Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin(*)

Aim: This study assessed the influence of various degrees of renal impairment on the exposure of linagliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor with a primarily non‐renal route of excretion, in subjects with type 2 diabetes mellitus (T2DM). Methods: Linagliptin pharmacokinetics was studied under single‐dose and steady‐state conditions in subjects with mild, moderate and severe renal impairment (with and without T2DM) and end‐stage renal disease and compared with the pharmacokinetics in subjects with normal renal function (with and without T2DM). Results: Renal excretion of unchanged linagliptin was <7% in all groups. Under single‐dose conditions, the degree of renal impairment did not affect mean plasma linagliptin concentration–time profiles. These showed a similar decline and almost identical plasma concentrations 24 h postdosing in subjects with mild, moderate or severe renal impairment and in subjects with T2DM with and without renal impairment. Although there was a tendency towards slightly higher (20–60%) exposure in renally impaired subjects (with and without T2DM) compared with subjects with normal renal function, the steady‐state AUC and C_max values showed a large overlap and were not affected by the degree of renal impairment. The accumulation half‐life of linagliptin ranged from 14–15 h in subjects with normal renal function to 18 h in severe renal impairment. Only a weak correlation (r² = 0.18) was seen between creatinine clearance and steady‐state exposure. Conclusions: Renal impairment has only a minor effect on linagliptin pharmacokinetics. Consequently, there will be no need for adjusting the linagliptin dose in renally impaired patients with T2DM.     

Linagliptin: the newest dipeptidyl peptidase-4 inhibitor for type 2 diabetes mellitus

Dipeptidyl peptidase-4 (DPP-4) inhibitors are some of the newest medications in our armamentarium for the management of type 2 diabetes mellitus. Through inhibition of the DPP-4 enzyme, these agents increase the amount of circulating incretin hormones, leading to an increase in insulin release and a suppression of glucagon secretion. Linagliptin is the third DPP-4 inhibitor approved by the Food and Drug Administration in the United States. It has been studied as monotherapy and as an adjunctive therapy to other oral agents in a dual or triple combination regimen. Linagliptin lowers glycosylated hemoglobin by about 0.4% when used as monotherapy and by about 0.5% to 1.1% when used in combination with other oral antihyperglycemic agents. Since linagliptin is mostly eliminated via the enterohepatic system (80%) and not to a significant extent through renal excretion, dosage adjustment is not necessary in patients with renal impairment. Linagliptin also has a favorable safety profile; nasopharyngitis is one of the more common observed side effects. Given its encouraging safety and efficacy profile, linagliptin is a good alternative to the other 2 agents in this class, especially for patients with renal impairment. This article provides a review of the pharmacologic and pharmacokinetic properties of linagliptin. The differences among the 3 available DPP-4 inhibitors will also be examined.     

The oral DPP-4 inhibitor linagliptin significantly lowers HbA1c after 4 weeks of treatment in patients with type 2 diabetes mellitus

Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of linagliptin in patients with type 2 diabetes mellitus (T2DM). Methods: After screening and a 14‐day washout, subjects received linagliptin 2.5, 5 or 10 mg or placebo once‐daily for 28 days in this randomized, double‐blind, parallel, placebo‐controlled within‐dose groups study. Results: Seventy‐seven patients entered the study (linagliptin: 61; placebo: 16). Four patients withdrew prematurely. There was little evidence of linagliptin accumulation. Exposure, maximum and trough plasma concentrations of linagliptin increased less than dose‐proportionally. Rapid and sustained inhibition of dipeptidyl peptidase‐4 reached 91–93% across linagliptin doses at steady state. At the end of the 24‐h dosing interval, inhibition was still high (82–90%). There were marked increases in plasma glucagon‐like peptide‐1 after 28 days of dosing. Compared to placebo, all linagliptin doses resulted in statistically significant decreases of the area under the glucose curve following a meal tolerance test on day 29, that is, 24 h after the last study drug intake. After 28 days of treatment with linagliptin the placebo‐corrected mean change in haemoglobin A1c (HbA1c) (median baseline 7.0%) was ?0.31% (2.5‐mg dose), ?0.37% (5‐mg dose) and ?0.28% (10‐mg dose). The frequency of adverse events was similar for linagliptin (31%) and placebo (34%). There were no notable safety concerns. Conclusions: Linagliptin administration led to attenuation of postprandial glucose excursions and, despite a low HbA1c at baseline, statistically significant reductions in HbA1c after only 4 weeks of treatment. Linagliptin had a safety and tolerability profile similar to placebo in T2DM patients.     

