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. 2022 Aug 26;101(34):e30072. doi: 10.1097/MD.0000000000030072

Meta-analysis of the association between new hypoglycemic agents and digestive diseases

Yu-Wen Wang a,b,*, Jin-Hao Lin c,✉, Cui-Shan Yang b
PMCID: PMC9410596  PMID: 36042668

Background:

New hypoglycemic agents include sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide 1 receptor agonists (GLP1RAs), and dipeptidyl peptidase-4 inhibitors (DPP4is). The association between each class of these new hypoglycemic drugs and the risks of various digestive system diseases is unknown. We aimed to explore this relationship by performing a meta-analysis.

Methods:

We included large randomized trials of SGLT2is, GLP1RAs, and DPP4is. Outcomes of interest were 91 kinds of digestive diseases including 75 kinds of gastrointestinal disorders and 16 kinds of hepatobiliary disorders. Meta-analysis was done to generate pooled risk ratio (RR) and 95% confidence interval (CI). Subgroup analysis was conducted according to 3 different drug classes.

Results:

We included 21 large trials in this meta-analysis. Compared with placebo, GLP1RAs were associated with the higher risks of gastric ulcer hemorrhage (RR 2.68, 95% CI 1.07–6.68; Pdrug = .035; I2 = 0), pancreatitis (RR 1.48, 95% CI 1.02–2.15; Pdrug = .041; I2 = 0), cholangitis acute (RR 5.96, 95% CI 1.04–34.08; Pdrug = .045; I2 = 0), and cholecystitis acute (RR 1.52, 95% CI 1.08–2.15; Pdrug = .017; I2 = 1.5%), but were not significantly associated with the occurrences of the other 87 kinds of digestive diseases (Pdrug ranged from .064 to .999). SGLT2is versus placebo were not significantly associated with the occurrences of 91 kinds of digestive diseases (Pdrug ranged from .077 to .995). DPP4is versus placebo were not significantly associated with the occurrences of 91 kinds of digestive diseases (Pdrug ranged from .085 to .999).

Conclusions:

Neither SGLT2is nor DPP4is are associated with the occurrences of various kinds of digestive diseases, whereas GLP1RAs are associated with the higher risks of 4 kinds of digestive diseases, namely, gastric ulcer hemorrhage, pancreatitis, cholangitis acute, and cholecystitis acute. These findings seem to suggest that GLP1RAs are not applicable for patients at high risk of 4 specific digestive diseases, whereas SGLT2is and DPP4is are safe for patients susceptible to digestive diseases. However, our findings require to be further verified by future studies with sufficient statistical power.

Keywords: cholangitis, cholecystitis, digestive diseases, gastric ulcer hemorrhage, GLP1RAs, hypoglycemic agents, pancreatitis, SGLT2is

1. Introduction

New hypoglycemic agents for the treatment of diabetes are divided into 3 classes: sodium-glucose cotransporter-2 inhibitors (SGLT2is) such as canagliflozin and empagliflozin, glucagon-like peptide 1 receptor agonists (GLP1RAs) such as liraglutide and semaglutide, and dipeptidyl peptidase-4 inhibitors (DPP4is) such as sitagliptin and linagliptin. SGLT2is and GLP1RAs can also exert the cardiovascular and renal protection effects except having the antihyperglycemic effects. Moreover, the cardiorenal benefits that SGLT2is exhibit have been confirmed not only in patients with type 2 diabetes[1–3] but also in patients with cardiac or renal failure without type 2 diabetes.[4]

Studies focusing on the efficacy of these new hypoglycemic agents are plentiful enough, whereas studies focusing on the safety of these drugs are relatively lacking. Previous meta-analyses reveal that SGLT2is[5] and DPP4is[6] are not associated with a higher risk of overall gastrointestinal adverse events, whereas GLP1RAs[7,8] are associated with that risk. However, there are no relevant meta-analyses that have evaluated whether these new drug classes lead to the higher risks of various specific digestive diseases. In the absence of the trials that treated the occurrences of various digestive diseases as primary endpoints and meanwhile assessed the risks of these new hypoglycemic drugs in leading to various digestive diseases, we failed to include them to conduct a meta-analysis to evaluate the association between these hypoglycemic drugs and the risks of various digestive diseases. Fortunately, the occurrences of various digestive diseases were reported in detail as digestive adverse events among those large randomized trials which aimed to assess cardiorenal outcomes in patients receiving SGLT2is, GLP1RAs, or DPP4is. Hence, we aimed to, using these safety data relevant with digestive system, conduct a meta-analysis to define the association between each class of these new hypoglycemic drugs and 91 kinds of digestive system diseases.

2. Methods

2.1. Inclusion criteria and quality assessment

Studies that were eligible to be included in this meta-analysis were large randomized, placebo-controlled, cardiorenal outcome trials, which assessed any SGLT2i, GLP1RA, or DPP4i, enrolled at least 1000 participants in each study group, and reported the occurrences of various kinds of digestive system diseases. Outcomes of interest were 91 kinds of digestive diseases which consisted of 75 kinds of gastrointestinal disorders (ID 1-75 in Table S1, Supplemental Digital Content, http://links.lww.com/MD/H18, which shows the names of gastrointestinal and hepatobiliary disorders) and 16 kinds of hepatobiliary disorders (ID 76-91 in Table S1, Supplemental Digital Content, http://links.lww.com/MD/H18, which shows the names of gastrointestinal and hepatobiliary disorders). Relevant articles published before April 2021 were searched in 3 online databases, namely PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase. The search keywords we mainly used in this meta-analysis were “Empagliflozin”, “Dapagliflozin”, “Sotagliflozin”, “Canagliflozin”, “Ertugliflozin”, “Gliflozins”, “SGLT2 inhibitors”, “Liraglutide”, “Exenatide”, “Lixisenatide”, “Dulaglutide”, “Semaglutide”, “Albiglutide”, “GIP-1 Receptor Agonists”, “Linagliptin”, “Sitagliptin”, “Omarigliptin”, “Alogliptin”, “Saxagliptin”, “DPP-4 Inhibitors”, “Renal”, “Cardiovascular”, “Cardiorenal”, and “Randomized controlled trial”. The numbers of subjects developing digestive diseases of interest and the numbers of total subjects in active drug and placebo groups among included trials were extracted from the website of ClinicalTrials (https://clinicaltrials.gov/) respectively by 2 authors. Moreover, the 2 authors evaluated the quality of included trials according to the Cochrane’ tool assessing risk of bias for randomized trials.[9] All the disagreements between them were examined and addressed by a third author.

