J Endocrinol Metab

Journal of Endocrinology and Metabolism, ISSN 1923-2861 print, 1923-287X online, Open Access

Article copyright, the authors; Journal compilation copyright, J Endocrinol Metab and Elmer Press Inc

Journal website https://www.jofem.org

Original Article

Volume 13, Number 4, November 2023, pages 153-163

Improvement of Glycemic Control by Metformin Is Associated With Frequency of Defecation Before Treatment in Patients With Type 2 Diabetes Mellitus

Figure 1. Changes in FD before and after administration of metformin or an SGLT2i during hospitalization. (a) Comparison of FD before (left panel) and after (right panel) initiation of metformin (n = 30) or an SGLT2i (n = 25). (b) Line (left) and dot plot (right) comparisons of FD among individuals in the metformin group. (c) Line (left) and dot plot (right) comparisons of FD among individuals in the SGLT2i group. Data were analyzed using the unpaired t-test in (a) and the paired t-test in (b) and (c). *P < 0.05. **P < 0.01. FD: frequency of defecation; SGLT2i: sodium-glucose cotransporter-2 inhibitor.

Figure 2. Relationship between ΔFD and FD before initiation of metformin or an SGLT2i. (a) Metformin group (n = 30). (b) SGLT2i group (n = 25). Data were analyzed using Spearman’s correlation analysis. *P < 0.01. ΔFD: change in FD; FD: frequency of defecation; SGLT2i: sodium-glucose cotransporter-2 inhibitor.

Figure 3. Relationship between ΔHbA_1c and change in FD (ΔFD or FD ratio) or FD before and after initiation of metformin (n = 30) or an SGLT2i (n = 25). (a) ΔFD after initiation of metformin, (b) FD ratio before and after initiation of metformin, (c) FD before initiation of metformin, (d) FD after initiation of metformin, (e) ΔFD after initiation of SGLT2i, (f) FD ratio before and after initiation of SGLT2i, (g) FD before initiation of SGLT2i, and (h) FD after initiation of SGLT2i. Data in (a), (b), (e), and (f) were analyzed using Spearman’s correlation analysis and data in (c), (d), (g), and (h) were analyzed using the unpaired t-test. *P < 0.01. ΔHbA_1c: change in glycated hemoglobin; ΔFD: change in FD; FD: frequency of defecation; SGLT2i: sodium-glucose cotransporter-2 inhibitor.

**Table 1.** Baseline Characteristics of the Patients Who Were Taking Metformin or SGLT2i
Variable	Treatment	P-value
Data are presented as mean ± SD, median (IQR) or %.^aWilcoxon rank sum test. ^bPearson’s χ²-test. ^cUnpaired t-test. eGFR: estimated glomerular filtration rate; HbA_1c: glycated hemoglobin; IQR: interquartile range; SD: standard deviation; SGLT2i: sodium-glucose cotransporter 2 inhibitors.
Age (years) (median (IQR))	56.0 (51.0 - 69.0)	60.0 (52.0 - 66.5)	0.899^a
Sex, male (%)	70.0	60.0	0.437^b
Body mass (kg) (mean ± SD)	67.3 ± 13.8	66.5 ± 12.7	0.834^c
Body mass index (kg/m²)	25.3 ± 3.81	25.8 ± 4.80	0.664^c
Duration of diabetes (years)	6 (0.5 - 13.0)	3 (0.5 - 13.5)	0.637^a
Fasting plasma glucose (mg/dL)	208 (146 - 265)	171 (146 - 245)	0.335^a
HbA_1c at admission (%)	10.2 (8.8 - 12.2)	9.5 (7.9 - 12.4)	0.310^a
Fasting C-peptide (ng/mL)	1.78 ± 0.62 (n = 29)	2.06 ± 0.76 (n = 20)	0.172^c
eGFR (mL/min/1.73 m²)	77.9 ± 15.9	71.6 ± 24.9	0.266^c
Hypertension (%)	40.0	28.0	0.351^b
Dyslipidemia (%)	86.7	84.0	0.780^b
Smoking (%)	34.5	16.0	0.122^b
Alcohol (%)	24.1	28.0	0.740^b
Diabetes polyneuropathy (%)	35.7	28.0	0.548^b
Diabetes retinopathy (%)	50.0	36.0	0.297^b
Diabetes nephropathy (%)	36.7	16.0	0.087^b

