POSITION STATEMENT

Simplifying Type 2 DM Care with Linagliptin: A Position

Paper
Ambrish Mithal1, Ambady Ramachandran2*, Arpandev Bhattacharyya3, Manoj Chadha4, Mala Dharmalingam5,
Anirban Majumder6, Debmalya Sanyal7
Received: 28 February 2023; Accepted: 23 March 2023

A b s t r ac t They should be evaluated for their effectiveness,

risk of hypoglycemia, impact on weight,
Introduction: The burden of type 2 diabetes mellitus (T2DM) is raising dramatically both
internationally and in India. It is often observed that multiple therapies or combinations of different cardiovascular (CV) and renal comorbidities,
drugs are usually required to successfully control hyperglycemia in patients with T2DM. To facilitate cost and accessibility, potential adverse effects,
effective control of glucose levels, many new agents have been developed over the past few years. and patient preferences. Pharmacotherapy
Materials and methods: Multiple Advisory Board Meetings were conducted with 87 leading key should be started at the time T2DM is diagnosed
opinion leaders (KOLs) from diabetes specialty PAN India to understand the simplicity aspect of unless there are contraindications; for many
linagliptin therapy in T2DM patients. patients, this will be metformin monotherapy
Discussion: Linagliptin is a xanthine-based, non-peptidomimetic, selective dipeptidyl peptidase in combination with lifestyle modification.4
4 (DPP-4) inhibitor with a different pharmacological profile when compared to other DPP-4 However, medication(s) from other antidiabetic
inhibitors already available in India. It is known to decrease the risk of hypoglycemia compared classes should be provided for the ones
to sulphonylurea (SU), is weight neutral, and no dose modification is required over a broad range intolerant to or have contraindications to
of patient populations. This consensus paper discusses the clinical efficacy of DPP-4 inhibitors and using metformin. Among individuals with
linagliptin in T2DM. It also highlights the evidence for the safety of linagliptin in T2DM patients T2DM who have established atherosclerotic CV
with renal impairment (RI), cardiovascular (CV) risk, and heart failure (HF). disease or indicators of high CV risk, established
Conclusion: Linagliptin therapy is simplifying the management of T2DM with good efficacy and kidney disease, or heart failure (HF), a sodium-
its use across a wide range of patients without any dose modification. glucose cotransporter 2 inhibitor (SGLT2i) and/
Journal of the Association of Physicians of India (2023): 10.59556/japi.71.0324 or glucagon-like peptide 1 receptor agonist
(GLP-1) with demonstrated CV disease benefit is
recommended as part of the glucose-lowering
Introduction in the year 2015 had risen to 69.2 million.2
regimen and comprehensive CV risk reduction,
In India, district level household survey data
T ype 2 diabetes mellitus (T2DM) is one
of the prevalent forms of diabetes
worldwide, contributing to approximately
showed a rise to 7.7% in 2016 from 5.5% in
1990 in diabetes prevalence in individuals
independent of A1C and in consideration of
patient-specific factors.4 If the A1C levels are
above the individualized target and there is
aged 20 years or more.3 It is predicted that in
90% of all cases. It occurs when the pancreas a compelling need to reduce hypoglycemia,
the year 2040, the prevalence will rise to 123.5
cannot produce sufficient insulin, and the GLP-1 RA, SGLT2i, dipeptidyl peptidase 4
million people.2
body is unable to effectively utilize the insulin (DPP-4) inhibitor, or thiazolidinedione class of
First-line therapy in T2DM depends
produced. Diabetes has a global incidence of drugs may be administered. If the A1C levels
o n co m o r b i d i t i e s , p at i e nt- ce nte r e d
10.8% in urban settings and a slightly lower remain still beyond the target, the patient
treatment factors, and management needs
prevalence of 7.2% in rural regions. Over the therapy can be continued in combination with
but will generally include metformin and
years, the number of individuals living with
comprehensive lifestyle modification.4 While
diabetes has continuously increased. In 2000, 1
metformin therapy offers numerous benefits, Chairman and Head, Department of
the estimated global count was 151 million, Endocrinology and Diabetes, Max Healthcare,
it is important to acknowledge that it can
which rose by 88% to 285 million in 2009. As Delhi; 2Chairman, Dr A Ramachandran’s
be accompanied by gastrointestinal adverse
per the International Diabetes Federation Diabetes Hospitals; President, India Diabetes
effects. These effects may hinder or restrict
(IDF) estimates, in 2021, approximately Research Foundation (IDRF), Chennai, Tamil
its usage in certain patients. Sulphonylurea Nadu; 3Consultant Endocrinologist, Manipal
537 million adults aged 20–79 years are
(SU) has been a preferred second-line glucose- Hospital, Bengaluru, Karnataka; 4Senior
living with diabetes. Projections indicate
lowering therapy in T2DM patients. SU are Consultant Endocrinologist, Hinduja Hospital,
that this number will rise to 643 million by Mumbai, Maharashtra; 5Director and Head,
commonly used to effectively reduce plasma
2030 and further to 783 million by 2045. Department of Endocrinology, Bangalore
glucose levels, but they can also lead to
Unfortunately, diabetes and its complexities Endocrinology and Diabetes Research Centre,
varying degrees of hypoglycemia, β-cell death,
have a significant impact on mortality rates. Bengaluru, Karnataka; 6Professor, Department
weight gain, and potentially adverse cardiac of Endocrinology, KPC Medical College;
In 2021 alone, an estimated 6.7 million
outcomes. On the other hand, gliptins are newer 7
Professor, Department of Endocrinology,
deaths were attributed to diabetes-related
incretin-based therapies for treating T2DM. KPC Medical College, Kolkata, India; Conjoint
causes. India is the second leading country
They possess antihyperglycemic properties Professor, University of Newcastle, Callaghan
in the global diabetes epidemic.1 Based Australia; *Corresponding Author
with a relatively safe adverse effect profile.
on the epidemiological studies that were
Gliptins carry a low risk of hypoglycemia How to cite this article: Mithal A,
conducted in India, the IDF Diabetes Atlas Ramachandran A, Bhattacharyya A, et al.
and are weight neutral. The selection of
2021 reported 74.2 million adults (20–79 years) Simplifying Type 2 DM Care with Linagliptin:
pharmacologic agents should be guided by
with diabetes.1 From 32.7 million in the year A Position Paper. J Assoc Physicians India
a patient-centered approach, as stated in the
2000, the number of people with diabetes 2023;71(8):90–96.
2022 American Diabetes Association guidelines.