2.2. Statistical analyses

We performed meta-analysis respectively based on trials of SGLT2is, trials of GLP1RAs, and trials of DPP4is. Meta-analysis was conducted respectively using random-effects model and fixed-effects model to synthesize risk ratio (RR) and 95% confidence interval (CI). I2 was used to reflect heterogeneity magnitude. When I2 was <50%, we selected fixed-effects results as the results of pooled analysis. Otherwise, we selected random-effects results as the results of pooled analysis. The robustness of pooled results was evaluated by the similarity between fixed-effects results and random-effects results. A P value of <.05 means statistical significance. We did all the statistical analyses in this study using the Stata 16.0 software.

2.3. Ethical statement

The data analyzed in this study were extracted from previously published studies, and thus ethical approval was not necessary.

3. Results

3.1. Characteristics of included trials

We finally included 21 large randomized trials for this meta-analysis after we performed study selection. The whole process of study selection is presented in Figure S1 (Supplemental Digital Content, http://links.lww.com/MD/H19, which is the flow chart of study selection). The 21 included trials consisted of 9 SGLT2i trials (i.e., EMPA-REG OUTCOME [NCT01131676],[10] CANVAS [NCT01032629],[11] CANVAS-R [NCT01989754],[11] DECLARE–TIMI 58 [NCT01730534],[12] VERTIS CV [NCT01986881],[13] CREDENCE [NCT02065791],[14] DAPA-HF [NCT03036124],[15] DAPA-CKD [NCT03036150],[16] and EMPEROR-Reduced [NCT03057977][17]), 7 GLP1RA trials (i.e., ELIXA [NCT01147250],[18] SUSTAIN-6 [NCT01720446],[19] LEADER [NCT01179048],[20] EXSCEL [NCT01144338],[21] REWIND [NCT01394952],[22] Harmony Outcomes [NCT02465515],[23] and PIONEER 6 [NCT02692716][24]), and 5 DPP4i trials (i.e., SAVOR-TIMI 53 [NCT01107886],[25] TECOS [NCT00790205],[26] EXAMINE [NCT00968708],[27] CARMELINA [NCT01897532],[28] and OMNEON [NCT01703208][29]). The bias risk of all the included trials was assessed as low risk (Figure S2, Supplemental Digital Content, http://links.lww.com/MD/H20, which is the plot of quality assessment). Nine SGLT2i trials involved 33,124 patients receiving SGLT2is (versus 26,568 patients receiving placebo), 7 GLP1RA trials involved 27,942 patients receiving GLP1RAs (versus 27,980 patients receiving placebo), and 5 DPP4i trials involved 23,833 patients receiving DPP4is (versus 23,750 patients receiving placebo).

3.2. Meta-analyses

Table 1 shows the summary results for meta-analysis of 3 new classes of hypoglycemic agents and 91 kinds of digestive system diseases. Compared with placebo, GLP1RAs were associated with the higher risks of gastric ulcer hemorrhage (RR 2.68, 95% CI 1.07–6.68; Pdrug = 0.035; I2 = 0), pancreatitis (RR 1.48, 95% CI 1.02–2.15; Pdrug = .041; I2 = 0), cholangitis acute (RR 5.96, 95% CI 1.04–34.08; Pdrug = .045; I2 = 0), and cholecystitis acute (RR 1.52, 95% CI 1.08–2.15; Pdrug = .017; I2 = 1.5%), but were not significantly associated with the occurrences of the other 87 kinds of digestive diseases (Pdrug ranged from .064 to .999), with RR (0.23–3.22), low limit of 95% CI of RR (0.04–0.95), upper limit of 95% CI of RR (1.07–28.89), and I2 (most was 0). SGLT2is versus placebo were not significantly associated with the occurrences of 91 kinds of digestive diseases (Pdrug ranged from 0.077 to 0.995), with RR (0.26–3.92), low limit of 95% CI of RR (0.04–0.82), upper limit of 95% CI of RR (1.07–35.51), and I2 (most was 0). DPP4is versus placebo were not significantly associated with the occurrences of 91 kinds of digestive diseases (Pdrug ranged from .085 to .999), with RR (0.18–5.94), low limit of 95% CI of RR (0.02–0.93), upper limit of 95% CI of RR (1.28–49.48), and I2 (most was 0). The detailed results for meta-analysis on 91 outcomes of interest stratified by 3 drug classes are presented in Figures S3 to S93 (Supplemental Digital Content, http://links.lww.com/MD/H21, which are the forest plots of meta-analysis on 91 outcomes), which suggested that the results from random-effects model were not substantially different with those from fixed-effects model.

Table 1.

Summary results for meta-analysis of 3 new classes of hypoglycemic agents and 91 kinds of digestive system diseases.

