Effects of PPIs on Glycemic Control and Incident Diabetes

Table 1. Characteristics of the 7 included studies on the glycemic control among patients with diabetes with and without PPI as an add-on to standard therapy
Author	Year	Study design	Country	Funding source	No. of participants	Mean age (SD), yr	Female (%)	Type of DM	On insulin (%)	Baseline HbA1c (SD), %	Intervention^a	Control^a	Treatment duration
Singh (13)	2012	RCT	India	Non-industrial and industrial	31	56.5 (8.4)	NA	Type 2	0	7.7 (1.2)	Pantoprazole 40 mg BID	Placebo	12 weeks
Hove (15)	2013	RCT	Denmark	Industrial	41	59.4 (6.7)	NA	Type 2	0	7.0 (0.6)	Esomeprazole 40 mg QD	Placebo	12 weeks
Takebayashi (16)	2014	RCT	Japan	NA	89	65.3 (10.8)	47	Type 2	0	7.6 (0.6)	Lansoprazole 15 mg QD	None	12 weeks
Gonzalez-Ortiz (14)	2015	RCT	Mexico	Non-industrial	14	48.0 (8.3)	79	Type 2	NA	7.7 (0.4)	Pantoprazole 40 mg QD	Placebo	45 days
Agrawal(26)	2018	RCT	India	None	60	57.2 (8.7)	28	Type 2	0	7.8 (0.6)	Pantoprazole 40 mg BID	Placebo	24 weeks
Rajput (37)	2020	RCT	Pakistan	None	75	30 – 60 (age range)	NA	Type 2	NA	7.7 (0.1)	Omeprazole 20 mg BID	None	12 weeks
Bozkuş (38)	2020	Non-RCT	Turkey	Non-industrial	32	59.4 (6.2)	69	Type 2	15.6	6.25 (0.6)	Esomeprazole 40 mg QD	None	12 weeks

Abbreviations: BID, twice daily; DM, diabetes mellitus; NA, not applicable; PPI, proton pump inhibitor; QD, once daily; RCT, randomized controlled trial.
^aAll participants in the interventional and control groups received standard care for diabetes mellitus

Table 2. Characteristics of the 5 included studies on the risk of incident diabetes with PPI use
Author	Year	Participants (database/trial name)	Study design	Country	Funding source	Study size (n)	Diabetes event	Mean age (SD), yr	Female (%)	Assessment of PPI use	Mean follow-up, (yr)	Ascertainment of diabetes mellitus
Lin (17)	2016	LHID	Retrospective cohort	Taiwan	Non-industrial	22 152	2243	55.4 (17.0)	40.3	Per prescription record	5 or until DM was diagnosed	ICD-9 code 250.0 for ≥ 2 times with Hb1AC
Moayyedi (39)	2019	COMPASS	RCT	33 countries	Industrial	17 598	1045	67.7 (8.1)	21.6	Intervention in the trial: Pantoprazole 40 mg QD	3	NA
Yuan (18)	2020	NHS	Prospective cohort	USA	Industrial and non-industrial	80 500	4726	68.1 (7.1)	100	Questionnaires. Regular use: ≥2 times/week	12 (Median)	ADA criteria^a
		NHS II	Prospective cohort	USA	Industrial and non-industrial	95 500	4631	48.7 (4.6)	100	Questionnaires. Regular use: ≥ 2 times/week	12 (Median)	ADA criteria^a
		HPFS	Prospective cohort	USA	Industrial and non-industrial	28 639	748	71.5 (8.6)	0	Questionnaires. Regular use: ≥ 2 times/week	9.8 (Median)	ADA criteria^a

Abbreviations: ADA, American Diabetes Association; HPFS, Health Professionals Follow-up Study; LHID, Longitudinal Insurance Database; NA, not applicable; NHS, Nurses' Health Study; PPI, proton pump inhibitor; QD, once daily; RCT, randomized controlled trial.
^aConfirmed diabetes should meet at least one of the following criteria: (1) ≥ 1 classic symptoms (excessive thirst, polyuria, weight loss, hunger, pruritus, or coma) plus a fasting serum glucose ≥126 mg/dL or random serum glucose ≥200 mg/dL; (2) ≥ 2 elevated serum glucose levels on different occasions (fasting serum glucose ≥140 mg/dL and/or random serum glucose ≥200 mg/dL and/or serum glucose ≥200 mg/dL at 2 hours on oral glucose tolerance testing) in the absence of symptoms; or (3) treatment with hypoglycemic medication (insulin or oral hypoglycemic agent).

