SITAGLIPTIN TREATMENT AT THE TIME

OF HOSPITALIZATION WAS ASSOCIATED

WITH REDUCED MORTALITY IN PATIENTS
WITH TYPE 2 DIABETES AND COVID-19:
A MULTICENTER, CASE-CONTROL,
RETROSPECTIVE,
OBSERVATIONAL STUDY

• Suriyanti Listin
• Dr dr. A. Makbul Aman , Sp.PD,KEMD
Coronavirus disease 2019 (COVID-
19) is a severe acute respiratory
syndrome coronavirus 2 (SARS-
CoV-2), which since late 2019 has
spread globally and severely
threatened public health and
economic systems, with a
particularly acute burden for
patients with type 2 diabetes.
 Sitagliptin is an oral and highly selective DPP-4 inhibitor

with glucose-lowering effects, and it was approved by the

Food and Drug Administration in 2006 as an antidiabetic

drug due to its efficacy in increasing the bioavailability of

glucagon-like peptide 1 (GLP-1).

 Type 2 diabetes increases the mortality risk in patients

with COVID-19 particularly in those with more severe

disease.
 In patients with type 2 diabetes and COVID-19, poorly

controlled blood glucose levels are associated with markedly

higher mortality as compared with subjects with better

metabolic control.
 Therefore, we examined whether sitagliptin, the DPP-4

inhibitor with higher selectivity for CD26, may be beneficial in

treating COVID-19, particularly in patients with type 2

diabetes who appear to be at high risk of mortality and of

cardiorenal or cerebrovascular complications.

RESEARCH DESIGN AND METHODS

Patients and Study Design

Patients with type 2 Near-normal hepatic Given the pandemic the Italian Society for the Every center also
diabetes, as defined function (up to fourfold evolution, the use of Study of Diabetes issued recruited at a 1:1 ratio
by the most recent increase in AST and ALT DPP-4 inhibitor sitagliptin a statement on the untreated control
American Diabetes values) and an estimated in patients with type 2 potential benefit for the subjects matched for age
Association guidelines , glomerular filtration rate diabetes as add on use of DPP-4 and sex. Data collection
who were (eGFR) ≥30 mL/ therapy to standard of inhibitors in patients with and analysis were
hospitalized for a min/1.73 m2 were care was considered by type 2 diabetes and performed
laboratory confirmed required in order for the treating physician in COVID-19 on top of the retrospectively and
SARS-CoV-2 infection patients to be included. view of the clinical insulin treatment, as covered
were included in practice, based on the standard of care, during by an appropriate
this multicenter, case- clinical evaluation of the hospitalization for Institutional
control, retrospective, moment, and according COVID-19. Review Board approval
observational study. to several reports at the central institution
released from the (SIDIACO-RETRO` ;
pandemic areas Luigi Sacco
Hospital, University of
Milan).
 RESEARCH DESIGN AND METHODS
P atien ts and Stu dy Design
For the sample, current The use of insulin Standard of care Of the 338 patients Nearly 23% of the
treatment for type 2 treatment in patients comprised included in the study, 169 patients who were
diabetes, including insulin injection were treated hospitalized in the different
with type 2 diabetes clinical centers for COVID-
he use of the DPP-4 administered according to with sitagliptin and 169
and admitted to the “modified Yale insulin were not. Sitagliptin was 19 between 1 March
inhibitor sitagliptin, was hospital for critical infusion protocol.” The administered at an and 30 April had diabetes,
stopped at hospital
clinical glycemic target was adjusted dosage for eGFR and around one third of
admission, and all (i.e., 100mg once daily if those patients with type 2
conditions has been between 140 and 180
patients were switched to mg/dL, with holding of eGFR ≥45 mL/min/1.73 diabetes and COVID-19,
insulin treatment
already included as a
insulin once blood glucose m2, or 50 mg if eGFR was comprising pneumonia,
(intravenously or standard protocol in
level approached 100 30–45 mL/min/1.73 m2). fever, and laboratory test
subcutaneously) as most hospitals Patients included in the for COVID-19, were eligible
mg/dL. For 2 months (from
standard of care. throughout the country 1 March through 30 April study did not take other to be included in this study.
according to the 2020), 338 consecutive glucose lowering Given the emergency
guidelines of the Italian adult in patients who were medications during their conditions, data on clinical
Society for the Study of hospitalized for SARS- hospitalization. Patients and laboratory parameters
Diabetes and CoV-2 infection were enrolled in seven may not be available in all
and had type 2 diabetes academic medical centers patients; therefore,
supported by the analyses were based on
were analyzed, and a in Northern Italy, the area
European Association defined outcome (death or with the highest prevalence non missing data.
for the Study of discharge) was considered of COVID-19 worldwide
Diabetes . the primary (35), and clinical outcomes
endpoint of the study were collected
retrospectively.
 First evaluated hospital discharge and death as primary end points.
Next, also assessed the proportion of patients within the two groups experiencing
Outcomes relevant clinical events, such as admission to the intensive care unit, the use of
Measures mechanical ventilation, and the need for extra corporeal membrane oxygenation
(ECMO) at hospital admission and at follow-up.