ID Outcome Drug class RR LOW UPPER Studies Events1 Patients1 Events0 Patients0 I2 (%) P drug
1 Abdominal adhesions SGLT2is 0.72 0.08 6.53 2 1 10,942 2 10,937 31.0 .771
1 Abdominal adhesions GLP1RAs 1.14 0.19 7.01 3 2 15,318 2 15,353 0.0 .886
1 Abdominal adhesions DPP4is 2.07 0.27 16.00 2 3 11,774 1 11,697 0.0 .487
2 Abdominal hernia SGLT2is 0.84 0.40 1.80 6 19 26,693 15 20,140 0.0 .660
2 Abdominal hernia GLP1RAs 0.93 0.49 1.77 5 19 24,703 21 24,740 0.0 .834
2 Abdominal hernia DPP4is 0.75 0.30 1.85 4 9 21,132 12 21,071 0.0 .528
3 Abdominal pain SGLT2is 1.00 0.64 1.57 9 47 33,124 36 26,568 0.0 .995
3 Abdominal pain GLP1RAs 1.10 0.71 1.69 7 45 27,942 42 27,980 0.0 .678
3 Abdominal pain DPP4is 1.30 0.75 2.25 5 29 23,833 22 23,750 0.0 .355
4 Abdominal pain lower SGLT2is 1.45 0.29 7.20 4 3 18,365 1 16,002 0.0 .646
4 Abdominal pain lower GLP1RAs 1.35 0.25 7.18 2 3 6316 2 6321 0.0 .725
4 Abdominal pain lower DPP4is 0.62 0.08 5.03 2 1 10,981 2 10,891 0.0 .654
5 Abdominal pain upper SGLT2is 1.00 0.37 2.67 7 14 28,607 8 22,051 2.9 .994
5 Abdominal pain upper GLP1RAs 1.00 0.50 2.00 7 16 27,942 16 27,980 0.0 .998
5 Abdominal pain upper DPP4is 1.75 0.53 5.82 4 9 21,741 4 21,650 0.0 .362
6 Abdominal wall hematoma SGLT2is 0.94 0.23 3.95 5 3 14,759 2 10,566 0.0 .937
6 Abdominal wall hematoma GLP1RAs 1.61 0.20 13.04 2 2 12,287 1 12,321 0.0 .658
6 Abdominal wall hematoma DPP4is 0.71 0.13 3.95 3 2 19,040 4 18,971 0.0 .698
7 Anal fistula SGLT2is 1.13 0.31 4.11 6 5 26,744 2 20,188 0.0 .858
7 Anal fistula GLP1RAs 0.55 0.15 2.09 5 2 24,703 5 24,740 0.0 .383
7 Anal fistula DPP4is 0.43 0.08 2.42 3 1 19,040 4 18,971 0.0 .339
8 Ascites SGLT2is 1.61 0.54 4.76 6 11 26,912 4 20,359 0.0 .391
8 Ascites GLP1RAs 1.02 0.32 3.24 5 6 23,320 6 23,357 0.0 .974
8 Ascites DPP4is 0.70 0.21 2.37 3 4 19,040 6 18,971 0.0 .567
9 Chronic gastritis SGLT2is 1.09 0.32 3.69 6 6 19,497 3 12,947 0.0 .891
9 Chronic gastritis GLP1RAs 0.69 0.25 1.88 6 7 26,351 12 26,389 0.0 .467
9 Chronic gastritis DPP4is 1.44 0.23 9.15 2 3 5586 2 5585 16.7 .698
10 Colitis SGLT2is 0.67 0.32 1.41 8 16 30,756 17 24,200 0.0 .289
10 Colitis GLP1RAs 1.04 0.53 2.03 7 18 27,942 17 27,980 0.0 .909
10 Colitis DPP4is 1.06 0.38 2.94 4 8 21,132 7 21,071 0.0 .914
11 Colitis ischemic SGLT2is 1.13 0.46 2.73 8 13 30,756 9 24,200 0.0 .793
11 Colitis ischemic GLP1RAs 1.09 0.40 2.95 6 8 24,911 7 24,948 0.0 .861
11 Colitis ischemic DPP4is 1.92 0.58 6.33 4 11 21,741 5 21,650 22.9 .284
12 Colitis ulcerative SGLT2is 1.25 0.25 6.36 3 4 14,364 2 12,913 0.0 .784
12 Colitis ulcerative GLP1RAs 3.22 0.87 11.89 5 8 23,320 1 23,357 0.0 .080
12 Colitis ulcerative DPP4is 2.98 0.31 28.60 2 2 10,981 0 10,891 0.0 .345
13 Constipation SGLT2is 1.25 0.64 2.43 9 30 33,124 16 26,568 19.2 .508
13 Constipation GLP1RAs 1.26 0.69 2.31 7 24 27,942 19 27,980 0.0 .456
13 Constipation DPP4is 1.03 0.46 2.31 5 13 23,833 13 23,750 0.0 .951
14 Diabetic gastroparesis SGLT2is 0.82 0.20 3.40 5 3 23,103 3 17,993 0.0 .790
14 Diabetic gastroparesis GLP1RAs 3.00 0.47 19.04 3 3 12,691 0 12,696 0.0 .244
14 Diabetic gastroparesis DPP4is 0.67 0.17 2.60 4 3 16,567 5 16,476 0.0 .563
15 Diarrhea SGLT2is 0.94 0.59 1.50 9 41 33,124 34 26,568 0.0 .801
15 Diarrhea GLP1RAs 1.45 0.89 2.36 6 43 20,598 28 20,608 0.0 .133
15 Diarrhea DPP4is 1.07 0.62 1.85 4 30 16,567 26 16,476 24.8 .805
16 Diverticular perforation SGLT2is 3.92 0.43 35.51 2 3 5053 0 5052 0.0 .224
16 Diverticular perforation GLP1RAs 0.83 0.25 2.73 4 5 19,986 6 20,025 0.0 .757
16 Diverticular perforation DPP4is 1.00 0.17 5.77 3 2 17,638 2 17,586 0.0 .999
17 Diverticulum SGLT2is 1.26 0.48 3.31 6 11 26,007 6 20,896 0.0 .645
17 Diverticulum GLP1RAs 0.87 0.36 2.15 5 10 21,634 12 21,674 10.4 .771
17 Diverticulum DPP4is 0.51 0.12 2.10 4 2 21,132 5 21,071 0.0 .351
18 Diverticulum intestinal SGLT2is 0.52 0.17 1.58 7 6 22,687 7 16,136 0.0 .247
18 Diverticulum intestinal GLP1RAs 2.53 0.88 7.24 5 12 23,320 4 23,357 0.0 .084
18 Diverticulum intestinal DPP4is 0.74 0.14 3.93 3 2 19,040 3 18,971 0.0 .723
19 Diverticulum intestinal hemorrhagic SGLT2is 1.06 0.34 3.31 6 7 23,670 5 19,469 0.0 .921
19 Diverticulum intestinal hemorrhagic GLP1RAs 0.62 0.14 2.70 3 3 16,955 6 16,993 0.0 .524
