The Effect and Safety Assessment of Metformin and DLBS3233 (A Bioactive Fraction of Lagerstroemia speciosa and Cinnamomum burmannii) on Improving Metabolic Parameters in Women with Polycystic Ovary Syndrome

Figures & data

Figure 1 Flow of study.

Table 1 Demographics and Biochemical Characteristics

Variable	Combination (N = 20)	DLBS3233 (N = 20)	Metformin XR (N = 20)	p-values
	Mean ± SD	Mean ± SD	Mean ± SD
Demographic
Age (years)	27.40 ± 2.44	28.60 ± 4.63	27.80 ± 2.55	0.740
Baseline characteristics
Height (m)	1.55 ± 0.04	1.58 ± 0.07	1.55 ± 0.05	0.119
Weight (kg)	73.10 ± 10.21	77.63 ± 13.46	74.43 ± 9.19	0.421
BMI (kg/m^2)	30.36 ± 3.88	30.88 ± 3.88	30.89 ± 3.25	0.875
SBP (mmHg)	116.00 ± 7.54	112.50 ± 5.50	116.50 ± 6.71	0.136
DBP (mmHg)	74.50 ± 7.59	75.00 ± 6.07	74.50 ± 6.05	0.859
Pulse (per minute)	80.30 ± 3.96	81.70 ± 4.60	80.35 ± 6.66	0.384
Respiratory rate (per minute)	19.00 ± 1.38	19.50 ± 1.10	18.70 ± 1.49	0.149
Waist circumference (cm)	87.80 ± 9.27	92.30 ± 9.24	86.20 ± 7.76	0.084
Ferriman-Gallwey score	7.85 ± 2.54	9.85 ± 3.03	9.25 ± 1.33	0.125
Baseline laboratory parameters
FPG (mg/dL)	84.68 ± 8.58	86.97 ± 10.02	88.60 ± 8.92	0.405
2h-PG (mg/dL)	128.87 ± 26.55	149.89 ± 23.42	128.85 ± 31.03	0.024*
Fasting insulin (mU/L)	15.59 ± 4.27	16.56 ± 5.02	18.34 ± 7.47	0.363
HOMA-IR	3.30 ± 1.14	3.55 ± 1.09	4.00 ± 1.78	0.374
LDL (mg/dL)	134.93 ± 27.14	152.52 ± 29.15	126.05 ± 43.98	0.053
HDL (mg/dL)	41.47 ± 9.18	40.52 ± 8.52	37.25 ± 7.23	0.253
Total cholesterol (mg/dL)	195.08 ± 24.83	214.41 ± 33.63	191.05 ± 34.58	0.049*
Triglycerides (mg/dL)	149.04 ± 62.92	156.28 ± 51.17	211.80 ± 173.96	0.591
AST (U/L)	20.94 ± 6.08	23.33 ± 8.64	22.35 ± 9.28	0.649
ALT (U/L)	30.41 ± 18.72	27.17 ± 15.08	28.95 ± 16.21	0.964
AP (U/L)	63.70 ± 17.36	71.20 ± 22.72	60.70 ± 15.36	0.304
Creatinine (mg/dL)	0.64 ± 0.07	0.62 ± 0.11	0.67 ± 0.10	0.312
BUN (mg/dL)	8.27 ± 1.77	9.13 ± 2.09	8.55 ± 1.49	0.306
General health status:
Good (n)	20	20	20	N/A
Moderate (n)	0	0	0
Poor (n)	0	0	0

Note: *Significant at significance criteria of 0.05.

Abbreviations: 2h-PG, 2-hour postprandial glucose; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BMI, body mass index; BUN = blood urea nitrogen; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL, high density lipoprotein; HOMA-IR, homeostasis model assessment – insulin resistance; LDL, low density lipoprotein; SBP, systolic blood pressure.