Table 3. Subgroup analyses for the mean difference in HbA1c in patients with diabetes with and without PPI as an add-on to standard therapy
Subgroups	No. of studies	WMD (95% CI)	P value	I² (%)	Results of meta-regression
Subgroups	No. of studies	WMD (95% CI)	P value	I² (%)	τ²	I² residual (%)	P value
Overall	7	-0.36 (-0.68, -0.05)^a	0.025	93.3	0.27	NA	NA
Study design					0.30	94.3	0.506
Randomized controlled trial	6	-0.43 (-0.79, -0.07)^a	0.018	94.3
Nonrandomized controlled trial	1	0.00 (-0.32, 0.32)	1.000	NA
Dose of PPI^b					0.16	89.8	0.097
Higher than standard	3	-0.76 (-1.26, -0.25)^a	0.003	95.2
Within standard	4	-0.01 (-0.24, 0.23)	0.964	59.2
Duration of PPI use					0.32	94.4	0.861
≥ 12 weeks	6	-0.35 (-0.69, -0.01)^a	0.044	94.4
< 12 weeks	1	-0.50 (-1.12, 0.12)	0.113	NA
Baseline HbA1c					0.27	94.2	0.360
HbA1c > 7.0	5	-0.50 (-0.92, -0.09)^a	0.017	95.4
HbA1c ≤ 7.0	2	-0.05 (-0.27, 0.16)	0.624	0.0
Mean age at entry					0.24	90.1	0.271
≤ 60 years	6	-0.47 (-0.79, -0.15)^a	0.004	90.1
> 60 years	1 0.20 (0.05, 0.36)^a	0.011	NA
Geographic location					0.32	94.4	0.795
Asian	5	-0.40 (-0.80, -0.01)^a	0.043	95.5
Non-Asian	2	-0.20 (-0.54, 0.14)	0.245	23.7
Types of PPI					0.08	65.0
Pantoprazole	3	-0.90 (-1.41, -0.39)^a	<0.001	76.1			NA^c
Esomeprazole	2	-0.05 (-0.27, 0.16)	0.624	0.0			0.090
Lansoprazole	1	0.20 (0.05, 0.36)^a	0.011	NA			0.071
Omeprazole	1	-0.24 (-0.34, -0.14)^a	<0.001	NA			0.194

Abbreviations: NA, not applicable; PPI, proton pump inhibitor; WMD, weighted mean difference.
^aStatistically significant (P < 0.05)
^bThe Food and Drug Administration–recommended dose of PPIs for treating erosive esophagitis was referenced as the standard dose.
^cDummy variables were created for the different types of PPI used when performing meta-regression, with pantoprazole used as the reference group.

Table 4. Subgroup analyses for mean difference of fasting blood glucose in patients with diabetes with and without PPI as an add-on to standard therapy
Subgroups	No. of studies	WMD (95% CI)	P value	I² (%)	Results of meta-regression
Subgroups	No. of studies	WMD (95% CI)	P value	I² (%)	τ ²	I² residual (%)	P value
Overall	7	-10.0 (-19.4, -0.6)^a	0.037	88.6	188.0	NA	NA
Study design					189.3	89.0	0.402
Randomized controlled trial	6	-12.1 (-21.8, -2.4)^a	0.015	89.0
Nonrandomized controlled trial	1	4.0 (-10.4, 18.4)	0.587	NA
Dose of PPI^b	69.5	77.8	0.069
Higher than standard	3	-19.6 (-28.0, -11.2)^a	<0.001	85.5
Within standard	4	-0.2 (-12.3, 12.0)	0.978	65.5
Duration of PPI use					203.1	90.4	0.447
≥ 12 weeks	6	-8.4 (-18.5, 1.7)	0.101	90.4
< 12 weeks	1	-23.4 (-42.8, -3.9)^a	0.019	NA
Baseline HbA1c	89.5	84.7	0.054
HbA1c > 7.0	5	-16.0 (-25.0, -6.9)^a	0.001	87.4
HbA1c ≤ 7.0	2	8.5 (-2.5, 19.4)	0.129	0.0
Mean age at entry					205.5	86.9	0.510
≤ 60 years	6	-12.1 (-21.7, -2.6)^a	0.013	86.9
> 60 years	1	0.4 (-8.3, 9.1)	0.929	NA
Geographic location					209.1	89.5	0.607
Asian	5	-12.0 (-21.8, -2.3)^a	0.016	89.9
Non-Asian	2	-4.1 (-41.2, 33.0)	0.829	88.0
Types of PPI 44.9 71.2
Pantoprazole	3	-21.8 (-32.7, -11.0)^a	<0.001	79.1			NA^c
Esomeprazole	2	8.5 (-2.5, 19.4)	0.129	0.0			0.040
Lansoprazole	1	0.4 (-8.3, 9.1)	0.929	NA			0.098
Omeprazole	1	-16.0 (-20.5, -11.5)^a	<0.001	NA			0.544