19 Diverticulum intestinal hemorrhagic DPP4is 1.60 0.31 8.30 3 4 13,461 2 13,438 0.0 .576
20 Duodenal ulcer SGLT2is 0.87 0.43 1.75 8 19 30,756 15 24,200 0.0 .694
20 Duodenal ulcer GLP1RAs 0.95 0.50 1.79 7 19 27,942 21 27,980 0.0 .864
20 Duodenal ulcer DPP4is 0.79 0.35 1.77 5 11 23,833 15 23,750 0.0 .566
21 Duodenal ulcer hemorrhage SGLT2is 0.93 0.32 2.68 6 9 26,226 7 21,115 0.0 .895
21 Duodenal ulcer hemorrhage GLP1RAs 0.89 0.39 2.01 7 13 27,942 13 27,980 0.0 .776
21 Duodenal ulcer hemorrhage DPP4is 0.99 0.23 4.37 3 3 18,247 3 18,165 0.0 .993
22 Duodenitis SGLT2is 1.28 0.28 5.83 4 4 17,829 2 15,467 0.0 .752
22 Duodenitis GLP1RAs 0.75 0.26 2.17 6 5 26,351 8 26,389 0.0 .594
22 Duodenitis DPP4is 0.38 0.07 2.11 3 1 13,461 5 13,438 0.0 .269
23 Dyspepsia SGLT2is 1.79 0.51 6.25 4 8 18,515 3 14,711 0.0 .360
23 Dyspepsia GLP1RAs 0.90 0.34 2.42 6 8 26,294 9 26,331 0.0 .837
23 Dyspepsia DPP4is 1.18 0.32 4.37 3 5 18,247 4 18,165 0.0 .804
24 Dysphagia SGLT2is 0.94 0.28 3.13 4 6 18,296 6 14,492 34.0 .916
24 Dysphagia GLP1RAs 1.58 0.53 4.72 5 9 24,703 5 24,740 0.0 .411
24 Dysphagia DPP4is 0.88 0.22 3.46 4 4 21,741 5 21,650 0.0 .851
25 Enteritis SGLT2is 0.50 0.18 1.39 7 4 24,727 10 20,920 0.0 .184
25 Enteritis GLP1RAs 0.23 0.05 1.09 3 1 14,328 8 14,336 0.0 .064
25 Enteritis DPP4is 4.07 0.67 24.60 3 5 14,475 0 14,376 0.0 .126
26 Enterovesical fistula SGLT2is 0.62 0.08 5.07 2 1 10,774 2 10,766 0.0 .659
26 Enterovesical fistula GLP1RAs 1.00 0.14 7.10 2 2 9611 2 9621 0.0 .999
26 Enterovesical fistula DPP4is 1.00 0.20 4.95 4 2 21,132 2 21,071 0.0 .999
27 Fecaloma SGLT2is 1.04 0.22 4.85 3 6 15,410 3 13,051 42.2 .962
27 Fecaloma GLP1RAs 0.54 0.13 2.30 4 2 21,672 5 21,708 0.0 .404
27 Fecaloma DPP4is 1.14 0.19 6.98 3 2 19,040 2 18,971 0.0 .890
28 Food poisoning SGLT2is 0.89 0.31 2.53 6 7 23,400 6 19,592 0.0 .820
28 Food poisoning GLP1RAs 1.00 0.17 5.78 3 2 12,642 2 12,653 0.0 .999
28 Food poisoning DPP4is 0.67 0.11 4.12 2 2 10,372 3 10,312 0.0 .666
29 Gastric hemorrhage SGLT2is 0.89 0.26 3.05 5 5 22,985 4 17,878 0.0 .854
29 Gastric hemorrhage GLP1RAs 0.69 0.11 4.40 3 1 14,328 2 14,336 0.0 .698
29 Gastric hemorrhage DPP4is 0.64 0.12 3.53 3 2 14,475 5 14,376 15.9 .611
30 Gastric polyps SGLT2is 1.12 0.28 4.56 3 4 16,165 3 13,805 0.0 .872
30 Gastric polyps GLP1RAs 0.89 0.30 2.63 5 6 21,634 7 21,674 0.0 .833
30 Gastric polyps DPP4is 1.93 0.34 11.16 3 3 12,852 1 12,859 0.0 .461
31 Gastric ulcer SGLT2is 0.90 0.47 1.69 8 21 30,220 18 23,665 0.0 .735
31 Gastric ulcer GLP1RAs 0.94 0.50 1.77 7 19 27,942 20 27,980 0.0 .856
31 Gastric ulcer DPP4is 0.77 0.36 1.62 5 13 23,833 17 23,750 0.0 .484
32 Gastric ulcer hemorrhage SGLT2is 1.36 0.50 3.68 5 10 23,271 6 18,164 0.0 .546
32 Gastric ulcer hemorrhage GLP1RAs 2.68 1.07 6.68 6 22 26,351 6 26,389 0.0 .035
32 Gastric ulcer hemorrhage DPP4is 0.89 0.32 2.43 4 7 20,339 8 20,265 0.0 .814
33 Gastritis SGLT2is 0.77 0.47 1.26 8 37 30,220 39 23,665 14.6 .294
33 Gastritis GLP1RAs 0.82 0.55 1.23 7 46 27,942 57 27,980 3.2 .340
33 Gastritis DPP4is 1.10 0.65 1.87 5 34 23,833 29 23,750 42.8 .715
34 Gastritis erosive SGLT2is 1.92 0.63 5.81 5 12 22,985 4 17,878 0.0 .248
34 Gastritis erosive GLP1RAs 0.53 0.23 1.25 5 9 24,703 18 24,740 0.0 .147
34 Gastritis erosive DPP4is 0.56 0.19 1.64 5 5 23,833 11 23,750 0.0 .287
35 Gastritis hemorrhagic SGLT2is 0.91 0.14 5.76 3 2 12,548 1 7446 0.0 .918
35 Gastritis hemorrhagic GLP1RAs 2.16 0.36 12.84 3 4 9347 1 9353 0.0 .397
35 Gastritis hemorrhagic DPP4is 1.34 0.25 7.15 3 3 19,040 2 18,971 0.0 .728
36 Gastrointestinal hemorrhage SGLT2is 0.85 0.59 1.21 9 65 33,124 61 26,568 0.0 .361
36 Gastrointestinal hemorrhage GLP1RAs 0.78 0.57 1.07 7 70 27,942 90 27,980 0.0 .129
36 Gastrointestinal hemorrhage DPP4is 0.86 0.58 1.28 5 46 23,833 53 23,750 0.0 .468
37 Gastrointestinal necrosis SGLT2is 0.70 0.11 4.30 3 2 13,323 2 11,873 22.8 .701
37 Gastrointestinal necrosis GLP1RAs 1.35 0.25 7.18 3 3 14,328 2 14,336 0.0 .725
37 Gastrointestinal necrosis DPP4is 1.00 0.14 7.09 2 2 10,760 2 10,759 0.0 .999
38 Gastrointestinal ulcer hemorrhage SGLT2is 1.44 0.23 9.15 3 2 12,586 1 12,581 0.0 .698
38 Gastrointestinal ulcer hemorrhage GLP1RAs 1.39 0.15 12.56 2 2 9611 1 9621 30.9 .771
