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Am J Med Sci. Author manuscript; available in PMC 2023 Jul 1. PMCID: PMC9453653   
Published in final edited form as: NIHMSID: NIHMS1773940
Am J Med Sci. 2022 Jul; 364(1): 53–58. PMID: 35077701 RESOURCES
Published online 2022 Jan 22. doi: 10.1016/j.amjms.2022.01.003
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Titulo

Use of Oral Anti-Diabetic Drugs and Risk of Hospital and Intensive Care Unit Cited by other articles

Admissions for Infections

Links to NCBI Databases
Jeeyon Rim, MD,1 Julia Gallini, MSPH,2 Christine Jasien, BS,2 Xiangqin Cui, PhD,3 Lawrence Phillips, MD,2,4
Aaron Trammell, MD, MSc,5 and Ruxana T Sadikot, MD, MRCP6,*

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The publisher's final edited version of this article is available at Am J Med Sci

Associated Data

▸ Supplementary Materials

Abstract Go to: ▸

Background:

Sepsis is one of the leading causes of hospital mortality, and diabetes is a risk factor for the
development of infections. Although strong evidence has shown an association between metformin
and reduced risk of infections, the risk of developing infections with newer classes of oral anti-
diabetic drugs (OADs) has been less certain. Our study aims to examine the association between
outpatient OAD use and hospital admissions for infections.

Methods:
Tipo de estudio

The study cohort included 1.39 million adults with diabetes utilizing the Veterans Health Affairs
Corporate Data Warehouse. Multivariate logistic regression was used to estimate the effect of each
drug class on hospital admission for infection while adjusting for covariates.

Results:

After adjusting for covariates, those who took metformin during the study period had 3.3% lower
odds of hospital admission for infection compared to those who were never on metformin (OR 0.97,
95% CI 0.95–0.98). OADs that were associated with a statistically signi icant increased odds of being
admitted included meglitinides (OR 1.22, 95% CI 1.07–1.38), SGLT2 inhibitors (OR 1.16, 95% CI
1.08–1.24), alpha-glucosidase inhibitors (OR 1.09, 95% CI 1.04–1.15), and DPP4 inhibitors (OR 1.04,
95% CI 1.01–1.06).

Conclusions:

Metformin was associated with lower odds of hospital admission for infection while meglitinides,
SGLT2 inhibitors, alpha-glucosidase inhibitors, and DPP4 inhibitors were associated with higher
odds of admission for infection.

Keywords: infections, infection, oral anti-diabetic drugs, glucose lowering drugs

Introduction Go to: ▸

Diabetes is one of the most common chronic diseases with an estimated 34.2 million diagnosed and
undiagnosed cases in the United States, accounting for 10.5% of the US population.1 Morbidity and
mortality continue to be high due to a variety of causes including complications of diabetes,
atherosclerosis, cardiovascular diseases, stroke, and severe infections including pneumonia and
sepsis. Hyperglycemia has been associated with altered immune function, in lammation, and
increased severity of infections,2, 3 and patients with type 2 diabetes have an increased risk of death Razones

associated with hospitalizations for infections.4 During the recent pandemic, diabetes was found to
be one of the most frequent comorbidities in people with COVID-19 with a prevalence rate reported
between 7 and 30%.5, 6 Furthermore, patients with diabetes who developed COVID had severe
complications with increased morbidity and mortality.7

Patients with type II diabetes are often treated with oral antidiabetic medications, and over the last
few years, several new classes of oral antidiabetic medications have been developed. Clinicians now
have many options for oral therapies including, metformin, sulfonylureas, alpha-glucosidase
inhibitors, meglitinides, thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors, and
sodium-glucose cotransporter 2 (SGLT2) inhibitors. Interestingly, many of these agents have effects
beyond control of hyperglycemia, which include anti-in lammatory, antiaging and
immunomodulatory properties.8 In preclinical studies, we and others have shown that metformin
and pioglitazone can enhance host response to infections in vitro and in vivo models of infections.9–
12 However, repurposing of these drugs for immunomodulatory effects will need further

investigations.

