Effect of the Combination of Dipeptidyl Peptidase-4 Inhibitor (DPP4i) and Insulin in Comparison to Insulin on Metabolic Control and Prognosis in Hospitalized Patients With COVID-19
Phase: PHASE3
Conditions: Hyperglycemia, Covid19
Sponsor: Hospital Regional de Alta Especialidad del Bajio

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Research Protocol Covid-19H 
 
Effect of the Combination of DPP4i and insulin in comparison to insulin on metabolic 
control and prognosis in hospitalized patients with SARS-CoV-2 infection 
 
Rodolfo Guardado-Mendoza MD PhD, Research Department, Hospital Regional de Alta 
Especialidad del Bajío, León, Guanajuato, México.  
Alberto Aguilar-Garcìa MD, Department of Endocrinology, Hospital Regional de Alta 
Especialidad del Bajío 
Miguel Angel Garcìa MD, Department of Internal Medicine, Hospital Regional de Alta 
Especialidad del Bajío, León, Guanajuato, México 
Liz Jovanna Martìnez MD MS, Department of Internal Medicine, Hospital Regional de Alta 
Especialidad del Bajío, León, Guanajuato, México 
 
 
 
 
 
 
 
 
 
July 1st, 2020 
 

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Introduction 
Hyperglycemia in hospitalized patients 
Most of the cases with hospital hyperglycemia correspond to patients with type 2 diabetes 
(T2D), however, a significant percentage of patients without known T2D may also present 
hyperglycemia. This may be due to the fact that patients have a high risk of T2D, prediabetes 
or unknown hyperglycemia, but it is also due to the combination of other factors such as acute 
stress due to the patient's pathology and the different treatments used with hyperglycemic 
effect, in particular immunosuppressors and glucocorticoids. 
 
In the case of patients with T2D, it is clear that the disease itself increases the risk of hospital 
hyperglycemia, since T2D is characterized by different pathophysiological alterations such as: 
insulin resistance, pancreatic beta cell dysfunction, pancreatic alpha cells dysfunction, amyloid 
deposits, reduction of the incretin effect, etc., which together contribute to the development of 
hyperglycemia1 
 
Hyperglycemia in hospitalized patients has a high incidence since 30% to 40% of patients 
seen in the emergency services and 25% to 40% of those hospitalized in medical or surgical 
areas are patients with T2D. In a retrospective study carried out in a regional Mexican hospital, 
69% of diabetic patients had hyperglycemia at the time of their hospitalization. Other studies 
have identified that 38% of hospitalized patients had hyperglycemia, where 26% of the patients 
knew the diagnosis of T2D and 12% of the patients did not know it2.  
 
Impact of hyperglycemia in the hospitalized patient 
Hyperglycemia in hospitalized patients generates greater morbidity and mortality both in 
patients with T2D and in patients without T2D. A multicenter prospective cohort study that 
included 2471 patients in 6 hospitals with community-acquired pneumonia revealed that 
glucose concentration of more than 198 mg / dL at hospital admission was associated with 
higher mortality (13% vs. 9% , p = 0.03) and complications (29% vs 22%, p = 0.01) compared 
to those patients with a lower glucose concentration 3. Observational studies suggest that 
elevated glucose levels, especially in patients without T2D, are associated with greater 
adverse events, higher mortality and less functional recovery in patients with stroke4.  In 
patients suffering from an acute coronary syndrome, hyperglycemia in both patients with T2D 
and without T2D has been associated with increased morbidity and mortality5. Surgical 
patients with hyperglycemia also show an increased risk of negative results. In a case-control 

