5. Fixed Dose Combination (FDC) Types: Glucovance®, Amaryl-M®, Galvusmet®, Janumet®, Kombiglyze®XR, Trajenta®Duo, ACTOSmet®, Duet act® 6. Other Specific Types: Sodium GLucose co Transporter-2 (SGLT2)-Inhibitors: ASP1941, BI 10773, Cana- gliflozin, Dapagliflozin, Seragliflozin, Remogliflozin, AVE-2268, KGT-1681, LX-4211, TS-033, YM-543; Glu- cokinase Activator (GKA): MTBL1, MK-0941; OXPHOS-blocker; FBPase-Inhibitor, INCB13739 (11βHSD1- Berberine (Shan et al 2013), a natural plant alkaloid isolated from Chinese herb Coptis chinensis (Huan- glian), stimulates GLP-1 secretion (co-secreted with GLP-2) from intestinal L-cells. Berberine treatment is efficient in repairing the damaged intestinal mucosa, restoring intestinal permeability and improving endotoxemia, all simultaneously while showing antidiabetic effects and a modulation of GLP-2 release in the ileum. Berberine may improve hyperinsulinemia and insulin resistance. On the basis of clinical experiences in daily practice, the map of OADs can be illustrated below (TABLE-1).
TABLE-1. Map of Oral Anti Diabetes (OAD) in Daily Practice
(Summarized : Tjokroprawiro1996-2013)
INSULIN SECRETAGOGUE 1 SUs : Gliquidone, Glipizide, Gliclazide, Glibenclamide, Glimepiride
2 NON-SUs (Metaglinides : Nateglinide, REPAGLINIDE)
3 GPR40 Agonist (TAK-875) : 50-200 mg once/day. Long-chain FAs amplify glucose-stimulated insulin secretion, GLP-1 4 GLIMIN (new tetrahydrotriazine-containing class) : IMEGLIMIN (1500 mg twice/day) : Insulin, Muscle glucose uptake, HGP (Rosi-*), Pio-, Neto-, Dar-glitazone) 1 THIAZOLIDINEDIONES (TZDs): Glitazone Class
2 NON-TZDs :
a Glitazar Class (Mura-*), Raga-, Ima-, Tesaglitazar) : MRIT
b Non-Glitazar Class (Metaglidasen : Non Edema and Non Weight Gain) 3 BIGUANIDE : - Metformin , Metformin XR (Glucophage® XR), 3-Guanidinopropionic-Acid
4 DLBS-3233 (INLACIN®)
I I INTESTINAL ENZYME INHIBITOR
-Glucosidase Inhibitor (AGI): Acarbose -Amylase Inhibitor (AMI): Tendamistase (Sita-, Vilda-**) , Saxa-, Lina-Alo-, Dena-, Duto-, Melo-, Teneli-gliptin, SYR-322, TA-666) V FIXED DOSE COMBINATION (FDC) TYPE
Glucovance®, Amaryl-M®, Galvusmet®, Janumet®, Kombiglyze®XR, Trajenta®Duo, ACTOplusmet®, Duet act® VI OTHER SPECIFIC (OS) TYPE
1 Sodium GLucose co Transporter-2 (SGLT2)-Inhibitors:
1 ASP1941, BI 10773 , Canagliflozin, Dapagliflozin, Seragliflozin, Remogliflozin, AVE-2268,
KGT-1681, LX-4211, TS-033, YM-543 2 Glucokinase Activator (GKA): MTBL1, MK-0941.
