Is GFR decline induced by SGLT2 inhibitor of clinical importance?

BACKGROUND: Use of sodium-glucose-cotransporter-2 (SGLT2) inhibitors often causes an initial decline in glomerular filtration rate (GFR). This study addresses the question whether the initial decline of renal function with SGLT2 inhibitor treatment is related to vascular changes in the systemic circulation. METHODS: We measured GFR (mGFR) and estimated GFR (eGFR) in 65 patients with type 2 diabetes (T2D) at baseline and after 12 weeks of treatment randomized either to a combination of empagliflozin and linagliptin (SGLT2 inhibitor based treatment group) (n = 34) or metformin and insulin (non-SGLT2 inhibitor based treatment group) (n = 31). mGFR was measured using the gold standard clearance technique by constant infusion of inulin. In addition to blood pressure (BP), we measured pulse wave velocity (PWV) under standardized conditions reflecting vascular compliance of large arteries, as PWV is considered to be one of the most reliable vascular parameter of cardiovascular (CV) prognosis. RESULTS: Both mGFR and eGFR decreased significantly after initiating treatment, but no correlation was found between change in mGFR and change in eGFR in either treatment group (SGLT2 inhibitor based treatment group: r=-0.148, p = 0.404; non-SGLT2 inhibitor based treatment group: r = 0.138, p = 0.460). Noticeably, change in mGFR correlated with change in PWV (r = 0.476, p = 0.005) in the SGLT2 inhibitor based treatment group only and remained significant after adjustment for the change in systolic BP and the change in heart rate (r = 0.422, p = 0.018). No such correlation was observed between the change in eGFR and the change in PWV in either treatment group. CONCLUSIONS: Our main finding is that after initiating a SGLT2 inhibitor based therapy an exaggerated decline in mGFR was related with improved vascular compliance of large arteries reflecting the pharmacologic effects of SGLT2 inhibitor in the renal and systemic vascular bed. Second, in a single patient with T2D, eGFR may not be an appropriate parameter to assess the true change of renal function after receiving SGLT2 inhibitor based therapy. TRIAL REGISTRATION: clinicaltrials.gov (NCT02752113).

Safety of Linagliptin in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

BACKGROUND: Linagliptin is an oral dipeptidyl peptidase DPP-4 inhibitor, which is indicated for the treatment of Type 2 diabetes mellitus (T2DM) as monotherapy or add-on to therapy with other hypoglycemic drugs. OBJECTIVES: We aimed to summarize the evidence from randomized controlled trials (RCTs) to assess the safety of linagliptin focusing on cardiovascular risks among subjects with type 2 diabetes mellitus. METHODS: We conducted a systematic search across the following databases: Medline, Embase, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov from inception to November 2021. Randomized controlled trials (RCTs) of linagliptin compared to placebo in patients with Type 2 diabetes were included. The primary safety points were cardiovascular (CV) adverse events including non-fatal stroke, non-fatal myocardial infarction (MI), CV death, MI, stroke, and hospitalization for unstable angina. While, secondary safety points included 17 reported adverse events such as infections, hypoglycemia and abdominal pain. Three reviewers independently screened and reviewed each study to extract relevant information. Any discrepancies were resolved by consensus. We conducted a meta-analysis using the random effects model. Pooled risk ratios (RRs) of targeted adverse events with linagliptin compared to placebo were estimated using the Mantel-Haenszel test. RESULTS: A total of 24 studies with 19,981 adult patients were included. There was no difference in the incidence of all CV adverse events or individual CV adverse events between linagliptin and the placebo arms. The pooled estimate of the risk of upper respiratory tract infection was reported in twelve trials with a 38% risk reduction among patients treated with the linagliptin group compared to the placebo group (RR = 0.62, 95% CI: 0.45-0.85, and I2 = 0%), while no difference was found in other infections. For gastrointestinal disorders, the risk of abdominal pain showed a 65% risk reduction among patients treated with the linagliptin group compared to the placebo group (RR = 0.35, 95% CI: 0.16-0.77, and I2 = 0%). CONCLUSION: Our study showed an overall acceptable safety profile of linagliptin in patients with T2DM. Moreover, our study showed a risk reduction of upper respiratory tract infection and abdominal pain when using linagliptin compared to placebo.

