Linagliptin Monotherapy Research Articles

Clinicians Perspectives of Linagliptin Monotherapy and Linagliptin + Dapagliflozin Combination Therapy in the Management of Type 2 Diabetes Mellitus with Chronic Kidney Disease in Indian Settings

Objective: The objective of the study was to gather clinician’s perspectives on the use of linagliptin monotherapy and the linagliptin + dapagliflozin fixed-dose combination (FDC) in the management of patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in the Indian clinical settings. Methodology: The cross-sectional study employed a 25-item, multiple-response questionnaire to collect expert opinions from specialists experienced in managing T2DM with CKD. The survey covered topics such as current prescribing practices, clinical observations, preferences, and experiences regarding the use of linagliptin monotherapy and linagliptin + dapagliflozin FDC in routine settings. Data analysis was conducted using descriptive statistics. Results: Overall, 1848 participants were included and the majority (77%) of them preferred linagliptin as the dipeptidyl peptidase-4 inhibitor (DPP4i) of choice, while 65% observed improved estimated glomerular filtration rate (eGFR) with linagliptin in their practice. Nearly 44% of the respondents noted that 11%–25% of patients needed multiple drugs alongside metformin for glycemic control. Nearly 76% favored linagliptin when combined with dapagliflozin, and 61% preferred the dapagliflozin + linagliptin FDC for elderly diabetic patients with obesity or cardiac/renal issues. Approximately 68% of the clinicians reported a 3–6 mmHg reduction in blood pressure with dapagliflozin. About 60% of the clinicians stated the occurrence of urinary tract infections with the DPP4i and sodium–glucose co-transporter-2 inhibitor combination, and approximately 42% indicated effective synergy between dapagliflozin + linagliptin. Conclusion: The study findings indicated that linagliptin monotherapy and linagliptin + dapagliflozin FDC were preferred in managing T2DM with CKD due to their potency, minimal side effects, and efficacy. The study has also underscored the additional benefits conferred by linagliptin, including improved eGFR and reduced blood pressure.

A Randomized, Double-Blind, Parallel-Group PhaseIII Trial Investigating the Glycemic Efficacy and Safety Profile of Fixed-Dose Combination Dapagliflozin and Linagliptin Over Linagliptin Monotherapy in Patients with Inadequately Controlled Type2 Diabetes with Metformin.

The aim of the study was to evaluate the efficacy and safety of fixed-dose combination (FDC) of dapagliflozin (10mg) and linagliptin (5mg) in comparison to linagliptin 5mg (Trajenta) in patients with insufficiently controlled type2 diabetes mellitus (T2DM) on metformin monotherapy. The double-blind, randomized, multicentric, parallel-group phaseIII trial screened 287 adult patients with T2DM (age 18-65years) from 16 sites across India. The recruited subjects were undergoing metformin monotherapy ≥ 1000mg/day for at least 28days. Patients with HbA1c of 7.5-10.5% (58-91mmol/l) (n = 232) after 2weeks of run-in period with linagliptin monotherapy and placebo dapagliflozin/linagliptin on metformin monotherapy were randomized (1:1) in parallel to once daily dapagliflozin/linagliptin 10/5mg or linagliptin 5mg for 16weeks. Patients were stratified on the basis of HbA1c (≤ 9.0% and > 9.0%; ≤ 75mmol/l and > 75mmol/l)). A total of 225 subjects completed 16weeks of treatment, 115 patients in the test group and 110 patients in the reference group. Dapagliflozin/linagliptin (p = 0.0003) exhibited a greater change in HbA1c from baseline than linagliptin (p < 0.0001) in 16weeks (mean reduction, - 1.28% vs - 0.83%). Test group showed a significant decrease in fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and body weight compared to the reference group. The FDC was well tolerated with adverse events being more frequent in the reference group. No serious adverse events (SAEs) were reported in the study. Dapagliflozin/linagliptin combination is a novel dipeptidyl peptidase4 (DPP4)/sodium-glucose co-transporter2 (SGLT2) inhibitor FDC approved in India for patients with T2DM. Potential limitations of this study are a small dose of dapagliflozin (10mg) in the FDC, a short study duration (30weeks) and a high minimum threshold for HbA1c (≤ 7.5%; ≤ 53mmol/l). Results indicate the FDC to be a superior therapeutic option over linagliptin for patients with T2DM on metformin monotherapy. CTRI/2022/08/044563; 01/08/2022.