Table 1. Baseline Characteristics of the Patients Who Were Taking Metformin or SGLT2i

Variable

Treatment

P-value

Metformin (n = 30)

SGLT2i (n = 25)

Data are presented as mean ± SD, median (IQR) or %.^aWilcoxon rank sum test. ^bPearson’s χ²-test. ^cUnpaired t-test. eGFR: estimated glomerular filtration rate; HbA_1c: glycated hemoglobin; IQR: interquartile range; SD: standard deviation; SGLT2i: sodium-glucose cotransporter 2 inhibitors.

Age (years) (median (IQR))

56.0 (51.0 - 69.0)

60.0 (52.0 - 66.5)

0.899^a

Sex, male (%)

70.0

60.0

0.437^b

Body mass (kg) (mean ± SD)

67.3 ± 13.8

66.5 ± 12.7

0.834^c

Body mass index (kg/m²)

25.3 ± 3.81

25.8 ± 4.80

0.664^c

Duration of diabetes (years)

6 (0.5 - 13.0)

3 (0.5 - 13.5)

0.637^a

Fasting plasma glucose (mg/dL)

208 (146 - 265)

171 (146 - 245)

0.335^a

HbA_1c at admission (%)

10.2 (8.8 - 12.2)

9.5 (7.9 - 12.4)

0.310^a

Fasting C-peptide (ng/mL)

1.78 ± 0.62 (n = 29)

2.06 ± 0.76 (n = 20)

0.172^c

eGFR (mL/min/1.73 m²)

77.9 ± 15.9

71.6 ± 24.9

0.266^c

Hypertension (%)

40.0

28.0

0.351^b

Dyslipidemia (%)

86.7

84.0

0.780^b

Smoking (%)

34.5

16.0

0.122^b

Alcohol (%)

24.1

28.0

0.740^b

Diabetes polyneuropathy (%)

35.7

28.0

0.548^b

Diabetes retinopathy (%)

50.0

36.0

0.297^b

Diabetes nephropathy (%)

36.7

16.0

0.087^b

**Table 2.** Frequency of Defecation Parameters and Characteristics of the Patients After Admission According to Type of Treatment Initiated
Variable	Treatment	P-value
Data are presented as mean ± SD, median (IQR) or %. P < 0.05. *P < 0.01.^aWilcoxon rank sum test. ^bUnpaired t-test. ^cPearson’s χ²-test. DPP4i: dipeptidyl peptidase-4 inhibitors; FD: frequency of defecation; ΔFD: change in FD; GLP-1: glucagon-like peptide 1; HbA_1c: glycated hemoglobin; ΔHbA_1c: change in HbA1c; IQR: interquartile range; SD: standard deviation; SGLT2i: sodium-glucose cotransporter 2 inhibitors.
Days on which FD was recorded before initiation of treatment (days)	7.0 (4.8 - 10.0)	7.0 (3.5 - 9.5)	0.507^a
Days on which FD was recorded after initiation of treatment (days)	6.0 (5.0 - 10.3)	7.0 (5.0 - 9.5)	0.980^a
Time to starting recording of FD after initiation of treatment (days)	0 (0 - 3)	0 (0 - 0)	0.014*^a
FD before initiation of treatment (times/day)	0.70 ± 0.19	0.74 ± 0.21	0.428^b
FD after initiation of treatment (times/day)	0.83 ± 0.18	0.73 ± 0.20	0.047*^b
ΔFD (FD after - FD before) (times/day)	0.06 (0.00 - 0.29)	0.00 (-0.24 - 0.27)	0.062^a
FD ratio (FD after/FD before initiation of treatment)	1.22 (1.00 - 1.31)	1.00 (0.69 - 1.46)	0.110^a
Diarrhea after initiation of treatment (%)	10.0	4.0	0.394^c
HbA_1c 1.5 months after discharge (%)	7.34 ± 0.81	7.20 ± 0.69	0.477^b
HbA_1c 6 months after discharge (%)	6.95 ± 0.90	6.74 ± 0.85	0.399^b
ΔHbA_1c (%)	-0.40 ± 0.44	-0.44 ± 0.79	0.796^b
Use of medication
Insulin (%)	73.3	68.0	0.665^c
Metformin (%)	100	0.0	< 0.000**^c
Sulfonylureas (%)	3.3	4.0	0.895^c
DPP4i (%)	46.7	32.0	0.269^c
α-Glucosidase inhibitors (%)	10.0	4.0	0.394^c
Thiazolidinedione (%)	10.0	0.0	0.104^c
Glinides (%)	20.0	20.0	1.000^c
SGLT2i (%)	56.7	100	0.000**^c
GLP-1 receptor agonists (%)	30.0	36.0	0.637^c
Osmotic laxatives (%)	10.0	8.0	0.797^c
Stimulant laxatives (%)	23.3	40.0	0.183^c