© The Author(s). 2023 Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/
by-nc/4.0/). Please refer to the link for more details.
 Simplifying Type 2 DM Care with Linagliptin

the other antidiabetic agents from the category • Clinical efficacy of a DPP-4 inhibitor. of treatment. Mentioned below are some
of drugs mentioned. If the glycemic target is still • Clinical efficacy of linagliptin in T2DM. studies which testify to the positive impact
not achieved, SU or basal insulin can be added • Cardiovascular (CV) and HF safety evidence of linagliptin on glycemic control. Del Prato
to the therapy.4 DPP-4 inhibitors, as a class of of linagliptin from (CV outcome trial) et al. conducted a study to assess the safety
antidiabetic agents, are effective in the treatment CVOTs. and efficacy of linagliptin. It demonstrated
of diabetes. The most widely used DPP-4 • Clinical evidence of linagliptin in T2DM that linagliptin treatment caused a placebo-
inhibitors are saxagliptin, alogliptin, sitagliptin, with renal impairment (RI). corrected change in HbA1C from a baseline of
vildagliptin, and linagliptin. Linagliptin is a • Co nvenience an d a dh erence w ith approximately—0.69% (p < 0.0001) after the
DPP-4 inhibitor that has shown high efficacy linagliptin in T2DM. treatment period of 24 weeks. The adjusted
by inhibiting 80–90% of DPP-4 but not all • Safety of linagliptin across a broad range HbA1C reduction in patients with baseline
DPP-4 inhibitors are administered as once-daily of T2DM patients. HbA1C of 9.0% was 1.01% (p < 0.0001).
dosing.5 DPP-4 inhibitors have an oral route of Improvements in FPG (p < 0.0001) and PPG
administration and a mechanism of action based Results from the Expert Panel (p < 0.0001) were seen, and there were no
on the inhibition of the DPP-4 enzyme, thus Discussion significant hypoglycemic episodes.8
preventing the breakdown of both GLP-1 and Studies by Taskinen et al. and Groop et al.
glucose-dependent insulinotropic polypeptide Clinical Efficacy of a DPP-4 Inhibitor that were conducted to evaluate the efficacy
(GIP), thereby prolonging their activity and Dipeptidyl peptidase 4 (DPP-4) inhibitors and safety of linagliptin administered as an
glucose-stimulated insulin secretion, thereby possess a unique mode of action by inhibiting add-on therapy to metformin in patients
resulting in a low risk of hypoglycemia.6 DPP-4 the DPP-4 enzyme, which plays a role in with T2DM with inadequate glycemic control
inhibitors are weight neutral with an acceptable the rapid degradation of two important (n = 701), significant reductions were observed
safety profile. incretin hormones: GLP-1 and GIP. The clinical from baseline in HbA1C (−0.49 vs 0.15%), FPG
The objective of this position paper efficacy of several DPP-4 inhibitors, such as (−0.59 vs 0.58 mmol/L), and PPG (−2.7 vs 1.0
is to understand the role of linagliptin in saxagliptin, alogliptin, vildagliptin, linagliptin, mmol/L); p < 0.0001 in linagliptin patients.
simplifying the management of T2DM with and sitagliptin, has been demonstrated in Hypoglycemic events were also rare (0.6%)
good efficacy, robust CV, and renal safety numerous studies. A decrease in hemoglobin in linagliptin-treated patients. No significant
evidence and its use across broad patients A1C (HbA1C) and improvement in parameters
without any dose modification. like fasting plasma glucose (FPG) and
postprandial glucose (PPG) are characteristic
changes associated with the DPP-4 inhibitors
M at e r ia l s and Methods treatment. Table 2, given below, lists the
To understand the simplicity aspect of clinical trials which prove these results. Craddy
linagliptin therapy in T2DM patients, multiple et al. did a comprehensive study to compare
Advisory Board Meetings were conducted the efficacy of DPP-4 inhibitors in T2DM. The
with 87 leading key opinion leaders (KOLs) review found no significant differences in the
from diabetes specialty PAN India. For the average change from baseline in body weight
Advisory Board, 16 statements on simplicity or glycosylated HbA1C, nor in the proportions
aspects of linagliptin were drafted and of patients achieving HbA1C levels below
supported with data from the scientific 7% or experiencing hypoglycemic events
literature. These statements were presented to among patients using DPP-4 inhibitors
a small group of expert panels for validation. (Fig. 2). Thus, the presented evidence suggests
After the validation of these statements that linagliptin is equally efficacious as other
by the expert panel, the statements were DPP-4 inhibitors.7
presented as poll questions to 87 KOLs from
the diabetes specialty in five zonal advisory
board meetings, which were executed on a Opinions from experts on the efficacy of DPP-4
inhibitor in T2DM Fig. 1: Summary of the process
virtual platform. During the Advisory board
meetings, the opinions of these thought DPP-4 inhibitor reduces HbA1C up to
leaders were gathered to determine the areas 0.7–0.8%.
of agreement, neutrality, and disagreement. Linagliptin is as efficacious as other DPP-4
The statements were considered valid only inhibitors in T2DM treatment (92.3%).
if 30% of KOLs had responded during poll
questions in the advisory board meetings. The Clinical Efficacy of Linagliptin in
results of the poll questions were collected,
T2DM
analyzed, and presented to a group of seven
experts from the diabetes specialty, along Efficacy of Linagliptin in Drug Naïve
with supportive scientific data to a respective Patients and as an Add-on Therapy to
statement during the national advisory board Metformin
meeting to form expert opinions. A >50% As per the experts, achieving good glycemic
agreement on a statement was taken into control with linagliptin is the reason for
consideration to form an expert opinion its growing use in therapy. A reduction in
(Fig. 1). The statements are listed in Table 1 and HbA1C and PPG and an improvement in
addressed in the sections mentioned below: FPG levels make linagliptin a suitable choice Fig. 2: Comparative efficacy of DDP4 inhibitors7