Identification of Risk Factors for Gliptin-associated Bullous Pemphigoid among Diabetic Patients.

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008-2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer's disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer's and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.

Two cases of linagliptin-associated bullous pemphigoid resulting in sepsis and endocarditis.

We describe two patients, in their 70s, each presenting to the emergency department, with 6-week histories of progressively developing pruritic bullae. Both individuals had multiple comorbidities, including type 2 diabetes-for which they took linagliptin, chronic kidney disease, hypertension and prosthetic heart valves. Owing to systemic illness and endocarditis secondary to superadded bacterial infections, they both required intensive treatment and prolonged hospital admissions.Despite the beneficial effect of linagliptin on glycaemic control and its reported cardiovascular and renal safety profiles, we add our cases as evidence of the significant risk of developing bullous pemphigoid while taking this medication. Secondary infection of bullous pemphigoid increased the risk of developing endocarditis, particularly among individuals with a medical history of valve replacement surgery. Considering this, we advocate caution when prescribing this medication.

Gliptin-induced bullous pemphigoid.

OBJECTIVES: Bullous pemphigoid (BP) is a rare, autoimmune, blistering disease in elderly patients that can be triggered by external factors including drugs. Drug-induced bullous pemphigoid (DIBP) does not always follow a self-limiting course after the withdrawal of the offending drug. Dipeptidyl peptidase-4 (DPP-4) inhibitors or gliptins seem to be associated with a significant risk of inducing BP. CASE PRESENTATION: We report 2 cases of BP attributed to the DPP-4 inhibitor linagliptin. In both cases, the clinical manifestation was strongly suggestive of BP. The diagnosis was verified by histology and direct immunofluorescence (DIF). Linagliptin and all other possible drug triggers of BP were discontinued after consultation with an endocrinologist and a cardiologist. Systemic treatment of BP consisted of methylprednisolone and tetracycline. During the follow-up period, one of the patients suffered a fatal brain stroke while the other was managed with reduced doses of corticosteroids. CONCLUSION: The proper management of autoimmune bullous skin disorders in elderly patients includes a scrupulous assessment of plausible drug triggers. Systemic corticosteroids for treating severe cases of DIBP can worsen concomitant diseases which often necessitates multidisciplinary care.

Simplifying Type 2 DM Care with Linagliptin: A Position Paper.

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 drugs are usually required to successfully control hyperglycemia in patients with T2DM. To facilitate effective control of glucose levels, many new agents have been developed over the past few years. MATERIALS AND METHODS: Multiple Advisory Board Meetings were conducted with 87 leading key opinion leaders (KOLs) from diabetes specialty PAN India to understand the simplicity aspect of linagliptin therapy in T2DM patients. DISCUSSION: Linagliptin is a xanthine-based, non-peptidomimetic, selective dipeptidyl peptidase 4 (DPP-4) inhibitor with a different pharmacological profile when compared to other DPP-4 inhibitors already available in India. It is known to decrease the risk of hypoglycemia compared to sulphonylurea (SU), is weight neutral, and no dose modification is required over a broad range of patient populations. This consensus paper discusses the clinical efficacy of DPP-4 inhibitors and linagliptin in T2DM. It also highlights the evidence for the safety of linagliptin in T2DM patients with renal impairment (RI), cardiovascular (CV) risk, and heart failure (HF). CONCLUSION: Linagliptin therapy is simplifying the management of T2DM with good efficacy and its use across a wide range of patients without any dose modification.

Baseline Cardiovascular Risk Factor Control in Patients With Type 2 Diabetes and Coronary Disease Versus Stroke: Secondary Analysis of Cardiovascular Outcome Trials.