415-P: Reduction in the Risk of Peripheral Neuropathy and Preservation of Kidney Function with Metformin, Linagliptin, or Their Fixed-Dose Combination, Compared with Placebo in Prediabetes—A Randomized Controlled Trial

Objective: To compare the effect of glucose-lowering drugs plus lifestyle modification with lifestyle alone on peripheral nerve and kidney function in people with prediabetes. Methods: Multicenter, randomized, placebo-controlled trial in 658 individuals aged 45-74 years with prediabetes (IFG or IGT), were randomized to either metformin monotherapy, linagliptin monotherapy, fixed-dose combination of linagliptin/metformin or masked placebo. Main outcomes: 1-year reduction in the risk of small fiber peripheral neuropathy (SFPN) estimated by foot electrochemical skin conductance &amp;lt;70 µSiemens, measured with the SUDOSCAN® and estimated glomerular filtration rate (eGFR). Results: The percentage of people at high-risk of SFPN increased by 29.6% in the placebo group, while the increase was significantly lower in the three active-drug groups:1.8% in the metformin group, 4.3% in the linagliptin group, and 3.9% in the combination linagliptin/metformin group (p&amp;lt;0.001 for all three comparisons). eGFR remained significantly higher with the fixed-dose combination linagliptin/metformin (3.3 mL/min; 95% CI: 0.38; 6.22, p = 0.03) than with placebo. FPG was significantly lower with metformin monotherapy (-0.3 mmol/L: 95%CI: -0.48; 0.12, p=0.0009), and with the fixed-dose combination metformin/linagliptin (-0,2 mmol/L; 95% CI: -0.37; -0.03, p = 0.0219) than with placebo. Reduction in body weight was significantly greater (-2.0 kg/year, 95% CI:-5.65; -1.65, p=0.0006) with metformin monotherapy, and with the combination metformin/linagliptin (-1.9 kg/year; 95% CI: -3.02; -0.97, p=0.0002) than with placebo. Conclusion: In people with prediabetes, 1-year treatment with metformin and linagliptin, combined or in monotherapy, was associated with a lower risk of SFPN, and with a better preservation of kidney function than with placebo. Disclosure R.Gabriel: None. J.Tuomilehto: Stock/Shareholder; Orion pharma. Funding European Commission (FP7EC-GA 279074); Boehringer Ingelheim Germany (1218.166); Merck Healthcare KGaA (EMR200084_621); Instituto de Salud Carlos III (PI11/01653)

Effects of Linagliptin and Pioglitazone on Fracture Healing in an Experimental Type 2 Diabetes Rat Model.

Our study aimed to examine the effects of Linagliptin, Pioglitazone, and their combination on fracture healing in a diabetes rat femur fracture model. Type 2 diabetes mellitus (T2DM) induced rats were randomly divided into four groups: non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). Daily oral dosage of pioglitazone (10 mg/kg/day), linagliptin (10 mg/kg/day), and their combination were administered. Femur fractures were stabilized intramedullary. At weeks 2 and 6, rats were sacrificed for evaluation radiologically, biomechanically, histopathologically, histomorphometrically, and immunohistochemically. Flexural strength of the L and PL groups were significantly higher compared to the P group. The highest healing score was in the L group and lowest in the P group, while the highest inflammation score was in the P group and lowest in the L group. A cluster of differentiation (CD) CD 34 reactivity was highest in the L group and lowest in the PL group. Linagliptin treatment significantly increased histological healing scores, callus volume, biomechanical strength, and vascularity, however, minimized the inflammatory process, which was increased by pioglitazone. The combination of linagliptin and pioglitazone restored BMD and increased biomechanical strength. Linagliptin monotherapy is rarely indicated; hence, T2DM patients with a high risk of bone fractures can be considered for combined therapy of pioglitazone and linagliptin.

