Updates on gastric electrical stimulation to treat obesity: Systematic review and future perspectives

Table 1 Search terms and results obtained from different databases

Search terms	Database 1 Pubmed	Overlapping Pubmed articles	Total number of articles from Pubmed	Database 2 Cochrane	Database 3 Medline
Gastric electrical stimulation and obesity	145	0	145	51	91
TANTALUS® and obesity	12	7	5	11	61
Enterra® and obesity	6	6	0	01	21
Transcend® and obesity	13	5	8	01	41
Implantable gastric stimulator and obesity	22	12	10	31	21
Retrograde gastric electrical stimulation and obesity	13	3	10	01	21
Gastric pacing and obesity	26	20	6	11	81
Neural gastric electrical stimulation and obesity	6	6	0	01	31
Total number of articles after duplicate removal	184

¹Duplicate articles (i.e., these articles are already included in the results of the Pubmed literature search).

Table 2 Summary of TANTALUS^® trials

Ref.1	Sample size (n), enrolled/completed	Mean age (yr)	Mean weight, (kg)/mean BMI (kg/m2)	Follow-up (mo)	Lifestyle change (required/advice given)	Co-morbidities
Lebovitz et al[38], 2013	40/40	NR	110.5 ± 3.5/NR	NR	NR/NR	NR
Sanmiguel et al[70], 2009	14/11	42	107.3 ± 20.1/39 ± 1	6	N/Y	T2DM
Bohdjalian et al[39], 2009	24/21	50.0 ± 1.6	123.7 ± 4.5/41.9 ± 1.0	12	NR/NR	T2DM
Policker et al[37], 2009	50/50	NR	NR/NR	6+	NR/NR	T2DM
Bohdjalian et al[71], 2009	13/13	53.8 ± 2.6	104.4 ± 4.4/37.2 ± 1.1	3	N/Y	T2DM
Policker et al[69], 2008	12/12	50.8 ± 2.2	130 ± 6.5/NR	9	N/Y	T2DM
Sanmiguel et al[43], 2007	12/11	39.1 ± 8.9	NR/41.6 ± 3.4	1.5	N/NR	T2DM
Bohdjalian et al[72], 2006	12/9	36.1 ± 2.8	128.8 ± 5.2/43.2 ± 2.7	12	N/Y	HTN

¹All trials were open-label and none were randomized. T2DM: Type 2 diabetes.

Table 3 Implantable gastric stimulator Transcend^®: Studies summary

Ref.	Type of research	Sample size, (enrolled/completed)	Mean age (yr)	Mean weight, (kg)/mean BMI (kg/m2)	Follow-up (mo)	Lifestyle change (required/advice given)	Baroscreen®
Korner et al[28], 2011	Randomized + D, PC (SHAPE)	13/13	48.8	113.1/40.6	24	Y/Y	Y
Shikora et al[21], 2009	Randomized + P, D, M, PC (SHAPE)	190/180	43.9	NR/41	12	Y/Y	Y
Hoeller et al[73], 2006	Non-randomized	8/7	48.1	112.5/41.3	23	NR/NR	N
Champion et al[29], 2006	Non-randomized + O	24/21	43	92/33	6	Y/Y	Y
Miller et al[30], 2006	Non-randomized + P, M (LOSS trial)	91/25	41	116/41	24	N/Y	Y
Shikora et al[20], 2005	randomized + D, PC	103/34	40	129/46	29	NR/NR	N
	(O-01 trial)
Shikora et al[20], 2005	Non- randomized + O, M (DIGEST)	30/23	39	NR/42	24	Y/Y	N1
Cigaina et al[32], 2004	Non- randomized	65/NR	39.4 ± 3.4	132.7 ± 27.3/46.9 ± 7.07	962	Y/Y	NR1
Favretti et al[74], 2004	Non- randomized	20/20	40	115/40.9	10	N/Y	NR
De Luca et al[36], 2004	Non- randomized + P (LOSS trial)	69/20	41	115/41	15	NR/NR	NR
Cigaina et al[75], 2003	Non- randomized	11/11	39.4 ± 3.4	121.7 ± 5.1/46.0 ± 2.5	8	N/Y	NR
McCallum et al[35], 2002	randomized + D	103/NR	40	NR/46	12	NR/NR	NR
D'Argent et al[76], 2002	Non- randomized + P, O	12/NR	40.6	122.2/42.7	9	NR/NR	NR

¹No Baroscreen^® conducted but binge eating assessment questionnaire and a psychological evaluation were carried out;

²This study had four different cohorts over the 8-yr period, from 1996 to 2004.