Recent clinical studies suggest an association between pre-admission metformin use and decreased
rates of sepsis and inpatient mortality.13, 14 However, the development of infections associated with
hospitalizations, among patients with type 2 diabetes taking newer classes of OADs has not been as
well studied and have provided con licting results.13, 15–17 Given the immunomodulatory effects of
oral antidiabetics, we questioned if patients with diabetes who receive these medications are less Hipotesis
prone to infections. The objective of our study is to examine the association between outpatient OAD
use and hospital admissions for infections. objetivo

Methods: Go to: ▸

Study design, setting, and population

This is a nationwide retrospective cohort study utilizing the Veterans Health Affairs Corporate Data
Warehouse. A HIPAA waiver was obtained, as this research provided minimal risk to the subjects as tipo de estudio

it did not involve contact with patients or any intervention. The only risk possible is a loss of
con identiality which was minimized as all data was only accessed behind VINCI irewall and only
accessible by essential personnel. In addition, an informed consent waiver was obtained as the
patients were not in contact with the research staff and obtaining such consent for each subject
would have made this study impractical to carry out.

We identi ied patients age 18–100 with diabetes who illed at least one OAD prescription from
January 1st, 2013 to December 31st, 2017. Diabetes was de ined as one use of the diagnostic codes
Fechas importantes

ICD-9 code 250.xx or ICD-10 code E09–14.x associated with an outpatient visit with a primary care
physician, or any two uses of the diagnostic codes, and outpatient prescription of a medication with
Veterans Health Administration National Drug File Code for antihyperglycemic medications (HS500,
HS501, HS5009).

Exposure Assessment

We assessed seven OAD drug classes and their individual impact on hospital admission for infection:
Sulfonylureas, Meglitinides, Metformin, Alpha-glucosidase inhibitors, TZD’s, DPP-4 inhibitors, and
SGLT2 inhibitors. Patients were classi ied as yes/no for each drug class. A patient who illed a
prescription for a drug within any of the seven drug classes of interest at any point during the study
period was classi ied as taking the drug class; otherwise the patient was classi ied as not taking the
drug class.

Outcome Assessment

The primary endpoint was admission to a hospital for an infection yes/no. Admission for infection
was de ined based on the presence of an ICD9 or ICD10 code associated with an infectious condition
on the admission or discharge problem list. A list of the ICD9 and ICD10 codes can be found on
supplemental table 1 and 2. Patients with one or more admissions with an infection over the study
period were counted as yes, patients with zero admissions for infection over the study period were criterios de inclusion y exclusion

counted as no. Patients who reached the primary endpoint within the irst three months of the study
period were excluded from analysis since for these patients we did not have suf icient clinical data
prior to admission.

Covariates

Covariates included patient age, smoking status, birth sex, Elixhauser comorbidity index (to adjust
for general health), and race. Patient age was calculated on 2/7/2020 for all subjects. Smoking
status was derived from ICD codes and de ined as yes/no. Subjects who had at least two diagnoses variables tomadas en cuenta y como la midieron

of current smoker or current tobacco user during the study period were classi ied as smokers;
subjects who had one or zero diagnoses were considered non-smokers. Elixhauser score during the
study period was calculated using ICD codes for each patient using the readmission index developed
by Moore, et al.18

Statistical Analysis

Descriptive statistics were calculated for exposures and covariates. To analyze the association of
each drug class with admission for infection we used seven multivariate logistic regression models, Medidas de asociación, intervalo de confianza

one for each drug class of interest. Odds ratios and 95% con idence intervals were calculated for
each drug class to determine their association with admission for infection. For each model the
outcome was hospital admission for infection (yes/no) and the main exposure was the drug class
(yes/no). All models were adjusted for the same ive covariates. Analyses were done in SAS 9.4 (SAS Programas utilizados

Institute Cary, NC) and R Studio v4.0.2.19

Results: Go to: ▸

This cohort included 1,393,825 patients with diabetes. Their baseline characteristics are shown on total de pacientes en el estudio y las características de ellos

Table 1. As expected, patients with a hospital admission for an infectious condition had a higher
Elixhauser Comorbidity Index as compared to those who were never admitted for an infectious
condition (14.2 vs 1.87).

Table 1.
Baseline Characteristics of not admitted vs admitted patients

Demographics

Age (SD) 70.52 (11.00) 70.65 (10.38)

Sex

Male 1,252,658 (95.7%) 81,945 (96.3%)

Female 56,064 (4.3%) 3,158 (3.7%)

Race

White 942,714 (72.0%) 63,519 (74.6%)

Black 244,305 (18.7%) 16,376 (19.2%)

Asian 11,848 (0.9%) 400 (0.5%)

American Indian or Alaskan Native 12,969 (1.0%) 923 (1.1%)

Native Hawaiian or Other Paci ic Islander 14,835 (1.1%) 809 (1.0%)

Clinical Data

Smoking Status

Yes 262,588 (20.1%) 21,374 (25.1%)

No 1,046,134 (79.9%) 63,729 (74.9%)

