Efficacy Of Dipeptidyl Peptidase-4 Inhibitors Research Articles

Incretin-based drugs for type 2 diabetes: Focus on East Asian perspectives.

Type 2 diabetes in East Asians is characterized primarily by β‐cell dysfunction, and with less adiposity and less insulin resistance compared with that in Caucasians. Such pathophysiological differences can determine the appropriate therapeutics for the disease. Incretins, glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1, are secreted in response to meal ingestion, and enhance insulin secretion glucose‐dependently. Incretin‐based drugs, dipeptidyl peptidase‐4 inhibitors (DPP‐4i) and glucagon‐like peptide‐1 receptor agonists, that ameliorate β‐cell dysfunction with limited hypoglycemia risk are now widely used in type 2 diabetes management. Recent meta‐analyses of clinical trials on DPP‐4i and glucagon‐like peptide‐1 receptor agonists found that the drugs were more effective in Asians, most likely because of amelioration of β‐cell dysfunction. In addition, we found increased glycated hemoglobin‐lowering effects of DPP‐4i to be associated with intake of fish in type 2 diabetes, which suggests that dietary customs of East Asians might also underlie the greater efficacy of DPP‐4i. Despite the limited risk, cases of severe hypoglycemia were reported for DPP‐4i/sulfonylureas combinations. Importantly, hypoglycemia was more frequent in patients also receiving glibenclamide or glimepiride, which activate exchange protein directly activated by cyclic adenosine monophosphate 2, a critical mediator of incretin signaling, and was less frequent in patients receiving gliclazide, which does not activate exchange protein directly activated by cyclic adenosine monophosphate 2. Prevention of insulin‐associated hypoglycemia by DPP‐4i has gained attention with regard to the enhancement of hypoglycemia‐induced glucagon secretion by insulinotropic polypeptide, but remains to be investigated in East Asians. Despite the safety issues, which are paramount and must be carefully monitored, the incretin‐based drugs could have potential as a first choice therapy in East Asian type 2 diabetes patients.

Factors Contributing to the Clinical Effectiveness of the DPP-4 Inhibitor Sitagliptin in Patients With Type 2 Diabetes

PurposeTreatment with dipeptidyl peptidase 4 (DPP-4) inhibitors may have responders or nonresponders. However, agreement on the effects of patient background and/or contributory factors that have a negative effect on the efficacy of DPP-4 inhibitors is lacking. The aim of the present study was to investigate the effect of resistance factors on the clinical efficacy of sitagliptin (SITA) for patients with type 2 diabetes. MethodsWe performed a retrospective study based on the medical records of patients who were treated with SITA alone (SITA-A; n = 16), a combination of a sulfonylurea (SU) without a change in dose and add-on SITA (SU + SITA; n = 29), SITA alone after the discontinuation of premedication with antidiabetic agents (SITA-AD; n = 18), or a combination of an SU with a dose reduction and SITA (L-SU + SITA; n = 17). Multivariate logistic regression analysis was employed to estimate the influence of resistance factors on hemoglobin (Hb) A1c lowering by SITA treatment for 3 months. FindingsThe HbA1c levels were significantly lower after 3-month treatment with SITA-A (6.3% [0.2%]), SU + SITA (7.1% [0.2%]), and L-SU + SITA (6.6% [0.2%]), but not with SITA-AD (6.3% [0.2%]), than baseline levels before treatment. Multivariate logistic regression analysis established that a decreased efficacy of SITA was markedly related to baseline HbA1c levels of ≥7.5% and dyslipidemia. ImplicationsThese results suggest that checking for the presence or absence of resistance factors, including elevated HbA1c levels and dyslipidemia, may contribute to the appropriate usage of SITA.

Dipeptidyl peptidase-4 inhibitors or sodium glucose co-transporter-2 inhibitors as an add-on to insulin therapy: A comparative review.