Long-term efficacy and safety of anti-hyperglycaemic agents in new-onset diabetes after transplant: Results from outpatient-based 1-year follow-up and a brief review of treatment options

Background and aimsEvaluation of long-term efficacy and safety of various anti-hyperglycaemic agents (AHA) for glycaemic control in NODAT, in stable kidney transplant recipients (KTRs) during 1-year outpatient follow-up. MethodsWe collected FPG, PPG, HbA1c, serum creatinine, eGFR, blood tacrolimus level, hypoglycaemia and body weight values from an existing database of KTRs diagnosed to have NODAT. Those newly initiated on AHA over 3 months post-transplant; received standard triple immunosuppressive therapy; and followed up for 1-year after referral, were included. ResultsIn ninety-five patients’ (Male = 65), mean decrease at 1-year from baseline in FPG (185.01 ± 62.11 mg/dL), PPG (293.21 ± 85.23 mg/dL) and HbA1c (8.48 ± 1.08%) was 67.09, 126.11 and 1.4 respectively (p < 0.0001). At 1-year, mean HbA1c was 7.08 ± 0.38%, ninety-one patients achieving HbA1c ≤ 7.5%. Fifty-two patients received oral combination therapy based on linagliptin/metformin/repaglinide/gliclazide, 19 received insulin-based regimen, and 24 received linagliptin monotharapey. Thirty patients reported hypoglycaemia (10 with gliclazide and 15 with insulin) and fifty patients gained body-weight at 1-year. Mean serum creatinine and eGFR significantly improved by 0.29 and 15.77 from baseline of 1.56 ± 0.62 mg/dL and 53.95 ± 16.10 mL/min/1.73 m2 respectively. ConclusionsSignificant proportion of NODAT patients achieved long-term glycemic control with improved renal function. Combination therapy was needed in most within 1-year. Linagliptin monotherapy was effective, without producing hypoglycaemia or weight gain.

Safety and tolerability of empagliflozin and linagliptin combination therapy in patients with type 2 diabetes mellitus: a pooled analysis of data from five randomized, controlled clinical trials

ABSTRACT Objectives The fixed-dose combination of empagliflozin and linagliptin, two glucose-lowering drugs prescribed for type 2 diabetes mellitus, has demonstrated good tolerability in phase III clinical trials. To further evaluate the safety profile of this combination, the data from these trials were pooled and analyzed. Methods This was a post-hoc pooled analysis of five randomized, double-blind, clinical trials of the empagliflozin/linagliptin fixed-dose combination. Data for adverse events and laboratory parameters were evaluated. Results The analysis included 2895 patients: 1410, 1015, and 470 receiving the empagliflozin/linagliptin combination, empagliflozin monotherapy, and linagliptin monotherapy, respectively. Overall, the incidence of adverse events with the empagliflozin/linagliptin combination was similar to that with empagliflozin or linagliptin alone. Fewer than 2% of patients experienced hypoglycemia, and its incidence was similar across treatment groups. Genital infections occurred in more patients receiving empagliflozin/linagliptin (3.0%) or empagliflozin monotherapy (5.1%) than in those receiving linagliptin monotherapy (1.9%). No cases of Fournier’s gangrene, diabetic ketoacidosis, or pemphigoid occurred, and no clinically relevant mean changes in laboratory parameters were noted. Conclusion The safety profile of the fixed-dose combination of empagliflozin and linagliptin was similar to the individual monotherapies. No new safety signals were identified.

Fixed-dose combination of empagliflozin and linagliptin for the treatment of patients with type 2 diabetes mellitus: A systematic review and meta-analysis.

The present meta-analysis evaluated the efficacy and safety of empagliflozin + linagliptin combination compared with either monotherapy [n=6 randomized controlled trials; 2857 adults with type 2 diabetes (T2DM) on diet + exercise ± metformin; 39.7% women; mean age: 54.6-59.9 years]. The combination of empagliflozin 10 mg + linagliptin 5 mg led to significantly greater reductions in glycated haemoglobin (HbA1c) compared with either drug alone over 24 weeks: weighted mean difference [WMD; -0.72%, 95% confidence interval (CI): -1.04, -0.40], and fasting plasma glucose (-1.60 mmol/L 95% CI: -2.21, -1.00). Similar results were observed when empagliflozin 25 mg + linagliptin 5 mg was compared with linagliptin 5 mg monotherapy or with empagliflozin 10 or 25 mg monotherapy. Patients with T2DM treated with the drug combination had more than three times higher likelihood of achieving HbA1c <7% than those on either monotherapy. Weight reduction was significantly greater in the combination group only when compared with linagliptin monotherapy. Safety profile was similar between combination treatment and monotherapies. Overall, the empagliflozin + linagliptin combination had superior efficacy and similar safety in achieving euglycaemia compared with either monotherapy. This combination, administered once daily, has the potential to reduce regimen complexity, enhance adherence and improve outcomes in clinical practice.

Long-Term Safety and Effectiveness of Linagliptin in Japanese Patients with Type 2 Diabetes Mellitus: A 3-Year Post-Marketing Surveillance Study.