Table 2. Frequency of Defecation Parameters and Characteristics of the Patients After Admission According to Type of Treatment Initiated

Variable

Treatment

P-value

Metformin (n = 30)

SGLT2i (n = 25)

Data are presented as mean ± SD, median (IQR) or %. *P < 0.05. **P < 0.01.^aWilcoxon rank sum test. ^bUnpaired t-test. ^cPearson’s χ²-test. DPP4i: dipeptidyl peptidase-4 inhibitors; FD: frequency of defecation; ΔFD: change in FD; GLP-1: glucagon-like peptide 1; HbA_1c: glycated hemoglobin; ΔHbA_1c: change in HbA1c; IQR: interquartile range; SD: standard deviation; SGLT2i: sodium-glucose cotransporter 2 inhibitors.

Days on which FD was recorded before initiation of treatment (days)

7.0 (4.8 - 10.0)

7.0 (3.5 - 9.5)

0.507^a

Days on which FD was recorded after initiation of treatment (days)

6.0 (5.0 - 10.3)

7.0 (5.0 - 9.5)

0.980^a

Time to starting recording of FD after initiation of treatment (days)

0 (0 - 3)

0 (0 - 0)

0.014*^a

FD before initiation of treatment (times/day)

0.70 ± 0.19

0.74 ± 0.21

0.428^b

FD after initiation of treatment (times/day)

0.83 ± 0.18

0.73 ± 0.20

0.047*^b

ΔFD (FD after - FD before) (times/day)

0.06 (0.00 - 0.29)

0.00 (-0.24 - 0.27)

0.062^a

FD ratio (FD after/FD before initiation of treatment)

1.22 (1.00 - 1.31)

1.00 (0.69 - 1.46)

0.110^a

Diarrhea after initiation of treatment (%)

10.0

4.0

0.394^c

HbA_1c 1.5 months after discharge (%)

7.34 ± 0.81

7.20 ± 0.69

0.477^b

HbA_1c 6 months after discharge (%)

6.95 ± 0.90

6.74 ± 0.85

0.399^b

ΔHbA_1c (%)

-0.40 ± 0.44

-0.44 ± 0.79

0.796^b

Use of medication

Insulin (%)

73.3

68.0

0.665^c

Metformin (%)

100

0.0

< 0.000**^c

Sulfonylureas (%)

3.3

4.0

0.895^c

DPP4i (%)

46.7

32.0

0.269^c

α-Glucosidase inhibitors (%)

10.0

4.0

0.394^c

Thiazolidinedione (%)

10.0

0.0

0.104^c

Glinides (%)