Journal of the Association of Physicians of India, Volume 71 Issue 8 (August 2023) 91

 Simplifying Type 2 DM Care with Linagliptin

Table 1: The questionnaire to rate each item using a 9-point scale (1–5, disagreement; 5, neutral; 6–9, agreement)
Sr. No. Question Disagree Neutral Agree Total
Clinical efficacy of DPP-4 Inhibitor
1 The efficacy of linagliptin is comparable to other gliptins (n = 65) 4.60% 3.10% 92.30% 100%
Clinical efficacy of linagliptin in T2DM
2 Linagliptin can be administered as a single agent in drug naïve patients when contraindicated/ 0.00% 4.90% 95.10% 100%
intolerant to metformin (n = 61)
3 Linagliptin can be considered a viable option for second-line treatment after metformin failure 1.60% 4.90% 93.50% 100%
(n = 61)
4 Linagliptin-metformin FDC as a 1st line shows better efficacy as compared to metformin 0.00% 4.90% 95.10% 100%
monotherapy (n = 61)
5 Linagliptin has comparable efficacy with relatively better durability and safety compared to SU 7.70% 27.70% 64.60% 100%
(n = 65)
6 Linagliptin has better efficacy across the Asian population compared to Caucasians (n = 65) 0.00% 21.50% 78.50% 100%
7 Linagliptin can be an effective oral antidiabetic drug (OAD) as an add-on to insulin (n = 64) 0.00% 14.10% 85.90% 100%
CV and HF safety evidence of linagliptin from CVOTS
8 Linagliptin has a reassuring safety profile with robust evidence across the cardiac and renal 0.00% 2.90% 97.10% 100%
comorbidities with CARMELINA (n = 69)
9 Linagliptin has been shown to have a favorable effect on hHF and may be considered in T2DM 1.50% 15.90% 82.60% 100%
with a risk of HF (n = 69)
Clinical evidence of linagliptin in T2DM with RI
10 Linagliptin has the best renal safety evidence among the gliptins (n = 70) 2.90% 12.80% 84.30% 100%
11 Linagliptin has proven safety and effectiveness across the spectrum of CKD in T2DM (n = 70) 1.40% 4.30% 94.30% 100%
12 The use of a single 5mg once-daily dose of linagliptin simplifies the management of T2DM 1.40% 4.30% 94.30% 100%
across a wide patient profile, regardless of cardiac, renal, or hepatic comorbidities (n = 70)
Convenience and adherence with linagliptin in T2DM
13 The ease of use and simplicity aspect of linagliptin make it a preferred choice in teleconsultation 2.90% 21.40% 75.70% 100%
among the gliptins (n = 70)
Safety of linagliptin across a broad range of T2DM
14 Patients with T2DM who have mild-moderate liver dysfunction can utilize linagliptin without risk 1.60% 11.50% 86.90% 100%
(n = 61)
15 Linagliptin can be safely considered in the broad patient profile, including elderly patients with 0.00% 1.70% 98.30% 100%
T2DM (n = 60)
16 Compared to glimepiride, linagliptin offers the benefit of weight neutrality and a lower risk 0.00% 3.30% 96.70% 100%
of hypoglycemia which helps alleviate concerns related to weight gain and hypoglycemia in
patients with T2DM (n = 60)

Table 2: Due to variations in study design, methodology, and populations, comparison of studies of ≤6. 5%) without raising the risk of
should be evaluated cautiously40–43 hypoglycemia or other side effects.11
Condition SAVOR TIMI 53 (saxagliptin) TECOS (sitagliptin) CARMELINA (linagliptin)
Efficacy of Linagliptin vs Sulfonylureas
HHF HR 1.27‡ (95% CI 1.07–1.51) HR 1.00‡ (95% CI 0.83–1.20) HR 0.90‡ (95% CI (SU) in T2DM
0.74–1.08)
The usage of SU is linked to a higher risk
CV death HR 1.03 (95% CI 0.87–1.22) HR 1.03 (95% CI 0.89–1.19) HR 0.96 (95% CI 0.81–1.14)
of weight gain and hypoglycemia. SU has
3P-MACE HR 1.00† (95% CI 0.89–1.12) HR 0.99† (95% CI 0.89–1.10) HR 1.02† (95% CI reliable efficacy, particularly in patients with
0.89–1.17) recently diagnosed diabetes.12 They are the
†
Testing for superiority for 3P-MACE was the primary endpoint (4P-MACE for sitagliptin); ‡exploratory most extensively used antihyperglycemic
outcome; 3P-MACE, 3-point major adverse CV events; CI, confidence interval; HR, hazard ratio medications that act by lowering glucose
levels by exhibiting their effect on β-cells
change in body weight was observed in both alone, combination therapy increased the and inducing an insulinotropic response.13
groups.9,10 proportion of patients who achieved HbA1C Outpatients suffering from T2DM to HbA1C
Lv et al. investigated the possibility ≤ 6.5%, both for metformin doses of 1000 readings of 6.5–10.0% participated in a 2-year
that the initial combination therapy with mg (49.5 vs 35.4%, respectively) and 500 mg parallel-group, noninferiority double-blind
metformin and linagliptin could of fer (4 0 .1 v s 2 2 .9 % , r e s p e c t i v e l y). E a r l y experiment conducted by Gallwitz et al. in
better glycemic control (HbA1C ≤ 6.5%) combination therapy with met formin 2012. Then, these patients were randomly
than metformin alone without aggravating and linagliptin increases the likelihood of assigned to receive either oral linagliptin
hypoglycemia. In comparison to metformin obtaining tight glycemic control (HbA1C (5 mg) or oral glimepiride (1–4 mg) once