Table 4 Retrograde gastric electrical stimulation-studies summary

Ref.1	Sample size (enrolled/completed)	Mean age(yr)	Mean weight, (kg)/mean BMI (kg/m2)
Zhang et al[41], 2013	16/16	39	NR/32.1
Yao et al[44], 2005	12/12	29.4 ± 8.6	62.62 ± 8.29/23.2 ± 2.6
Yao et al[77], 2005	12/12	29.4 ± 8.6	62.62 ± 8.29/23.18 ± 2.62

¹All trials were non-randomized; no follow-up length and lifestyle change advice reported.

Table 5 Vagal nerve electrical stimulation studies summary

Ref.	Type of research	Sample size (enrolled/completed)	Mean age (yr)	Mean weight, (kg)/mean BMI (kg/m2)	Follow-up (mo)	Lifestyle change (required/advice given)	Co-morbidities
Sarr et al[34], 2012	Randomized, Prospective	294/253	46	NR/41	12	Y/Y	T2DM
[EMPOWER study]	Double blind, Multicentre						HTN
Camilleri et al[78], 2009	Prospective1, Multicentre, O	27/25	40.1 ± 1.8	NR/39.3 ± 0.8	6	NR/NR	N
Camilleri et al[79], 2008	Prospective, Multicentre, O	31/NR	41.4 ± 1.4	NR/41.2 ± 0.7	6	NR/NR	T2DM

¹There were two phases in this study. The first one was a retrospective analysis of therapy algorithms used and excess weight loss. The second phase (included in this review data analysis) looked into prospective evaluation of selected therapy algorithms from phase 1. T2DM: Type 2 diabetes.

Table 6 Gastric Pacing studies summary

Ref.1	Sample size (enrolled/completed)	Mean age (yr)	Mean weight, (kg)/mean BMI (kg/m2)	Follow-up (mo)	Lifestyle change (required/advice given)
Cigaina et al[40], 2007	11/11	39.4 ± 3.4	121.7 ± 5.1/46.0 ± 2.5	8	N/Y
Liu et al[45], 2006	12/12	29.9 ± 12.3	58.6/21.4	3 d	NR/NR
Yao et al[42], 2005	12/12	29.4 ± 8.6	62.6 ± 8.3/23.18 ± 2.62	3 d	NR/NR
Cigaina et al[33], 2002	4/3 (1995/6 cohort)	31 ± 10	146 ± 25/55.9 ± 3	60	N/Y
Cigaina et al[33], 2002	10/10 (1998 cohort)	34.8 ± 8.6	142 ± 23.75/47.9 ± 5.8	30	N/Y
Cigaina et al[33], 2002	10/7 (2000 cohort)	41.8 ± 11.9	131.9 ± 33.1/51.41 ± 9.2	12	N/Y

¹All trials were non-randomized.

Table 7 Comparison of stimulation variables by different devices

Device (total number of studies)	Operation technique				Electrode implanted layer							Device active after n weeks				Type of pulse				Endoscopy			Postop image
	L	O	E	NR	M	SM	Mus	SMus	SS	V	NR	0	≤3 (1 ≤)	4 ≤	NR	Lo	T	NR	UC	Y	N	NR	XR	E-US	B	NR
TANTALUS® (8)	8	0	0	0	3	0	0	0	4		1	0	1	6	1	0	0	6	2	3	0	5	1	0	0	7
IGS-Transcend® (13)	121	21	0	1	0	0	2	4	1		52 (14)	0	43	93	0	0	9	3 (14)	0	7	5 (14)	0	5	15	15	7 (14)
RGES (3)	0	0	3	0	36	36	0	0	0		0	3	0	0	0	27	27	0	0	3	0	0	2	0	0	1
Vagal (3)	3	0	0	0						3	0	0	3	0	0	0	0	0	3	0	0	3	0	0	0	3
Pacing (4)	21	21	2	0	26	16	2	0	0		0	2	0	1	1	28	18	1	1	4	0	0	2	0	0	2
Total (33)	25	4	5	1	8	4	4	4	5	3	6 (14)	5	9	16	2	4	12	10 (14)	6	17	5 (14)	8	10	1	1	20 (14)