BACKGROUND: Patients with type 2 diabetes (T2D) and cardiovascular disease are at increased risk for recurrent ischemic events. Cardiovascular risk factor control is vital for secondary prevention, but how this compares among individuals with different T2D macrovascular complications is unknown. We aimed to determine if there might be differences in risk factor control in patients with T2D with previous stroke versus coronary artery disease (CAD). METHODS: Cross-sectional analyses were performed on 12 856 patients with T2D with prior history of stroke with or without CAD from 3 diabetes cardiovascular outcome trials: CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), and CAROLINA (The Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes). Risk factors at baseline assessed included dyslipidemia, hypertension, smoking, and current antiplatelet/anticoagulant therapy. Control, respectively, was defined as LDL (low-density lipoprotein)-C <100 mg/dL or statin use, systolic blood pressure <140 and diastolic blood pressure <90 mm Hg, not currently smoking, and use of an antiplatelet/anticoagulant medication. The odds ratio of 3 to 4 (or good) versus 0 to 2 (or suboptimal) risk factors controlled was analyzed by logistic regression models. RESULTS: The odds for good versus suboptimal risk factor control in patients with CAD alone was higher than in those with stroke alone across all 3 trials odds ratios (95% CI): CARMELINA, 2.05 (1.67-2.51), EMPA-REG OUTCOME, 2.50 (2.10-2.99), and CAROLINA, 1.63 (1.21-2.20). The respective odds ratios were lower (and rendered nonsignificant in CAROLINA) when cardiovascular risk factor control in patients with both CAD and stroke were compared with those with stroke alone: CARMELINA, 1.45 (1.13-1.87); EMPA-REG OUTCOME, 1.62 (1.25-2.08); and CAROLINA, 1.16 (0.74-1.83). CONCLUSIONS: In contemporary populations of patients with T2D, there was significant discordance in control of cardiovascular risk factors between patients with stroke versus CAD, with the former having less optimal control. The intermediate results in patients with both CAD and stroke suggest that these differences could be related at least in part to clinician factors. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT01243424, NCT01131676, NCT01897532.

Neuroprotective Role of DPP-4 Inhibitor Linagliptin Against Neurodegeneration, Neuronal Insulin Resistance and Neuroinflammation Induced by Intracerebroventricular Streptozotocin in Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related, multifactorial progressive neurodegenerative disorder manifested by cognitive impairment and neuronal death in the brain areas like hippocampus, yet the precise neuropathology of AD is still unclear. Continuous failure of various clinical trial studies demands the utmost need to explore more therapeutic targets against AD. Type 2 Diabetes Mellitus and neuronal insulin resistance due to serine phosphorylation of Insulin Receptor Substrate-1 at 307 exhibits correlation with AD. Dipeptidyl Peptidase-4 inhibitors (DPP-4i) have also indicated therapeutic effects in AD by increasing the level of Glucagon-like peptide-1 in the brain after crossing Blood Brain Barrier. The present study is hypothesized to examine Linagliptin, a DPP-4i in intracerebroventricular streptozotocin induced neurodegeneration, and neuroinflammation and hippocampal insulin resistance in rat model of AD. Following infusion on 1st and 3rd day, animals were treated orally with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) and donepezil (5 mg/kg) as a standard for 8 weeks. Neurobehavioral, biochemical and histopathological analysis was done at the end of treatment. Dose-dependently Linagliptin significantly reversed behavioral alterations done through locomotor activity (LA) and morris water maze (MWM) test. Moreover, Linagliptin augmented hippocampal GLP-1 and Akt-ser473 level and mitigated soluble Aß (1-42), IRS-1 (s307), GSK-3ß, TNF-α, IL-1ß, IL-6, AchE and oxidative/nitrosative stress level. Histopathological analysis also exhibited neuroprotective and anti-amylodogenic effect in Hematoxylin and eosin and Congo red staining respectively. The findings of our study concludes remarkable dose-dependent therapeutic potential of Linagliptin against neuronal insulin resistance via IRS-1 and AD-related complication. Thus, demonstrates unique molecular mechanism that underlie AD.