3 Oxphos-Blocker 4 FBPase – Inhibitor 5 INCB13739 (11 HSD1–inhibitor) 6 Berberine
Thiazolidinediones (TZDs) such as pioglitazone and biguanide (metformin) as previous insulin sensiti- ve been available in Indonesia for years. However, Inlacin® (DBLS3233), the novel sensitizer (see the Insulin Sensitizer Groupγγαθδ in TABLE 1), has been recently launched and available in the first months TABLE-2 CURRENT CRITERIA FOR THE DIAGNOSIS OF DIABETES-ADA 2013
aim of this article is to introduce the novel insulin sensitizer, Inlacin® (DLBS3233) with its 7 (seven) STANDARDS of MEDICAL CARE in DIABETES-2013
unique possible mechanisms of ac Diabetes Care tion under
36 (Suppl 1), S12 lying sev
y 2013, al metabolic impr
Summarized : Tjokroprawio
ts demonstrated in nlacin®-study performed in Surabaya), to the residents of internal medicine and their associates, internists, and associated spesialists.
A1C >6.5%. The test should be performed in a laboratory using a
method that in NGSP certified and standardized to the DCCT assay. *)
2 FPG >126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at
least 8 h. *)
Vol. 27, No. 1 April 2014 3 2-h PLASMA GLUCOSE >200 mg/dL (11.1 mmol/L) during an OGTT. The test should be
performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.
In a PATIENT with CLASSIC SYMPTOMS of HYPERGLYCEMIA or 4 HYPERGLYCEMIC CRISIS, a RANDOM PLASMA GLUCOSE >200 mg/dL
*)In the ABSENCE of UNEQUIVOCAL HYPERGLYCEMIA, RESULT SHOULD
BE CONFIRMED BY REPEAT TESTING.
NORMAL : A1C < 5.7 %
Pre-Diabetes: A1C 5.7 – 6.4%
This article comprises 5 1. M opics
ap of Or men
al An-ti Diabetes (OAD) in Daily Practice
The summarized criteria for the diagnosis of dia- tioned below.
(Summarized : Tjokroprawiro1996-2013)
betes of ADA-2013 can be seen in TABLE-2.
INSULIN SECRETAGOGUE 1 SUs : Gliquidone, Glipizide, Gliclazide, Glibenclamide, Glimepiride
2 NON-SUs (Metaglinides : Nateglinide, REPAGLINIDE)
P TION ABOUT DIABE R40 Agonist (TAK-875) : 50-200 mg once/ TES Long-chain FAs amplify glucose-stimulated insulin secretion, GLP-1 In 2009, an International Expert Committee that MEL LITUS IN 2011-2013 4 GLIMIN (new tetrahydrotriazine-containing class) : IMEGLIMIN (1500 mg twice/day) : Insulin, Muscle glucose uptake, HGP included representatives of the ADA, the Inter- II. INLACIN® (DLBS INSULI THE NOVEL INSULIN
N SENSITIZER
tional Diabet -, Ne tion (IDF), and the Euro- SENSITIZER: AN OVER 1 THIAZOLIDINEDIONES (TZDs): Glitazone Class
pean Association for the Study of Diabetes (EASD) III. SUMMARY AND C Glitaz USIONS OF ar Class (Mura-*), RTHE RE
aga-, Ima --, Tesaglit
ec ar) : MRIT
ommended the use of the A1C test to diagnose b Non-Glitazar Class (Metaglidasen : Non Edema and Non Weight Gain) diabetes, with a threshold of > 6.5%, and ADA 3 BIGUANIDE : - Metformin , Metformin XR (Glucophage® XR)
IV. PROSPECTIVE OPEN STUDY ON 4 DLBS-3233 (INLACIN®)
adopted this criterion in 2010. The diagnostic test should be performed using a method that is certi- V. THE RESULTS OF I I INT THE SUR
ESTINAL E ABA
INHIBI CIN®
-Glucosidase Inhibitor (AGI): Acarbose fied b-Amylase Inhibit ohemoglobin Standardi- zation Program (NGSP) and standardized or trace- VI. CONCLUSIONS OF (Sita-, Vilda-**) , Saxa-, Lina-Alo-, Dena-, Duto-, 1 Enhancers
able t -, Teneli-gliptin, SYR o the Diabet -322, T ontrol and Complications V FIXED DOSE COMBINATION (FDC) TYPETrial (DCCT) reference assay.