We also analyzed the proportion of patients within the two groups who displayed
clinical improvement, as defined by hospital discharge and/or a reduction of at least
two points from baseline on a modified ordinal score comprising seven major points
as follows and already reported

Not hospitalized with resumption of normal activities;

Not hospitalized, but unable to resume normal activities;

Hospitalized, not requiring supplemental oxygen;

Hospitalized, requiring supplemental oxygen;
Hospitalized, requiring non invasive mechanical ventilation;

Hospitalized, requiring invasive mechanical ventilation or ECMO

Death
Statistical Analysis

Continuous variables are presented as means with SEs,

and categorical variables are presented as proportions.
Independent sample t tests and x2 test/Fisher exact test
were used as appropriate to compare continuous
variables and categorical variables, respectively. Two-
tailed P values of 0.05 were considered statistically
significant.

Univariable and multivariable logistic regression

methods were used to model the relationships between
risk factors and outcomes of interest (Stata version 12;
Stata Corp, College Station, TX). Log-rank (Mantel-Cox)
test was used in the time to clinical end point analysis
between the two groups (GraphPad Prism version 7.0;
GraphPad Software, Inc., San Diego, CA).
 RESULTS
169
PATIENT CHARACTERISTICS
A total of 169 patients with type 2 diabetes and
diagnosed with COVID-19 infection were treated with the Type 2
diabetes
DPP-4 inhibitor sitagliptin as an add-on therapy to
standard of care, while 169 patients with type 2 diabetes
and COVID-19 receiving standard-of-care treatment only
were considered. Baseline demographic and clinical
characteristics of the two groups of patients are
reported in Table 1.
 RESULTS

PATIENT CHARACTERISTICS
A total All patients were admitted to the hospital with
respiratory symptoms and fever. Type 2 diabetes was
a known diagnosis in 322 (95%) patients, while in 16
patients (5%), type 2 diabetes was diagnosed during
hospitalization through routine metabolic screening.
No differences were observed with regard to duration
of diabetes, renal function, vital signs, use of
glucose-loweringmedication, laboratory tests, and
comorbidities such as cardiovascular disease (38%
vs. 40%), cancer (14% vs. 17%), or hypertension (67%
vs. 74%) in the two groups at baseline (Table 1).
 RESULTS
PATIENT CHARACTERISTICS
Overall, characteristics at admission to
hospital were comparable in the two groups.
Patients were switched from current
treatment for type 2 diabetes,
whichincludedmostlymetformin,but also
insulin, sulfonylureas, DPP-4 inhibitors,
sodium–glucose cotransporter 2 inhibitors,
GLP-1 receptor agonists, glinides, and
thiazolidinediones, to insulin treatment
(intravenously or subcutaneously at hospital
admission as standard of care (Table 1).
 RESULTS
PATIENT CHARACTERISTICS
No difference was evident in
antihypertensive treatment between groups
or for other medications such as diuretics,
anticoagulants, and antiplatelet drugs, while
a higher proportion of patients in the
standard-of-care group was receiving b-
blockers (Table 1). With regard to other
treatments, hydroxychloroquine was initiated
in 252 patients and antiviral agents in 171
patients during hospitalization, similarly
distributed within the two groups.
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 Mortality
The use of sitagliptin at the time of
hospitalization was associated
with a reduced mortality (Table 2).
A total of 31 out of 169 (18%)
patients died in the sitagliptin-
treated group as compared with 63
out of 169 (37%) patients in the
control group (P = 0.0001).
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 Mortality
Treatment with sitagliptin in patients
with type 2 diabetes and COVID-19
was thus associated with a
decreased odds ratio (OR) for in-
hospital death (OR 0.37 [CI 0.23–
0.62]; P 5 0.0001), which was
confirmed after adjustment for
clinically relevant factors (age, sex,
comorbidities, and ongoing
treatments), as shown in Table 3.
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 Mortality
A time to clinical end point (death/
discharge) analysis also confirmed
better outcomes in the sitagliptin-
treated patient group as compared
with the standard of care group in
the overall population studied
(hazard ratio [HR] 0.44 [95% CI
0.29–0.66]; P 5 0.0001) (Fig. 1A).
 Mortality
Given the importance that the
glycometabolic control may have in
increasing the mortality rate, we
analyzed the mean blood glucose
level measured during the
hospitalization and demonstrated
that it was lower in the sitagliptin-
treated patients as compared with
the standard-of-care group (Fig. 1B).
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Clinical Outcomes
Patients treated with sitagliptin add-on therapy at the
time of hospitalization showed significant
improvement in clinical outcomes (Tables 2 and 4).
With regard to relevant clinical parameters, the use
of sitagliptin was associated with a decreased risk
for the need of.