Risk heterogeneity of bullous pemphigoid among dipeptidyl peptidase-4 inhibitors: A population-based cohort study using Japanese Latter-Stage Elderly Healthcare Database.

AIMS/INTRODUCTION: Although the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and bullous pemphigoid (BP) has begun to be established, some studies have suggested there are risk differences among DPP-4 inhibitors. We conducted a population-based cohort study to examine the risk differences. MATERIALS AND METHODS: Using the claims databases of the Fukuoka Prefecture Wide-Area Association of Latter-Stage Elderly Healthcare between April 1, 2013 and March 31, 2017, we conducted a retrospective cohort study to compare patients receiving one DPP-4 inhibitor with those who were prescribed another antidiabetic drug. The primary outcome was an adjusted hazard ratio (HR) of the development of bullous pemphigoid during a 3-year follow-up. The secondary outcome was the development of BP requiring systemic steroids immediately after the diagnosis. These were estimated using Cox proportional hazards regression models. RESULTS: The study comprised 33,241 patients, of which 0.26% (n = 88) developed bullous pemphigoid during follow-up. The percentages of patients with bullous pemphigoid who required immediate systemic steroid treatment was 0.11% (n = 37). We analyzed four DPP-4 inhibitors: sitagliptin, vildagliptin, alogliptin, and linagliptin. Vildagliptin and linagliptin raised the risk of BP significantly (primary outcome, vildagliptin, HR 2.411 [95% confidence interval (CI) 1.325-4.387], linagliptin, HR 2.550 [95% CI 1.266-5.136], secondary outcome, vildagliptin HR 3.616 [95% CI 1.495-8.745], linagliptin HR 3.556 [95% CI 1.262-10.024]). A statistically significant risk elevation was not observed with sitagliptin and alogliptin (primary outcome, sitagliptin, HR 0.911 [95% CI 0.508-1.635], alogliptin, HR 1.600 [95% CI 0.714-3.584], secondary outcome, sitagliptin, HR 1.192 [95% CI 0.475-2.992], alogliptin, HR 2.007 [95% CI 0.571-7.053]). CONCLUSIONS: Not all the DPP-4 inhibitors could induce bullous pemphigoid significantly. Therefore, the association warrants further investigations before generalization.

Incident and recurrent hypoglycaemia with linagliptin and glimepiride over a median of 6 years in the CAROLINA cardiovascular outcome trial.

AIM: The CAROLINA trial established non-inferiority of linagliptin versus glimepiride for major adverse cardiovascular events in patients with relatively early type 2 diabetes at increased cardiovascular risk. In pre-specified and post-hoc analyses, we investigated treatment effects on total hypoglycaemic burden in CAROLINA. MATERIALS AND METHODS: Patients were randomized and treated with 5 mg linagliptin (n = 3014) or 1-4 mg glimepiride (n = 3000) once daily added to standard care. Hypoglycaemia captured from investigator-reported adverse events was analysed with Poisson and negative binomial regressions for the first and total (first plus recurrent) events, respectively. The influence of insulin initiation and glycated haemoglobin (HbA1c) change on the treatment effect for hypoglycaemia was also explored. RESULTS: Over 6.3 years median follow-up, average HbA1c over time did not differ between linagliptin versus glimepiride (weighted mean difference [95% confidence interval]: 0.00%, [-0.05, 0.05]), nor did insulin initiation (18.6% vs. 19.2% of patients, respectively), whereas body weight was lower with linagliptin (-1.54 kg, [-1.80, -1.28]). Hypoglycaemia frequency was lower with linagliptin across all hypoglycaemia categories, including severe episodes. Rate ratios (95% confidence interval) for first and total events for investigator-reported hypoglycaemia were 0.21 (0.19-0.24) and 0.12 (0.10-0.14), respectively, with 8.7 first and 60.8 total estimated events prevented/100 patient-years with linagliptin versus glimepiride. These differences occurred during night-time and daytime, and in subgroup analyses of total events. Treatment differences in hypoglycaemia were neither impacted by HbA1c changes nor insulin initiation. CONCLUSIONS: Across the severity spectrum, linagliptin substantially reduced the hypoglycaemic burden versus glimepiride in patients with relatively early type 2 diabetes at increased cardiovascular risk.