Glucovance®, Amaryl-M®, Galvusmet®, Janumet®, Kombiglyze®XR, Trajenta®Duo, ACTOplusmet®, Duet act® I. RECENT INFORMATION ABOUT DIABETES
VI OTHER SPECIFIC (OS) TYPE
1 Sodium G
an ansporter-2 (SGLT2)-Inhi
tages and disadv bitor tages of A1C meas- MELLITUS IN 2011-2013
1 ASP1941, BI 10773 , Canagliflozin, Dapagliflozin,
ts arRemogliflozin, KGT-1681, LX-4211, TS-033, YM-543 2 Glucokinase Activator (GKA): MTBL1, MK-0941.
3 Oxphos-Blocker 4 FBPase – Inhibitor 5 INCB1
dvan11 HSD1–inhibitor) 6 Berb
tages of A1C measur erine
Based on the report of Clinical Practice Recom- 1. A1C, a picture of the average of BG level over the mendation 2011 of the American Diabetes Asso- preceding 2-3 months ciation (ADA) published in Diabetes Care Janu- 2. Its values vary less than FPG (Fasting Plasma TABLE-2 CURRENT CRITERIA FOR THE DIAGNOSIS OF DIABETES-ADA 2013
STANDARDS of MEDICAL CARE in DIABETES-2013
Diabetes Care 36 (Suppl 1), S12, January 2013, Summarized : Tjokroprawiro 2013
A1C >6.5%. The test should be performed in a laboratory using a
method that in NGSP certified and standardized to the DCCT assay. *)
2 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 be
performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.
In a PATIENT with CLASSIC SYMPTOMS of HYPERGLYCEMIA or 4 HYPERGLYCEMIC CRISIS, a RANDOM PLASMA GLUCOSE >200 mg/dL
*)In the ABSENCE of UNEQUIVOCAL HYPERGLYCEMIA, RESULT SHOULD
BE CONFIRMED BY REPEAT TESTING.
NORMAL : A1C < 5.7 %
Pre-Diabetes: A1C 5.7 – 6.4%
ary 2011 (Vol. 34, Supplement 1), categories of 3. More stable chemical moiety eased risk for diabetes (IRDM) or prediabetes 4. More convenient (PreDM) can be listed below.
5. No fasting; thus, A1C measurement can be per- 1. FPG 100 mg/dL to 125 mg/dL: IFG–prediabetes 2. 2-h PG 140 mg/dL to 199 mg/dL in the 75 g 6. Correlated tightly with the risk of retinopathy OGTT: IGT–prediabetes 7. Sufficiently sensitive and specific.
3. A1C 5.7 %–6.4%: IRDM or prediabetes. The term Pre DM may be applied if desired Disadvantages of A1C Measurement: 4. Patients with any of the abovementioned cri- 1. More expensive (Costly) teria: 1, 2, 3 or its combination of each with other.
2. Inaccurate in case of severely low Hb levels (se- Vol. 27, No. 1 April 2014 vere chronic anemia, hemolytic anemia, etc).
Based on AACE Diabetes Care Plan Guidelines 3. Inlacin® (DLBS3233) increases genes expression 2012, there are 3 interpretations : of PPARγ and PPARδ which results in increased A1C < 5.4 : Normal GLUT-4 synthesis, increased PPARγ number, sti- A1C 5.5–6.4: High risk/prediabetes; requires mulated GLUT-4 activities (translocation, etc).
screening by glucose criteria 4. Inlacin® stimulates GLUT-4 translocation from A1C > 6.5: Diabetes, confirmed by repeating the cytoplasm to membrane.
test on a different day.
5. Inlacin® decreases TNFα leading to a decreased FFA ® decreased translocation of PKCξ and de- II. INLACIN® (DLBS-3233), THE NOVEL INSULIN
creased PKCθ ® decreased serine phosphoryla- SENSITIZER : AN OVERVIEW
tion ® and finally resulting in a decreased insulin resistance. Inlacin® also directly decreases trans- Inlacin® (DLBS3233) is extracted from Lagerstro- location of PKCξ and decreases PKCθ and then emin speciosa and Cinnamomum burmanii. The suppresses serine phosphorylation; and on the bioactive fraction DLBS3233 is standardized by its other hand, it stimulates phosphorylation of ty- content of lagerstroemin, an ellagitannin.
rosine, and hence, decreased insulin resistance can be pursued.