IntroductionClinical trials of linagliptin in Japanese patients conducted to date have had limited observational periods; therefore, there is a need for additional longer-term real-world data. The aim of this study was to investigate the long-term safety and effectiveness of linagliptin in routine clinical practice.MethodsThis was a prospective, observational, post-marketing surveillance study conducted over 156 weeks in patients with type 2 diabetes mellitus who started linagliptin monotherapy. The primary endpoint was the incidence of adverse drug reactions (ADRs). The secondary endpoint was the change in glycated hemoglobin (HbA1c) from baseline to last available observation. Other effectiveness endpoints included the change in HbA1c and change in fasting plasma glucose (FPG) from baseline to week 26 and over the course of the treatment period.ResultsOverall, 2235 and 2054 patients were included in the safety and effectiveness analysis sets, respectively. Patients were mostly male (58.4%), and the mean age was 66.7 years. The incidence of ADRs was 10.7% (n = 240). The most frequent ADRs according to MedDRA preferred terms were diabetes mellitus (n = 35 patients, 1.6%), constipation (n = 21, 0.9%), diabetes mellitus inadequate control (n = 13, 0.6%) and hypertension (n = 13, 0.6%). The mean change in HbA1c from baseline to last observation was − 0.67% [standard deviation (SD) 1.27%, 95% confidence interval − 0.72, − 0.61]. At week 26, HbA1c and FPG showed mean ± SD changes from baseline of – 0.73 ± 1.20% and − 21.02 ± 44.33 mg/dL, respectively, that were sustained until week 156.ConclusionsIn Japanese patients with type 2 diabetes mellitus, linagliptin produced sustained reductions in HbA1c and had a safety profile consistent with the established safety profile of linagliptin.Trial RegistrationClinicalTrials.gov (NCT01650259).Electronic supplementary materialThe online version of this article (10.1007/s13300-019-00723-x) contains supplementary material, which is available to authorized users.

Preferential prescribing of linagliptin in type2 diabetes patients in an expanded post-marketing surveillance study in Japan.

Aims/IntroductionTo evaluate linagliptin prescribing in type 2 diabetes mellitus patients with different comorbidities, an expanded Japanese post‐marketing surveillance also collected baseline data for patients initiating other glucose‐lowering drugs.Materials and MethodsPatients initiating linagliptin monotherapy were enrolled, then the next patient starting monotherapy with another glucose‐lowering drug was enrolled (2012–2014). Baseline data were collected and analyzed by the Medical Dictionary for Regulatory Activities system organ class. Analyses were descriptive, and meaningful differences defined as absolute standardized difference >10%.ResultsOver 4,200 type 2 diabetes mellitus patients were enrolled. Most system‐organ class comorbidities were more common in patients initiating linagliptin versus other glucose‐lowering drugs, with meaningful differences observed for metabolism/nutritional (50.5 vs 45.5%, respectively), cardiac (12.2 vs 8.6%, respectively), vascular (56.4 vs 51.3%, respectively) and renal/urinary disorders (9.9 vs 5.7%, respectively).ConclusionsExpanding the linagliptin Japanese post‐marketing surveillance revealed linagliptin prescribing to a type 2 diabetes mellitus population with more comorbidities versus other glucose‐lowering drugs. Although such preferential prescribing might be expected, as linagliptin requires no dose adjustment or monitoring in renally or hepatically impaired patients, this innovative post‐marketing surveillance approach generated important evidence that could only be shown in such a non‐randomized comparative study. These data generated insights important for the design and interpretation of observational studies and spontaneous reports, which are key for public health.

Combination Linagliptin and Empagliflozin Therapy Improves Diastolic Function in Female Diabetic db/db Mice