Management of older hospitalized patients with type 2 diabetes using linagliptin: Lina-Older study.

BACKGROUND: Older patients managed with intensive antidiabetic therapy are more likely to be harmed. Our study's primary endpoint was to analyze the safety and efficacy of linagliptin in combination with basal insulin versus basal-bolus insulin in patients with 75 years of age or older hospitalized in medicine and surgery departments in real-world clinical practice. METHODS: We retrospectively enrolled non-critically patients ≥75 years with type 2 diabetes admitted to medicine and non-cardiac surgery departments with admission glycated hemoglobin <8%, admission blood glucose <240 mg/dL, and without at-home injectable therapies managed with our hospital's antihyperglycemic protocol (basal-bolus or linagliptin-basal regimens) between January 2016 and December 2018. To match each patient who started on the basal-bolus regimen with a patient who started on the linagliptin-basal regimen, a propensity matching analysis was used. RESULTS: Postmatching, 198 patients were included in each group. There were no significant differences in mean daily blood glucose levels after admission (P=0.203); patients with mean blood glucose 100-140mg/dL (P=0.134), 140-180mg/dL (P=0.109), or >200mg/dL (P=0.299); and number and day of treatment failure (P=0.159 and P=0.175, respectively). The total insulin dose and the number of daily injections were significantly lower in the linagliptin-basal group (both, P<0.001). Patients on the basal-bolus insulin regimen had more total hypoglycemic events than patients on the linagliptin-basal insulin regimen (P<0.001). CONCLUSIONS: The linagliptin-basal insulin regimen was an effective alternative with fewer hypoglycemic events and daily insulin injections than intensive basal-bolus insulin in very old patients with type 2 diabetes with mild-to-moderate hyperglycemia treated at home without injectable therapies.

Architecting novel multilayer nanosponges for co-administration of two drugs managing high-risk type II diabetes mellitus patients suffering from cardiovascular diseases.

Nanosponges are porous solid nanoparticles composed of hyper-cross-linked polymers that serve as specific micro-domains designed for the co-encapsulation of two drugs with different chemical structures. Our goal was to engineer a novel assembly of multilayer nanosponges (MLNS) based on a layer-by-layer approach. This MLNS was engineered to incorporate two drugs (linagliptin and empagliflozin) in a new drug delivery route. Linagliptin has a low oral bioavailability due to intestinal degradation and low permeability. Its pharmacokinetics shows a non-linear profile which leads to a disproportionate increase in its effectiveness with increasing the dose frequency. Empagliflozin has a low permeability and is very slightly soluble in aqueous media between pH 1-7.5. MLNS could improve their bioavailability along with resolving possible risks due to the non-linear pharmacokinetics of linagliptin and maximizing its dose efficiency. 23 factorial design was used to optimize the novel systems. MLNS (F4) was chosen as the optimal system with an average diameter of 40 nm and the highest entrapment efficiency which accounts for 92.93 % ± 2.27 and 100.94 % ± 0.55 for linagliptin and empagliflozin respectively. Förster resonance energy transfer confirmed the formation of a multilayer structure in MLNS. The optimized system was incorporated within chitosan mucoadhesive buccal films which were optimized through 22factorial design. The permeation study from optimized MLNS-film (B4) ensured an improved empagliflozin permeation along with a controlled efflux for linagliptin, resolving possible risks due to the nonlinear plasma profile. The in-vivo study of MLNS-film (B4) revealed that AUC(0-∞)of linagliptin and empagliflozin was enhanced by two-fold and ten-fold, respectively. Therefore, the nano-buccal formulation for the co-delivered hypoglycemic drugs could contribute to improved clinical efficacy in the treatment of diabetes.

Pharmacokinetics and Bioequivalence of Single-Oral-Dose Linagliptin: A Randomized, 2-Period Crossover Trial in Chinese Healthy Subjects Under Fasting and Fed Conditions.