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study, elevated glucose levels increased the risk of postoperative mortality in elective non-
cardiac and non-vascular surgery. Patients with a random preoperative glucose concentration 
of 110–200 mg / dL, or more than 200 mg / dL, had 1.7 and 2.1 times higher mortality, 
respectively, compared to those with glucose levels less than 110 mg / dL6. There is also a 
strong association between elevated glucose levels in the perioperative period with infections. 
The infection rate increases 2.7 times in those patients who reach a serum glucose greater 
than 200 mg / dL on the first postoperative day. Additionally, patients with glucose levels 
greater than 200 mg / dL have a 5.7 times increased risk of severe infection 7.  
Several factors are involved in the development of hyperglycemia in hospitalized patients, 
infectious and inflammatory processes and the use of different medications, for example 
glucocorticoids, are associated with hyperglycemic events. Hyperglycemia can be an initial 
manifestation of a serious disease as a metabolic and hormonal response. As previously 
mentioned, the possible mechanisms by which hyperglycemia increases mortality are: 
changes in coagulation, alterations in endothelial function and an increase in inflammatory 
cytokines. Direct evidence to support the above was provided by Esposito et al., Who 
demonstrated that in normal subjects and people with glucose intolerance (IGT), 
hyperglycemia induces the production of inflammatory cytokines interleukin (IL) -6, tumor 
necrosis factor -α (TNF-α) and IL-18 by an oxidative mechanism8. Using an artificial pancreas 
(Biostator, Life Sciences) they induced acute hypeglycemia set at 15 mmol / L for 5 hours 
while blocking endogenous insulin secretion with octreotide. Inflammatory cytokines increased 
in response to hyperglycemia both in normal individuals and in the IGT group, but the response 
was greater in the latter. The cytokine response could be blocked by glutathione infusion, 
suggesting that the cytokine response induced by hyperglycemia occurs mediated by an 
oxidative mechanism. They also showed that the effects of sustained hyperglycemia could be 
produced by transient fluctuations in glucose levels and that this response was greater in 
patients with IGT. This may be relevant for people with stress hyperglycemia, as these patients 
may only have elevations in blood glucose. Increases in TNF-a can alter insulin receptor 
signaling and increase insulin resistance8. Thus, elevated blood glucose levels cause an 
inflammatory response, leading to the production of cytokines and oxygen free radical species, 
which can induce hyperglycemia 9.  In patients with hyperglycemia without an obvious infection 
or cardiovascular disease, Stentz et al. Demonstrated that there is an increase in pro-
inflammatory cytokines such as IL-1ª, IL-6, IL-8 and TNF-α, and these levels decrease once 
the initiation of the insulin therapy and resolution of hyperglycemia9 10 10 
SARS-CoV-2 Infection 

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SARR-CoV-2 infection is a highly transmissible viral infection caused by a coronavirus that 
uses angiotensin converting enzyme 2 (ACE2) as a receptor on the surface of host cells, and 
is widely distributed in the respiratory tract and mucosa intestinal. The approximate incubation 
period is 14 days. The main clinical symptoms are fever, cough, general malaise, among 
others, and up to more than 50% of patients may be asymptomatic. Other symptoms can be 
nausea, loss of appetite, diarrhea, and hyposmia. The diagnosis is usually made by the history 
of exposure, the clinical picture, and confirmation through a virus detection test by RT-PCR. It 
is important to note that to date there is no definitive and effective treatment for SARS-CoV-2 
infection 11. 
ACE2 is a transmembrane enzyme and a functional receptor of the coronavirus S1, which 
from angiotensin II produces vasodilator effects from angiotensin12. ACE2 has been 
upregulated in the lungs in the context of SARS-CoV-2 infection, with type II pneumocytes 
being the facilitators of the inflammatory response13. However, ACE2 is also found in other 
tissues, in addition to the lungs, its influence on cardiovascular function associated with SARS-
CoV-2 infection has been studied in recent years14. 
Type 2 diabetes (T2D) is associated with a high risk of different types of infections15. 
Approximately 15-35% of patients hospitalized for SARS-CoV-2 present with T2D, and 
probably an even higher percentage may present a high risk of hyperglycemia or early 
disturbances in glucose metabolism, not yet identified. Different recent reports consider T2D 
and obesity as variables associated with a worse prognosis in patients with SARS-CoV-2 
infection16-20. 
There is evidence that T2D is a poor prognostic factor in patients with SARS-CoV-2 infection, 
in addition to the fact that patients with T2D have a greater susceptibility to any type of infection 
as well as a greater risk of complications once they present an acute decompensation21. In 
the CORONADO study, carried out in France, it was found that the main factors associated 
with poor prognosis in patients with T2D and SARS-CoV-2 were age, BMI and a history of 
micro and macrovascular complications21. 
 