38 Gastrointestinal ulcer hemorrhage DPP4is 0.47 0.10 2.17 4 1 20,339 4 20,265 0.0 .330
39 Gastroesophageal reflux disease SGLT2is 0.70 0.36 1.35 7 21 28,357 21 21,802 0.0 .289
39 Gastroesophageal reflux disease GLP1RAs 1.19 0.73 1.96 7 38 27,942 30 27,980 0.0 .485
39 Gastroesophageal reflux disease DPP4is 1.30 0.58 2.92 5 21 23,833 11 23,750 30.5 .520
40 Gingival bleeding SGLT2is 0.26 0.04 1.68 3 0 15,124 3 12,765 0.0 .158
40 Gingival bleeding GLP1RAs 3.01 0.31 28.89 2 2 10,375 0 10,404 0.0 .340
40 Gingival bleeding DPP4is 0.99 0.10 9.53 2 1 10,981 1 10,891 0.0 .994
41 Hematemesis SGLT2is 0.67 0.22 2.03 7 6 29,112 7 22,556 0.0 .477
41 Hematemesis GLP1RAs 0.52 0.12 2.17 5 1 19,007 4 19,017 0.0 .367
41 Hematemesis DPP4is 3.90 0.43 35.32 2 3 11,774 0 11,697 0.0 .226
42 Hematochezia SGLT2is 0.63 0.16 2.47 5 4 22,985 4 17,878 0.0 .508
42 Hematochezia GLP1RAs 0.80 0.22 2.89 4 5 18,546 7 18,584 22.3 .737
42 Hematochezia DPP4is 0.86 0.20 3.73 3 3 19,040 4 18,971 0.0 .844
43 Haemorrhoidal hemorrhage SGLT2is 0.45 0.16 1.33 7 4 28,357 8 21,802 0.0 .149
43 Haemorrhoidal hemorrhage GLP1RAs 1.26 0.34 4.72 4 5 17,359 4 17,368 0.0 .730
43 Hemorrhoidal hemorrhage DPP4is 0.18 0.02 1.57 2 0 10,981 5 10,891 0.0 .121
44 Hemorrhoids SGLT2is 1.33 0.56 3.13 6 16 25,652 7 19,100 0.0 .519
44 Hemorrhoids GLP1RAs 1.30 0.53 3.18 6 11 26,294 8 26,331 0.0 .572
44 Hemorrhoids DPP4is 1.17 0.52 2.64 4 13 21,741 11 21,650 0.0 .707
45 Hiatus hernia SGLT2is 1.12 0.33 3.79 3 6 16,147 4 12,343 0.0 .854
45 Hiatus hernia GLP1RAs 1.31 0.44 3.88 5 12 23,320 11 23,357 45.7 .626
45 Hiatus hernia DPP4is 1.21 0.18 7.93 2 3 11,774 2 11,697 26.1 .845
46 Ileus SGLT2is 1.15 0.49 2.73 9 14 33,124 8 26,568 0.0 .747
46 Ileus GLP1RAs 0.94 0.40 2.22 5 11 24,703 11 24,740 0.0 .892
46 Ileus DPP4is 1.15 0.27 4.98 4 4 21,132 3 21,071 0.0 .849
47 Ileus paralytic SGLT2is 0.51 0.16 1.65 6 4 25,871 6 19,319 0.0 .260
47 Ileus paralytic GLP1RAs 0.50 0.09 2.73 2 2 9611 4 9621 0.0 .424
47 Ileus paralytic DPP4is 0.63 0.08 5.09 2 1 9358 2 9374 0.0 .661
48 Impaired gastric emptying SGLT2is 0.88 0.23 3.31 4 5 18,314 4 15,954 0.0 .851
48 Impaired gastric emptying GLP1RAs 1.16 0.41 3.26 7 9 27,942 7 27,980 0.0 .783
48 Impaired gastric emptying DPP4is 2.04 0.34 12.32 3 4 13,073 1 12,991 0.0 .437
49 Inguinal hernia SGLT2is 1.34 0.82 2.18 9 55 33,124 29 26,568 9.6 .245
49 Inguinal hernia GLP1RAs 1.45 0.95 2.23 7 55 27,942 37 27,980 0.0 .085
49 Inguinal hernia DPP4is 1.24 0.71 2.17 5 29 23,833 23 23,750 0.0 .439
50 Intestinal hemorrhage SGLT2is 0.40 0.11 1.45 6 2 26,912 6 20,359 0.0 .164
50 Intestinal hemorrhage GLP1RAs 1.22 0.35 4.28 4 5 16,966 4 17,002 0.0 .753
50 Intestinal hemorrhage DPP4is 0.62 0.08 5.07 2 1 10,760 2 10,759 0.0 .659
51 Intestinal ischemia SGLT2is 0.90 0.33 2.47 7 9 28,775 8 22,222 0.0 .839
51 Intestinal ischemia GLP1RAs 1.84 0.60 5.63 5 9 15,881 4 15,893 0.0 .284
51 Intestinal ischemia DPP4is 1.52 0.30 7.71 3 4 18,247 2 18,165 0.0 .612
52 Intestinal obstruction SGLT2is 0.93 0.46 1.88 8 21 30,238 15 25,127 0.0 .848
52 Intestinal obstruction GLP1RAs 0.74 0.40 1.39 6 19 26,351 25 26,389 7.4 .352
52 Intestinal obstruction DPP4is 1.26 0.52 3.04 5 12 23,833 9 23,750 0.0 .607
53 Intestinal perforation SGLT2is 1.25 0.30 5.14 5 4 23,322 2 18,212 0.0 .758
53 Intestinal perforation GLP1RAs 3.00 0.61 14.88 4 4 18,652 0 18,685 0.0 .178
53 Intestinal perforation DPP4is 0.23 0.04 1.39 3 0 19,040 5 18,971 0.0 .110
54 Intestinal polyp SGLT2is 1.42 0.18 11.01 2 3 11,460 1 10,010 17.1 .736
54 Intestinal polyp GLP1RAs 0.43 0.08 2.43 3 1 14,328 4 14,336 0.0 .341
54 Intestinal polyp DPP4is 0.43 0.06 2.95 2 1 10,760 3 10,759 0.0 .392
55 Irritable bowel syndrome SGLT2is 1.50 0.16 14.38 2 2 10,180 0 5078 0.0 .727
55 Irritable bowel syndrome GLP1RAs 0.23 0.04 1.39 3 0 14,328 5 14,336 0.0 .111
55 Irritable bowel syndrome DPP4is 1.34 0.25 7.13 3 3 14,475 2 14,376 0.0 .731
56 Large intestine perforation SGLT2is 1.22 0.37 4.01 5 6 24,544 3 17,991 0.0 .748
56 Large intestine perforation GLP1RAs 1.00 0.23 4.41 4 3 19,986 3 20,025 0.0 .998
56 Large intestine perforation DPP4is 1.59 0.20 12.96 2 2 15,546 1 15,486 0.0 .662