The summarized 7 unique mechanisms of action 6. Inlacin® increases adiponectin level of Inlacin® (DLBS3233) are listed in TABLE-3 and il- 7. Inlacin® may lower resistin level.
lustrated in FIGURE-1. Based on the available data of DLBS3233 (Release Inlacin® (DLBS3233) has 7 (seven) unique mecha- Date: December 2010) and recent publications of nisms of action briefly illustrated in the followings Tjandrawinata et al 2010, Nailufar et al 2011, and Tandrasasmita et al 2011, Inlacin® (DLBS3233) can 1. To stimulate insulin – insulin receptor binding be regarded as the novel insulin sensitizer with 2. To increase phosphorylation of tyrosine re- metabolic-cardiovascular (MECAR) properties. sulting in an increased insulin sensitivity. Thus, The eighteen (18) supporting findings for MECAR Inlacin® decreases insulin resistance. Inlacin® properties of Inlacin® are listed below (FIGURE-2).
(DLBS3233) increases phosphorylation of tyros- 1. Decreased fasting plasma glucose (FPG): 31.41% ine ® IRS (IRS-Ptyr) ® improve cellular responses 2. Decreased prandial plasma glucose (PPG): ® increased insulin sensitivity ® decreased insulin 3. Lowered A1C after 6 weeks of treatment: 1.13% Vol. 27, No. 1 April 2014 4. Decreased random plasma glucose: 29.64% benefits (TABLE-3 and FIGURE-1) 5. Enhanced PPARγ expression: 80% 3. Inlacin® (DLBS3233) is more than just an OAD- 6. Enhanced PPARδ expression: 80% since this novel OAD also shows metabolic car- 7. Stimulated PI3 kinase: 80% diovascular (MECAR) properties (FIGURE-2) 8. Stimulated Akt Expression (esp. Akt): 50% 4. In conclusion, Inlacin® can be used either as 9. Enhanced GLUT-4 expression: 100% monotherapy or as an add-on-therapy for pa- 10. Stimulated glucose uptake: 20% tients with type 2 diabetes mellitus. On the ba- 11. Lowered insulin plasma levels: 64.71% sis of its metabolic-cardiovascular properties, 12. Decreased HOMA-R after 6 weeks of treat- this novel insulin sensitizer can be assumed as the promising drug for diabetic patients with 13. Increased adiponectin expression: 80% prominant insulin resistance and vascular com- 14. Decreased resistin expression: 80% compared plications (FIGURE-3) 5. In clinical experiences with Inlacin® as an add-on 15. Lowered total cholesterol plasma level: 21.36% therapy in more than 300 patients with T2DM, 16. Lowered LDL-cholesterol plasma level: 30.81% improved glycemic control was demonstrated 17. Lowered triglyceride plasma level: 33.78% and promising, and no significant adverse reac- 18. Increased HDL cholesterol level: 18.20% tion was observed.
For practical point of view, such 18 supporting Inlacin® at a dose of 50 mg and 100 mg daily can properties of Inlacin® (DLBS3233) with its 7 unique be prescribed, depending on the previous level of mechanisms of action can be illustrated in FIG- the blood sugar. For practical point of view and based on clinical experiences, FIGURE-2 and FIG- URE-3 can be used as daily guideline to prescribe III. SUMMARY AND CONCLUSIONS OF THE RE-
Inlacin®. In general, there are 4 (four) possible clin- ical indications of Inlacin® as listed below.