Linagliptin: a novel xanthine-based dipeptidyl peptidase-4 inhibitor for treatment of type II diabetes mellitus

Type 2 diabetes mellitus causes significant morbidity and mortality on account of its progressive nature and results in considerable burden on healthcare resources. Current treatment strategies have only limited long-term efficacy and tolerability given the progressive nature of the disease leading to inadequate glycemic control and are also associated with undesirable side effects such as weight gain, hypoglycemia and gastrointestinal distress. In the light of these existing limitations, exploring new treatment targets and new therapies have become the need of the hour at present. The incretin pathway, in particular, glucagon-like peptide (GLP-1), plays an important pathological role in the development of type 2 diabetes mellitus, and treatments targeting the incretin system have recently generated surmount interest. These can mainly be categorized into two broad classes; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase- 4 inhibitors (sitagliptin, vildagliptin). The gliptins act by prolonging the action of incretins, the gut hormones which can boost insulin levels. Linagliptin is the latest dipeptidyl peptidase-4 inhibitor to complete pivotal phase III trials, which have demonstrated its superiority to its competitors based on its low therapeutic dose, long-lasting inhibition of DPP-4 activity and a good safety/tolerability profile. One of the unique characteristics of linagliptin is its primarily non-renal route of excretion. The drug has recently been approved by the US Food and Drug Administration and has been portrayed as a promising treatment option for patients in whom metformin and the other DPP-4 inhibitors are either contraindicated or require dose adjustment because of moderate to severe renal impairment.     

Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients

Aims:  To investigate the safety, tolerability, pharmacokinetic and pharmacodynamic properties of multiple oral doses of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (BI 1356) in patients with type 2 diabetes mellitus.
Methods:  Forty-seven male type 2 diabetic patients received linagliptin 1, 2.5, 5 or 10 mg, or placebo, once daily for 12 days.
Results:  Linagliptin exposure [area under the plasma concentration–time curve and maximum plasma concentration ( C _max)] increased less than proportionally with dose. Accumulation half-life was short (8.6–23.9 h), resulting in rapid attainment of steady state (2–5 days) and little accumulation (range: 1.18–2.03). The long terminal half-life (113–131 h) led to a sustained inhibition of DPP-4 activity. Renal excretion was below 1% on day 1 in all dose groups. Inhibition of plasma DPP-4 activity correlated well with linagliptin plasma concentrations, resulting in DPP-4 inhibition >90% in the two highest dose groups; even 24 h postdose, DPP-4 inhibition was >80%. Following an oral glucose tolerance test, 24 h after the last dose, statistically significant reductions of glucose excursions were observed with linagliptin (2.5, 5 and 10 mg doses) compared with placebo. Linagliptin was well tolerated. The frequency of adverse events (AEs) was not higher with linagliptin (54%) than with placebo (75%). No serious AEs and no episodes of hypoglycaemia were reported.
Conclusions:  In type 2 diabetic patients, multiple rising doses of linagliptin were well tolerated and resulted in significant improvements of glucose parameters. Together with the favourable pharmacokinetics, these results confirm the unique profile of linagliptin in the DPP-4 inhibitor class.     

