Effects of Proton Pump Inhibitors on Glycemic Control and Incident Diabetes

A Systematic Review and Meta-analysis

Carol Chiung-Hui Peng; Yu-Kang Tu; Gin Yi Lee; Rachel Huai-En Chang; Yuting Huang; Khulood Bukhari; Yao-Chou Tsai; Yunting Fu; Huei-Kai Huang; Kashif M. Munir

Disclosures

J Clin Endocrinol Metab. 2021;106(11):3354-3366.

Abstract and Introduction

Abstract

Context: Whether proton pump inhibitors (PPI) can improve glycemic control among individuals with diabetes or decrease the risk of incident diabetes in the general population is unclear.

Objective: To evaluate the impact of PPI therapy on glycemic control among individuals with diabetes and the risk of diabetes among those without diabetes.

Results: PubMed, Embase, Scopus, and ClinicalTrials.gov were searched from inception to November 21, 2020. We included studies comparing glycosylated hemoglobin (HbA1c) or fasting blood glucose (FBG) among individuals with diabetes treated with and without PPI therapy as an add-on to standard therapy. Studies evaluating the risk of incident diabetes among individuals taking PPI were assessed. We performed dual independent review, data extraction, and quality assessment. Weighted mean differences between groups or relative risks were imputed using random-effects models.

Results: Seven studies (n = 342) for glycemic control and 5 studies (n = 244 439) for risk of incident diabetes were included. Compared with standard therapy, add-on PPI was associated with a significant decrease in HbA1c (WMD, −0.36 %; 95% CI, −0.68 to −0.05; P = 0.025) and FBG (WMD, −10.0 mg/dL; 95% CI, −19.4 to −0.6; P = 0.037). PPI use did not reduce the risk of incident diabetes (pooled RR, 1.10; 95% CI, 0.89 to 1.34; P = 0.385).

Conclusion: Add-on PPI improved glycemic indices among individuals with diabetes but did not alter the risk of incident diabetes. The effects of PPI on glycemic control should be considered when prescribing antacids to patients with diabetes.

Introduction

Type 2 diabetes mellitus (T2DM) is a global public health concern, with a worldwide prevalence of 9.3% in 2019.^[1] It is a complex, heterogenous metabolic disorder characterized by hyperglycemia, insulin resistance, and impaired insulin secretion.^[2] A higher prevalence of upper gastrointestinal symptoms is observed in patients with diabetes, especially among those with poor glycemic control.^[3,4] Currently, there are multiple pharmacologic treatment options to improve glycemic control and prevent vascular complications, each having different glycemic efficacies.^[5]

Proton pump inhibitors (PPI), recommended for gastroesophageal-related disorders, are commonly prescribed worldwide.^[6] By blocking H+/K + ATPase, PPI are potent gastric acid inhibitors; however, PPI do elevate gastrin levels through negative feedback.^[7] Gastrin is considered to be an early incretin candidate as it stimulates β cells to secrete insulin in diabetes animal models.^[8,9] Incretin-based therapeutic options for diabetes, such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors, have proven efficacy in lowering blood glucose.^[5,10] Several observational studies^[11,12] and randomized controlled trials^[13,14] have demonstrated that PPI decrease glycosylated hemoglobin (HbA1c) levels, although such effects were not observed in other studies.^[15,16] Also, evidence about the risk of diabetes associated with the use of PPI among individuals without diabetes is inconclusive.^[17,18]

Despite emerging evidence of the potential glucose-lowering effect of PPI in diabetes and of the risk of incident diabetes among individuals without diabetes who use PPI, the effect of PPI on these 2 populations remains unclear. Herein, we conducted a systematic review and meta-analysis to evaluate whether PPI are associated with improved glycemic control in diabetes and a decreased risk of incident diabetes.

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Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

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)