A. TYPE 2 DIABETES MELLITUS : 1. Inlacin® (DLBS3233) is the novel OAD and this METFORMIN-, GLITAZONE-, ACARBOSE-, Sus-, IN- drug can be included in insulin sensitizer ca- SULIN- TREATED, ELDERLY, OBESITY tegory in the map of OAD (TABLE-1) 2. Inlacin® (DLBS3233) has 7 unique mechanisms of C. MODY (MONOGENIC DM – AACE 2011) action which results in 18 possible therapeutic D.TYPE-X DM (Tjokroprawiro, 1991). Type-X DM is Vol. 27, No. 1 April 2014 "insulin dependent" (partially: X1 and X2, or totally - dr. Sri Murtiwi, Sp.PD-KEMD, FINASIM X3) DM, derived from T2DM. Most patients are those - dr. Jongky Hendro Prayitno, Sp.PD T2DM tho are suffering from poorly controlled - dr. Hermina Novida, Sp.PD T2DM who have been long time. Mostly, they are of - dr. Hermawan, Sp.PD more than 50 years old.
- dr. Musofa Rusli, Sp.PD - dr. M. Miftahussurur, Sp.PD IV. PROSPECTIVE OPEN STUDY ON INLACIN®
• Study Site : Surabaya Diabetes and Nutrition Centre,
Dr. Soetomo Teaching Hospital Faculty of Medicine Airlangga University Surabaya Study title: Effect of add-on therapy with DLBS-
• Study population
3233 on glycemic control, lipid profile and adi-
- T2DM patients with A1C level of ≥ 7.0% after at least ponectin in patients with type-2-diabetes mel-
a 3-month therapy with a combination of metformin plus one or more oral anti-diabetic agents (uncon- Investigators and Study Site trolled / persistent hyperglycemia), sample size : 50 • Principal Investigator: Prof. Dr. dr. Askandar
• Study treatment : DLBS3233 on top of current OHAs
Tjokroprawiro, Sp.PD-KEMD, FINASIM used by each subject. Co-Investigators : • Study Design (FIGURE-4)
Vol. 27, No. 1 April 2014 • Study Objectives
1. To investigate clinical efficacy of add-on therapy with DLBS3233 in improving blood glucose control, lipid profile and adiponectin in subjects with type-2-diabetes mellitus.
2. To investigate the safety of add-on therapy with DLBS3233 in subjects with type-2-diabetes mellitus.
V. THE RESULTS OF THE SURABAYA-INLACIN® STUDY (SIS)
is much better.
The results of the Surabaya-Inlacin® Study (SIS) can 7. ADIPONECTIN (Apn, TABLE-E) : be described shortly in several points mentioned +0.45mg/mL (W 6: 8.99%) p = 0.148 (not signifi- 1. FASTING PLASMA GLUCOSE : +1.05mg/mL (W 12: 21.18%) p = 0.001. – 18.98 mg/dL (W 6:↓ –10.14%) p = 0.072; But for Routine Exercise subgroup: – 11.71 mg/dL (W 12:↓ –6.26%) p = 0.298 (NS). +0.98mg/mL (W 6: 17.98%) p=0.028.
For routine exercise subgroup of patients (n=25): +1.07mg/mL (W 12: 19.23%) p = 0.019 – 27.92 mg/dL (W6:↓ –17.45%) p=0.049. W = weeks 8. HOMA-R: –0.77 (W 6:↓–16.84%) p = 0.043; –0.50 2. 1-h PRANDIAL PLASMA GLUCOSE: (W 12: ↓ –10.88%) p = 0.281 (NS). – 23.31 mg/dL (W 6:↓ – 8.46%) p = 0.047; For Routine Exercise subgroup (n=25): –1.12 (W 6: – 26.06 mg/dL (W 12:↓ – 9.46%) p = 0.021 ↓ –32.13%) p=0.050 3. A1C (TABLE-B) : 9. IMPROVEMENT IN HOMA-B (overall) was not – 0.36 mg/dL (W 6:↓ –3.69%) p = 0.009; significant, but improvement in routine Exercise – 0.65 mg/dL (W 12:↓ –6.76%) p = 0.001 Group is much better than that in Non-routine 4. LDL CHOLESTEROL (TABLE-C): Exercise subgroup.