The gradual decline in β-cell function is inevitable in type 2 diabetes mellitus and therefore, substantial proportions of patients require insulin subsequently, in order to achieve optimal glucose control. While weight gain, hypoglycemia, and fluid retention especially during dose intensification is a known limitation to insulin therapy, these adverse effects also reduce patient satisfaction and treatment adherence. It is also possible that the benefits of intensive control achieved by insulin therapy, perhaps get nullified by the weight gain and hypoglycemia. In addition, improvement in plasma glucose or glycated hemoglobin (HbA1c) itself is associated with weight gain. Notably, studies have already suggested that reduction in body weight by ~3–5%, may allow a significantly better glycemic control. Thus, a class of drugs, which can reduce HbA1c effectively, yet are weight neutral or preferably reduce body weight, could be the most sought out strategy as an add-on therapy to insulin. While sulfonylureas (SUs) are associated with weight gain and hypoglycemia, pioglitazone increases body weight and fluid retention. Moreover, SUs are not recommended once premix or prandial insulin is commenced. The addition of newer agents, such as glucagon-like peptide-1 receptor agonist to insulin certainly appears to be an effective tool in reducing both HbA1c and body weight as is evident across the studies; however, this approach incurs an additional injection as well as cost. Dipeptidyl peptidase-4 inhibitors (DPP-4I) and sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are other exciting options, as an add-on to insulin therapy primarily because these are oral drugs and do not possess any intrinsic potential of hypoglycemia. Furthermore, these are either weight neutral or induce significant weight loss. This review article aims to comparatively analyze the safety and efficacy of DPP-4I and SGLT-2I, as an add-on therapy to insulin.

Predictive Factors for Efficacy of Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes Mellitus.

BackgroundPredictive factors for the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors for lowering glycosylated hemoglobin (HbA1c) remain unclear in patients with type 2 diabetes mellitus. The aim of this study is therefore to clarify predictive factors of the efficacy of DPP-4 inhibitors for lowering HbA1c after 12 months of treatment.MethodsA total of 191 consecutive type 2 diabetic patients (male sex 55%, mean age, 68.3±35.8 years), who had been treated with DPP-4 inhibitors for 12 months, were enrolled in this study and evaluated retrospectively.ResultsAfter 12 months of DPP-4 inhibitor treatment, random blood glucose level, and HbA1c level, decreased from 167±63 to 151±49 mg/dL (P<0.01), and from 7.5%±1.3% to 6.9%±0.9% (P<0.01) respectively, without severe side effects. Multiple regression analysis showed that predictors of DPP-4 inhibitor treatment efficacy in lowering HbA1c level after 12 months were a decrease in HbA1c level after 3 months of treatment, a high baseline HbA1c level, a low baseline body mass index, and the absence of coronary artery disease.ConclusionMost suitable candidates for treatment with DPP-4 inhibitors are diabetics who are not obese and do not have coronary artery disease. In addition, long-term efficacy of DPP-4 inhibitors can be predicted by decrement of HbA1c after 3 months of treatment.

Response: Predictive Factors for Efficacy of Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes Mellitus (Diabetes Metab J 2015;39:342-7).

We appreciate Dr. Ye An Kim's comments on our study entitled Predictive factors for efficacy of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus, which was published in the Diabetes and Metabolism Journal [1].

Letter: Predictive Factors for Efficacy of Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes Mellitus (Diabetes Metab J 2015;39:342-7).