57 Large intestine polyp SGLT2is 1.31 0.72 2.41 8 31 30,220 17 23,665 0.0 .379
57 Large intestine polyp GLP1RAs 1.02 0.59 1.76 7 28 27,942 32 27,980 6.3 .942
57 Large intestine polyp DPP4is 1.29 0.49 3.44 3 11 12,852 9 12,859 37.9 .606
58 Lower gastrointestinal hemorrhage SGLT2is 1.70 0.62 4.70 7 11 26,574 4 22,372 0.0 .304
58 Lower gastrointestinal hemorrhage GLP1RAs 0.97 0.51 1.85 7 20 27,942 21 27,980 0.0 .922
58 Lower gastrointestinal hemorrhage DPP4is 0.63 0.24 1.68 5 6 23,833 13 23,750 0.0 .356
59 Mallory-Weiss syndrome SGLT2is 1.48 0.22 10.10 2 3 6550 1 4196 0.0 .689
59 Mallory-Weiss syndrome GLP1RAs 2.85 0.43 18.71 2 4 7699 1 7704 0.0 .276
59 Mallory-Weiss syndrome DPP4is 2.87 0.57 14.56 3 5 18,247 1 18,165 0.0 .203
60 Melaena SGLT2is 2.00 0.55 7.20 6 7 26,226 1 21,115 0.0 .291
60 Melaena GLP1RAs 0.87 0.31 2.39 6 7 26,351 8 26,389 0.0 .783
60 Melaena DPP4is 5.94 0.71 49.48 2 5 10,760 0 10,759 0.0 .100
61 Nausea SGLT2is 0.93 0.38 2.31 6 12 25,134 9 20,027 0.0 .881
61 Nausea GLP1RAs 1.04 0.52 2.07 6 17 20,598 17 20,608 0.0 .922
61 Nausea DPP4is 2.82 0.38 21.03 2 5 11,774 1 11,697 12.1 .313
62 Esophageal varices hemorrhage SGLT2is 1.12 0.21 5.94 2 3 11,460 2 10,010 0.0 .897
62 Esophageal varices hemorrhage GLP1RAs 1.53 0.38 6.05 5 6 23,263 3 23,299 8.4 .548
62 Esophageal varices hemorrhage DPP4is 0.33 0.05 2.11 3 0 19,040 3 18,971 0.0 .242
63 Esophagitis SGLT2is 0.96 0.18 4.97 3 3 18,754 2 13,647 0.0 .960
63 Esophagitis GLP1RAs 0.77 0.27 2.18 6 6 26,294 8 26,331 0.0 .627
63 Esophagitis DPP4is 2.65 0.65 10.87 4 9 16,567 2 16,476 0.0 .175
64 Pancreatic cyst SGLT2is 0.35 0.07 1.68 4 1 19,102 4 14,904 0.0 .189
64 Pancreatic cyst GLP1RAs 0.83 0.23 2.92 4 4 18,603 5 18,642 0.0 .768
64 Pancreatic cyst DPP4is 0.97 0.16 5.89 3 2 8287 3 8264 22.0 .978
65 Pancreatitis SGLT2is 1.21 0.70 2.08 9 38 33,124 22 26,568 0.0 .493
65 Pancreatitis GLP1RAs 1.48 1.02 2.15 7 70 27,942 48 27,980 0.0 .041
65 Pancreatitis DPP4is 1.54 0.87 2.70 4 31 16,567 20 16,476 0.0 .135
66 Pancreatitis acute SGLT2is 1.16 0.74 1.82 9 53 33,124 35 26,568 0.0 .511
66 Pancreatitis acute GLP1RAs 1.04 0.65 1.66 6 37 20,598 36 20,608 8.9 .876
66 Pancreatitis acute DPP4is 1.05 0.49 2.26 4 15 16,567 14 16,476 0.0 .903
67 Pancreatitis chronic SGLT2is 0.81 0.27 2.44 6 6 25,134 6 20,027 0.0 .703
67 Pancreatitis chronic GLP1RAs 1.17 0.35 3.92 5 5 18,950 4 18,959 0.0 .799
67 Pancreatitis chronic DPP4is 0.63 0.22 1.80 4 6 16,567 10 16,476 0.0 .391
68 Peptic ulcer SGLT2is 1.04 0.38 2.85 7 9 28,893 6 22,337 0.0 .943
68 Peptic ulcer GLP1RAs 1.21 0.47 3.07 5 11 23,320 8 23,357 0.0 .693
68 Peptic ulcer DPP4is 0.98 0.27 3.48 5 5 23,833 5 23,750 0.0 .969
69 Rectal hemorrhage SGLT2is 1.44 0.70 2.96 6 25 25,703 11 19,148 0.0 .317
69 Rectal hemorrhage GLP1RAs 1.27 0.63 2.53 5 18 24,703 14 24,740 0.0 .506
69 Rectal hemorrhage DPP4is 0.59 0.20 1.75 5 5 23,833 10 23,750 0.0 .342
70 Rectal polyp SGLT2is 0.72 0.15 3.47 3 3 10,061 3 7310 0.0 .679
70 Rectal polyp GLP1RAs 1.88 0.54 6.50 4 7 21,672 3 21,708 0.0 .319
70 Rectal polyp DPP4is 0.50 0.12 2.13 3 2 19,040 6 18,971 0.0 .345
71 Small intestinal obstruction SGLT2is 1.31 0.70 2.47 9 30 33,124 16 26,568 0.0 .397
71 Small intestinal obstruction GLP1RAs 0.92 0.54 1.57 5 27 23,320 30 23,357 5.9 .753
71 Small intestinal obstruction DPP4is 1.14 0.55 2.36 5 16 23,833 14 23,750 0.0 .719
72 Umbilical hernia SGLT2is 1.01 0.49 2.08 7 26 29,112 15 22,556 40.4 .988
72 Umbilical hernia GLP1RAs 0.69 0.38 1.25 7 20 27,942 30 27,980 0.0 .218
72 Umbilical hernia DPP4is 1.15 0.43 3.06 3 9 19,040 9 18,971 14.2 .783
73 Upper gastrointestinal hemorrhage SGLT2is 0.89 0.53 1.49 9 37 33,124 31 26,568 0.0 .648
73 Upper gastrointestinal hemorrhage GLP1RAs 0.87 0.54 1.39 6 33 26,351 38 26,389 0.0 .560
73 Upper gastrointestinal hemorrhage DPP4is 0.86 0.48 1.53 5 23 23,833 27 23,750 0.0 .610
74 Varices esophageal SGLT2is 1.49 0.44 5.01 4 7 18,296 3 14,492 0.0 .517
74 Varices esophageal GLP1RAs 1.94 0.34 11.17 3 3 17,004 1 17,036 0.0 .460
74 Varices esophageal DPP4is 0.72 0.08 6.50 2 1 15,546 2 15,486 31.4 .769
75 Vomiting SGLT2is 0.51 0.24 1.07 8 15 30,220 23 23,665 0.0 .077
75 Vomiting GLP1RAs 1.59 0.92 2.74 6 37 20,598 21 20,608 0.0 .098