– 10.04 mg/dL (W 6: –6.93%) p = 0.006; 10. NO EFFECT ON BODY WEIGHT : +0.36 kg (W 6) – 10.59 mg/dL (W 12: –7.31%) p = 0.020 p = 0.218; +0.23 kg (W 12) p = 0.412 5. TOTAL CHOLESTEROL (TABLE-D): 11. NO SIGNIFICANT CHANGE IN HEART RATE AND – 11.49 mg/dL (W 6: –5.05%) p = 0.002; DIASTOLIC BLOOD PRESSURE (BP), HOWEVER – 10.39 mg/dL (W 12: –4.56%) p = 0.013 THERE IS A SIGNIFICANT REDUCTION IN SYSTOL- 6. TRIGLYCERIDE (TG): IC BP FROM BASELINE AT WEEK-6 (from 131,12 to – 8.39 mg/dL (p = 0.405); –8,00 mg/dL (p = 0.217). 124,29 mmHg, p=0.006), AND AT WEEK-12 (from For Routine Exercise subgroup, the reduction in TG 131,12 to 123,67 mmHg, p=0.004) 12. NO CLINICALLY SIGNIFICANT ADVERSE EVENTS Vol. 27, No. 1 April 2014 (AEs). Most AEs were mild and resolved at the end At WEEK 12, about 12.0% of subjects reached the tar- of study. The most observed AEs are dizziness and get A1C level of less than 7.0% feeling general weekness.
13. TAKEN TOGETHER, COMBINING WITH PHYSI- CAL ACTIVITY, THE EFFICACY OF DLBS3233 WILL RESULT IN A MORE POWERFULL EFFECT.
For practical point of view, six tables on 1-h post prandial glucose (TABLE-A), Reduction in A1C (TABLE-B), Reduction in LDL (TABLE-C), Reduc- tion in total cholesterol (TABLE-D), Elevation of Adiponectin (TABLE-E), and Reduction in HOMA- R in Routine Exercise Group of Patients, either at Week-6 or at Week-12 (TABLE-F) will be illustrated in the following TABLES. A. REDUCTION IN 1-h POST PRANDIAL GLUCOSE
TABLE-A shows a significant reduction on one hour-plasma glucose (1-h PG) after 6 weeks and 12 weeks of treatment with DLBS3233 from baseline with p = 0.047 and p = 0.021, respectively. This re- sult showed that DLBS3233 was effective in reduc- C. REDUCTION IN LDL (TABLE-C)
TABLE-C shows a significant reduction from base- line in LDL cholesterol level, after 6 weeks and 12 weeks of treatment with DLBS3233 with p = 0.006, and p = 0.020, respectively. This result showed that DLBS3233 was effective in reducing LDL cholesterol. Of the total of 50 evaluable study subjects, only one subject took statin (i.e. simvastatin) during the study B. REDUCTION IN A1C (TABLE-B)
TABLE-B shows a marked reduction in A1C from baseline, after 6 and 12 weeks of treatment with DLBS-3233 with p = 0.009 and p = 0.001, respec- tively. These results showed that DLBS3233 was ef- fective in reducing A1C. Vol. 27, No. 1 April 2014 D. REDUCTION IN TOTAL CHOLESTEROL (TABLE-D)
TABLE-D shows that treatment with DLBS-3233 sig- nificantly reduced total cholesterol level after 6 and 12 weeks with p = 0.002 and p = 0.013, respectively. These results showed that DLBS3233 was effective in reducing total 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 of adiponectin (Apn), after 12 weeks of treatment with DLBS3233 (p = 0.001). This result showed that DLBS3233 was 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 on HOMA-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 exercise demonstrated a more powerful effect on HOMA-R re- duction (–1.12, p=0.05). This is especially true because exercise and DLBS3233 act in synergy in inducing insu- lin-signaling pathway. In Week 12, Non-Routine Exercise Group showed better HOMA-R reduction than that of the Routine Exercise sub- group (–0.63 vs –0.37). This also indicates that the effect Vol. 27, No. 1 April 2014 of DLBS3233 was continuing while the more modest effect in the Routine Exercise subgroup might be as- sociated to non-compliance of subjects to lifestyle.