¹Two studies implanted leads either by laparoscopic or open approach;

²Two studies reported “gastric wall”, but did not specify which particular layer;

³One study activated its device after 3 or 4 wk, so each category was counted once;

⁴No full text for LOSS trial, and this information was also not provided on another study, which reviewed this particular trial;

⁵One study did both X-ray and endoscopic USS. Similarly another study did both X-ray and GI Barium test;

⁶Implanted electrodes in mucosa and submucosa (3 studies in RGES; 1 study in Gastric Pacing);

⁷One study carried out two different pulses;

⁸One study carried out two different pulses. L: Laparoscopic; O: Open; E: Endoscopic; NR: Not reported; M: Mucosa; SM: Submucosa; Mus: Muscular; SMus: Seromuscular; SS: Subserosa; V: Vagal nerve; Lo: Long pulse; T: Train of short pulses; UC: Uncertain; Y: Yes; N: No; XR: X-ray; E-US: Endoscopic ultrasound scan; B: Gastrointestinal Barium test.

Table 8 Comparison of outcomes of different devices (statistically significant outcomes only)

Device (total number of studies)	Significant weight loss achieved ≤ 12 mo (number of trials)	Follow-up beyond 12 mo and significant weight loss maintained from the first 12 mo (number of trials)1	Appetite reduction/satiety increase (number of trials)	Food and/or water intake reduction, comparing study group to control (number of trials)	Changes in gastric emptying (number of trials)	Biochemistry changes reported (number of trials)4
TANTALUS® (8)	62	None (maximum of 12 mo follow-up)	2 (25%)		Increased (1)	45
IGS-Transcend (13)	103	5	3 (23%)			1
Vagal stimulation (3)	2	None (maximum of 12 mo follow-up)	3 (100%)			1
Gastric Pacing (6)	4	2		2	Delayed (26)	1
Total (30)	22	7	8 (26.6%)	3	5	7

¹Maintained weight loss means that studies had shown significant weight loss during the first year of their follow-up;

²One study showed a weight loss of 3.62% from baseline at 37 wk, but p value was not given, so this was not included in the count;

³One study demonstrated significant weight loss at 12 mo only after procedural correction;

⁴Significant biochemistry changes include any gastrointestinal hormones (such as ghrelin, peptide YY, leptin, somatostatin, cholecystokinin, Glucagon-like Peptide-1), HbA1c, fasting blood glucose, cholesterol;

⁵One study showed a reduction of -12.2% in HbA1c levels at 37 wk but P value was not given so it was not included in the count;

⁶In one study, gastric emptying was achieved only after 45 min, and there was no significant delaying afterwards.

Table 9 TANTALUS^® studies significant outcomes

	Weight, kg	Average Weight loss, kg (%)			HbA1c (%)	Average HbA1c reduction, % (% change)			Other statistically significant or important negative results3
	Baseline	At 3 mo ± 2 wk	At 6 mo ± 2 wk	At 12 mo ± 3 mo	Baseline	At 3 mo ± 2 wk	At 6 mo ± 2 wk	At 12 mo ± 3 mo
T1[38]	110.5 ± 3.5		-5.38 (-4.87%), P < 0.01		8.3% ± 0.12%		-1.0 (-12.0%), P < 0.001		Lower BP (S/D)
T2[70]	107.7 ± 21.1 (n = 11)	-3.00 (-2.79%), P < 0.05	-5.30 (-4.92%), P < 0.05		8.5% ± 0.7%	-1.0 (-11.8%), P < 0.05	-0.9 (-10.6%), P < 0.05		Lower BP (S) Lower total cholesterol Lower LDL
T3[39]	123.7 ± 4.5		-5.80 (-4.70%), P < 0.05 at 5 mo	-4.50 (-3.70%) [P < 0.05]	8.0% ± 0.2%		-0.6 (-7.5%), P < 0.05 at 5 mo	-0.5 (-6.3%), P < 0.05	Lower FBG Lower ghrelin4 Higher adiponectin4 Reduced appetite2 (P < 0.05)
T4[37]	NR		-5.50 (P < 0.01)		8.4% ± 0.1%		-1.1 (-12.1%), P < 0.01		Lower BP if hypertensive at baseline
T5[71]	104.4 ± 4.4	-4.70 (-4.52%), P < 0.001			8.0% ± 0.2%	-1.1 (-12.8%), P < 0.001			Lower BP (S/D) Lower FBG
T6[69]	130 ± 6.5			-4.70 (-3.62%) (P value NR) at 37 wk	8.2% ± 0.2%			-1.0 (-12.2%) (P value NR) at 37 wk
T7[43]	NR								Increased GE Reduced gastric retention (No significant changes in Ghrelin)
T8[72]	128.8 ± 5.2		-8.90 (-6.91%), P < 0.05 at 5 mo	-16.4 (-12.7%) (P value NR)1					Lower BP if hypertensive at baseline Reduced appetite (P < 0.05)