The effect of linagliptin on glycaemic control and tolerability in patients with type 2 diabetes mellitus: a systematic review and meta-analysis

Aim: Linagliptin is a new dipeptidyl peptidase‐4 inhibitor recently approved for use in the USA. The objective of this systematic review and meta‐analysis was to assess effect of linagliptin on glycaemic control, biomarkers and incidence of adverse events (AEs) in patients with type 2 diabetes mellitus. Methods: Five published and four unpublished randomized, clinical trials were identified from multiple databases. Qualitative assessments and quantitative analyses were performed. Results: Nine studies included 4246 participants with 53% men, 59.4% Caucasians, 38.7% Asians, and age range 45–69 years. Linagliptin was given as monotherapy (vs. placebo) or combined with metformin (vs. metformin + placebo), sulphonylurea (vs. sulphonylurea + placebo) or pioglitazone (vs. pioglitazone + placebo). Linagliptin 5 mg/day for 12–24 weeks, significantly reduced haemoglobin A1c (HbA1c) (?0.63%, p < 0.00001), fasting plasma glucose (FPG) (?1.01 mmol/l, p < 0.00001) and improved disposition index (DI, product of insulin sensitivity and acute insulin secretion) (p = 0.0001). Linagliptin monotherapy was not more effective than metformin at reducing HbA1c or FPG. Similar proportion of patients in linagliptin and placebo groups reported AEs including upper respiratory tract infections, headaches, nausea, hypertension and back pain. Conclusions: Linagliptin was associated with modest but significant reduction in HbA1c and FPG and improved DI after 12–24 weeks. Patients who would probably benefit most are those with HbA1c <9%, already on an active agent, compliant with weight reduction strategies, and can recognize and manage hypoglycaemia, fluid retention and upper respiratory tract infections. Long‐term studies are needed to determine durability of response, incidence of microvascular and macrovacular complications, cost‐effectiveness and safety.     

Dipeptidyl peptidase‐4 inhibitors: pharmacokinetics,efficacy, tolerability and safety in renal impairment

The dipeptidyl peptidase‐4 (DPP‐4) inhibitors are a new class of blood glucose‐lowering therapy with proven efficacy, tolerability and safety. Four of the five commercially available DPP‐4 inhibitors are subject to significant renal clearance, and pharmacokinetic studies in people with renal impairment have led to lower recommended doses based on creatinine clearance in order to prevent drug accumulation. Data from these pharmacokinetic studies and from supratherapeutic doses in healthy individuals and people with uncomplicated diabetes during development suggest, however, that there is a wide therapeutic margin. This should protect against toxicity if people with renal impairment are inadvertently prescribed higher doses than recommended. Doses appropriate to renal function are associated with reductions in HbA1c that are equivalent to those observed in people with type 2 diabetes who do not have renal impairment. Recent large‐scale cardiovascular safety trials of saxagliptin and alogliptin have identified heart failure as a potential concern and renal impairment may increase the risk of this complication. Although the incidence of pancreatitis does not appear to be significantly increased by DPP‐4 inhibitor therapy, renal impairment is also an independent risk factor. Additional data from other ongoing DPP‐4 inhibitor cardiovascular safety trials should provide a more precise assessment of the risks of these uncommon complications, including in people with renal impairment.     

Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial

Aim: To assess the safety and efficacy of the potent and selective dipeptidyl peptidase‐4 inhibitor linagliptin 5 mg when given for 24 weeks to patients with type 2 diabetes who were either treatment‐naive or who had received one oral antidiabetes drug (OAD). Methods: This multicentre, randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336) with placebo (n = 167) for 24 weeks in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 weeks, which included a placebo run‐in period during the last 2 weeks. Patients previously untreated with an OAD underwent a 2‐week placebo run‐in period. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment. Results: Linagliptin treatment resulted in a placebo‐corrected change in HbA1c from baseline of ?0.69% (p < 0.0001) at 24 weeks. In patients with baseline HbA1c ≥ 9.0%, the adjusted reduction in HbA1c was 1.01% (p < 0.0001). Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of ≥0.5% at 24 weeks than those in the placebo arm (47.1 and 19.0%, respectively; odds ratio, OR = 4.2, p < 0.0001). Fasting plasma glucose improved by ?1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2‐h postprandial glucose of ?3.2 mmol/l (p < 0.0001). Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio (p = 0.025), Homeostasis Model Assessment‐%B (p = 0.049) and disposition index (p = 0.0005). There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third‐party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin. Conclusions: Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control, accompanied by enhanced parameters of β‐cell function. The safety profile of linagliptin was comparable with that of placebo.     