92 Journal of the Association of Physicians of India, Volume 71 Issue 8 (August 2023)

 Simplifying Type 2 DM Care with Linagliptin

daily. In the linagliptin [−0.16% (standard Efficacy of Linagliptin as an Add-on to p < 0.74 for superiority]. Hospitalization for
error 0.03)] and glimepiride [−0.36% (0.03)] Insulin in T2DM HF (hHF) was noted in 209 (6.0%) linagliptin
groups, comparable patterns of declines A 24-week, double-blind, placebo-controlled, patients compared to 226 (6.5%) placebo
in adjusted mean HbA1C were observed phase III trial conducted by Yang et al. patients. Linagliptin did not increase the
[difference 0.20%, 97.5% confidence interval assessed the safety and efficacy of linagliptin probability of a composite CV outcome over
(CI): 0.09–0.30]. Consequently, the trial’s in 206 Chinese patients with inadequately a median of 2.2 years compared to placebo in
predetermined noninferiority threshold controlled T2DM having HbA1C values T2DM patients with high CV and/or renal risk
of 0.35% was achieved. When compared between 7.5–10.0%, receiving metformin when added to usual therapy.17
to the glimepiride group, the incidence of and insulin (basal or premixed). The cohort Similarly, patients with relatively early
hypoglycemia and severe hypoglycemia was randomized to receive a placebo or 5 mg T2DM and risk factors for established
was lower in the linagliptin group [one (1%) linagliptin. With linagliptin, the drop in HbA1C evidence of atherosclerotic CV disease were
vs 12 (2%) patients]. When compared to the from baseline was higher than with placebo included in the CAROLINA study to compare
glimepiride group, the linagliptin group’s (p = 0.0016). Significantly better improvements the linagliptin (n = 3,203) and glimepiride
patients reported considerably fewer CV in 2-hour PPG (p < 0.001) were observed with (n = 3,010) CV outcomes. In the linagliptin
events (12 vs 26 patients). According to the linagliptin, and numerical reductions in group, 356 out of 3,023 participants (11.8%)
study’s findings, linagliptin is noninferior FPG (p = 0.2241) versus placebo were also and, in the glimepiride group, 362 out of 3,010
to glimepiride in terms of efficacy and noted. A higher percentage of patients on (12.0%) experienced the primary endpoint,
has a reduced risk of adverse events than linagliptin achieved an HbA1C reduction of 3-point MACE. The noninferiority requirement
glimepiride.14 ≥0.5% vs those on placebo (odds ratio 2.293, (p < 0.001 for noninferiority) was therefore
p < 0.01). Hypoglycemic events identified by satisfied, but not the superiority criterion
the investigators were reported, but none (p = 0.76).18
Opinions from experts on the efficacy of
linagliptin in T2DM were severe (linagliptin: 17.3%; placebo: The European Society of Cardiology:
12.7%). Linagliptin as an add-on to insulin European Association for the Study of Diabetes
Linagliptin can be used as monotherapy in guideline 2019 also states that among the
drug naïve patients when contraindicated/ in Chinese patients with T2DM improved
glycemic control and was well tolerated.16 available DPP-4 inhibitor, linagliptin and
intolerant to metformin (95.1%).
sitagliptin have neutral effects on the risk
Linagliptin can be considered a second-line
of hHF and may be considered for T2DM
therapy after metformin failure (93.5%). Opinions from experts on the efficacy of treatment in patients with HF.19
Linagliptin-metformin fixed dose linagliptin compared to SUs in Asians, an add-
combination (FDC) as a 1st line shows on to insulin therapy
better efficacy as compared to metformin Linagliptin has comparable efficacy with Opinions from experts on linagliptin—CV and
monotherapy (95.1%). relatively better durability and safety HF safety evidence from CVOTS
compared to glimepiride (64.6%). Linagliptin has a reassuring safety profile with
Linagliptin has better efficacy across the robust evidence across the cardiac and renal
Efficacy of Linagliptin in Asians with T2DM Asian population compared to Caucasians comorbidities with CARMELINA (97.1%).
In a study conducted by Sarashina et al., the (78.5%). Linagliptin has a neutral effect on hHF and
impact of race on the pharmacodynamics, Linagliptin can be an effective OAD as an may be considered in T2DM with a risk of HF
pharmacokinetics, safety and efficacy of add-on to insulin (85.9%). (82.6%).
linagliptin monotherapy was assessed in
patients with T2DM. It consisted of two
studies: study 1 consisted of Japanese Cardiovascular (CV) and HF Safety Clinical Evidence of Linagliptin in
patients exclusively, and study 2 enrolled both Evidence of Linagliptin from CVOTS T2DM with RI
White and Asian patients. The results showed As various glucose-lowering medications One of the most prevalent comorbidities
that linagliptin effectively inhibited DPP-4 are associated with many CV safety issues, among people with T2DM is RI. The choice
activity in plasma, with concentrations more CV disease is the primary cause of mortality of glucose-lowering medications in T2DM
than half-maximal inhibitory concentration among diabetic individuals. The effects of is significantly influenced by impaired renal
and DPP-4 inhibition of >80% at the trough. linagliptin on CV safety have been examined in function. Linagliptin may offer a novel
This inhibition was consistent in study 1 and significant, large landmark trials like CAROLINA therapy option for T2DM patients with RI
study 2, indicating similar pharmacokinetics and CARMELINA. Participants with T2DM who because it is primarily eliminated through the
and pharmacodynamics across the different were at high CV risk (history of vascular disease hepatobiliary route, and only 5% is eliminated
racial groups. Furthermore, the reduction in and urine-albumin creatinine ratio [UACR] 30 through the renal route. 20 According to a
FPG concentrations was similar in magnitude mg/gm) and high renal risk were examined for pooled study of three clinical trials examining
across all groups. However, there was a their reactions to linagliptin in the CARMELINA the impact of renal function on the efficacy
greater decrease in HbA1C levels observed randomized clinical investigation performed and safety of linagliptin concluded that renal
in study 1 (Japanese) and the Asian (non- by Rosenstock et al., Randomly assigned function was unaffected after 24 weeks of
Japanese) patients in study 2. The safety patients were given linagliptin (n = 3494) or a linagliptin treatment in all normal, mild, and
profile of linagliptin was favorable in each placebo (n = 3485). Major adverse CV events moderate renal function groups. Linagliptin
racial group, indicating the medication can (MACE) with a 3-point outcome occurred has a favorable efficacy and safety profile
be safely used in patients of different races. in 434 of 3,494 subjects (12.4%) receiving in T2DM patients with more severe renal
Based on these findings, the study concluded linagliptin and 420 of 3,485 subjects (12.1%) complications. Linagliptin showed consistent
that a daily dose of 5 mg of linagliptin is receiving a placebo [hazard ratio (HR), 1.02; efficacy in all stages of RI with mean change
appropriate for use in various racial groups.15 95% CI, 0.89–1.17; p < 0.001 for noninferiority; in HbA1C: normal renal function (–0.63%),