Table 2 Test of Primary Efficacy Endpoint: the Improvement (Reduction) of HOMA-IR from Baseline

Time	Combination (N = 20) Mean (SE)	Difference (95% CI)^a	p-value^b	DLBS3233 (N = 20)Mean (SE)	Difference (95% CI)^c	p-value^d	Metformin XR (N = 20)Mean (SE)
Month 3	−0.45 (0.42)	1.31 (0.12,2.50)	0.031*	−0.003 (0.43)	1.75 (0.55,2.96)	0.021*	−1.76 (0.43)
Month 6	−0.17 (0.60)	−0.59 (−2.24,1.06)	0.478	0.20 (0.68)	−0.22 (−2.00,1.56)	0.211	0.42 (0.57)

Notes: *Significant at significance criteria of 0.05. ^aDifference = mean reduction of HOMA-IR in Combination group subtracted by mean reduction of HOMA-IR in metformin XR group (reduction of HOMA-IR was calculated as the value of HOMA-IR at the corresponding visit subtracted by the value of HOMA-IR at baseline). ^bp-value from 2-tailed test for superiority. ^cDifference = mean reduction of HOMA-IR in DLBS3233 group subtracted by mean reduction of HOMA-IR of metformin XR group. ^dp-value from 1-tailed test for non-inferiority.

Abbreviations: SE, standard error; CI, confidence interval.

Table 3 Comparison of HOMA-IR Value Between- and Within-Group

ITT
Time	Combination (N = 20) Mean (SE)	p-value^a	Difference (95% CI)^b	p-value^c	DLBS3233 (N = 20) Mean (SE)	p-value^d	Difference (95% CI)^e	p-value^f	Metformin XR (N = 20) Mean (SE)	p-value^g
Month 0	3.30 (0.30)	-	−0.70 (−1.54,0.15)	0.105	3.55 (0.30)	-	−0.45 (−1.30,0.40)	0.291	4.00 (0.30)	-
Month 3	2.86 (0.35)	0.288	0.65 (−0.35,1.65)	0.202	3.59 (0.36)	0.914	1.38 (0.37,2.39)	0.008*	2.21 (0.36)	0.000*
Month 6	3.12 (0.67)	0.768	−1.28 (−3.15,0.59)	0.176	3.80 (0.75)	0.718	−0.61 (−2.59,1.37)	0.542	4.40 (0.65)	0.482
PP
Time	Combination (N = 19) Mean (SE)	p-value^a	Difference (95% CI)^b	p-value^c	DLBS3233 (N = 12) Mean (SE)	p-value^d	Difference (95% CI)^e	p-value^f	Metformin XR (N = 18) Mean (SE)	p-value^g
Month 0	3.26 (0.33)	-	−0.75 (−1.68,0.18)	0.110	3.61 (0.41)	-	−0.41 (−1.46,0.65)	0.443	4.01 (0.33)	-
Month 3	2.74 (0.28)	0.192	0.46 (−0.35,1.28)	0.257	3.06 (0.37)	0.290	0.79 (−0.16,1.73)	0.100	2.27 (0.29)	0.000*
Month 6	3.04 (0.68)	0.707	−1.47 (−3.37,0.44)	0.128	3.96 (0.82)	0.621	−0.55 (−2.66,1.57)	0.606	4.51 (0.66)	0.397

Notes: *Significant at significance criteria of 0.05. ^ap-value within Combination group, the value of HOMA-IR at baseline as reference. ^bDifference = mean HOMA-IR of Combination group subtracted by mean HOMA-IR of metformin XR group. ^cp-value of the difference between Combination group and metformin XR group. ^dp-value within DLBS3233 group, the value of HOMA-IR at baseline as reference. ^eDifference = mean HOMA-IR of DLBS3233 group subtracted by mean HOMA-IR of metformin XR group. ^fp-value of the difference between DLBS3233 group and metformin XR group. ^gp-value within metformin XR group, the value of HOMA-IR at baseline as reference.

Abbreviations: SE, standard error; CI, confidence interval.

Figure 2 Absolute values of HOMA-IR at each time point.