Hyperglycemia treatment in the hospitalized patient  
The management of hospitalized patients with hyperglycemia can be complicated by various 
circumstances, such as irregular adherence to diet, concomitant use of medications that affect 
glucose levels, the patient's variable neurological status, and even the variability and severity 

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of the disease that affects glucose metabolism. All these factors have an important influence 
on the daily dose of insulin that should be applied. 
It is recommended that all hospitalized patients with hyperglycemia be treated with an insulin 
regimen that adheres to the body's physiological responses to glucose levels. The stepped 
insulin regimen is no longer a recommended regimen, since it does not adjust to the previous 
administration of insulin, at mealtime or the sensitivity of the patient, in addition there is no 
evidence to support its safety and effectiveness8. 
For non-critical patients, programmed subcutaneous insulin schemes are the preferred one 
since it allows to achieve and maintain glucose levels under control, since it includes a basal, 
nutritional and correction regimen. The basal bolus scheme is recommended because, among 
other advantages, it mimics physiological patterns of endogenous insulin excretion; It consists 
of the use of a basal insulin applied once or twice a day supplemented with boluses of prandial 
insulin plus a correction dose. 
 
Correction schemes based on premixed insulin or biphasic action have shown a higher risk of 
hypoglycemia compared to basal-bolus insulin schemes according to a clinical trial carried out 
by Bellido and Cols. Where 64% of the patients treated with premixed insulin had 
hypoglycemia compared to 24% of the patients in the basal bolus group (P <0.001)22. 
 
DPP4 inhibitors 
On the other hand, traditional oral hypoglycemic agents have a limited role, due to the potential 
adverse effects, the slow onset of action and the long duration that determine the lack of 
flexibility to adapt to changing requirements throughout the day and most of them traditionally 
tend to be avoided in the hospitalized patient23. 
However, in recent years, and with the advent of new therapies in DM2, the usefulness that 
some of these new drugs could have in hospitalized patients, particularly the incretins, has 
been partially proposed and evaluated. Two gut-derived hormones - glucagon-like peptide -1 
(GLP-1), released by L cells in the distal ileum and colon, and glucose-dependent 
insulinotropic peptide (GIP), released by the proximal small intestine, both of which stimulate 
insulin secretion from the pancreas in response to food intake: they offer a new way to reduce 
hyperglycemia by targeting the incretin system. Although both DPP-4 inhibitors and GLP-1 
receptor (RA) agonists are well tolerated, oral administration of DPP-4 inhibitors might be 
preferred by some patients who can take oral medications. The efficacy and safety of incretin-
based therapy for hospitalized patients is something that has not yet been fully established 

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and its use is currently based on expert recommendations and few research studies, it is not 
covered by clinical guidelines, however , the potential metabolic and cardiovascular benefits 
make this an attractive possibility. Native GLP-1 infusion has been reported to improve left 
ventricular function and cardiac performance status in patients with severe heart failure24. 
 
Native GLP-1, as well as GLP-1 receptor (RA) agonists such as exenatide and liraglutide, 
exert a number of metabolic effects that are advantageous in hospitalized patients. Most small 
trials have been carried out with native GLP-1, with some studies using GLP-1 RA. 
In general, when GLP-1 infusion is administered to patients with or without T2D, it has been 
shown to normalize the glycemic response after a meal or enteral nutrition similar to insulin 
administration, and it has been shown to reduce exogenous insulin requirements 25,26.  
Similarly, the use of a GLP-1 analog, such as exenatide, has shown some usefulness for the 
control of hyperglycemia due to the use of corticosteroids in hospitalized patients27. 
Dipeptidyl peptidase type 4, DPP4, is an enzyme found on the cell surface that interacts with 
different peptide hormones in the regulation of the immune response28,29. One of its main 
known effects is the inactivation of endogenous incretins (GLP-1 and GIP, and others not 
known), thus increasing the half-life of endogenous GLP-1, and thus stimulating insulin 
secretion by pancreatic beta cells and by reducing glucagon secretion by pancreatic alpha 
cells, effects for which it is used in patients with T2D30. Studies carried out by our group, in our 
hospital, have shown the usefulness of DPP4 (linagliptin) inhibitors both in patients with 
prediabetes to prevent and reduce the risk of developing T2D by improving the function of 
pancreatic beta cells31, as well as in patients with hospital hyperglycemia after kidney 
transplantation when combined with basal insulin and reducing its requirements and the 
severity of hypoglycemia, as well as increasing the response and metabolic control24. Besides 
that, DPP4 has been associated with inflammation and its soluble levels have been reported 
both reduced and elevated in different inflammatory processes 32-34. 
It is important to mention that all DPP-IV inhibitors are reversible competitive inhibitors and it 
is difficult to compare their effects when analyzing individual studies since the experimental 
conditions may be different; However, there is a study in which the inhibitors were compared 
under identical conditions showing similar efficacy (maximum effect) to inhibit DPP-IV in vitro, 
although there were differences in terms of potency, the most potent being linagliptin 35.    
Regarding its half-life, vildagliptin and saxagliptin 36 have shorter half-lifes, on the other hand, 
linagliptin 37 and sitagliptin 38 have a longer duration of their effect 38 37 
The selectivity of the different DPP-IV inhibitors for this enzyme has been evaluated in in vitro 
studies and it has been reported that both linagliptin35 and sitagliptin39 are the ones with the 