The effect of linagliptin on renal progression in type-2 diabetes mellitus patients with chronic kidney disease: A prospective randomized controlled study

BackgroundLinagliptin does not require dose adjustment in diabetes mellitus patients with chronic kidney disease (CKD). But, renal effects of linagliptin are not clear. Our aim was to examine the effect of linagliptin on renal disease progression in only insulin dependent type 2 diabetes mellitus (DM) patients with CKD.MethodsStage 3–4 CKD patients were randomized into 2 groups in this prospective randomized controlled study. In the first group, linagliptin 5 mg was added in addition to the background insulin therapy. In the second group, patients continued their insulin therapy. Patients were followed up at 3-month intervals for one year.ResultsThe study population consisted of 164 patients (90 patients in linagliptin group, 74 patients in other group) with a mean age of 67.5 ± 8.8 years. eGFR significantly increased in linagliptin group (p = 0.033), but decreased in other group (p = 0.003). No significant change was observed in total insulin dose in linagliptin group (p = 0.111), but in other group, total insulin dose significantly increased (p < 0.001). Proteinuria levels decreased in both groups, but there was no significant change. In the multiple logistic regression analysis, male gender and proteinuria emerged as variables that showed significant association with increased risk and the use of linagliptin emerged as variable that showed significant association with decreased risk for CKD progression.ConclusionLinagliptin in DM patients with CKD was able to improve renal progression without significant effect on proteinuria and glucose control. With regard to treating diabetic nephropathy, linagliptin may offer a new therapeutic approach.     

Antidiabetika bei Patienten mit Niereninsuffizienz

Background

Many antidiabetic drugs have to be adjusted for administration to patients with renal impairment.

Objectives

Drug dose adjustment of antidiabetic drugs to renal function, specific risks and contraindications.

Material and methods

Review of current recommendations based on the German summary of product characteristics and published articles from the scientific literature.

Results

The selection of an antidiabetic drug should be made after individual consideration of expected benefits and potential risks. Metformin is contraindicated in patients with renal impairment. Pioglitazone may be used but a number of potential risks have to be considered. Gliquidone and repaglinide are considered as being kidney-independent. Glucagon-like peptide 1 (GLP-1) analogues should be avoided in patients with severe renal impairment but dipeptidyl peptidase 4 (DPP-4) inhibitors may be used (with dose adjustment). Sodium-glucose linked transporter 2 (SGLT2) inhibitors are inefficient in patients with renal impairment and alpha glucosidase inhibitors are contraindicated in cases of severe renal impairment.

Conclusion

Oral antidiabetic drugs can also be prescribed for patients with renal impairment but recommended drug dose adjustments and contraindications must be considered.     

Recent advances in incretin‐based therapies

The global burden of type 2 diabetes is growing. Traditional therapies are suboptimal and there is a clear unmet need for treatments that offer effective glucose control while addressing the comorbid factors associated with diabetes, such as obesity and risk of cardiovascular disease, without the fear of hypoglycaemia. Glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors offer a novel way of reducing hyperglycaemia by targeting the incretin system. This review provides an overview of the development of incretin‐based therapies and explains their differing modes of action compared with traditional interventions. A comparison of the clinical profiles of current glucagon‐like peptide‐1 receptor agonists [liraglutide and exenatide (twice‐daily and once‐weekly)] and dipeptidyl peptidase‐4 inhibitors (sitagliptin, saxagliptin, vildagliptin and linagliptin) is performed alongside a discussion of the placement of incretin‐based therapies in treatment guidelines. Further improvements in this class are expected, and we will examine some of the novel glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors currently under development.     