Elixhauser Comorbidity Index (SD) 1.07(11.37) 14.2 (15.99

Requiring ICU Stay

Yes N/A 6,400 (7.5%)

No N/A 78,703 (92.5%)

Drug Class

Sulfonylureas
Open in a separate window

Table 2 presents the odds ratios (ORs) for hospital admission for an infectious condition in
association with each class of OAD compared to patients who were not on that class of OAD. After
adjusting for age, sex, race, smoking status, and Elixhauser Comorbidity Index, those who took
metformin during the study period had 3.3% lower odds of hospital admission for infection
compared to those who were never on metformin (OR 0.97, 95% CI 0.95–0.98). OADs observed to
have higher odds of admissions for infections as compared to non-users of that class of medication
included meglitinides (OR 1.22, 95% CI 1.07–1.38), SGLT2 inhibitors (OR 1.16, 95% CI 1.08–1.24),
alpha-glucosidase inhibitors (OR 1.09, 95% CI 1.04–1.15), and DPP4 inhibitors (OR 1.04, 95% CI
1.01–1.06). There was no statistically signi icant difference in admission for infections observed
with sulfonylurea or TZD use.

Table 2.
ORs for hospital admission for an infectious condition in association with each class of OAD compared to patients
who were not on that class of OAD

Meglitinides 1.22 1.07–1.38

SGLT2 Inhibitors 1.16 1.08–1.24

Alpha-glucosidase inhibitors 1.09 1.04–1.15

DPP-4 Inhibitors 1.04 1.01–1.07

Sulfonuryeas 0.99 0.97–1.00

TZDs 0.98 0.94–1.02

Metformin 0.97 0.95–0.98

Open in a separate window

Discussion: Go to: ▸

To our knowledge, this is the largest national retrospective cohort study using a Veterans Affairs
Administration database to examine the relationship between outpatient OAD use and the risk of
resultados asociados con los objetivos planteados
hospitalization for infections. We found that metformin was associated with lower odds of
admission for infection while meglitinides, SGLT2 inhibitors, alpha-glucosidase inhibitors, and DPP4
inhibitors were associated with higher odds of admission for infection. The effect sizes for most
OADs were small with likely limited clinical relevance to individual patients. However, as OADs are
widely prescribed, there could be implications at a population level.

Our results corroborate indings from a nationwide cohort of diabetic patients treated with OADs in
Taiwan. This study observed lower odds for sepsis in metformin users vs never users (OR 0.80, 95%
CI 0.77– 0.83) and increased odds for sepsis in meglitinide users vs never users (OR 1.32, 95% CI
1.25–1.40).17 In addition, similar observations were reported in a Swedish study where metformin
therapy showed reduced risk of acidosis and serious infection in patients with diabetes (adjusted
HR 0.85, 95% CI 0.74–0.97).20

Emerging evidence indicates that metformin has favorable effects on health beyond those associated
with improvement in glycemia. Observational studies suggest that diabetic individuals treated with
metformin manifest a survival bene it even when compared to non-diabetic controls. 21, 22 Our
indings add to the growing amount of evidence that supports metformin’s bene icial role in the
prevention of infections.13, 17, 20, 23 In vitro studies have demonstrated that hyperglycemia disrupts
host immunity via several mechanisms including the suppression of polymorphonuclear neutrophil
function and intracellular opsonic and bactericidal activity.24, 25 However, several studies have
demonstrated metformin’s effect on the integrity of host immunity independent of its effects on
blood glucose levels26–30. Metformin in itself has been shown to have some anti-microbial Beneficios según la literatura del medicamento asociado a los objetivos
properties against several bacterial and viral pathogens. 26, 27, 31 In addition, metformin has been
demonstrated to counteract the inhibition of chemotaxis induced by exposure of neutrophils to
lipopolysaccharide through its role in the inhibition of mitochondrial complex I and activation of 5’
adenosine monophosphate-activated protein kinase (AMPK).32 Metformin continues to be
recommended as irst line therapy for patients with diabetes, and our indings are consistent with
this recommendation from the perspective of infection prevention.

