Linagliptin Plus Insulin for Hyperglycemia Immediately After Renal Transplantation: A Comparative Study
Conditions: Transplanted Kidney Complication
Sponsor: Universidad de Guanajuato

 
Research Protocol 
Linagliptin plus insulin for hyperglycemia immediately after renal 
transplantation: A comparative study 
 
Rodolfo Guardado Mendoza MD PhD, Hospital Regional de Alta Especialidad del Bajío, 
University of Guanajuato, guardamen@gmail.com  
Alberto 
Aguilar 
García 
MD, 
Hospital 
Regional 
de 
Alta 
Especialidad 
del 
Bajío, 
betaag@yahoo.com.mx  
María Lola Evia Viscarra MD, Hospital Regional de Alta Especialidad del Bajío, 
evialola@hotmail.com  
David 
Cázares 
Sánchez, 
Hospital 
Regional 
de 
Alta 
Especialidad 
del 
Bajío, 
david_cazares@outlook.com  
Edgar 
Gerardo 
Durán 
Pérez, 
Hospital 
Regional 
de 
Alta 
Especialidad 
del 
Bajío, 
edurandr@gmail.com  
 
 
 
 
September 30, 2018 
 

Introduction 
Hyperglycemia in hospitalized patients, defined as blood glucose equals to or greater to 140 mg/dl 
(7.8 mmol/L), is a common problem, since about one third of the patients have blood glucose levels 
above 126 mg/dl (6.99 mmol/l). Umpierrez et al, found that 26% of the admitted patients to a 
hospital had T2D (type 2 diabetes)  and 12 % had hyperglycemia without history of diabetes (1). 
Other studies have reported frequencies varying from 32 % of hospitalized patients in general 
wards, and increasing to 40% in non-cardiac surgery, 58 % in patients with Acute Coronary 
Syndrome and 80% in cardiac surgery patients. The treatment goals are blood glucose between 140 
to 180 mg/dl (7.77 to 9.99 mmol/l) for critically ill patients, and 110 to 140 mg/dl (6.11 to 7.77 
mmol/l) in selected populations(2, 3). 
In hospitalized patients, the blood glucose levels that are safer are not known, but apparently, they 
are narrow. General mortality rate for normoglycemic patients has been reported to be 1.7%, for 
previously known diabetic patients, 3.0% and for new hyperglycemic patients 16%; in patients 
admitted to ICU (intensive care unit), the mortality rate was 10% for normoglycemic patients, 11% 
for diabetic patients and 31 % for new hyperglycemic patients. The increment of death risk was 2.7-
fold for diabetic patients and 18.3-fold for new hyperglycemic patients (1). 
The variations in blood glucose levels (lower or higher than normal) are related to an increased 
mortality, longer hospitalizations and increased morbidity (infections, impaired immune response 
and wound healing, activation of inflammatory cytokines, pro thrombotic state, increased 
production of reactive oxygen species in the mitochondria), and are not limited to diabetic-known 
patients (2-4).  
The minimal risk of death has been related to plasmatic glucose levels of 89 mg/dl (4.94 mmol/l) 
(range 78 -101 mg/dl or 4.33-5.6 mmol/l), glucose levels between 60 to 80 mg/dl (3.33 to 4.44 
mmol/l) had an OR of 1.06, and glucose levels between 100 to 200 mg/dl (5.55 to 11.10 mml/l) 