20.0

1.000^c

SGLT2i (%)

56.7

100

0.000**^c

GLP-1 receptor agonists (%)

30.0

36.0

0.637^c

Osmotic laxatives (%)

10.0

8.0

0.797^c

Stimulant laxatives (%)

23.3

40.0

0.183^c

**Table 3.** Multiple Regression Analysis Showing the Relationships Between ΔHbA_1c and Variables in the Metformin Group
	Standardized coefficient β	95% confidence interval for B	t-value	P-value	VIF
P < 0.05. *P < 0.01. B: raw coefficient; FD: frequency of defecation; GLP-1: glucagon-like peptide-1; ΔHbA_1c: change in HbA_1c; VIF: variance inflation factor.
Constant	0.000	-0.404	1.462	1.17	0.255
Age	-0.066	-0.018	0.012	-0.39	0.720	1.095
Sex (female)	0.301	-0.018	0.304	1.82	0.080	1.019
FD before starting metformin	-0.433	-1.821	-0.195	-2.55	0.017*	1.086
Constant	0.000	-0.330	0.824	0.88	0.386
Duration of diabetes	0.182	-0.009	0.028	1.05	0.304	1.147
Use of stimulant laxative	0.249	-0.065	0.322	1.37	0.183	1.257
FD before starting metformin	-0.403	-1.752	-0.115	-2.35	0.027*	1.118
Constant	0.000	-0.081	1.121	1.78	0.087
Use of GLP-1 receptor agonists	0.096	-0.118	0.210	0.57	0.572	1.060
Use of osmotic laxative	0.306	-0.028	0.473	1.82	0.080	1.060
FD before starting metformin	-0.450	-1.823	-0.249	-2.71	0.012*	1.020
Constant	0.000	-0.252	1.028	1.25	0.224
Diabetic polyneuropathy	-0.110	-0.251	0.147	-0.54	0.592	1.345
Smoking	-0.115	-0.230	0.124	-0.62	0.540	1.122
FD before starting metformin	-0.504	-2.088	-0.249	-2.62	0.015*	1.219
Constant	0.000	-0.428	0.768	0.58	0.564
Diabetic nephropathy	-0.362	-0.327	-0.003	-2.10	0.046*	1.132
Alcohol	-0.159	-0.262	0.098	-0.94	0.355	1.087
FD before starting metformin	-0.398	-1.715	-0.130	-2.40	0.025*	1.047
Constant	0.000	-0.221	1.767	1.60	0.122
Age	-0.067	-0.018	0.012	-0.40	0.693	1.087
Sex (female)	0.259	-0.038	0.284	1.57	0.129	1.044
FD after starting metformin	-0.455	-2.024	-0.272	-2.69	0.012*	1.097
Constant	0.000	0.131	1.401	2.48	0.020*
Duration of diabetes	0.371	0.002	0.037	2.27	0.032*	1.326
Use of stimulant laxative	0.235	-0.044	0.287	1.51	0.143	1.202
FD after starting metformin	-0.596	-2.341	-0.707	-3.84	0.001**	1.195
Constant	0.000	0.166	1.681	2.51	0.019*
Use of GLP-1 receptor agonists	0.215	-0.062	0.266	1.28	0.211	1.147
Use of osmotic laxative	0.296	-0.025	0.455	1.84	0.077	1.059
FD after starting metformin	-0.530	-2.195	-0.480	-3.21	0.004**	1.119
Constant	0.000	-0.104	1.425	1.78	0.087
Diabetic polyneuropathy	0.104	-0.127	0.227	0.58	0.569	1.122
Smoking	-0.080	-0.210	0.135	-0.44	0.661	1.125
FD after starting metformin	-0.497	-2.167	-0.373	-2.91	0.007**	1.003
Constant	0.000	-0.386	1.176	1.04	0.307
Diabetic nephropathy	-0.314	-0.310	0.023	-1.77	0.089	1.202
Alcohol	-0.169	-0.267	0.092	-1.00	0.325	1.084
FD after starting metformin	-0.412	-1.953	-0.153	-2.41	0.024*	1.114

Table 3. Multiple Regression Analysis Showing the Relationships Between ΔHbA_1c and Variables in the Metformin Group

Standardized coefficient β

95% confidence interval for B

t-value

P-value

VIF

Lower limit

Upper limit

*P < 0.05. **P < 0.01. B: raw coefficient; FD: frequency of defecation; GLP-1: glucagon-like peptide-1; ΔHbA_1c: change in HbA_1c; VIF: variance inflation factor.