1. Dexa Medica (2010). Product Monograph DLBS3233 VI. CONCLUSIONS OF THE SURABAYA-INLACIN®
2. Investigator's Brochure DLBS3233. Dexa Medica (2010) 3. Nailufar F, and Tjandrawinata RR (2011). Effects of DLBS3233, STUDY (SIS)
an insulin sensitizer, on fructose-induced insulin resistance rat. Medicinus 24,13 Inlacin® (DLBS3233), the novel insulin sensitizer 4. Shan CY, Yang JH, Kong Y, Wang XY, Zheng NY, XU YG, et al (2013). is able to demonstrate several significant benefits Alteration of the Intestinal Barriers and GLP-2 secretion in Ber-berine-treated type 2 diabetic rats. Journal of Endocrinology which are important for the management of patients with diabetes mellitus and also for the prevention 5. Tandrasasmita OM, Wulan DDDR, Nailufar F, et al (2011). and treatment of its cardiovascular complications. DLBS3233 increases glucose uptake by mediating upregulation of PPARγ and GLUT4 expression. Biomedicine and Preventive Such beneficial effects of DLBS3233 are listed below.
Nutrition (In press) 6. Tjandrawinata R, Suastika K, Noflarny D (2010). DLBS-3233 ex- A. reduced 1 hour post prandial glucose p<0.021 tract and its low risk of hypoglycemia in normoglycemic non-obese healthy subjects: a phase-I study. Phytotherapy Research. B. reduced A1C p<0.001 (TABLE-B) 7. Tjokroprawiro A (1978). The Dietetic Regimen for Indonesian C. reduced LDL Chol p<0.020 (TABLE-C) Patients with Diabetes Mellitus. Surabaya, Airlangga University D. reduced total Chol. p<0.013 (TABLE-D) Press, Surabaya January 14 8. Tjokroprawiro A (2010). GalvusMet®: the Novel FDC of Vildaglip- E. increased adiponectin p<0.001 (TABLE-E) tin and Metformin (Its Roles on Metabolic Cardiovascular Com- F. reduced HOMA-R (for overall) at week-6 (p<0.043) plications in T2DM). Joint Symposium SUMETSU-7, MECARSU-7, but not significant at week-12. However, in patients and SOBU-2. Surabaya, 12-13 February 9. Tjokroprawiro A (2011A). Inlacin® : The Novel Insulin Sensitizer with routine exercise the reduction is even greater (i.e. with Mecar Effects (From 4 Unique Mechanisms to 18 Possible a significant reduction HOMA-R at week-6 (p<0.050, Therapeutic Benefits). Launching Symposium. Surabaya 19 TABLE-F) a that found in patients without routine ex- 10. Tjokroprawiro A (2011B). Inlacin® (DLBS-3233): The Novel Insulin Sensitizer (From Theory to Clinical Benefits for Pts with Diabetes Mellitus). Symposium III. Makassar, 16 - 17 July Taken together, the conclusions of the Surabaya- 11. Tjokroprawiro A (2011C). InlacinÒ (DLBS-3233): The Novel Insulin Inlacin® Study can be summarized below: Sensitizer with Multiple Unique Mechanism (Its Clinical Benefits for Patients with Diabetes Mellitus). Symposium PKB-XXVI. Sura- 1. Add-on therapy with DLBS32233 in uncontrolled T2DM subjects was effective in 12. Tjokroprawiro A (2011D). Clinical Uses of Inlacin® in Daily Practice - Improving glycemic control, by significantly for Pts with T2DM (Its Clinical Benefits for Patients with Diabetes Mellitus). Symposium SDU-XXI & SOBU-3. Surabaya, 8-9 October reducing post-prandial glucose level as well as 13. Tjokroprawiro A (2011E). Inlacin® (DLBS3233) : the Novel Insulin Sensitizer with 5 Unique Mechanisms (Its Roles on Mono–and - Improving lipid profile, by significantly reducing Add–on Therapy in Pts with T2DM). Medan, 20 November LDL and total cholesterol level and reducing tri- 14. Tjokroprawiro A (2012A). Inlacin®, the Novel Insulin Sensitizer for Patients with T2DM (Its Roles on Mono–and Add–on Therapy). glyceride level but insignificant Banda Aceh, 28 January 2. Significantly increasing adiponectin level.