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highest selectivity for the DPP-IV enzyme; linagliptin has a selectivity of 10,000 for DPP-IV 
than for DPP-8/9 compared to sitagliptin which is 5550; This is important because the inhibition 
of these two DPP-8/9 enzymes is what has theoretically been thought to be associated with 
side effects of inhibition of lymphocyte activity, although this effect has not been observed in 
the clinic since, since these 2 enzymes are found intracellularly 40-42.  On the other hand, 
linagliptin only has lower selectivity over the fibroblast activation protein α (FAPα), which is a 
protein that is not found in adult tissue, so the implications of this data are even less, since the 
inhibitors of the DPP-IV are only indicated in adults 43. 
Sitagliptin, vildagliptin and saxagliptin are eliminated in more than 80% via the kidney, whereas 
linagliptin is eliminated in more than 80% via the bile, so it can be used in patients with any 
degree of renal failure without the need to adjust the dose. and without losing the 
pharmacological effect. 
Regarding the clinical efficacy and the capacity of the different DPP-IV inhibitors to reduce 
HbA1c, fasting glucose and postprandial glucose, various meta-analyzes and clinical studies 
have shown similar efficacy, achieving a reduction in HbA1c of between 0.5 - 1.0% (≈0.8%), 
with greater reductions when baseline values are higher 40-42,44,45. 
 
Side effects and safety 
To date, no higher rate of side effects have been found with DPP-IV inhibitors compared to 
control groups, and likewise, no differences in side effects have been reported between the 
various DPP-IV inhibitors 40,41,44,45; In addition, its safety in terms of risk of pancreatitis and 
pancreatic cancer has recently been validated by the FDA and the European Medicines 
Agency 46. 
 
Linagliptin 
The mechanism of action of linagliptin consists in inhibiting the DPP-IV enzyme (dipeptidyl 
peptidase type IV); This enzyme (DPP-IV) has the biological effect of inactivating the 
glucagon-like peptide 1 (GLP-1), so when it is inhibited by linagliptin this favors endogenous 
GLP-1 levels to rise up to 3.2 times per above the previous values (which are reduced in 
patients with type 2 diabetes mellitus, which partly explains that these patients have a 
reduction in the incretin effect), which conditions the biological effects of GLP-1 as stimulation 
of the insulin secretion by pancreatic beta cells and inhibition of glucagon secretion by 
pancreatic alpha cells. This effect on the stimulation of insulin secretion is totally dependent 

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on glucose levels, so it does not cause hypoglycemia. Linagliptin has a half-life of 12 hrs so it 
can be used every 12 or 24 hrs, it is eliminated by the bile duct in more than 70% so it can be 
used in patients with nephropathy without the need to adjust the dose, it offers a power to 
achieve a sustained inhibition of more than 90% in DPP-IV for 24 hrs and is highly selective 
for inhibiting DPP-IV compared to other enzymes such as DPP-8 and DPP-9. Linagliptin is 
indicated in the treatment of patients with uncontrolled type 2 diabetes mellitus, which does 
not meet the control goals such as: Hb glycosylated less than 7%, fasting glucose less than 
110mg / dl and postprandial glucose less than 140mg / dl. It can be used as therapy in 
combination with metformin, sulfonylureas, thiazolidinediones, and insulins, either as double 
or triple therapies. Recent studies have documented the renal and cardiovascular safety of 
linagliptin in patients with T2D 47,48. 
DPP4 has also been documented to function as a receptor for coronavirus49, and some studies 
in animal models have shown that by inhibiting DPP4, infection by coronavirus of the MERS-
CoV type is reduced, and mice transgenes for DPP4 develop lethal infection by MERS-CoV50-
53. Recent models from in vitro studies suggest that DPP4 is a SARS-CoV co-receptor54, and 
in different studies a higher expression of DPP4 has been found in different tissues, even 
higher than the expression in different tissues of ACE255. 
Experimental studies have documented that the use of some DPP4 inhibitors reduce the 
inflammatory response in different clinical settings 56,57. 
DPP4 inhibitors improve metabolic control by increasing prandial endogenous insulin 
secretion and inhibiting glucagon secretion by reducing postprandial blood glucose peaks; the 
low risk of hypoglycemia and good tolerability make these drugs attractive for use in 
hospitalized patients. Furthermore, different studies have shown an anti-inflammatory effect 
of IDPP4 in different models of T2D 58,59, although in a case-control study it was not 
documented that exposure to DPP4 inhibitors had any role in preventing or reducing the risk 
of SARS-CoV-2 infection60. 
 