We recently reported that linagliptin (LINA) and empagliflozin (EMPA) monotherapies exhibit favorable effects in the heart, vasculature and kidneys in murine models of prediabetes and diabetes. Herein, we extend those studies by testing whether these two drugs used in combination improve diastolic function in diabetic female db/db mice. Eleven week old db/db mice were fed a diet containing LINA (2mg/kg/day) or EMPA (10mg/kg/day) monotherapy for 10 weeks (dbE10, dbL10). Additional groups received add-on therapy after 5 weeks on monotherapy (LINA added to EMPA (dbE10/L5) or EMPA added to LINA (dbL10/E5)). One group received LINA and EMPA combination therapy for the entire 10 week test period (dbL10/E10). One group was untreated (DbC). Glycemia, cardiac function, fibrosis and hypertrophy were examined by HbA1c, tissue Doppler ultrasound and histology. With the exception of LINA monotherapy, HbA1c was reduced in all other treated groups (p&amp;lt;0.05). Compared to lean mice on background strain (CkC), myocardial wall motion during diastole was impaired in untreated db/db mice, indicated by increased E/E’ ratio (LV filling pressure), and this was improved with mono- and add-on therapies. Myocardial fibrosis and hypertrophy were improved with mono- and add-on therapies. In summary, the combination of LINA and EMPA appeared to be as cardioprotective as monotherapies of each drug.# weeks on E or LType of therapyDiastolic FunctionGlycemiaCardiac RemodelingE, EMPA L, LINAE/E’ RatioHbA1c %Intersititial Fibrosis (AGSI)Cardiomyocyte cross sectional area (μm2)CkCuntreated18 ± 34.3 ± 0.2---368 ± 33DbCuntreated56 ± 3*11.0 ±0.6*4.9 ± 0.6533 ± 34†db E10mono38 ± 3*†5.9±0.2*†2.8 ± 0.2†433 ± 15†dbL10mono36 ± 2*†10.8±0.5*2.8 ± 0.2†411 ± 11†dbE10/L5L added to E35 ± 4*†6.5±0.2*†3.2 ± 0.2†421 ± 26†dbL10/E5E added to L34 ± 2*†6.9±0.3*†2.8 ± 0.1†358 ±12†dbL10/E10combo44 ± 6*†6.1±0.2*†3.2 ± 0.1†430 ± 21†*p&amp;lt;0.vs CkC †p&amp;lt;0.vs DbC Disclosure J. Habibi: None. A.R. Aroor: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. E. Mayoux: None. V. DeMarco: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc..

Effects of linagliptin monotherapy compared with voglibose on postprandial lipid profiles in Japanese patients with type 2 diabetes: linagliptin study of effects on postprandial blood glucose (L-STEP) sub-study 1.

Recently, we reported that linagliptin had equivalent efficacy to voglibose in reducing postprandial blood glucose levels in drug-naïve patients with type 2 diabetes (L-STEP Study). As a sub-study of the L-STEP Study we examined the effect of linagliptin on postprandial lipids profile. Between October 2012 and April 2014, the study enrolled patients with type 2 diabetes mellitus who had inadequate glycemic control. Patients were randomly assigned to either the linagliptin group (5 mg once daily, n = 85) or the voglibose group (0.2 mg/meal thrice daily, n = 71). Meal tolerance tests were performed at baseline (week 0) and endpoint (week 12). The increments in 4-h postprandial triglyceride, remnant lipoprotein cholesterol (RLP-C), and apolipoprotein B48 (ApoB48) from baseline to endpoint in the linagliptin group were lower (p < 0.001, p = 0.025 and p < 0.001). 4-h postprandial ApoB48 at endpoint was lower in the linagliptin group (p = 0.007), and positive correlation was detected between change of ApoB48 and changes in both triglyceride (r = 0.67, p < 0.001) and RLP-C (r = 0.73, p < 0.001) at 4 h. This study revealed that in drug-naïve Japanese patients with relatively mild type 2 diabetes mellitus, linagliptin improves not only postprandial blood glucose level but also levels of lipids such as TG and RLP-C by reducing the ApoB48 level compared with voglibose.

Oral glucose lowering with linagliptin and metformin compared with linagliptin alone as initial treatment in Asian patients with newly diagnosed type 2 diabetes and marked hyperglycemia: Subgroup analysis of a randomized clinical trial.