Constant

0.000

-0.404

1.462

1.17

0.255

Age

-0.066

-0.018

0.012

-0.39

0.720

1.095

Sex (female)

0.301

-0.018

0.304

1.82

0.080

1.019

FD before starting metformin

-0.433

-1.821

-0.195

-2.55

0.017*

1.086

Constant

0.000

-0.330

0.824

0.88

0.386

Duration of diabetes

0.182

-0.009

0.028

1.05

0.304

1.147

Use of stimulant laxative

0.249

-0.065

0.322

1.37

0.183

1.257

FD before starting metformin

-0.403

-1.752

-0.115

-2.35

0.027*

1.118

Constant

0.000

-0.081

1.121

1.78

0.087

Use of GLP-1 receptor agonists

0.096

-0.118

0.210

0.57

0.572

1.060

Use of osmotic laxative

0.306

-0.028

0.473

1.82

0.080

1.060

FD before starting metformin

-0.450

-1.823

-0.249

-2.71

0.012*

1.020

Constant

0.000

-0.252

1.028

1.25

0.224

Diabetic polyneuropathy

-0.110

-0.251

0.147

-0.54

0.592

1.345

Smoking

-0.115

-0.230

0.124

-0.62

0.540

1.122

FD before starting metformin

-0.504

-2.088

-0.249

-2.62

0.015*

1.219

Constant

0.000

-0.428

0.768

0.58

0.564

Diabetic nephropathy

-0.362

-0.327

-0.003

-2.10

0.046*

1.132

Alcohol

-0.159

-0.262

0.098

-0.94

0.355

1.087

FD before starting metformin

-0.398

-1.715

-0.130

-2.40

0.025*

1.047

Constant

0.000

-0.221

1.767

1.60

0.122

Age

-0.067

-0.018

0.012

-0.40

0.693

1.087

Sex (female)

0.259

-0.038

0.284

1.57

0.129

1.044

FD after starting metformin

-0.455

-2.024

-0.272

-2.69

0.012*

1.097

Constant

0.000

0.131

1.401

2.48

0.020*

Duration of diabetes

0.371

0.002

0.037

2.27

0.032*

1.326

Use of stimulant laxative

0.235

-0.044

0.287

1.51

0.143

1.202

FD after starting metformin

-0.596

-2.341

-0.707

-3.84

0.001**

1.195

Constant

0.000

0.166

1.681

2.51

0.019*

Use of GLP-1 receptor agonists

0.215

-0.062

0.266

1.28

0.211

1.147

Use of osmotic laxative

0.296

-0.025

0.455

1.84

0.077

1.059

FD after starting metformin

-0.530

-2.195

-0.480

-3.21

0.004**

1.119

Constant

0.000

-0.104

1.425

1.78

0.087

Diabetic polyneuropathy

0.104

-0.127

0.227

0.58

0.569

1.122

Smoking

-0.080

-0.210

0.135

-0.44

0.661

1.125

FD after starting metformin

-0.497

-2.167

-0.373

-2.91

0.007**

1.003

Constant

0.000

-0.386

1.176

1.04

0.307

Diabetic nephropathy

-0.314

-0.310

0.023

-1.77

0.089

1.202

Alcohol

-0.169

-0.267

0.092

-1.00

0.325

1.084

FD after starting metformin

-0.412

-1.953

-0.153

-2.41

0.024*

1.114