Abbreviations: NA, not applicable; PPI, proton pump inhibitor; WMD, weighted mean difference.
^aStatistically significant (P < 0.05)
^bFood and Drug Administration–recommended dose of PPIs in treating erosive esophagitis was referenced as standard dose.
^cDummy variables were created for types of PPI when performing meta-regression using pantoprazole as the reference group.

Table 5. Analyses for the mean difference of secondary outcomes in patients with diabetes with and without PPI as an add-on to standard therapy
Outcomes	No. of studies	WMD (95% CI)	P value	I² (%)
Fasting serum gastrin level (pg/mL)	4	43.9 (18.5, 69.3)^a	0.001	82.2
Fasting serum insulin level (μU/mL)	3	0.51 (-1.94, 2.95)	0.685	18.0
HOMA-IR	3	-0.06 (-0.54, 0.42)	0.798	0.0
HOMA-β	2	22.4 (-19.8, 64.6)	0.299	87.3
Body mass index (kg/m²)	4	-0.10 (-0.54, 0.35)	0.661	0.0
Body weight (kg)	4	-0.5 (-2.1, 1.1)	0.526	0.0
Total cholesterol (mg/dL)	3	2.0 (-12.4, 16.3)	0.787	63.8
HDL (mg/dL)	4	-0.1 (-2.5, 2.3)	0.934	22.7
LDL (mg/dL)	4	-1.9 (-7.4, 3.6)	0.493	0.0
Triglycerides (mg/dL)	4	11.1 (-26.8, 48.9)	0.567	71.7

Abbreviations: HDL, high-density lipoprotein; HOMA-β, homeostatic model assessment–beta cell function; HOMA-IR, homeostatic model assessment–insulin resistance; LDL, low-density lipoprotein; PPI, proton pump inhibitor; WMD, weighted mean difference.
^aStatistically significant (P < 0.05)

Authors and Disclosures

Carol Chiung-Hui Peng¹, Yu-Kang Tu^2–4, Gin Yi Lee⁵, Rachel Huai-En Chang⁶, Yuting Huang¹, Khulood Bukhari¹, Yao-Chou Tsai^7,8, Yunting Fu⁹, Huei-Kai Huang^2,10, and Kashif M. Munir¹¹

¹Department of Internal Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, Maryland 21201, USA; ²Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 100, Taiwan; ³Department of Dentistry, National Taiwan University Hospital and School of Dentistry, National Taiwan University, Taipei 100, Taiwan; ⁴Research Center of Big Data and Meta-analysis, Wan Fang Hospital, Taipei Medical University, Taipei 100, Taiwan; ⁵Department of Medicine, Danbury Hospital, Danbury, Connecticut 06810, USA; ⁶Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA; ⁷Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 100, Taiwan; ⁸Department of Urology, Taipei Medical University Hospital, Taipei Medical University, Taipei 100, Taiwan; ⁹Health Sciences and Human Services Library, University of Maryland, Baltimore, MD 21201, USA; ¹⁰Departments of Family Medicine and Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan; and ¹¹Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA

Correspondence
Kashif M. Munir, MD, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 827 Linden Ave, Baltimore, MD 21201, USA. Email: kmunir@som.umaryland.edu; or Huei-Kai Huang, Department of Medical Research, Buddhist Tzu Chi General Hospital, No. 707, Sec. 3, Chung Yang Rd., Hualien 97002, Taiwan. Email: drhkhuang@gmail.com.

Disclosures
There are no disclosures. The authors have no conflicts of interest to declare.

Author Contributions
Study conception and design: CCP and HKH. Acquisition of data: CCP, HKH, YF, GYL, RHC, YH, KB. Analysis and interpretation of data: HKH, YKT, KMM, CCP. Preparation of manuscript: CCP, HKH. Critical revisions: KMM, YKT, HKH, CCP, YCT. All authors have read and approved the final version of the manuscript for publication.