were associated with an odds ratio of 1.32 for in-hospital death. Interestingly, the relation of 
plasmatic glucose with mortality showed a “J” shape curve, suggesting that low or high blood 
glucose levels are both deleterious (5). In cardiac surgery patients and Acute Coronary Syndrome 
(ACS), the risk threshold begins with blood glucose levels as low as 140 mg/dl (7.77 mmol/l). 
Other authors mention this “J” shape curve in the relation between blood glucose levels and 
mortality (2, 3). 
Mortality, length of in-hospital stay and acute kidney failure have been associated to  
hyperglycemia in different studies postoperatively (3, 6). 
During acute inflammation, hyperglycemia decreases vasodilatory response and reduces the blood 
flow to the sites of infection (or inflammation), it also increases endothelial permeability and tissue 
edema, which can cause multisystem organ dysfunction (4).Hypoglycemia is one of the main 
limitations for the tight glycemic control. Frequency of hypoglycemia varied between 24.3 to 27.8 
%, in the glucose-controlled patients, and between 72.2 to 75.6%  in non-controlled patients(6).  
Not only hyperglycemia causes damage, glycemic variability and hypoglycemia does too, and it 
seems to be worse than hyperglycemia itself. 
Mean amplitude of glycemic excursions keeps and almost lineal relation (r 0.86) with the renal 
excretion of 8-iso prostaglandin F2α, a marker of oxidative stress (7). Hypoglycemia itself increases 
C-reactive protein and pro-inflammatory cytokines (TNF-α, interleukin-1β, IL-6, and interleukin-8), 
markers of lipid peroxidation, ROS, and leukocytosis (3). 
There is an apparent paradox: hyperglycemia increases the danger of death and morbidities in 
hospitalized patients, but the best treatment option – insulin – can be more dangerous itself, because 
of the hypoglycemia risk.  
The recommended treatment of hospitalized patients with hyperglycemia is a combination of insulin 
analogs This is accomplished using insulin analogs with slow release rate (basal insulin) and other 

ones with fast or very fast release rate (prandial insulin); the so-called basal bolus insulin regimen. 
As general rule point of care capillary glucose determinations are performed before meals, to adjust 
the dose of prandial insulin (8). 
The incidence of cardiovascular events in T2D patients are a set of adverse outcomes of interest; 
drugs used for the treatment of T2D are required to probe that do not increase the risk of 
cardiovascular diseases (9). 
The evaluation of DPP4 (dipeptidyl peptidase-4) inhibitors has provided variable evidence. Most of 
the studies have proved that the use of DDP4 inhibitors is safe, regarding cardiovascular 
outcomes(10, 11).  The odds ratio for hospitalization for heart failure (HF) in iDPP4 users were 
1.00 (95% CI 0.94 to 1.07), incident HF 1.01 (95% CI 0.92 to 1.11) recurrent HF 1.02 (95% CI 0.84 
to 1.22). All-cause mortality was 6% lower in iDPP4 users (p < 0.001). Insulin users showed an 
excess of risk for any type of hospital admission (19%) and death (20%) (p<0.001) (12).  
Different studies in patients with acute coronary syndrome and high cardiovascular risk have shown 
a safe profile of linagliptin regarding cardiovascular and renal function (13-15). 
Post-transplanted renal patients have a particularly high risk of hyperglycemia after renal 
transplantation (RT). Surgery procedures are related with elevation of blood glucose levels; as result 
of the trauma itself there is release of cytokines and stress response hormones that cause insulin 
resistance. In post transplanted patients, we must add the use of immunosuppressive therapy that 
worseness this insulin resistance effect. The incidence of hyperglycemia is common in these 
patients; for example, in post kidney transplanted patients the frequency reported is between 80 to 
90 %. Sometimes, the patients were already diabetic previous to the transplant (but unaware); other 
times, they are actually new diabetes cases. Hyperglycemia in the perioperative period, 
independently if the patients continues with post-transplant diabetes mellitus (PTDM) or remits to 

normoglycemia, has been related to increased graft rejection, infections or readmission to the 
hospital because of infection (16). 
The recommended treatment of hyperglycemia in kidney transplanted patient is insulin analogs. 
There are several algorithms that had proven to be effective; but as the conditions of these patients 
can change rapidly (adjustment of the immunosuppressive drugs, changes in renal function or 
nutrition therapy), they require intensive blood glucose monitoring, effective communication among 
the health care team (nurses and physicians), flexible treatment algorithms, and training of the 
personal to understand and implement properly these algorithms. All these conditions create a very 
challenging environment for the adequate use of insulin analogs. The use of DPP4 inhibitors in the 
treatment of diabetic patients that had underwent kidney transplantation is increasing. There are, 
nevertheless, few studies that had assessed the efficacy and security of these drugs, in the setting of 
diabetic kidney transplanted patients (16). 
 