Table 4 Secondary Efficacy Endpoints: Comparison of the Absolute, Between- and Within-Group Values

Variable	Time	Combination (N = 20) Mean (SE)	p-value^a	Difference (95% CI)^b	p-value^c	DLBS3233 (N = 20) Mean (SE)	p-value	Difference (95% CI)^e	p-value^f	Metformin XR(N = 20) Mean (SE)	p-value^g
FPG	Month 0	84.68 (2.00)	-	−3.92 (−9.58,1.75)	0.172	86.97 (2.00)	-	−1.63 (−7.30,4.04)	0.567	88.60 (2.00)	-
	Month 3	86.25 (2.39)	0.506	2.00 (−4.79,8.79)	0.558	87.16 (2.41)	0.936	2.91 (−3.91,9.74)	0.397	84.25 (2.41)	0.071
	Month 6	90.39 (3.68)	0.111	−0.39 (−10.76,9.98)	0.940	90.53 (4.01)	0.360	−0.25 (−11.08,10.58)	0.964	90.78 (3.63)	0.533
2h-PG	Month 0	128.87 (5.92)	-	0.02 (−16.74,16.77)	0.999	149.89 (5.92)	-	21.04 (4.28,37.80)	0.015*	128.85 (5.92)	-
	Month 3	134.97 (7.58)	0.481	4.96 (−16.78,26.70)	0.649	161.57 (8.42)	0.216	31.56 (8.62,54.49)	0.008*	130.01 (7.75)	0.895
	Month 6	139.89 (8.00)	0.168	4.55 (−18.17,27.27)	0.689	151.86 (9.16)	0.828	16.52 (−7.88,40.92)	0.180	135.35 (8.00)	0.414
ET	Month 0	5.94 (0.64)	-	−0.79 (−2.59,1.02)	0.387	5.50 (0.64)	-	−1.23 (−3.03,0.58)	0.179	6.73 (0.64)	-
	Month 3	6.17 (0.97)	0.845	0.34 (−2.47,3.15)	0.807	5.38 (1.05)	0.923	−0.45 (−3.37,2.48)	0.761	5.83 (1.02)	0.461
	Month 6	7.04 (1.66)	0.544	0.98 (−3.73,5.69)	0.678	9.41 (1.92)	0.061	3.35 (−1.74,8.44)	0.193	6.06 (1.66)	0.713
LDL	Month 0	134.93 (7.47)	-	8.88 (−12.24,30.00)	0.404	152.52 (7.47)	-	26.47 (5.35,47.59)	0.015*	126.05 (7.47)	-
	Month 3	128.67 (5.81)	0.212	−1.61 (−18.12,14.91)	0.846	145.47 (6.11)	0.188	15.19 (−1.73,32.11)	0.078	130.27 (5.86)	0.404
	Month 6	139.05 (6.37)	0.468	6.66 (−11.38,24.69)	0.463	139.31 (6.94)	0.039*	6.92 (−11.92,25.75)	0.465	132.39 (6.37)	0.265
HDL	Month 0	41.47 (1.82)	-	4.22 (−0.93,9.37)	0.106	40.52 (1.82)	-	3.27 (−1.88,8.42)	0.209	37.25 (1.82)	-
	Month 3	41.07 (1.67)	0.746	0.54 (−4.22,5.29)	0.822	41.16 (1.75)	0.632	0.62 (−4.25,5.49)	0.800	40.54 (1.69)	0.010*
	Month 6	43.09 (1.66)	0.257	4.14 (−0.57,8.86)	0.084	40.72 (1.82)	0.898	1.77 (−3.16,6.71)	0.475	38.95 (1.66)	0.235
TC	Month 0	195.08 (6.83)	-	4.03 (−15.28,23.34)	0.678	214.41 (6.83)	-	23.36 (4.05,42.67)	0.019*	191.05 (6.83)	-
	Month 3	190.03 (6.29)	0.317	−2.28 (−20.14,15.58)	0.799	199.95 (6.62)	0.010*	7.65 (−10.67,25.97)	0.407	192.31 (6.34)	0.805
	Month 6	201.22 (6.61)	0.311	3.25 (−15.48,21.98)	0.730	195.12 (7.24)	0.005*	−2.85 (−22.45,16.76)	0.773	197.97 (6.61)	0.254
TG	Month 0	149.04 (24.15)	-	−62.76 (−131.08,5.56)	0.071	156.28 (24.15)	-	−55.52 (−123.84,12.81)	0.109	211.80 (24.15)	-