The bioequivalence of the reference and test linagliptin formulations was assessed in healthy Chinese subjects under fasting and fed conditions. The study was designed as a single-dose, randomized, open-label, 2-period crossover study with a 35-day washout period between 2 administrations. Forty-eight healthy subjects received 5 mg of test and reference linagliptin formulation orally under fasting condition. The geometric mean of the maximum observed linagliptin concentration (Cmax ) for the test formulation was 4.9 ng/mL (reference, 5.0 ng/mL), the area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72 ) was 154.7 ng · h/mL (reference, 157.4 ng · h/mL). Thirty-six subjects received 5 mg of test and reference linagliptin formulation orally under fed conditions. The geometric mean of Cmax for the test linagliptin formulation was 2.8 ng/mL (reference, 2.8 ng/mL), AUC0-72 was 133.5 ng · h/mL (reference, 136.6 ng · h/mL). The 90%CIs for the test/reference ratio for Cmax and AUC0-72 met the bioequivalence criteria (80%-125%). The test and reference formulations of linagliptin were well tolerated and bioequivalent under fasting and fed conditions.

Long-term safety and effectiveness of linagliptin by baseline body mass index in Japanese patients with type 2 diabetes: a 3-year post-marketing surveillance study.

BACKGROUND: A recent 3-year post-marketing surveillance (PMS) study reaffirmed the safety and effectiveness of linagliptin in linagliptin-naïve Japanese patients with type 2 diabetes (T2D). We present further analyses from this study by body mass index (BMI). RESEARCH DESIGN AND METHODS: Safety and effectiveness were assessed across BMI subgroups (<25, 25 to <30, and ≥30 kg/m2). RESULTS: Data were available for 876, 566, and 201 patients in the BMI subgroups, respectively. Incidence of adverse drug reactions [ADR] with linagliptin was 11.42%, 11.31%, 10.45%, respectively. The most common ADR of special interest was hepatic disorders (n [%]: 6 [0.68], 7 [1.24], and 3 [1.49], respectively). Additional use of glucose-lowering drugs (GLDs) increased with BMI (15.0%, 19.1%, 24.4% of patients; P < 0.001). In the overall population, HbA1c change (adjusted mean %±SE) until week 156 was -0.71±0.04, -0.68±0.04 and -0.74±0.09. In patients receiving linagliptin with no additional GLDs, HbA1c changes were -0.58%±0.04, -0.62%±0.04, and -0.77%±0.11. CONCLUSIONS: In this study of linagliptin in Japanese patients with T2D, across BMI subgroups no new safety concerns were observed. The proportion of patients with additional GLD use increased with baseline BMI. Decreases in HbA1c were observed in all subgroups, including in patients with no additional GLD use. CLINICALTRIALS.GOV: NCT01650259.

Dipeptidyl peptidase-4 inhibitor-associated cutaneous eruptions: a retrospective observational study.

BACKGROUND: Dipeptidyl peptidase (DPP)-4 plays a complex role in immune regulation and its inhibition can have effects on the pathogenesis of various skin diseases. Studies have shown that DPP-4 inhibitors are associated with an increased risk of bullous pemphigoid (BP). AIM: To analyse the clinical and histopathological features of cutaneous adverse events in patients on DPP-4 inhibitors. METHODS: We performed a retrospective review of patients with suspected DPP-4 inhibitor-associated cutaneous adverse events, at a tertiary teaching hospital from 1 January 2017 to 31 December 2020. Exclusion criteria included previous history of chronic skin disease and lack of histopathological reports or follow-up records. The clinical characteristics, latency period, Naranjo Adverse Drug Reaction Probability Scale and clinical outcomes were evaluated. RESULTS: In total, 18 patients (10 men, 8 women; mean age 68.6 years, range 38-89 years) were included. The DPP-4 inhibitors used were teneligliptin (n = 6), vildagliptin (n = 6), sitagliptin (n = 4), linagliptin (n = 1) and saxagliptin (n = 1). The mean interval between therapy initiation and lesion onset was 8.8 months (range 1-24 months). The dermatoses noted were BP (n = 12; 66.6%), lichenoid dermatitis (n = 4; 22.2%), psoriasiform dermatitis (n = 1; 5.6%) and spongiotic dermatitis (n = 1; 5.6%). Eight patients (44.4%) had necrotic keratinocytes as one of the distinct histological features. Causality assessment using the Naranjo scale rated the causative role of DPP-4 inhibitors as 'possible' in all patients. Of the 18 patients, 11 (61.1%) noted improvement in their condition following discontinuation of DPP-4 inhibitors, with 5 having complete remission within 6 months of stopping the drug. CONCLUSION: DPP-4 inhibitor-associated dermatoses are not necessarily limited to BP. It is necessary to recognize the possibility of other dermatoses in patients on DPP-4 inhibitors as drug substitution/cessation may improve disease morbidity.