Journal of the Association of Physicians of India, Volume 71 Issue 8 (August 2023) 93

 Simplifying Type 2 DM Care with Linagliptin

mild RI (–0.69%), moderate RI (–0.69%), and creatinine ratio > 300 mg/gm) were compared the use of sitagliptin, vildagliptin, saxagliptin,
severe RI (–0.72%). Linagliptin is generally across the groups, and it was noted that and teneligliptin. Tmax of linagliptin
well-tolerated in all stages of RI.21 linagliptin in its CVOT had the highest occurred approximately 1.5 hours after oral
In solid organ transplants like kidneys, new- baseline renal risk compared to another DPP-4 administration of a 5 mg OD dosage to healthy
onset diabetes after transplantation (NODAT) inhibitor’s [linagliptin: reduced renal function participants; the mean plasma area under the
is a significant and common metabolic at baseline (eGFR < 60 mL/minute/1.73 m2)— curve (AUC) was 139 nmol*hour/L, and Cmax
complication.22 In a retrospective analysis by 62%, severely reduced renal function was 8.9 nmol/L. Following oral treatment,
Sanyal et al., a total of 21 subjects with NODAT (eGFR < 30 mL /minute/1.73 m 2 )—15%, the bulk of linagliptin (about 90%) is excreted
received linagliptin. A decrease in PPG, FPG, macroalbuminuria—39%].25 unaltered, showing that metabolism is a minor
and HbA1C was observed after 24 weeks. No elimination mechanism. Renal clearance at
significant change in tacrolimus level and a steady state was approximately 70 mL/
Opinions from experts on renal evidence with
dose of tacrolimus remained unchanged over minute. Treatment with 5 mg OD linagliptin
linagliptin
the study period. There were no changes in has shown efficacy and safety in all stages of
the estimated glomerular filtration rate (eGFR) Linagliptin has the best renal safety evidence RI, including hemodialysis. The adjustment
among the gliptins (84.3%).
with linagliptin. Minimal weight gain and only of dose can be a major challenge in diabetic
a single minor hypoglycemic episode were Linagliptin has proven safety and patients with RI, and therefore linagliptin may
reported.23 effectiveness across the spectrum of chronic be an ideal choice of treatment in such insta
Patients with kidney disease have been kidney disease (CKD) in T2DM (94.3%). nces.7,20,27–31 Hence, a single 5 mg OD dosing
appropriately investigated for linagliptin’s without dose adjustment with linagliptin is
safety and efficacy in CARMELINA CVOT, Convenience and Adherence with convenient for the management of T2DM and
where 74% of the trial population had Linagliptin in T2DM increases patient adherence to the dosing
prevalent kidney disease. Time to the first regimen across the broad patient profiles, as
adjudicated mortality owing to renal failure, Inappropriate Renal Dose Adjustment of per the experts’ opinion.
end-stage renal disease (ESRD), or a persistent DPP-4 inhibitor is Associated with Poor
40% or more drop in eGFR from baseline Clinical Outcomes in T2DM
were the kidney-related outcomes. The Gliptins have similar efficacy profiles but Opinions from experts on convenience and
occurrence of kidney outcomes was noted for distinct pharmacokinetic characteristics. adherence of linagliptin in T2DM
9.4% of those taking linagliptin vs 8.8% in the Patients with T2DM and CKD were studied in A single 5 mg OD dosing of linagliptin across
placebo (p = 0.62). Death due to renal failure a retrospective observational cohort study the T2DM patient profile, irrespective of
and an exploratory composite of prolonged (N = 82,332). The cohort was separated cardiac, renal, or hepatic comorbidities, eases
ESRD were recorded in similar patients depending on the prescription of DPP-4 up management of T2DM (94.3%).
with linagliptin vs placebo (3.9 vs 4.4%, inhibitor (with or without dosage modifying The ease of use and simplicity aspect of
respectively). Progression of albuminuria them based on eGFR). The suitable or incorrect linagliptin makes it a preferred choice in
was less frequent in the linagliptin group dosage of DPP-4 inhibitors was determined teleconsultation among gliptins (75.7%).
(763/2162 [35.3%]); 21.4 per 100 person-years) based on the daily dose of DPP-4 inhibitor,
as compared to the placebo group (819/2129 the patient’s eGFR, and the manufacturer’s
[38.5%]; p = 0.003).17 guidelines. Between 2009 and 2012, over Safety of Linagliptin across a Broad
A study by Wanner et al. reported 40% of patients with T2DM and CKD received Range of T2DM Patients
nephrotic range proteinuria (NRP) in a total incorrect DPP-4 inhibitor dosages, which Linagliptin’s clinical safety has been evaluated
of 646/6979 patients [9.3% (linagliptin/ decreased to 24.4% in 2015. In individuals with in more than 14,000 T2DM patients. 20
placebo n = 317/n = 329). The median UACR in T2DM and CKD stage 3 or 4, inappropriate Among the DDP-4 inhibitors available in
NRP participants was 3486 (Q1: 2746/Q3: 4941) DPP-4 inhibitor dosing was associated with the market, linagliptin has some data which
mg/g] and had a lower eGFR (39.9/56.1 mL/ a 15% higher risk of death from any cause, a demonstrate that dose modification is not
minute/1.73 m2). Regardless of the NRP status, 7.6% higher risk of emergency department essential for any mild/moderate, or severe
the linagliptin group showed a neutral effect. visits, and a 19.9% higher risk of serious hepatic impairment.20,27–31 Graefe-Mody et al.
The occurrence rate of parameters like a hypoglycemia compared to individuals given investigated the effect of hepatic impairment
composite of time to renal death, end-stage an appropriate dose. 26 In the case of mild on the pharmacodynamics, pharmacokinetics,
kidney disease (ESKD), or reduction of ≥40 or RI, sitagliptin, saxagliptin and vildagliptin and tolerability of linagliptin. An open-label,
≥50% in eGFR was 12.3 and 13.6-fold higher are given in the following doses: 100 mg parallel-group, single-center study was
with NRP (placebo group). A reduction in once a day (OD), 5 mg OD and 50 mg twice conducted that enrolled healthy subjects
the levels of glycated HbA1C was observed a day, respectively. However, for moderate (n = 8) and patients with severe (n = 8), moderate
regardless of NRP status.24 to severe RI, dosage adjustment is clinically (n = 9), and mild (n = 8) hepatic impairment.
Schernthaner et al. interpreted the necessary. Saxagliptin is adjusted at 2.5 mg Renal excretion of unaltered linagliptin (≤7%)
CARMELINA study and compared the OD dosage for moderate/severe RI, whereas and accumulation determined by AUC or
percentage of patients with impaired renal vildagliptin is changed at 50 mg OD dose. In Cmax were comparable between groups. At
function or microalbuminuria in patients of the case of sitagliptin, 50 mg OD is prescribed steady-state trough levels, median plasma
CVOTs conducted with alogliptin, linagliptin, for moderate RI and 25 mg OD for severe DPP-4 inhibition was similar in healthy (91%),
saxagliptin, and sitagliptin. Reduced RI. Linagliptin, on the other hand, does not mild (90%), and moderate (89%) hepatic
renal function at baseline (eGFR < 60 mL/ require dosage change in RI.20,27–30 Instances impairment patients, as well as in patients
minute/1.73 m 2), severely reduced renal of a necessity to modify the DPP-4 inhibitor with severe hepatic impairment receiving
function (eGFR < 30 mL/minute/1.73 m 2), dosage for diabetic patients suffering from RI a single dosage 24 hours later (84%). Since
and macroalbuminuria (urinary albumin-to- have been reported for therapies that involve linagliptin was well tolerated, the patient