75 Vomiting DPP4is 1.68 0.62 4.54 4 13 16,567 7 16,476 11.8 .303
76 Bile duct stone SGLT2is 0.87 0.45 1.70 9 22 33,124 20 26,568 0.0 .684
76 Bile duct stone GLP1RAs 1.27 0.61 2.63 6 17 20,598 13 20,608 0.0 .523
76 Bile duct stone DPP4is 0.67 0.25 1.76 5 6 23,833 10 23,750 0.0 .412
77 Biliary colic SGLT2is 0.71 0.16 3.08 4 3 19,120 4 16,366 0.0 .651
77 Biliary colic GLP1RAs 2.10 0.71 6.27 5 10 23,320 4 23,357 0.0 .182
77 Biliary colic DPP4is 0.65 0.15 2.89 4 3 21,741 6 21,650 12.1 .576
78 Cholangitis SGLT2is 1.17 0.59 2.31 9 19 33,124 14 26,568 0.0 .657
78 Cholangitis GLP1RAs 1.22 0.44 3.45 4 9 14,290 7 14,302 6.6 .701
78 Cholangitis DPP4is 0.36 0.08 1.60 4 1 16,567 6 16,476 0.0 .178
79 Cholangitis acute SGLT2is 1.19 0.44 3.23 7 8 22,944 6 21,490 0.0 .735
79 Cholangitis acute GLP1RAs 5.96 1.04 34.08 3 8 11,202 0 11,212 0.0 .045
79 Cholangitis acute DPP4is 0.99 0.17 5.73 3 2 14,475 2 14,376 0.0 .994
80 Cholecystitis SGLT2is 0.87 0.58 1.29 9 58 33,124 51 26,568 0.0 .482
80 Cholecystitis GLP1RAs 1.26 0.83 1.89 6 54 20,598 45 20,608 14.4 .277
80 Cholecystitis DPP4is 1.66 0.93 2.94 5 32 23,833 19 23,750 0.0 .085
81 Cholecystitis acute SGLT2is 0.96 0.68 1.34 9 80 33,124 64 26,568 0.0 .802
81 Cholecystitis acute GLP1RAs 1.52 1.08 2.15 6 84 20,598 56 20,608 1.5 .017
81 Cholecystitis acute DPP4is 1.47 0.90 2.40 4 40 16,567 27 16,476 0.0 .122
82 Cholecystitis chronic SGLT2is 0.81 0.33 2.01 8 12 30,220 12 23,665 0.0 .654
82 Cholecystitis chronic GLP1RAs 1.54 0.71 3.37 6 17 20,598 11 20,608 0.0 .277
82 Cholecystitis chronic DPP4is 0.48 0.12 1.84 4 3 16,567 8 16,476 0.0 .284
83 Cholelithiasis SGLT2is 0.90 0.65 1.24 9 93 33,124 74 26,568 0.0 .509
83 Cholelithiasis GLP1RAs 1.17 0.90 1.53 6 119 20,598 101 20,608 20.6 .242
83 Cholelithiasis DPP4is 0.98 0.66 1.45 5 48 23,833 49 23,750 0.0 .904
84 Drug-induced liver injury SGLT2is 0.87 0.22 3.42 5 4 21,184 3 16,986 0.0 .839
84 Drug-induced liver injury GLP1RAs 0.47 0.14 1.59 6 2 26,294 7 26,331 0.0 .224
84 Drug-induced liver injury DPP4is 0.72 0.08 6.50 2 1 15,546 2 15,486 31.4 .769
85 Hepatic cirrhosis SGLT2is 0.80 0.44 1.45 9 22 33,124 22 26,568 0.0 .458
85 Hepatic cirrhosis GLP1RAs 0.90 0.46 1.75 7 17 27,942 19 27,980 0.0 .761
85 Hepatic cirrhosis DPP4is 0.57 0.22 1.48 5 7 23,833 14 23,750 18.9 .247
86 Hepatic failure SGLT2is 0.88 0.33 2.38 6 7 22,527 7 18,723 0.0 .803
86 Hepatic failure GLP1RAs 0.74 0.18 2.99 4 4 15,976 6 15,985 23.4 .674
86 Hepatic failure DPP4is 1.64 0.51 5.32 3 7 19,040 4 18,971 0.0 .410
87 Hepatitis SGLT2is 0.56 0.09 3.45 3 1 12,805 3 12,800 0.0 .534
87 Hepatitis GLP1RAs 1.00 0.10 9.62 2 1 6534 1 6540 0.0 .999
87 Hepatitis DPP4is 1.59 0.20 12.96 2 2 15,546 1 15,486 0.0 .662
88 Hepatitis acute SGLT2is 2.38 0.38 15.10 3 3 16,435 0 13,682 0.0 .358
88 Hepatitis acute GLP1RAs 1.14 0.19 7.00 3 2 12,416 2 12,419 0.0 .887
88 Hepatitis acute DPP4is 1.00 0.10 9.58 2 1 9967 1 9953 0.0 .997
89 Ischemic hepatitis SGLT2is 0.48 0.10 2.40 4 1 17,829 3 15,467 0.0 .375
89 Ischemic hepatitis GLP1RAs 0.71 0.20 2.61 5 3 19,007 5 19,017 0.0 .610
89 Ischemic hepatitis DPP4is 0.33 0.03 3.19 2 0 11,774 2 11,697 0.0 .339
90 Jaundice SGLT2is 0.45 0.07 2.76 3 1 16,435 3 13,682 0.0 .389
90 Jaundice GLP1RAs 1.29 0.28 6.00 4 3 18,603 2 18,642 0.0 .745
90 Jaundice DPP4is 1.14 0.19 6.98 3 2 13,866 2 13,797 0.0 .889
91 Portal vein thrombosis SGLT2is 0.32 0.07 1.39 3 2 16,953 5 12,755 0.0 .128
91 Portal vein thrombosis GLP1RAs 1.39 0.27 7.20 3 3 16,955 2 16,993 0.0 .696
91 Portal vein thrombosis DPP4is 2.98 0.31 28.68 2 2 11,774 0 11,697 0.0 .344
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CI = confidence interval, DPP4is = dipeptidyl peptidase-4 inhibitors, Events0 = the number of events in the control group, Events1 = the number of events in the intervention group, GLP1RAs = glucagon-like peptide 1 receptor agonists, LOW = the low limit of 95% CI of RR, Patients0 = the number of patients in the control group, Patients1 = the number of patients in the intervention group, Pdrug = P for drug effect, RR = risk ratio, SGLT2is = sodium-glucose cotransporter-2 inhibitors, Studies = the number of included studies, UPPER = the upper limit of 95% CI of RR.