¹Only 9 out of 12 subjects remained by the 12^th month;

²Except from week 20 to week 52, there was a slight increase (P = NS) in hunger score, but otherwise, all scores were significant (P < 0.05);

³Significant results in reference to baseline values;

⁴Results based on a smaller subset of participants. BP: Blood pressure; LDL: Low-density lipoproteins; FBG: Fasting blood glucose.

Table 10 Implantable Gastric Stimulator Transcend^® outcomes

	Weight, kg	Average Weight loss, kg (%)-In the treatment group compared to baseline weight				Hunger reduction/ Reduced appetite	Other statistically significant or important negative results3
	Baseline	At 3 mo ± 2 wk	At 6 mo ± 2 wk	At 12 mo ± 3 mo	Beyond 12 mo
I1[28]	113.1		-7.0 (-6.2%), P < 0.05	-5.5 (-4.9%), P < 0.05	-2.1 (-1.9%), P < 0.05 at 24 mo		In control group, weight gain despite IGS activation from 12 to 24 mo
							No significant change in fasting ghrelin or Peptide YY levels
I2[21]	NR						No significant weight loss observed
I3[73]	112.5		-2 (-1.8%) NS	+3.5 (+3.1%) NS			No significant weight loss observed
I4[29]	92		%EWL = 5.9%
I5[30]	116	%EWL = 14%	%EWL = 19%	%EWL = 20%	%EWL = 25%
I6[20]	129		%EWL = 1.3% (study group); 2.4% (control) NS	Mean %EWL = 2.5%	%EWL = 20% at 29 mo1		Only a subset (23%) of patients lost significant amount of weight (> 5% EWL)
				(P value NR)
I7[20]	NR			%EWL > 10% in 54% of subjects; > 20% in 23%	%EWL = 23% at 16 mo	Yes2, P = 0.0433	Satiety increased between and at the end of meals
I8[32]	132.7± 27.3	%EWL for 2 yr period for each cohort = 20%-40%					Lower blood pressure
I9[74]	115	%EWL = 16.3%	%EWL = 16.9%	%EWL = 23.8% at 10 mo		Yes	Satiety increased between and at the end of meals
		-8.2 (-7.11%), P = 0.0011	-8.4 (-7.29%), P = 0.0310	-11.7 (-10.1%), P = 0.0112
I10[36]	115	%EWL = 15.8%	%EWL = 17.8%	%EWL = 21.0% at 10 mo	%EWL = 21.0% at 15 mo	Yes	Satiety increased between and at the end of meals
							No significant change in ghrelin level
I11[75]	121.7± 5.1		-10.4 (-8.5%), P < 0.01				Reduced meal-related CCK response
							Lower basal and meal-related somatostatin level
							Lower basal GLP-1 level (Not meal-related)
							Lower basal leptin level (Not meal-related)
I12[35]	NR			-2.7%, P = 0.03			Significant weight loss at 12 mo was observed after procedural corrections
I13[76]	122.2	%EWL = 17.8%	%EWL = 18.6	%EWL 30.2 at 9 mo
		-9.4 (-7.7%)	-10.0 (-8.2%)	-16.0 (-13.1%)
		(P value NR)	(P value NR)	(P value NR)

¹Very small number of remaining subjects (n = 34);

²Responses to the Satiety and Dietary Analysis Questionnaire;

³Significant results in reference to baseline values. NR: Not reported; EWL: Excess weight loss; CCK: Cholecystokinin; GLP-1: Glucagon like peptide-1.