Aims/IntroductionType 2 diabetes mellitus is an epidemic in Asia, yet clinical trials of glucose‐lowering therapies often enroll predominantly Western populations. We explored the initial combination of metformin and linagliptin, a dipeptidyl peptidase‐4 inhibitor, in newly diagnosed type 2 diabetes mellitus patients in Asia with marked hyperglycemia.Materials and MethodsThis was a post‐hoc subgroup analysis of a multinational, parallel‐group clinical trial in which 316 newly diagnosed type 2 diabetes mellitus patients with glycated hemoglobin A1c (HbA1c) 8.5–12.0% were randomized to double‐blind oral treatment with linagliptin/metformin or linagliptin monotherapy. The primary end‐point was the change from baseline in HbA1c at week 24. We evaluated data for the 125 participants from Asian countries.ResultsAfter 24 weeks, the mean ± standard error reduction from baseline in HbA1c (mean 10.0%) was −2.99 ± 0.18% with linagliptin/metformin and −1.84 ± 0.18% with linagliptin; a treatment difference of −1.15% (95% confidence interval −1.65 to −0.66, P < 0.0001). HbA1c <7.0% was achieved by 60% of participants receiving linagliptin/metformin. The mean bodyweight change after 24 weeks was −0.45 ± 0.41 kg and 1.33 ± 0.45 kg in the linagliptin/metformin and linagliptin groups, respectively (treatment difference −1.78 kg [95% confidence interval −2.99 to −0.57, P = 0.0043]). Drug‐related adverse events occurred in 9.7% of participants receiving linagliptin/metformin and 4.8% of those receiving linagliptin. Hypoglycemia occurred in 6.5% and 4.8% of the linagliptin/metformin and linagliptin groups, respectively, with no severe episodes. Gastrointestinal disorders occurred in 12.9% and 12.7% of the linagliptin/metformin and linagliptin groups, respectively, with no associated treatment discontinuations.ConclusionsIn people from Asia with newly diagnosed type 2 diabetes mellitus and marked hyperglycemia, the initial combination of linagliptin and metformin substantially improved glycemic control without weight gain and with infrequent hypoglycemia. Initial oral combination therapy might be a viable treatment for such individuals.

Linagliptin plus metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycemia

ABSTRACTObjectives: Few studies of oral glucose-lowering drugs exist in newly diagnosed type 2 diabetes (T2D) patients with marked hyperglycemia, and insulin is often proposed as initial treatment. We evaluated the oral initial combination of metformin and linagliptin, a dipeptidyl peptidase-4 inhibitor, in this population.Methods: We performed a pre-specified subgroup analysis of a randomized study in which newly diagnosed T2D patients with glycated hemoglobin A1c (HbA1c) 8.5%–12.0% received linagliptin/metformin or linagliptin monotherapy. Subgroups of baseline HbA1c, age, body-mass index (BMI), renal function, race, and ethnicity were evaluated, with efficacy measured by HbA1c change from baseline after 24 weeks.Results: HbA1c reductions from baseline (mean 9.7%) at week 24 in the overall population were an adjusted mean −2.81% ± 0.12% with linagliptin/metformin (n = 132) and −2.02% ± 0.13% with linagliptin (n = 113); treatment difference −0.79% (95% CI −1.13 to −0.46, P < 0.0001). In patients with baseline HbA1c ≥9.5%, HbA1c reduction was −3.37% with linagliptin/metformin (n = 76) and −2.53% with linagliptin (n = 61); difference −0.84% (95% CI −1.32 to −0.35). In those with baseline HbA1c <9.5%, HbA1c reduction was −2.08% with linagliptin/metformin (n = 56) and −1.39% with linagliptin (n = 52); difference −0.69% (95% CI −1.23 to −0.15). Changes in HbA1c and treatment differences between the linagliptin/metformin and linagliptin groups were of similar magnitudes to the overall population across patient subgroups based on age, BMI, renal function, and race. Drug-related adverse events occurred in 8.8% and 5.7% of linagliptin/metformin and linagliptin patients, respectively; no severe hypoglycemia occurred.Conclusion: Linagliptin/metformin combination in newly diagnosed T2D patients with marked hyperglycemia was well tolerated and elicited substantial improvements in glycemic control regardless of baseline HbA1c, age, BMI, renal function, or race. Thus, newly diagnosed, markedly hyperglycemic patients may be effectively treated by combinations of oral agents.Clinical trial registration: www.clinicaltrials.gov identifier is NCT01512979

Effects of linagliptin monotherapy compared with voglibose on postprandial blood glucose responses in Japanese patients with type 2 diabetes: Linagliptin Study of Effects on Postprandial blood glucose (L-STEP)