Different studies have been carried out comparing the use of different treatment regimens 
based on combinations with oral treatment and insulin. In a randomized, multicenter, 
prospective, open-label, non-inferiority clinical trial (Sita-Hospital) at five hospitals in the US, 
they enrolled patients between the ages of 18 and 80 years with type 2 diabetes and random 
blood glucose of 7.8-22.2 mmol / L who were being treated with diet or oral antidiabetics or 
had a total daily insulin dose of 0.6 units per kg or less, admitted to general medicine and 
surgery services. The trial met the non-inferiority threshold for the primary endpoint because 
there was no significant difference between the groups in mean daily blood glucose 

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concentrations. The study concludes that treatment with sitagliptin plus basal insulin is as 
effective and safe as a convenient alternative to the labor-intensive basal-bolus insulin 
regimen for the management of hyperglycemia in patients with type 2 diabetes admitted to 
general medicine and services. of hospital surgery in the non-intensive care setting61. In 
another study Umpierrez et al. Found that the total daily insulin dose and the number of insulin 
injections were significantly lower in the sitagliptin groups compared to the basal bolus group 
(both P, 0.001). There were no differences in the length of hospital stay (p = 0.78) or in the 
number of hypoglycemic episodes between the groups (p = 0.86) 62. 
 
Considering all this together, The SARS-CoV-2 infection pandemic has placed great demands 
on health systems and has further highlighted the high impact of chronic degenerative 
diseases, particularly type 2 diabetes. In Mexico, a number of Increasing cases of SARS-CoV-
2 infection and a large percentage of these patients have type 2 diabetes, leading to acute 
decompensation with hyperglycemia, hospitalization and a high risk of fatal complications. 
Another factor that also contributes to the prognosis in patients with type 2 diabetes is glycemic 
lack of control and glycemic variability, which is why it is extremely important to achieve 
adequate metabolic control with the minimum risk of hypoglycemia. The administration of 
insulin is the classic way to control hyperglycemia in hospitalized patients, however, the use 
of oral drugs as adjunct therapy to insulin is increasingly being proposed in order to reduce 
the risk of hypoglycemia, glycemic variability and metabolic lack of control. In our hospital we 
have carried out studies in this regard, although retrospective, where we have observed that 
the combination of DPP4 inhibitors with insulin provides better metabolic control and lower 
risk of hypoglycemia in hospitalized patients with hyperglycemia and kidney transplantation. 
In addition, there are several studies that compare the combination of drugs based on incretins 
and insulin with regimens of insulin alone, where they seem to find benefits such as the 
requirements and doses of insulin administered, decrease in the frequency of injections, 
improvement of ventricular function in infarcted patients, and decreased fluctuations in 
measured blood glucose levels, and theoretically, lower risk of hypoglycemia. Furthermore, 
biologically DPP4 has been linked to the regulation of the immune system and reduction of 
the inflammatory response in certain types of viral infections, in animal models and in vitro 
studies, the role that DPP4 inhibition plays on is not known to date. the prognosis of patients 
with SARS-CoV-2 infection. On the other hand, there are no studies performed with this type 
of therapy in patients hospitalized for SARS-CoV-2, an in-hospital population with difficult 
glycemic control due to systemic inflammatory response and the use of different drugs with 
hyperglycemic potential. The decision to use linagliptin as a DPP4 inhibitor is because it is the 
only one that does not have a renal elimination and therefore does not require dose adjustment 

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in patients with kidney damage. Searching for treatment alternatives that allow controlling 
hyperglycemia in this type of patients could contribute to improving the prognosis in the short 
and medium term, a lower risk of hypoglycemia, not prolonging their hospital stay or presenting 
concomitant infections, and therefore to better survival. 
 