94 Journal of the Association of Physicians of India, Volume 71 Issue 8 (August 2023)

 Simplifying Type 2 DM Care with Linagliptin

with liver impairment does not require dose Therefore, it can be suggested that linagliptin a single agent for drug naïve patients when
adjustment for linagliptin.32 A pooled analysis is effective in lowering glucose with a safety metformin is contraindicated/patients who
was conducted by Inagaki et al. in 2016 to profile similar to a placebo.37 Espeland et al. are intolerant to metformin or as second-
assess the effectiveness of linagliptin in conducted a study to compare the CV safety line therapy after metformin failure, or as an
patients with T2DM and hepatic difficulties. of linagliptin with glimepiride in older and effective OAD add-on to insulin.
Between participants with and without younger participants in the CAROLINA
baseline hepatic problems, there was no trial. Moderate-to-severe hypoglycemia F i n a n c ia l D i s c lo s u r e
discernible difference in HbA1C reduction was markedly reduced with linagliptin,
This academic initiative has been facilitated
(p = 0.4042).33 In patients taking linagliptin, with no differences among age groups
by Boehringer Ingelheim, India.
acute pancreatitis and bullous pemphigoid (p = 0.23). The mean weight was −1.54 kg
have been reported. In the CARMELINA (95% CI:−1.80–−1.28), lower for linagliptin
experiment, adjudicated acute pancreatitis versus glimepiride. A relative risk reduction A u t h o r s ’ D i s c lo s u r e s
was recorded in 0.3% of linagliptin-treated of 83% in hypoglycemia was reported in Ambrish Mithal has received honoraria as
patients and 0.1% of placebo-treated patients, older patients over 75 years with linagliptin. speaker and advisor from AstraZeneca,
while bullous pemphigoid was documented Weight neutrality across age groups was a vital Abbott, Boehringer Ingelheim, Cipla, Dr
in 0.2% of linagliptin-treated patients, but not observation with linagliptin. 38 Linagliptin- Reddy’s, Eli Lilly, Glenmark, GlaxoSmithKline,
in any placebo-treated patients. In such cases, basal insulin regimens are also an effective Ipca, Janssen, Lupin, Merck Sharp & Dohme,
linagliptin should be discontinued.20 alternative to intensive basal-bolus insulin in Novartis, Novo Nordisk, Pfizer, Sanofi, Serdia
Hypoglycemia in patients with T2DM very old T2DM patients.39 In the CARMELINA Servier, Sun Pharma, Torrent, Wockhardt and
often results in a series of physiologic effects study, it was concluded that treatment based Zydus Nutrition. Ambady Ramachandran
that may lead to cardiac arrhythmias and can on linagliptin does not elevate the risk of has received honoraria as an advisory board
cause oxidative stress. These consequences cardiorenal events in older patients.17 member from Boehringer Ingelheim India,
could result in ischemic cerebral damage and AstraZeneca; as a speaker from Boehringer
may cause sudden cardiac death. Thus acute Ingelheim India, Bayer, Novo Nordisk, Eli
Opinions from experts on the safety of
and chronic episodes of hypoglycemia may linagliptin across a broad range of T2DM Lilly, Sanofi, and grant from Novartis, Sanofi,
initiate several potential mechanisms that patients and AstraZeneca. Arpandev Bhattacharyya
raise the possibility of CV complications.34 A has no share in pharmaceutical companies.
Linagliptin can be safely used in T2DM
study conducted by Greco et al. concluded Manoj Chadha has received d honorarium
patients with mild to moderate liver
that, among elderly T2DM patients, severe as a speaker and advisory board member
dysfunction (86.9%).
hypoglycemia is a significant and frequent from Boehringer Ingelheim India, Astra
Linagliptin can be safely considered in broad
metabolic emergency.35 The glucose-lowering Zeneca, Jansen, Novo Nordisk, Eli Lilly, MSD,
patient profiles, including elderly patients
mechanisms of many pharmacological with T2DM (98.3%). Wockhardt, Alkem, USV and Sanofi-Aventis.
agents also contribute directly to weight Mala Dharmalingam has received honoraria
Linagliptin, with a lower risk of hypoglycemia
gain. 36 The CAROLINA study found that as a speaker from Abbott, Boehringer
and weight neutrality as compared
across all specified hypoglycemia severity Ingelheim, Cipla, Eli Lilly, Glenmark, Ipca,
to glimepiride, alleviates the fear of
categories, the incidence of hypoglycemic hypoglycemia and weight gain in T2DM Janssen, Lupin, Novartis, Novo Nordisk,
episodes (as assessed by the investigator) (96.7%). Sanofi, and Sun Pharma. Anirban Majumder
was lower in the linagliptin group than in the has received honoraria as a speaker and
glimepiride group. Lower hypoglycemia risk advisory board member from AstraZeneca,
in the analyzed subgroups was consistently C o n c lu s i o n Abbot t, Boehringer Ingelheim, Cipla,
observed in the linagliptin group vs the The current position paper has been developed Dr Reddy’s, El I Lilly, GlaxoSmithKline,
glimepiride group.18 based on expert opinions, experience, and Janssen, Lupin, Novartis, Novo Nordisk,
A study by Barnett et al. assessed the common therapy practices in India while Pfizer, Sanofi-Aventis, Jansen, Serdia Servier,
safety and efficacy of linagliptin in elderly providing relevant clinical evidence to support Wockhardt and Zydus Nutrition. Debmalya
patients. HbA1C was −0.61 vs −0.04%, placebo, the guidance that has been developed for the Sanyal has received an honorarium as an
p < 0.0001. A 0.64% placebo-corrected use of linagliptin. To effectively treat a patient advisory board member from Boehringer
reduction was observed. Both the linagliptin with T2DM, healthcare professionals must (Fig. 2) Ingelheim, India.
and placebo groups had roughly comparable take into account a number of factors when
levels of overall safety and tolerability; 75.9% choosing a regimen for drug treatment, A c k n o w l e d g m e n ts
of patients in each group experienced a including the patient’s preferences, age,
negative side effect (placebo n = 60, linagliptin reduction of CV risk, individualized glycemic The authors would like to acknowledge
n = 123). There was no fatality. The study targets, avoidance of hypoglycemia, renal medical writing support provided by Shalaka
drug was not deemed to be responsible protection, comorbidities, cost, weight gain, Marfatia from Pharmedge (Mumbai) and
for any of the severe adverse events that and other side effects of the medication. The Harsha Sasi, N. Senduran, Rudraksh Sharma
occurred, but it did impact 6.3% (five) of the expert opinions documented in this paper and Prashant Rana from Boehringer Ingelheim
patients in the placebo group and 8.6% (14) help justify the clinical role of linagliptin in India for extending scientific support.
of patients in the linagliptin group. The most managing T2DM. It is an efficacious and well-
frequent adverse event was hypoglycemia, tolerated drug for the management of T2DM. R e f e r e n c e s
which occurred in both groups but at similar It reduces the risk of hypoglycemia, is weight 1. International Diabetes Federation (IDF) Atlas. https://
rates, 16.5% (13) in the placebo group and neutral, and does not require dose adjustment www.diabetesatlas.org. Accessed 20 July 2021.
2. Pradeepa R, Mohan V. Prevalence of type 2 diabetes
[24% (39) in the linagliptin group; odds across the broad patient profile regardless of and its complications in India and economic costs to
ratio 1.58, 95% CI: 0 78–3 78, p = 0 2083]. hepatic or renal status. It can be utilized as the nation. Eur J Clin Nutr 2017;71(7):816–824.