AimsTo compare the efficacy on glycemic parameters between a 12-week administration of once-daily linagliptin and thrice-daily voglibose in Japanese patients with type 2 diabetes. MethodsIn a multi-center, randomized, parallel-group study, 382 patients with diabetes were randomized to the linagliptin group (n=192) or the voglibose group (n=190). A meal tolerance test was performed at weeks 0 and 12. Primary outcomes were the change from baseline to week 12 in serum glucose levels at 2h during the meal tolerance test, HbA1c levels, and serum fasting glucose levels, which were compared between the 2 groups. ResultsWhereas changes in serum glucose levels at 2h during the meal tolerance test did not differ between the groups, the mean change in HbA1c levels from baseline to week 12 in the linagliptin group (−0.5±0.5% [−5.1±5.4mmol/mol]) was significantly larger than in the voglibose group (−0.2±0.5% [−2.7±5.4mmol/mol]). In addition, there was significant difference in changes in serum fasting glucose levels (−0.51±0.95mmol/L in the linagliptin group vs. −0.18±0.92mmol/L in the voglibose group, P<0.001). The incidences of hypoglycemia, serious adverse events (AEs), and discontinuations due to AEs were low and similar in both groups. However, gastrointestinal AEs were significantly lower in the linagliptin group (1.05% vs. 5.85%; P=0.01). ConclusionsThese data suggested that linagliptin monotherapy had a stronger glucose-lowering effect than voglibose monotherapy with respect to HbA1c and serum fasting glucose levels, but not serum glucose levels 2h after the start of the meal tolerance test.

Linagliptin monotherapy compared with voglibose monotherapy in patients with type 2 diabetes undergoing hemodialysis: a 12-week randomized trial

ObjectiveFocusing on efficacy and tolerability, we compared linagliptin monotherapy with voglibose monotherapy in patients with type 2 diabetes undergoing hemodialysis (HD).Research design and methodsIn this multicenter, randomized, open-label, parallel-group, active-controlled...

Comparable pharmacodynamics, efficacy, and safety of linagliptin 5 mg among Japanese, Asian and white patients with type 2 diabetes.

Aims/IntroductionThe efficacy and safety of drugs can vary between different races or ethnic populations because of differences in the relationship of dose to exposure, pharmacodynamic response or clinical efficacy and safety. In the present post‐hoc analysis, we assessed the influence of race on the pharmacokinetics, pharmacodynamics, efficacy and safety of monotherapy with the dipeptidyl peptidase‐4 inhibitor, linagliptin, in patients with type 2 diabetes enrolled in two comparable, previously reported randomized phase III trials.Materials and MethodsStudy 1 (with a 12‐week placebo‐controlled phase) recruited Japanese patients only (linagliptin, n = 159; placebo, n = 80); study 2 (24‐week trial) enrolled Asian (non‐Japanese; linagliptin, n = 156; placebo, n = 76) and white patients (linagliptin, n = 180; placebo, n = 90).ResultsLinagliptin trough concentrations were equivalent across study and race groups, and were higher than half‐maximal inhibitory concentration, resulting in dipeptidyl peptidase‐4 inhibition >80% at trough. Linagliptin inhibited plasma dipeptidyl peptidase‐4 activity to a similar degree in study 1 and study 2. Linagliptin reduced fasting plasma glucose concentrations by a similar magnitude across groups, leading to clinically relevant reductions in glycated hemoglobin in all groups. Glycated hemoglobin levels decreased to a slightly greater extent in study 1 (Japanese) and in Asian (non‐Japanese) patients from study 2. Linagliptin had a favorable safety profile in each race group.ConclusionsTrough exposure, pharmacodynamic response, and efficacy and safety of linagliptin monotherapy were comparable among Japanese, Asian (non‐Japanese) and white patients, confirming that the recommended 5‐mg once‐daily dose of linagliptin is appropriate for use among different race groups.

Pleiotropic Effects of Linagliptin Monotherapy on Levels of Nitric Oxide, Nitric Oxide Synthase, and Superoxide Dismutase in Hemodialysis Patients with Diabetes

Pleiotropic Effects of Linagliptin Monotherapy on Levels of Nitric Oxide, Nitric Oxide Synthase, and Superoxide Dismutase in Hemodialysis Patients with Diabetes

The SGLT2 inhibitor empagliflozin improves insulin sensitivity in db/db mice both as monotherapy and in combination with linagliptin