RESEARCH QUESTION 
¿ Is here a difference in glycemic control and prognosis in patients hospitalized for SARS-
CoV-2 and hyperglycemia treated with the combination of DPP4 inhibitor + insulin compared 
to those treated with insulin alone? 
 
GOALS 
General: To assess the effect of the combination of DPP4  inhibitor + insulin compared to 
insulin alone on glycemic control and prognosis in patients hospitalized for infection with 
SARS-CoV-2 and hyperglycemia 
Specific: 
-Identify patients with SARS-CoV-2 infection and hyperglycemia who meet selection criteria 
for the present study 
-To evaluate the effect of the combination of DPP4 inhibitor + insulin on glycemic control and 
prognosis in hospitalized patients with SARS-CoV-2 and hyperglycemia 
- To evaluate the effect of an insulin regimen on glycemic control and prognosis in hospitalized 
patients with SARS-CoV-2 and hyperglycemia 
-Compare  glucose levels and prognosis between the treatment groups 
 
HYPOTHESIS 
ALTERNATE HYPOTHESIS: There is a difference in glycemic control and prognosis in 
patients hospitalized for SARS-CoV-2 and hyperglycemia treated with the combination of 
DPP4 inhibitor + insulin in comparison to those treated with insulin alone. 
 

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NULL HYPOTHESIS: There is not difference in glycemic control and prognosis of patients 
hospitalized for SARS-CoV-2 and hyperglycemia treated with the combination of DPP4 
inhibitor + insulin in comparison to those treated with insulin alone. 
 
STUDY DESIGN 
Single center parallel randomized clinical trial 
Design: Randomized clinical trial. The randomization will be carried out by means of an 
electronic random number system and will be by blocks, to guarantee an equal number of 
participants in both groups during the study and will be performed by a physician not involved 
in the study. Assignment to treatments group will be blinded for the Physicians who are 
providing the patient`s care, researchers and personal who collect and analyze the data and 
outcome variables. 
Study universe: Hospitalized patients with SARS-CoV-2 infection and hyperglycemia. 
Study population: Hospitalized patients with SARS-CoV-2 infection and hyperglycemia in the 
HRAEB. 
Type of sampling: Non-probabilistic of consecutive cases 
Sample size: The sample size was calculated based on the formula to compare means 
between two groups, and using data from the previous study carried out in hospitalized kidney 
transplant patients in which it was observed that the linagliptin + insulin group had a final 
glucose level of 135 ± 14 mg / dl compared to the insulin-only group that had a glucose level 
of 155 ± 19 mg / dl24, considering a two-sided hypothesis, an alpha value of 0.05 and a study 
power of 80% (beta 0.20), the minimum sample size required per group is 17 patients per 
group, which including 20% expected losses, rises to 20 patients per group. 
 
SELECTION CRITERIA 
Inclusion criteria 
Patient with confirmed SARS-CoV-2 infection by RT-PCR 
Patients with or without T2D with a plasma glucose between 140 mg / dl and 400 mg / dl, who 
require hypoglycemic treatment. 

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Patients with tolerance to take pills orally 
Patients of both sexes, older than 18 years of age 
Patients who, in case of having previous treatment with insulin, this is in low doses (<or = 0.4 
U / kg) before their admission. 
Patients with any hypoglycemic treatment prior to hospitalization 
Patients who have signed their informed consent 
Hospitalized patients at the HRAEB 
 
Exclusion criteria 
Patients whose mental condition makes it impossible for them to give their informed consent. 
Patients with assisted mechanical ventilation 
Pregnancy 
 