4. Discussion

Two previous meta-analyses[5,6] identified that SGLT2is[5] and DPP4is[6] did not lead to the higher risk of overall gastrointestinal adverse events, whereas our meta-analysis further identified that these 2 new classes of hypoglycemic agents were not significantly associated with the occurrences of 91 kinds of specific digestive diseases. Two another meta-analyses[7,8] identified that GLP1RAs led to the higher risk of overall gastrointestinal adverse events, whereas our meta-analysis further identified that this new class of hypoglycemic agents was significantly associated with the higher risks of 4 kinds of digestive diseases (i.e., gastric ulcer hemorrhage, pancreatitis, cholangitis acute, and cholecystitis acute). In this meta-analysis, GLP1RAs was observed with the higher risks of cholangitis acute and cholecystitis acute, which is probably because GLP1RAs could increase the risk of cholelithiasis[30,31] and therefore led to the higher risks of cholangitis and cholecystitis. On the other hand, GLP1RAs was observed with the higher risk of gastric ulcer hemorrhage in this meta-analysis, which is probably associated with the fact that GLP1RAs has higher risk of gastrointestinal adverse events such as vomiting.[32,33] On the contrary, previous studies[33–35] did not show the significant association between use of GLP1RAs and risk of pancreatitis, whereas our meta-analysis showed this significant association. The reason for this is probably that our meta-analysis included more large sample randomized trials. However, further research is needed to determine this issue.

Because the trials which considered the occurrences of various digestive diseases as primary endpoints and meanwhile compared SGLT2is, DPP4is, or GLP1RAs with placebo or compared a new hypoglycemic drug with another were lacking, we conducted this meta-analysis by incorporating those trials which considered the occurrences of cardiorenal events as primary endpoints and conversely reported the occurrences of various digestive diseases as digestive adverse events. Thus, patients among the included trials had a high risk of developing cardiorenal events but did not have a high risk of various digestive diseases. This led to the very low incidences of various digestive diseases among included trials. Each study group among included trials had at least 1000 participants, which suggested the included trials with large sample sizes. However, the limited numbers of occurrences of various digestive diseases, to a large extent, attenuated the statistical power of this meta-analysis. This is the main limitation of this meta-analysis. On the contrary, only low risk of bias observed among included trials, no heterogeneity observed in most of the meta-analyses conducted in this study, and the robustness of meta-analysis results revealed by the similarity between fixed-effects results and random-effects results are the 3 main advantages of this study.

In general, neither SGLT2is nor DPP4is are associated with the occurrences of various kinds of digestive diseases, whereas GLP1RAs are associated with the higher risks of 4 kinds of digestive diseases, namely, gastric ulcer hemorrhage, pancreatitis, cholangitis acute, and cholecystitis acute. These findings seem to suggest that GLP1RAs are not applicable for patients at high risk of 4 specific digestive diseases whereas SGLT2is and DPP4is are safe for patients susceptible to digestive diseases. However, our findings require to be further verified by future studies with sufficient statistical power.

Author contributions

Design: Yu-Wen Wang.

Conduct/data collection: Yu-Wen Wang, Jin-Hao Lin, and Cui-Shan Yang.

Analysis: Jin-Hao Lin.

Writing manuscript: Yu-Wen Wang, and Cui-Shan Yang.

All authors approved the manuscript.

Supplementary Material

medi-101-e30072-s001.xlsx (10.5KB, xlsx)
medi-101-e30072-s002.pdf (206.7KB, pdf)
medi-101-e30072-s003.pdf (98.9KB, pdf)

Abbreviations:

CENTRAL =
Cochrane Central Register of Controlled Trials
CI =
confidence interval
DPP4is =
dipeptidyl peptidase-4 inhibitors
GLP1RAs =
glucagon-like peptide 1 receptor agonists
RR =
risk ratio
SGLT2is =
sodium-glucose cotransporter-2 inhibitors

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

How to cite this article: Wang Y-W, Lin J-H, Yang C-S. Meta-analysis of the association between new hypoglycemic agents and digestive diseases. Medicine 2022;101:34(e30072).

Supplemental Digital Content is available for this article.

The authors have no conflicts of interest to disclose.

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medi-101-e30072-s001.xlsx (10.5KB, xlsx)
medi-101-e30072-s002.pdf (206.7KB, pdf)
medi-101-e30072-s003.pdf (98.9KB, pdf)
medi-101-e30072-s004.pdf (5.6MB, pdf)

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