A reduced risk for the need of intensive care unit

was also observed to a lesser extent in the
sitagliptin-treated group as compared with the
standard-of-care group (HR 0.51 [CI 0.27–0.95]; P=
0.03), while no difference was evident in the
requirement of ECMO (HR 1.15 [CI 0.41–3.17]).
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Clinical Outcomes

With regard to the clinical improvement as defined

by a reduction of two points or more in the modified
seven-point category scale at day 30 of follow-up,
this was available in 139 sitagliptin-treated patients
and in 145 patients of the standard- of-care group.

A total of 72 patients (52%) in the sitagliptin-treated

group were rated with a decrease of at least two
points, while only 50 (34%) were found to be clinically
improved in the standard-of-care group (Table 2 and
Supplementary Fig. 2)
Clinical Outcomes

A greater number of patients treated with

sitagliptin were discharged from the hospital
at day 30 as compared with the number of
discharged patients in the standard-of-care
group (Table 2).

No sitagliptin-related severe adverse events

were registered in patients enrolled in the
sitagliptin-treated group.
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Laboratory Analysis
A reduction in inflammatory parameters such
as procalcitonin and CRP wasYour
detected
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patients were increased compared

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baseline and compared with patients treated
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with standard of care (Table 2). Finally, an

improvement in glycemic control was evident
at follow-up in patients treated with sitagliptin
as compared with patients receiving standard-
of care insulin treatment only (Table 2)
Subgroup Analysis
A subanalysis in patients who were ≥70 years of age
confirmed a lower mortality (29% vs. 51%) and better
outcomes in a time to clinical end point analysis in the
sitagliptin-treated group as compared with those in the
standard-of-care group (HR 0.54 [CI 0.34–0.85]; P= 0.009)
(Fig. 2). A time to clinical end point analysis comparing
males versus females in the sitagliptin-treated group as
compared with those in the standard-of-care group did not
show any difference in the clinical outcomes within the group
of treatment (Fig. 2)

However, we must highlight that both males and females in

the standard of- care group had the worst outcome
(sitagliptin males vs. standard-of-care males: P= 0.001, HR
0.44 [CI 0.27– 0.73]; sitagliptin females vs. Standard of- care
females: P = 0.03, HR 0.42 [CI 0.20–0.87]).
Subgroup Analysis
Subanalysis in patients who had a glycated hemoglobin
(HbA1c) below the median (7.5%) demonstrated a better
outcome in both the sitagliptin-treated patients and the
standard-of-care group (Fig. 2). An HbA1c value above
the median of 7.5% was associated with worst outcomes,
particularly in patients treated with standard of care
(sitagliptin vs. Standard of care, HR 0.29 [CI 0.14–0.63];
P= 0.0003).

A stratification of patients based on the BMI, measured at

baseline, also confirmed better outcomes in those treated
with sitagliptin and in those who had a BMI below the
median of 29 kg/m2 (HR 0.40 [CI 0.16–0.99]; P=0.03)
(Fig. 2). Higher BMI was associated with worst outcomes
in the standard-of-care group (sitagliptin vs. standard of
care, HR 0.21 [CI0.09–0.45];P= 0.0002)
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 In conclusion, in patients with type 2 diabetes
and COVID-19, sitagliptin treatment as add-on
therapy to standard of care at the time of
hospitalization was associated with better
clinical outcomes, a greater number of patients
treated with sitagliptin discharged from the
hospital at day 30, and reduced mortality as
compared with standard of care.

The effects of sitagliptin in patients with type 2

D-1 9 diabetes and COVID-19 should be confirmed in

V I an ongoing, randomized, placebo-controlled trial
CO C that contains extended primary and secondary
M I end points, as compared with those reported in

A N DE this study, including the measurement of DPP-4

P level in biological samples collected and multiple
time points of assessment.
THANK YOU