AimsCombining different drug classes to improve glycemic control is one treatment strategy for type 2 diabetes. The effects on insulin sensitivity of long-term treatment with the sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin alone or co-administered with the dipeptidyl peptidase-4 inhibitor linagliptin (both approved antidiabetes drugs) were investigated in mice using euglycemic–hyperinsulinemic clamps. Materials and Methodsdb/db mice (n=15/group) were treated for 8weeks with 10mg/kg/day empagliflozin monotherapy, 10mg/kg/day empagliflozin plus 3mg/kg/day linagliptin combination therapy, or 3mg/kg/day linagliptin monotherapy. At the end of the study, euglycemic–hyperinsulinemic clamp studies were performed 4days after the last dose of treatment. ResultsHbA1c and 2-hour fasting glucose concentrations were improved with empagliflozin monotherapy and combination therapy compared with vehicle and linagliptin monotherapy. During the clamp, glucose disposal rates increased and hepatic glucose production decreased with empagliflozin monotherapy and combination therapy compared with vehicle and linagliptin monotherapy. Glucose uptake in liver and kidney was higher with empagliflozin monotherapy and combination therapy compared with vehicle; glucose uptake into both muscle and adipose tissue was only affected by linagliptin treatment. Empagliflozin and combination therapy altered the expression of genes involved in the inflammatory response, fatty acid synthesis and oxidation. ConclusionsThese findings suggest that the insulin-sensitizing effects of SGLT2 inhibition contribute to improvements in glycemic control in insulin-resistant states.

Efficacy and safety of linagliptin monotherapy in Asian patients with inadequately controlled type2 diabetes mellitus: A multinational, 24-week, randomized, clinical trial.

Aims/IntroductionAsian patients represent a large portion of the global population with type 2 diabetes mellitus, but are underrepresented in trials of glucose-lowering therapies. The present randomized, phase III, placebo-controlled, double-blind, 24-week study evaluated the dipeptidyl peptidase-4 inhibitor, linagliptin, as monotherapy in Asian patients with inadequately controlled type 2 diabetes mellitus.Materials and MethodsPatients who were treatment naïve or had been treated with one oral antidiabetes drug were randomized to either linagliptin 5 mg daily or a placebo after washout. The primary end-point was a change from baseline in glycated hemoglobin after 24 weeks.ResultsA total of 300 Asian (87% Chinese) patients with type 2 diabetes mellitus were randomized to linagliptin or placebo at a 2:1 ratio. After 24 weeks of treatment, adjusted mean (standard error) glycated hemoglobin decreased by a placebo-corrected −0.50 ± 0.11 (P < 0.0001). In patients with baseline glycated hemoglobin ≥8.5%, the placebo-corrected decrease in glycated hemoglobin was −0.91 ± 0.20% (P < 0.0001). Adverse events occurred in 28.0 and 28.3% of linagliptin and placebo patients, respectively, but few were drug-related (3.0 and 2.0%, respectively). Hypoglycemia was reported by one linagliptin patient and no placebo patients. Treatment with linagliptin was weight neutral.ConclusionsIn Asian patients with inadequately controlled type 2 diabetes mellitus, linagliptin 5 mg as monotherapy was efficacious and well tolerated over 24 weeks.

Anti‐inflammatory effects of linagliptin in hemodialysis patients with diabetes

Inflammation and glycemic control are important prognosis-related factors for hemodialysis (HD) patients; moreover, inflammation affects insulin secretion. Here, we evaluated the anti-inflammatory effects of monotherapy with linagliptin-a dipeptidase-4 inhibitor-in HD patients with type 2 diabetes. We examined 21 diabetic HD patients who were not receiving oral diabetes drugs or insulin therapy and with poor glycemic control (glycated albumin [GA] level, >20%). Linagliptin (5 mg) was administered to the patients daily. The levels of prostaglandin E2 (PGE2), interleukin-6 (IL-6), high-sensitivity C-reactive protein, GA, blood glucose, and active glucagon-like peptide-1 were determined before and 6 months after treatment. Body weight and serum levels of albumin, hemoglobin, total cholesterol, and low-density lipoprotein cholesterol were also recorded before and after treatment. The levels of PGE2 and GA were significantly decreased 1 month after starting linagliptin therapy, whereas the IL-6 levels were significantly decreased 6 months after starting linagliptin therapy. After 6 months of treatment, the PGE2 levels decreased from 188 ± 50 ng/mL to 26 ± 5 ng/mL; IL-6 levels, from 1.5 ± 0.4 pg/mL to 0.6 ± 0.1 pg/mL; and GA levels, from 21.3% ± 0.6% to 18.0% ± 0.6%. Glucagon-like peptide-1 levels increased 2.5-fold during the treatment. Over the 6-month treatment period, body weight and levels of high-sensitivity C-reactive protein, blood glucose, albumin, hemoglobin, and cholesterol did not change; none of the patients exhibited hypoglycemia. The anti-inflammatory effects of linagliptin monotherapy indicate that it may serve as a useful glucose control strategy for HD patients with diabetes.