The dipeptidyl peptidase‐4 inhibitor linagliptin lowers postprandial glucose and improves measures of β‐cell function in type 2 diabetes

Progressive deterioration of pancreatic β‐cell function in patients with type 2 diabetes mellitus (T2DM) contributes to worsening of hyperglycaemia. To investigate the effects of the dipeptidyl peptidase‐4 inhibitor linagliptin on β‐cell function parameters, a pooled analysis of six randomized, 24‐week, placebo‐controlled, phase 3 trials of 5 mg of linagliptin daily was performed in 2701 patients with T2DM (linagliptin, n = 1905; placebo, n = 796). At week 24, observed improvements in HbA1c, fasting plasma glucose, and 2‐h postprandial glucose were significantly greater for linagliptin than placebo (all p < 0.0001). Homeostasis model assessment (HOMA)‐%β, as a surrogate marker of fasting β‐cell function, was significantly improved with linagliptin, and did not change with placebo (placebo‐adjusted mean ± s.e. change for linagliptin: 16.5 ± 4.6 (mU/l)/(mmol/l); p = 0.0003). Further study is required to determine if the significant improvement in HOMA‐%β with linagliptin will translate into long‐term improvements in β‐cell function.     

Safety and efficacy of linagliptin as add‐on therapy to metformin in patients with type 2 diabetes: a randomized,double‐blind,placebo‐controlled study

Aim: To evaluate the efficacy and safety of the potent and selective dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin administered as add‐on therapy to metformin in patients with type 2 diabetes with inadequate glycaemic control. Methods: This 24‐week, randomized, placebo‐controlled, double‐blind, parallel‐group study was carried out in 82 centres in 10 countries. Patients with HbA1c levels of 7.0–10.0% on metformin and a maximum of one additional antidiabetes medication, which was discontinued at screening, continued on metformin ≥1500 mg/day for 6 weeks, including a placebo run‐in period of 2 weeks, before being randomized to linagliptin 5 mg once daily (n = 524) or placebo (n = 177) add‐on. The primary outcome was the change from baseline in HbA1c after 24 weeks of treatment, evaluated with an analysis of covariance (ANCOVA). Results: Mean baseline HbA1c and fasting plasma glucose (FPG) were 8.1% and 9.4 mmol/l, respectively. Linagliptin showed significant reductions vs. placebo in adjusted mean changes from baseline of HbA1c (?0.49 vs. 0.15%), FPG (?0.59 vs. 0.58 mmol/l) and 2hPPG (?2.7 vs. 1.0 mmol/l); all p < 0.0001. Hypoglycaemia was rare, occurring in three patients (0.6%) treated with linagliptin and five patients (2.8%) in the placebo group. Body weight did not change significantly from baseline in both groups (?0.5 kg placebo, ?0.4 kg linagliptin). Conclusions: The addition of linagliptin 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin resulted in a significant and clinically meaningful improvement in glycaemic control without weight gain or increased risk of hypoglycaemia.     

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/Introduction

Type 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 Methods

This 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.

Results

After 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.

Conclusions

In 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.

     

Probable linagliptin-induced liver toxicity: A case report

AimUnlike other dipeptidyl peptidase 4 (DPP-4) inhibitors, the excretion of linagliptin is mainly through a biliary route. Despite this fact, liver injury with linagliptin has thus far not been reported in the literature. However, this report describes the first case of probable linagliptin-induced liver toxicity.MethodsThe clinical history, diagnosis, investigations and drug treatment of the patient are reviewed here.ResultsA 58-year-old Japanese woman presented with fatigue, nausea, jaundice and marked elevations of hepatic enzymes 4 weeks after starting linagliptin 5 mg/day as monotherapy. No other medications were taken, and imaging studies revealed no other obvious causes of hepatic injury. Tests for viral serology and antinuclear antigen were negative. Symptoms disappeared and the levels of hepatic parameters (serum aminotransferases and biliary enzymes) slowly recovered after discontinuation of linagliptin. The slow recovery process may have been due to the very long half-life of the drug. The patient's Naranjo scale score was 6 and RUCAM score was 7.ConclusionAlthough linagliptin currently carries no liver warnings, it may be necessary to monitor hepatic function in some patients upon administration of this drug until further evidence is obtained.     