Journal of the Association of Physicians of India, Volume 71 Issue 8 (August 2023) 95

 Simplifying Type 2 DM Care with Linagliptin

3. Atre S, Deshmukh S, Kulkarni M. Prevalence of type patients with type 2 diabetes mellitus: A randomized, adjunct to diet and exercise to improve glycemic
2 diabetes mellitus (T2DM) in India: a systematic double-blind, placebo-controlled trial. Diabetes Obes control in adults with type 2 diabetes mellitus Stage
review (1994-2018). Diabetes Metab Syndr 2020;14(5): Metab 2021;23(2):642–647. E, Therapy C. https://www.accessdata.fda.gov/
897–906. 17. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of drugsatfda_docs/label/2012/021995s019lbl.pdf.
4. Draznin B, Aroda VR, Bakris G, et al. 9. Pharmacologic linagliptin vs placebo on major cardiovascular events 31. TENELIA®- Summary of Product Characteristics (SmPC)
approaches to glycemic treatment: standards in adults with type 2 diabetes and high cardiovascular 30 Apr 2020.
of medical care in diabetes-2022. Diabetes Care and renal risk: the CARMELINA randomized clinical 32. Graefe-Mody U, Rose P, Retlich S, et al. Pharmacokinetics
2022;45(Supplement_1):S125–S143. trial. JAMA 2019;321(1):69–79. of linagliptin in subjects with hepatic impairment. Br
5. Gallwitz B. Clinical Use of DPP-4 Inhibitors. Front 18. Rosenstock J, Kahn SE, Johansen OE, et al. Effect J Clin Pharmacol 2012;74(1):75–85.
Endocrinol (Lausanne) 2019;10:389. of linagliptin vs glimepiride on major adverse 33. Inagaki N, Sheu WH, Owens DR, et al. Efficacy and
6. Davidson JA. The placement of DPP-4 inhibitors in cardiovascular outcomes in patients with type 2 safety of linagliptin in type 2 diabetes patients with
clinical practice recommendations for the treatment diabetes: the CAROLINA randomized clinical trial. self-reported hepatic disorders: a retrospective
of type 2 diabetes. Endocr Pract 2013;19(6):1050–1061. JAMA 2019;322(12):1155–1166. pooled analysis of 17 randomized, double-blind,
7. Craddy P, Palin HJ, Johnson KI. Comparative 19. Cosentino F, Grant PJ, Aboyans V, et al. 2019 placebo - controlled clinical trials. J Diabetes
effectiveness of dipeptidylpeptidase-4 inhibitors ESC Guidelines on diabetes, pre-diabetes, and Complications 2016;30(8):1622–1630.
in type 2 diabetes: a systematic review and mixed cardiovascular diseases developed in collaboration 34. Snell-Bergeon JK, Wadwa RP. Hypoglycemia, diabetes,
treatment comparison. Diabetes Ther 2014;5(1):1–41. with the EASD. Eur Heart J 2020;41(2):255–323. and cardiovascular disease. Diabetes Technol Ther
8. Del Prato S, Barnett AH, Huisman H, et al. Effect 20. TRAJENTA®. India Pack Insert version: 09 Apr 2020. 2012;14(Suppl 1):S51–S58.
of linagliptin monotherapy on glycaemic control 21. McGill JB, Sloan L, Newman J, et al. Long-term 35. Greco D, Pisciotta M, Gambina F, et al. Severe
and markers of beta-cell function in patients efficacy and safety of linagliptin in patients with type hypoglycaemia leading to hospital admission in type
with inadequately controlled type 2 diabetes: a 2 diabetes and severe renal impairment: a 1-year, 2 diabetic patients aged 80 years or older. Exp Clin
randomized controlled trial. Diabetes Obes Metab. randomized, double-blind, placebo-controlled study. Endocrinol Diabetes 2010;118(4):215–219.
2011;13(3):258–267. Diabetes Care 2013;36(2):237–244. 36. Van Gaal L, Scheen A. Weight management in type
9. Taskinen MR, Rosenstock J, Tamminen I, et al. 22. Ghisdal L, Van Laecke S, Abramowicz MJ, et al. 2 diabetes: current and emerging approaches to
Safety and efficacy of linagliptin as add-on therapy New-onset diabetes after renal transplantation: treatment. Diabetes Care 2015;38(6):1161–1172.
to metformin in patients with type 2 diabetes: a risk assessment and management. Diabetes Care 37. Barnett AH, Huisman H, Jones R, et al. Linagliptin for
randomized, double-blind, placebo-controlled study. 2012;35(1):181–188. patients aged 70 years or older with type 2 diabetes
Diabetes Obes Metab 2011;13(1):65–74. 23. Sanyal D, Gupta S, Das P. A retrospective study inadequately controlled with common antidiabetes