Although they all are capable to lower glucose, they do not do so in the same proportion. In the 
study by Bae et al, they compared the hypoglycemic effect of three different DDP4 inhibitors 
(sitagliptin, vildagliptin and linagliptin) in a population of renal transplanted diabetic patients; it 
was found that the mean difference between the pre and post treatment glycated hemoglobin 
(HbA1c) were -0.53 for sitagliptin, -0.38 for vildagliptin and – 1.4 for linagliptin. In the same study, 
it was reported that the average cyclosporine blood levels in the pre and post treatment period 
changed +30.62 ng/mL in sitagliptin group, -24.22 ng/mL in vildagliptin group and -8.5 ng/mL in 
linagliptin group (17). 
The goal of this work was to evaluate the effect of the combined treatment with insulin plus 
linagliptin in comparison with insulin alone on glucose control and hypoglycemia in post-
transplanted renal patients who present hyperglycemia immediately after RT. 

 
Material and methods 
Study design and population 
This was a retrospective comparative study performed in a single center between 2016 and 2018, 
included the data collected from 28 hospitalized post-renal transplanted patients that presented 
hyperglycemia (>140 mg/dl or or 7.77 mmol/l) immediately after RT; 14 patients were treated with 
linagliptin 5mg daily plus a basal bolus insulin scheme prescribed by the Endocrinology group at 
the hospital, and 14 patients treated only with basal bolus insulin scheme were randomly selected 
from a list of patients treated during the same period of time and by the same Endocrinology group. 
Linagliptin dose was 5mg daily and the basal bolus insulin regimen was started and adjusted 
according to the international guidelines; in general, patients received a starting insulin dose of 
around 0.5 U/kg/day, given half as basal insulin (NPH or Glargine) once or twice daily and half as 
insulin lispro divided into three equal doses before meals. Insulin dose was adjusted daily to achieve 
the goal of fasting glucose between 80-140 mg/dl (4.44-7.77 mmol/l) or random glucose levels 
below 180 mg/dl (9.99 mmol/l). Correctional insulin dose was used before each meal, depending on 
the glucose measurements, starting at 1 unit for each 40mg above 140 mg/dl (7.77 mmol/l) of 
glucose. Glucose levels were monitored at fasting and before each meal, as well as at bedtime 
according to standard clinical practice. Data regarding fasting and preprandial glucose levels, 
hypoglycemia, renal function, and immunosuppression therapy were recorded from the patient´s file 
during the first 5 days after RT; fasting glucose and renal function were also recorded at 1, 6 and 12 
months after RT. Patients were included if they were between 18-65 years of age and presented 
fasting hyperglycemia (>140 mg/dl or 7.77 mmol/l) immediately after RT. 
Ethical and Research committee at the Hospital approved the study protocol with the number CEI-
49-18. 

Fasting glucose was measured by dry chemistry with colomitetric method (Vitros 5600; Ortho 
Clinical Diagnostics), pre-lunch and pre-dinner glucose were measured by capillary method using 
and Accu-check glucometer.  Hypoglycemia was defined when glucose levels were ˂70 mg/dl (3.88 
mmol/l). 
 
Main Outcomes were glucose levels during the first 5 days in hospital and after 6 and 12 months, 
insulin dose, frequency and severity of hypoglycemia, and renal function at 1, 6 and 12 months after 
RT. 
 
Statistical analysis 
We used unpaired t test for numerical comparisons between the groups treated with linagliptin + 
insulin vs insulin alone, and a paired t test for intra-group comparisons. Chi square test was used to 
compare proportions between the study groups. A p value <0.05 was considered statistically 
significant. Statistical analysis was performed with SPSS version 22 (SPSS, Chicago, IL). 
 
 
 
 
 
 
 
 
 
 
 

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