Comparative Safety of Dipeptidyl Peptidase-4 Inhibitors and Sudden Cardiac Arrest and Ventricular Arrhythmia: Population-Based Cohort Studies.

In vivo studies suggest that arrhythmia risk may be greater with less selective dipeptidyl peptidase-4 inhibitors, but evidence from population-based studies is missing. We aimed to compare saxagliptin, sitagliptin, and linagliptin with regard to risk of sudden cardiac arrest (SCA)/ventricular arrhythmia (VA). We conducted high-dimensional propensity score (hdPS) matched, new-user cohort studies. We analyzed Medicaid and Optum Clinformatics separately. We identified new users of saxagliptin, sitagliptin (both databases), and linagliptin (Optum only). We defined SCA/VA outcomes using emergency department and inpatient diagnoses. We identified and then controlled for confounders via a data-adaptive, hdPS approach. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression using a robust variance estimator while adjusting for calendar year. We identified the following matched comparisons: saxagliptin vs. sitagliptin (23,895 vs. 96,972) in Medicaid, saxagliptin vs. sitagliptin (48,388 vs. 117,383) in Optum, and linagliptin vs. sitagliptin (36,820 vs. 78,701) in Optum. In Medicaid, use of saxagliptin (vs. sitagliptin) was associated with an increased rate of SCA/VA (adjusted HR (aHR), 2.01, 95% confidence interval (CI) 1.24-3.25). However, in Optum data, this finding was not present (aHR, 0.79, 95% CI 0.41-1.51). Further, we found no association between linagliptin (vs. sitagliptin) and SCA/VA (aHR, 0.65, 95% CI 0.36-1.17). We found discordant results regarding the association between SCA/VA with saxagliptin compared with sitagliptin in two independent datasets. It remains unclear whether these findings are due to heterogeneity of treatment effect in the different populations, chance, or unmeasured confounding.

Safety and tolerability of linagliptin in Asians with type 2 diabetes: a pooled analysis of 4457 patients from 21 randomized, double-blind, placebo-controlled clinical trials.

BACKGROUND: Safety and tolerability of glucose-lowering drugs is a key consideration for use in type 2 diabetes (T2D). We evaluated the safety and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin in Asian patients with T2D. RESEARCH DESIGN AND METHODS: This was a post-hoc, descriptive pooled analysis of 21 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2D patients lasting ≤52 weeks. We evaluated adverse events (AEs) and laboratory parameters in Asian participants living in Asia, both overall and in the East Asian subgroup. RESULTS: This analysis included 4457 Asian patients overall (2712 receiving linagliptin; 1745 receiving placebo) and 3057 (68.6%) East Asians. AEs were reported in 1510 (55.7%) Asian patients receiving linagliptin and 1032 (59.1%) receiving placebo but were considered drug-related in only 13.0% of each group. Serious AEs occurred in 109 (4.0%) linagliptin patients and 90 (5.2%) placebo patients. The most common AEs were nasopharyngitis (6.4% linagliptin, 7.3% placebo), upper respiratory tract infection (5.7% linagliptin, 6.5% placebo), and hypoglycemia (7.3% linagliptin, 6.3% placebo). One linagliptin patient had pancreatitis; none had bullous pemphigoid. No clinically relevant mean changes in laboratory parameters occurred. These findings were consistent in East Asians. CONCLUSIONS: Linagliptin is well tolerated in Asian T2D patients, including East Asians, with low risk for AEs.