Pharmacokinetics of dipeptidylpeptidase‐4 inhibitors

Type 2 diabetes (T2DM) is a complex disease combining defects in insulin secretion and insulin action. New compounds have been developed for improving glucose‐induced insulin secretion and glucose control, without inducing hypoglycaemia or weight gain. Dipeptidylpeptidase‐4 (DPP‐4) inhibitors are new oral glucose‐lowering agents, so‐called incretin enhancers, which may be used as monotherapy or in combination with other antidiabetic compounds. Sitagliptin, vildaglipin and saxagliptin are already on the market in many countries, either as single agents or in fixed‐dose combined formulations with metformin. Other DPP‐4 inhibitors, such as alogliptin and linagliptin, are currently in late phase of development. The present paper summarizes and compares the main pharmacokinetics (PK) properties, that is, absorption, distribution, metabolism and elimination, of these five DPP‐4 inhibitors. Available data were obtained in clinical trials performed in healthy young male subjects, patients with T2DM, and patients with either renal insufficiency or hepatic impairment. PK characteristics were generally similar in young healthy subjects and in middle‐aged overweight patients with diabetes. All together gliptins have a good oral bioavailability which is not significantly influenced by food intake. PK/pharmacodynamics characteristics, that is, sufficiently prolonged half‐life and sustained DPP‐4 enzyme inactivation, generally allow one single oral administration per day for the management of T2DM; the only exception is vildagliptin for which a twice‐daily administration is recommended because of a shorter half‐life. DPP‐4 inhibitors are in general not substrates for cytochrome P450 (except saxagliptin that is metabolized via CYP 3A4/A5) and do not act as inducers or inhibitors of this system. Several metabolites have been documented but most of them are inactive; however, the main metabolite of saxagliptin also exerts a significant DPP‐4 inhibition and is half as potent as the parent compound. Renal excretion is the most important elimination pathway, except for linagliptin whose metabolism in the liver appears to be predominant. PK properties of gliptins, combined with their good safety profile, explain why no dose adjustment is necessary in elderly patients or in patients with mild to moderate hepatic impairment. As far as patients with renal impairment are concerned, significant increases in drug exposure for sitagliptin and saxagliptin have been reported so that appropriate reductions in daily dosages are recommended according to estimated glomerular filtration rate. The PK characteristics of DPP‐4 inhibitors suggest that these compounds are not exposed to a high risk of drug–drug interactions. However, the daily dose of saxagliptin should be reduced when coadministered with potent CYP 3A4 inhibitors. In conclusion, besides their pharmacodynamic properties leading to effective glucose‐lowering effect without inducing hypoglycaemia or weight gain, DPP‐4 inhibitors show favourable PK properties, which contribute to a good efficacy/safety ratio for the management of T2DM in clinical practice.     

Comparing treatment intensification and clinical outcomes of metformin and dipeptidyl peptidase‐4 inhibitors in treatment‐naïve patients with type 2 diabetes in Japan

Japan's guidelines emphasize tailored therapy, but do not guide physicians on the use of a specific regimen in drug‐naive patients. The role of long‐term initial therapy could be important in key elements of diabetes treatment, such as continuation of the initially prescribed drug. We investigated the frequency of occurrence to treatment intensification after the initiation of metformin or dipeptidyl peptidase‐4 inhibitor treatment. In multivariable‐adjusted Cox proportional hazards models, initiation of dipeptidyl peptidase‐4 inhibitor was associated with a low hazard of intensification. The findings of this survey showed that dipeptidyl peptidase‐4 inhibitors were the preferred first‐line treatment in Japan because of the high continuation rate of the treatment and hemoglobin A1c‐lowering effect. This information would provide guidance in selecting initial hypoglycemic drugs to optimize the treatment of type 2 diabetes mellitus patients in Japan and Asia.     