10. Groop PH, Del Prato S, Taskinen MR, et al. Linagliptin evaluating efficacy and safety of linagliptin in treatments: a randomized, double-blind, placebo-
treatment in subjects with type 2 diabetes with treatment of NODAT (in renal transplant recipients) controlled trial. Lancet 2013;382(9902):1413–1423.
and without mild-to-moderate renal impairment. in a real world setting. Indian J Endocrinol Metab 38. Espeland MA, Pratley RE, Rosenstock J, et al.
Diabetes Obes Metab 2014;16(6):560–568. 2013;17(Suppl 1):S203–S205. Cardiovascular outcomes and safety with linagliptin,
11. Lv Q, Shen J, Miao L, et al. Early combination therapy 24. Wanner C, Cooper ME, Johansen OE, et al. Effect of a dipeptidyl peptidase-4 inhibitor, compared with
with linagliptin and metformin in people with type 2 linagliptin versus placebo on cardiovascular and the sulphonylurea glimepiride in older people
diabetes improves glycemic control to hba1c ≤ 6.5% kidney outcomes in nephrotic-range proteinuria with type 2 diabetes: a subgroup analysis of the
without increasing hypoglycemia: pooled analysis and type 2 diabetes: the CARMELINA randomized randomized CAROLINA trial. Diabetes Obes Metab
of two randomized clinical trials. Diabetes Ther controlled trial. Clin Kidney J 2021;14(1):226–236. 2021;23(2):569–580.
2020;11(6):1317–1330. 25. Schernthaner G, Wanner C, Jurisic-Erzen D, et al. 39. Perez-Belmonte LM, Osuna-Sanchez J, Ricci M, et al.
12. Del Prato S, Pulizzi N. The place of sulfonylureas in CARMELINA: an important piece of the DPP-4 Management of older hospitalized patients with
the therapy for type 2 diabetes mellitus. Metabolism inhibitor CVOT puzzle. Diabetes Res Clin Pract type 2 diabetes using linagliptin: lina-older study.
2006;55(5 Suppl 1):S20–S27. 2019;153:30–40. Panminerva Med 2023;65(1):13–19.
13. Kalra S, Aamir AH, Raza A, et al. Place of sulfonylureas 26. Hong S, Han K, Park CY. Outcomes for inappropriate 40. McMurray JJV, Ponikowski P, Bolli GB, et al. Effects
in the management of type 2 diabetes mellitus renal dose adjustment of dipeptidyl peptidase-4 of vildagliptin on ventricular function in patients
in South Asia: a consensus statement. Indian J inhibitors in patient s with t y p e 2 diab etes with type 2 diabetes mellitus and heart failure: a
Endocrinol Metab 2015;19(5):577–596. mellitus: population-based study. Mayo Clin Proc randomized placebo-controlled trial. JACC Heart Fail
14. Gallwitz B, Rosenstock J, Rauch T, et al. 2-year efficacy 2020;95(1):101–112. 2018;6(1):8–17.
and safety of linagliptin compared with glimepiride 27. Galvus 50 mg Tablets - Summar y of Product 41. Green JB, Bethel MA, Armstrong PW, et al. Effect of
in patients with type 2 diabetes inadequately Characteristics (SmPC) - (emc).. https://www.medicines. sitagliptin on cardiovascular outcomes in type 2
controlled on metformin: a randomized, double-blind, org.uk/emc/product/6225/smpc Accessed 27 July 2021. diabetes. N Engl J Med 2015;373(3):232–242.
noninferiority trial. Lancet 2012;380(9840):475–483. 28. https://www.accessdata.fda.gov/drugsatfda_docs/ 42. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin
15. Sarashina A, Friedrich C, Crowe S, et al. Comparable label/2015/022350s016lbl.pdf. Accessed May 3, 2022. and cardiovascular outcomes in patients with type 2
pharmacodynamics, efficacy, and safety of linagliptin 29. White WB, Cannon CP, Heller SR, et al. Alogliptin after diabetes mellitus. N Engl J Med 2013;369(14):1317–1326.
5 mg among Japanese, Asian and white patients with acute coronary syndrome in patients with type 2 43. Singh AK. Efficacy and safety of teneligliptin. Indian
type 2 diabetes. J Diabetes Investig 2016;7(5):744–750. diabetes. N Engl j Med 2013;369:1327–1335. J Endocrinol Metab 2017;21(1):11–17.
16. Yang W, Xu X, Lei T, et al. Efficacy and safety of 30. JANUVIA ® (sitagliptin) Tablets Monotherapy and
linagliptin as add-on therapy to insulin in Chinese Combination Therapy JANUVIA ® is indicated as an

96 Journal of the Association of Physicians of India, Volume 71 Issue 8 (August 2023)