 
General procedure 
HRAEB hospitalized patients with SARS-CoV-2 infection and hyperglycemia who meet the 
inclusion criteria will be invited to participate in the study. Once the patient meets the inclusion 
criteria and agrees to participate, they will be asked to sign an informed consent, in which the 
characteristics of the study, the risks and benefits will be explained. Subsequently, a sheet will 
be filled out with the identification and clinical history of the patient. Then, basal levels of 
glucose, lipids, inflammatory markers and HbA1c will be quantified by standard methods. 
Subsequently, the patients will be randomized, within two treatment regimens: i) basal bolus 
insulin scheme, and ii) linagliptin + basal bolus insulin. Patients treated with linagliptin and 
basal insulin will receive an initial total daily dose of 0.25 U / Kg / d of insulin glargine, except 
for those patients older than or equal to 70 years of age and / or serum creatinine greater than 
or equal to 2 mg / day. dl, who will receive 0.15 U / Kg / d plus a daily dose of 5mg of linagliptin 
orally before breakfast. Patients treated with a basal bolus insulin scheme will start with a total 
insulin dose of 0.5 U / kg divided into 50% insulin glargine every 24 hours at 10-11pm and 
50% insulin lispro divided into three doses, one third 15 minutes before each meal. In patients 

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older than or equal to 70 years of age or with a serum creatinine greater than or equal to 2 mg 
/ dl, the total insulin dose will be reduced to 0.3 U / Kg. The insulin dose will be adjusted daily 
according to the following scheme: 
The correction factor will be calculated with the following formula: 
Correction factor = 1500 / total daily insulin dose. 
Total daily insulin dose = IU Glargine + IU Lispro 
Where one way to adjust preprandial glucose is to use the 1500 rule. 
This rule is used to determine the reduction in blood glucose level for each unit of insulin that 
is administered. It is used when the glucose level is above the established goals, it consists of 
dividing 1500 by the total insulin dose (TDD), the result obtained will be the correction factor 
that will refer to the effect that a unit of insulin will have on the glucose, thus, if a patient who 
uses a total daily dose of insulin of 50 IU has a preprandial glucose of 210 mg / dl and our 
goal is 130 mg / dl we can apply the rule of 1500 where we will divide 1500/50 giving by As a 
result, our correction factor would be 30, this refers to the fact that one unit of insulin will 
reduce 30mg / dl of glucose in this patient, thus applying 2IU more than the base dose to reach 
our goal of 130 mg / dl. 
The metabolic goals are: 
• Fasting and preprandial blood glucose between 100-140 mg / dl 
• Postprandial capillary glucose less than 180mg / dl 
After starting the scheme, the capillary blood glucose measurement will continue before and 
after each meal, at 23:00 and 03:00 hrs. In addition, capillary blood glucose can be measured 
at any time that the patient experiences symptoms of hypoglycemia or as required by the 
treating physician. This will be recorded on a data capture sheet each day of the hospital stay. 
Blood samples will be taken for glucose measurement by clinical chemistry every third day, 
and inflammation markers such as CRP, IL-6, TNFa, fibrinogen will be measured at the 
beginning and every 5 days, these by chemiluminescence. The lipid profile will only be 
measured initially by dry chemistry. All these studies are part of the evaluations that patients 
have during their hospital stay. 
 
VARIABLES 

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1) Group of treatment 
to. Type of variable: Independent 
b. Measurement level: Dichotomous nominal 
c. Unit of measurement: Group A (patients with hyperglycemia and SARS-CoV-2 infection 
receiving treatment with Linagliptin + insulin), and Group B (patients with hyperglycemia and 
SARS-CoV-2 infection receiving treatment with insulin only). 
d. Conceptual definition: Treatment that is started to control hyperglycemia in hospitalized 
patients 
and. Operational definition: Group A will be those patients with hyperglycemia and SARS-
CoV-2 infection who will receive treatment based on Linagliptin 5mg every 24 h + insulin for 
at least 48 hrs and who have follow-up of blood glucose and subsequent blood glucose tests 
for at least less 5 days. Group B will be those patients with hyperglycemia and SARS-CoV-2 
infection who will receive insulin-based treatment and who have follow-up of blood glucose 
and subsequent blood glucose tests for at least 5 days. 
 
2) Fasting glucose 
a) Type of variable: Dependent 
b) Measurement level: Quantitative 
c) Unit of measurement: mg / dL 
d) Conceptual definition: Measurement performed while fasting to record glucose levels by 
capillary glucometry. 
e) Operational definition: It will be the glucometry recorded in fasting prior to the first morning 
meal using capillary glucometry with Accu-Chek device and / or by clinical chemistry 
 
3) Postprandial glucose 
to. Type of variable: Dependent 
b. Measurement level: Quantitative 
c. Unit of measurement: mg / dl 

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d. Conceptual definition: Calipar glucose measurement that reflects the absorption and 
muscular consumption of glucose after food intake 
and. Operational definition: Glucose measurement 2 hours after food intake, using an Accu-
Check glucometer or whatever is available in the service. It will be held post-breakfast, post-
lunch and post-dinner. 
 