15. Tjokroprawiro A (2012B). Inlacin®, the Novel Insulin Sensitizer in 3. Add-on therapy with DLBS3233 was safe and toler- Clinical Practice (Its Roles on Mono–and Add–on Therapy for Pa-tients with Diabetes). Padang, 11-12 February able in T2DM subjects.
16. Tjokroprawiro A (2013A). The Roles of Inlacin® in the Manage- 4. Additional benefit on lowering systolic blood pres- ment of Patients with T2DM. (Clinical Experiences and the Results of Prospective Study on Inlacin®). Temu Ilmiah Penyakit Dalam 2013. Holistic Management in Internal Medicine, from EBM to 5. Implementing routine physical activity plus this Application . Palembang, 11 May novel insulin sensitizer may result in a more po- 17. Tjokroprawiro A (2013B). Clinical Review of DLBS3233 (Inlacin®) on Patients with T2DM (Prelimenary Results of the Prospective Study in Surabaya). The 7th DOCLink Jakarta, 14-16 June 18. Tjokroprawiro A (2013C). Clinical Review of DLBS-3233 (Inlacin®) Abbreviation: 2hPG = 2 hour Plasma Glucose; AACE =
on Patients with T2DM. Clinical Review of DLBS-3233 (Inlacin®) American Association of Clinical Endocrinologists; AC = Ante
on Patients with T2DM (Provided with the Results of Prospective Inlacin®-Study in Surabaya). Medical Seminar : Scientific Session- Coenam (before meal); ADA = American Diabetes Associa-
II. Balikpapan Diabetes Update-2013. Balikpapan, 13 October tion; DCCT = Diabetes Control and Complications Trial; EASD
19. Tjokroprawiro A (2013D). Inlacin as Add-on Therapy in Patients = European Association for the Study of Diabetes; FFA = Free
with T2DM (Provided with the Results of the Prospective Inla- Fatty Acid; FPG = Fasting Plasma Glucose; HOMA-R = Home-
cin®–Study in Surabaya). SUMETSU-10, MECARSU-10, SOBU-7, SDU-24. Surabaya, 19-20 October ostasis Model Assessment – Resistance; IDF = International
20. Tjokroprawiro A (2013E). Clinical Review of DLBS3233 (Inlacin®) Diabetes Federation; IFG = Impaired Fasting Glucose; IGT =
on Patients with T2DM (Provided with the Results of Prospective Impaired Glucose Tolerance; IR = Insulin Resistance; IRDM =
Study in Surabaya) HP EXTRA-I Healthy Palu Exhibition & Train-ing-I 2013. PALU, 2 November Increased Risk for Diabetes; MECAR = Metabolic-Cardiovas-
21. Tjokroprawiro A (2013F). Inlacin® : the Novel Insulin Sensitizer cular; NGSP = National Glycohemoglobin Standardization
Produced in Indonesia (Back up: the Results Surabaya-Inlacin® Program; OAD = Oral Anti Diabetes; OGTT = Oral Glucose
Study in Patients with Diabetes) East Indonesia Endometabolic Tolerance Test; Pre-DM = Prediabetes; SIS = Surabaya-Inla-
Up Date VIII. Manado, 9 November cin® Study; TZDs = Thiazolidinediones.
Vol. 27, No. 1 April 2014

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