In recent years, the addition of several newer classes of OADs has created a paradigm shift in the
treatment of diabetes. As more options are available, clinicians now consider far more than
hemoglobin A1c and blood glucose targets in choosing 2nd and 3rd step therapies after metformin.
While outcome studies have clearly demonstrated the cardioprotective and renoprotective effects of
SGLT-2 inhibitors in type 2 DM,33–35 the early inconsistent indings on the risk of urinary tract
infections (UTIs) generated confusion among clinicians. In 2015, after 19 cases of urosepsis and
pyelonephritis was reported to the US Food and Drug Administration (FDA), the FDA revised all
labels for SGLT2 inhibitor to include warnings about the risk of severe UTIs.36 However, despite this
early concern, 3 major outcome studies37–39 and a recent meta-analysis including data from 86
randomized clinical trials including a total of 50,880 patients failed to report a difference in risk of
UTIs when SGLT2 inhibitors were compared with placebo.40

The indings of our study report a modest increase odds of hospital admissions for all infections in
patients treated with SGLT2 inhibitors as compared to those not treated with SGLT2 inhibitors.
While the initial concern for UTIs is not supported by recent data, our study suggests that there may
be other infections that could contribute to the observed increased admissions for infections. Of
note, the same major trials that failed to show increased risk of UTIs in SGLT2 inhibitors did report
an observed 4 to 9 fold increase of mild genital mycotic infections generally responsive to topical
therapy in SGLT2 inhibitor groups as compared to placebo.37–39

Although our study found a statistically signi icant increase in risk of infections with DPP-4 inhibitor
use, the small effect size is likely of limited clinical relevance to individual patients. Aside from its
role in regulating plasma glucose, DPP-4 is known to have functions in immune regulation that give
rise to concerns regarding infection risk with its inhibition.41 CD26 is the membrane bound form of
DPP-4, and it is found on the surface of many cell lines including B,T, NK lymphocytes and
macrophages.42 CD26/ DPP-4 is thought to have many potential roles in immune regulation by
inducing cleavage of immunoregulating substrates,43 direct lymphocyte regulation44, and co-
stimulatory effects on T-cell activation.45 The existing clinical data on risk of infections related to
DPP-4 inhibitors is con licting. Data from clinical trials suggested an increase in upper respiratory
infections (URIs) and UTIs with DDP-4 inhibitors.46, 47 Furthermore, an analysis of the international
pharmacovigilance database VigiBase reported higher rate of URIs associated with DPP-4 inhibitors
as compared to metformin.16 However several large population based observational studies have
failed to show an increased risk for infections in DPP-4 inhibitor use,13, 17, 48, 49 and a meta-analysis
published in 2018 including 74 clinical trials did not demonstrate an increased overall risk of
infection with DDP-4 inhibitor use.42

The main strengths of our study are the population-based design and large cohort size that included
1.39 million patients across the United States. However, observational studies of this nature have fortalezas y desafios del estudio

several challenges. Firstly, our VA based cohort skewed heavily towards male (95.8%) patients as
compared to the general US population which is estimated to be 49.1% male.50 Second, in our
analysis, exposure to each OAD was independent to when the patient was admitted to the hospital
for an infection. Although retrospective cohort studies in general cannot infer causality, this
limitation in our analysis further emphasizes this point. Third although we utilized the Elixhauser
Co-morbidity Index to adjust for severity of illness, our data did not factor in duration since diabetes
diagnosis or severity of diabetes in general that could be a signi icant confounder to our indings.
Furthermore, prescription of different kinds of OAD is also related to the underlying conditions,
such as cardiac and renal disease, insulin usage was not considered because of the retrospective
nature of the study. Finally, an additional limitation is the lack of comparability between odds ratios
in this study due to variation in reference level groups. For each drug, the reference group is the
patients in the study who were not on that drug at any point during the study period. As a result, the
reference populations differ from drug to drug. Use of metformin was not found to be associated
with use of other drugs, so we think it unlikely that its effect was confounded by the other drugs
classes in this paper. Sulfonylureas were also found to be unrelated to use of other drugs. However,
the ive remaining drug classes were found to be associated with one another, resulting in similarity
of the odds ratios due to confounding. Conclusions based on effect sizes of these ive drugs are
limited in this sense and will need further studies to fully account for confounding by use of other
drugs. Additionally, it would also have been interesting to consider the types of infections, however,
was beyond the scope of our current study. Our ongoing prospective studies will incorporate many
of these details.

In conclusion, our indings suggest an association between outpatient use of certain OADs and the
development of infections requiring hospital admission. Metformin was associated with lower odds
of hospital admission for infection while meglitinides, SGLT2 inhibitors, alpha-glucosidase
inhibitors, and DPP4 inhibitors were associated with higher odds of admission for infection.
However, additional studies with time dependent exposure need to be carried out to further
evaluate this association and infer causality.

Supplementary Material Go to: ▸

MMC2

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MMC1

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Funding Go to: ▸

Grant funding for this work: VA Merit Award I01 BX001786 (RTS), NIH R01 HL144478 (RTS), Cystic
Fibrosis Foundation (RTS)

Footnotes Go to: ▸

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