Effect of renal impairment and haemodialysis on the pharmacokinetics of gemigliptin (LC15‐0444)

This study evaluated the effects of renal impairment (RI) and haemodialysis (HD) on the pharmacokinetics of gemigliptin, a novel dipeptidyl peptidase‐4 (DPP‐4) inhibitor. After a 100 mg administration to subjects with normal renal function (n = 23) or RI (n = 24), plasma, urine or dialysate samples were analysed. Control subjects were matched to patients based on age, gender and body mass index. Patients with mild, moderate, severe RI and end‐stage renal disease (ESRD) showed 1.20, 2.04, 1.50 and 1.66‐fold (1.10, 1.49, 1.22 and 1.21‐fold) increase of mean area under the time‐plasma concentration curve from 0 to infinity (AUC_inf) [maximum plasma concentration (C_max)] of gemigliptin, respectively. Pharmacokinetics of gemigliptin was comparable between HD and non‐HD periods in ESRD patients. Less than 4% of the dose was removed by 4 h HD. RI appeared to have modest effect on the gemigliptin disposition. No dose adjustment in patients with RI is proposed on the basis of exposure–response relationship. Impact of HD on the removal of gemigliptin was negligible.     

When metformin is not enough: Pros and cons of SGLT2 and DPP‐4 inhibitors as a second line therapy

The newer oral therapies for type 2 diabetes mellitus, dipeptidyl peptidase‐4 (DPP‐4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors, have advantages over older agents. Dipeptidyl peptidase‐4 inhibitors are weight neutral and have few adverse effects. Sodium glucose cotransporter 2 inhibitors have additional benefits: weight loss, blood pressure reduction, cardiovascular risk reduction, and renoprotective effects. Sodium glucose cotransporter 2 inhibitors have increased risk of urogenital infections and possible risk of “euglycaemic” diabetic ketoacidosis. It is important to balance the benefits over the older‐oral therapies as these agents are more expensive; yet some analyses suggest that they are within the limits of what is considered cost‐effective in health care. We discuss the relative merits and drawbacks of these 2 classes and consider their roles in the treatment of type 2 diabetes mellitus. We suggest a number of patient profiles where early use of these agents could be used. We favour the use of SGLT2 inhibitors over DPP‐4 inhibitors as add on therapy to metformin when glycaemic targets have not been achieved given their similar glycaemic efficacy and the additional benefits of SGLT2 inhibitors. We particularly favour SGLT2 inhibitors in those where additional weight loss and blood pressure reductions are desired, and in patients with heart failure or cardiovascular disease. Care should be taken to warn patients about genital fungal infections and to avoid use in people with risk factors for SGLT2 associated ketoacidosis. We favour DPP‐4 inhibitors in those where side effects of other agents are of concern, the frail elderly population, and those with renal disease precluding SGTL2 inhibitor use.     

The shifting paradigm in the treatment of type 2 diabetes mellitus—A cardiologist's perspective

In patients with diabetes mellitus, cardiovascular (CV) disease is the leading cause of morbidity and mortality. A multitude of contemporary antidiabetic agents presents different CV safety profiles. Metformin forms the cornerstone agent to reduce CV events. Newer agents, such as glucagon‐like peptide‐1 agonists and sodium‐glucose cotransporter‐2 inhibitors, have appealing CV benefits. Insulin, dipeptidyl peptidase‐4 inhibitors, and sulfonylureas have neutral CV effects. Cardiologists should familiarize themselves with these agents to promote comprehensive CV care in patients with diabetes mellitus.