4) Glycemic control 
a) Type of variable: Dependent 
b) Measurement level: Qualitative nominal dichotomous 
c) Unit of measurement: Yes or No 
d) Conceptual definition: fasting glycemic levels between 110 and 140 mg / dL in preprandial 
and fasting blood glucose tests, and less than 180 mg / dl in postprandial blood glucose tests. 
e) Operational definition: It will be considered as glycemic control when the fasting capillary 
glucose level is less than 140 mg / dl and the postprandial level is less than 180 mg / dl. 
 
5) Time in which glycemic control is reached 
a) Type of variable: Dependent 
b) Measurement level: Discrete quantitative 
c) Unit of measurement: Days it takes to achieve metabolic control in the study groups. 
d) Conceptual definition: Number of days in which patients achieve glycemic control from the 
beginning of the intervention in the study groups. 
e) Operational definition: Number of days in which patients reach preprandial capillary blood 
glucose levels less than 140 mg / dl and postprandial levels less than 180 mg / dl. 
 
6) Insulin dose: 
a) Type of variable: Dependent 
b) Measurement level: Discrete quantitative 

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c) Unit of measurement: Units of insulin used per day in groups: A (patients with post-renal 
transplant hyperglycemia receiving treatment with Linagliptin + insulin), and Group B (patients 
with post-renal transplant hyperglycemia receiving treatment only with insulin). 
d) Conceptual definition: The total amount of IU used per day in the two groups of patients. 
e) Operational definition: The total IU of insulin used per day in the two groups will be reviewed. 
 
7) Prognosis 
to. Type of variable: Dependent 
b. Measurement level: Dichotomous nominal 
c. Unit of measurement: Good or bad 
d. Conceptual definition: Prognosis of the patients included in the study groups, which can be 
modified by the course of the underlying disease, and which can include from recovery with 
discharge home, to in-hospital complications and death. 
Operational definition: Prognosis is Good when the patient has recovered and is discharged 
home due to improvement without needing mechanical ventilation, and Poor when the patient 
requires assisted mechanical ventilation and / or when the patient dies, which will be verified 
by a death certificate. 
 
8) Frequency and severity of hypoglycemia 
a) Type of variable: Dependent 
b) Measurement level: Dichotomous nominal 
c) Unit of measurement: Number and severity of hypoglycemia recorded in the time that the 
in-hospital treatment lasted. 
d) Conceptual definition: Serum glucose levels <70 mg / dL 
e) Operational definition: Record of blood glucose levels recorded by capillary blood glucose 
testing that were less than <70 mg / dL. 
Other variables: Age, sex, weight, BMI, HbA1c, lipid profile, inflammation markers (CRP, IL6, 
fibrinogen, TNFa), APACHE, SOFA. 

17 
 
 
STATISTICAL ANALYSIS 
Descriptive statistics will be used for the general presentation of the data; The comparison of 
numerical variables between the study groups before and after the intervention will be carried 
out using the Student's t test for independent groups, the comparisons in each initial-final study 
group will be carried out using the paired t test, as well as the ANOVA test for repeated 
measurements. Likewise, a risk analysis (RR, RRA, RRR, NNT) and Kaplan-Maier curves will 
be carried out to analyze the probability of glycemic control and the presence of complications 
and patient survival, and a model of analysis of Cox risk. The qualitative variables will be 
compared using the Chi square test. A statistically significant difference will be considered 
when the p value is less than 0.05. Statistical analysis will be performed with SPSS version 
21 and Stata version 15.1 software. 
 
ETHICAL ASPECTS 
This study has been approved by the Research Ethics and Research Committees of the 
Hospital Regional de Alta Especialidad del Bajío with the following numbers CEI-22-2020 and 
CI-HRAEB-42-2020, and will be carried out in adherence to the ethical standards, the 
Regulation of the General Health Law on Research for the health and the Declaration of 
Helsinki of the World Medical Association of the 64th General Assembly, Fortaleza, Brazil in 
2013 and current international codes and standards of good clinical research practices. 
Special attention will be paid to taking care of the confidentiality of patient information. Patients 
will be asked to sign an informed consent letter, and a confidentiality letter will also be signed 
by the authors of this Research Project. 
 
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