Rationality, Efficacy, Tolerability of Empagliflozin Plus Linagliptin Combination for the Management of Type 2 Diabetes Mellitus: A Systematic Review of Randomized Controlled Trials and Observational Studies.

BACKGROUND: Treatment of diabetes mellitus includes more than one drug of different groups, which may lead to a high pill burden and non-adherence to drugs. We have aimed to systematically analyze the clinical efficacy, safety, and pharmacoeconomic cost-effectiveness of the fixed-dose combination of empagliflozin plus a linagliptin in Type-2 Diabetes mellitus (T2DM) patients. METHODS: A literature search of PubMed/MEDLINE, SCOPUS, Google Scholar, and EMBASE was performed using the MeSH terms and/or keywords"((Single-pill combination) OR ((Fixeddose combination) OR (Combination therapy)) AND (Empagliflozin add on-to Linagliptin) OR (Empagliflozin combined with Linagliptin) OR ((Combination of Empagliflozin and Linagliptin)" from the inception to February 2021. RESULTS: Search results were found in a total of 13 clinical studies. After removing duplicates and studies not according to inclusion criteria, a total of eight clinical studies (Randomized controlled trials: 7; Observational cohort studies: 1) were included (n=7491). A significant reduction in the primary endpoint, the mean changes in baseline HbA1c at the end of 24 weeks and/or 52 weeks was found in the empagliflozin plus a linagliptin combination group in all included studies. In addition, significant efficacy was seen in decreasing the secondary endpoints such as the mean change in the fasting plasma glucose, systolic and diastolic blood pressure (DBP), and body weight with fewer adverse events than the adverse effects with either drug alone. CONCLUSION: After reviewing findings from the available clinical studies of the combination of empagliflozin plus linagliptin, we conclude that the combination is effective, safe, tolerable, and rationale cost effective compared to placebo and either drug alone for the management of T2DM in patients with inadequate glycemic control with metformin alone, patients with intolerance to metformin, increased baseline HbA1c, patients with overweight or obesity and diabetic hypertensive, CHF, atherosclerotic cardiovascular disease, and renal dysfunction patients. Future randomized controlled trials in a larger number of T2DM patients with or without CHF and renal failure patients are recommended.

Atypical Bullous Pemphigoid After Linagliptin Intake.

BACKGROUND Bullous pemphigoid is a common pruritic skin lesion reported in elderly patients. It is caused by an immunologic reaction between autoantibodies and hemidesmosome proteins of epithelial cells. The disease is characterized by a symmetrical blister distribution on the body. Diagnosis should be suspected in elderly patients presenting with a tense blister on normal-appearing skin or on an erythematous base. In the literature, several forms of typical bullous pemphigoid after treatment with linagliptin have been reported. However, this is the first reported case of atypical nonbullous pemphigoid after linagliptin intake. CASE REPORT A 77-year-old woman presented with multiple erythematous papules and nodules on the upper extremities and trunk. The patient was being treated with linagliptin for diabetes. Diagnosis was made with biopsy and histopathological studies, followed by direct immunofluorescence. The histopathological study showed a subepidermal blister with an underlying polymorphous infiltrate, mainly of an eosinophilic profile. Direct immunofluorescence showed linear IgG and C3 antibodies to hemidesmosomes at the lamina lucida of the basement membrane. Thus, the diagnosis of atypical nonbullous pemphigoid was made. CONCLUSIONS This report emphasizes the great variety of bullous pemphigoid presentation and the need for a greater level of awareness of the adverse effects of linagliptin. Thus, atypical nonbullous pemphigoid should be considered among the potential differential diagnoses in patients with multiple erythematous papules and nodules on the upper extremities and trunk.