	Month 3	162.57 (14.84)	0.523	4.78 (−37.51,47.08)	0.822	123.53 (16.03)	0.140	−34.25 (−78.22,9.71)	0.124	157.78 (15.02)	0.013*
	Month 6	155.57 (19.51)	0.764	−33.62 (−88.89,21.65)	0.228	138.75 (21.62)	0.459	−50.44 (−108.70,7.82)	0.088	189.19 (19.51)	0.301
FGS	Month 0	7.85 (0.53)	-	−1.40 (−2.89,0.09)	0.064	9.85 (0.53)	-	0.60 (−0.89,2.09)	0.422	9.25 (0.53)	-
	Month 3	8.10 (0.50)	0.268	−1.25 (−2.67,0.17)	0.082	9.70 (0.50)	0.505	0.35 (−1.07,1.77)	0.623	9.35 (0.50)	0.657
	Month 6	7.74 (0.52)	0.637	−1.46 (−2.94,0.01)	0.051	9.69 (0.53)	0.523	0.49 (−0.99,1.97)	0.512	9.20 (0.52)	0.832
BMI	Month 0	30.28 (0.80)	-	−0.61 (−2.87,1.65)	0.593	30.87 (0.80)	-	−0.02 (−2.28,2.24)	0.984	30.89 (0.80)	-
	Month 1	29.87 (0.80)	0.002*	−0.70 (−2.97,1.58)	0.543	30.73 (0.80)	0.287	0.16 (−2.11,2.43)	0.887	30.57 (0.80)	0.014*
	Month 2	29.50 (0.85)	0.000*	−0.96 (−3.37,1.44)	0.426	30.41 (0.85)	0.032*	−0.06 (−2.47,2.35)	0.961	30.47 (0.85)	0.048*
	Month 3	29.36 (0.87)	0.000*	−0.95 (−3.40,1.51)	0.442	30.52 (0.87)	0.136	0.21 (−2.25,2.66)	0.865	30.31 (0.87)	0.015*
	Month 4	29.23 (0.84)	0.000*	−1.05 (−3.44,1.33)	0.381	30.47 (0.85)	0.110	0.19 (−2.20,2.58)	0.875	30.28 (0.84)	0.014*
	Month 5	29.21 (0.85)	0.000*	−0.94 (−3.35,1.46)	0.436	30.52 (0.85)	0.208	0.36 (−2.05,2.77)	0.765	30.16 (0.85)	0.007*
	Month 6	29.32 (0.84)	0.001*	−0.84 (−3.21,1.53)	0.482	30.48 (0.84)	0.162	0.32 (−2.06,2.69)	0.789	30.16 (0.84)	0.006*
WC	Month 0	87.80 (1.92)	-	1.60 (−3.82,7.02)	0.557	92.30 (1.92)	-	6.10 (0.68,11.52)	0.028*	86.20 (1.92)	-
	Month 1	86.40 (1.96)	0.029*	0.25 (−5.30,5.80)	0.928	91.48 (1.96)	0.192	5.33 (−0.22,10.87)	0.060	86.15 (1.96)	0.936
	Month 2	85.65 (2.02)	0.003*	0.60 (−5.11,6.31)	0.834	90.75 (2.02)	0.027*	5.70 (−0.005,11.41)	0.050*	85.05 (2.02)	0.098
	Month 3	84.78 (2.03)	0.000*	0.40 (−5.33,6.13)	0.889	90.90 (2.03)	0.074	6.53 (0.79,12.26)	0.026*	84.38 (2.03)	0.021*
	Month 4	84.75 (1.94)	0.000*	0.05 (−5.45,5.55)	0.986	90.92 (1.95)	0.104	6.22 (0.71,11.73)	0.028*	84.70 (1.94)	0.074
	Month 5	85.56 (1.92)	0.014*	−0.29 (−5.71,5.14)	0.916	92.25 (1.95)	0.955	6.40 (0.93,11.86)	0.023*	85.85 (1.91)	0.689
	Month 6	84.92 (1.80)	0.004*	−0.23 (−5.32,4.85)	0.927	93.43 (1.84)	0.281	8.28 (3.14,13.42)	0.002*	85.15 (1.79)	0.275
FT	Month 0	8.27 (3.29)	-	1.41 (−7.79,10.61)	0.760	12.00 (3.21)	-	5.14 (−3.95,14.22)	0.262	6.86 (3.21)	-
	Month 6	5.78 (1.11)	0.461	−0.48 (−3.64,2.68)	0.762	7.14 (1.26)	0.150	0.89 (−2.49,4.26)	0.600	6.25 (1.11)	0.854

Notes: *Significant at significance criteria of 0.05. ^ap-value within Combination group, the value of variable at baseline as reference. ^bDifference = mean variable in Combination group subtracted by mean variable in metformin XR group. ^cp-value of the difference between Combination group and metformin XR group. ^dp-value within DLBS3233 group, the value of variable at baseline as reference. ^eDifference = mean variable in DLBS3233 group subtracted by mean variable in metformin XR group. ^fp-value of the difference between DLBS3233 group and metformin XR group. ^gp-value within metformin XR group, the value of variable at baseline as reference.

Abbreviations: SE, standard error; CI, confidence interval.

Figure 3 Absolute BMI values at each time point.

Table 5 Comparison of Safety Between Groups

Variable	Combination (N = 23) Mean (SE)	DLBS3233 (N = 24) Mean (SE)	Metformin XR (N = 23) Mean (SE)	p-value (2-tailed)
Vital signs
SBP (mmHg)	115.26 (1.60)	114.71 (1.51)	117.75 (1.28)	0.128^†
DBP (mmHg)	73.16 (1.34)	74.71 (1.25)	73.50 (1.09)	0.718^†
Pulse (per minute)	81.42 (0.68)	82.53 (0.92)	81.40 (0.96)	0.592
Respiratory rate (per minute)	18.84 (0.35)	19.18 (0.30)	19.10 (0.23)	0.685^†
Liver function
AST (U/L)	21.40 (14.28)	21.68 (9.19)	19.77 (6.96)	0.778^†
ALT (U/L)	28.57 (20.07)	27.72 (16.89)	29.56 (16.95)	0.868^†
AP (U/L)	62.35 (20.16)	65.41 (17.28)	61.48 (13.87)	0.688^†
Renal function
Creatinine (mg/dL)	0.63 (0.09)	0.64 (0.08)	0.65 (0.10)	0.733
BUN (mg/dL)	9.05 (3.42)	8.34 (2.87)	7.98 (1.89)	0.822^†
Serious Adverse Events	Severity	Relationship	Duration	Outcome
Measles (No. 130, Metformin Group)	Moderate	None	20–29 Oct 16	Recovered
Gastritis (No. 137, Metformin Group)	Moderate	None	5–11 Sep 16	Recovered
Tonsilitis (No. 137, Metformin Group)	Mild	None	5–19 Sep 16	Recovered
Urinary tract infection (No. 137, Metformin Group)	Mild	None	5–8 Oct 16	Recovered

Notes: *Significant at significance criteria of 0.05. ^†Analysis using non-parametric test (Kruskal–Wallis) because the assumption of normality and/or homogeneity of variances was not met.

Abbreviation: SE, standard error.