Dipeptidyl peptidase-4 (DPP-4) inhibitor is one of the widely used diabetic medications these days. In clinical practice, some patients respond more effectively to this drug and show better glycemic improvement. Several studies [1,2,3,4] analyzed the predictors of response to DPP-4 inhibitors, however the results were somewhat inconsistent. The discrepancy might be due to the different definition of efficacy predictors and heterogeneity of study population. In this article entitled Predictive factors for efficacy of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus, Yagi et al. [5] evaluated the predictive factors for the efficacy of DPP-4 inhibitors based on the change of glycosylated hemoglobin (HbA1c) after 12 months of treatment. They described the predictors to be a decrease in HbA1c level after 3 months of treatment, a high baseline HbA1c level, a low baseline body mass index, and no history of coronary artery disease (CAD). This article is interesting, especially in that the long-term effects of DPP-4 inhibitors on glycemic control could be predicted by the short term response, which might make it easier to identify the good responders to DPP-4 inhibitors. Although there are some clinical significances, some points need to be clarified. First, the criteria for DPP-4 inhibitor add-on therapy needs to be clarified better in this study. The study patients aged 68.3±35.8 years old, and baseline HbA1c were 7.5%±1.3%. Initially, 36.6% of patients already had HbA1c <7% when DPP-4 inhibitors are added on. Considering that the patients were relatively old with mild elevated HbA1c level, the reason for additional DPP-4 inhibitors might be helpful to understand and validate the efficacy of DPP-4 inhibitors. In addition, a majority of patients have already been treated with other anti-diabetic drugs. Forty-four percent of patients used α-glucosidase inhibitors, 32.5% for sulfonylurea, and 15.2% for biguanides. In these patients, the reason for additional DPP-4 inhibitor instead of the dose increment of baseline drugs could be informative. Second, combination therapy of other anti-diabetic drugs might affect glucose metabolism and exert confounding effects. A previous study has reported that combination treatment of alogliptin and voglibose increased plasma active glucagon-like peptide-1 (GLP-1) levels and pancreatic insulin content synergistically in db/db mice [6]. Another study showed that a combination of miglitol and sitagliptin effectively attenuate postprandial hyperglycemia with various patterns of insulin, glucagon, and GLP-1 release, suggesting that individual hormone-related glycemic responses to the DPP-4 inhibitors and α-glucosidase inhibitor are complex and multifactorial [7]. Synergistic effect of sulfonylurea and DPP-4 inhibitor has been suggested, because some patients showed dramatic glycemic improvement after this combination therapy [8]. Sulfonylurea added to DPP-4 inhibitor might potentiate insulin secretion by activating exchange protein activated by cyclic AMP 2 (Epac2) [9]. There are substantial synergistic or heterogenous responses to combination therapy of DPP-4 inhibitor with other anti-diabetic drugs. Analyzing the patients with similar baseline anti-diabetic drugs could be more appropriate to evaluate the predictive factors for the efficacy of DPP-4 inhibitors. Third, duration of diabetes is one of the substantial predictors for the response to DPP-4 inhibitors. Several studies have shown that shorter duration of diabetes is associated with greater reduction in HbA1c after DPP-4 inhibitor add-on [1,2,3]. Further information including duration of diabetes could support the interesting findings in this study. In addition, incidence rate of CAD increases with longer duration of diabetes [10]. As shown in this study, absence of CAD itself could be one of the predictors of DPP-4 inhibitor response, otherwise, shorter duration of diabetes might be the unrevealed connection link of good response for DPP-4 inhibitors. Lastly, the authors evaluated the predictive factors based on the change of HbA1c after 12 months of treatment. Baseline HbA1c, however, is an important factor that affects the change of glycemic control [4]. In this study, as baseline HbA1c was high, the change of HbA1c would also appear to be more significant. Identifying the predictive factors with reference to the baseline HbA1c could be more interesting if individual responses to DPP-4 inhibitors were considered. Based on the results of this study, short-term follow-up studies with a large patient population are warranted to investigate the predictors of DPP-4 inhibitor response.

Incretin physiology and pathophysiology from an Asian perspective.

Incretin hormones, such as glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are secreted on oral nutrient ingestion and regulate postprandial glucose homeostasis by conveying the signal of intestinal glucose flux. In East Asians, the secretion of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 is not reduced in type 2 diabetes relative to normal glucose tolerance. Although the incretin effect is blunted in European patients with type 2 diabetes, a few East Asian studies showed no difference in the incretin effect between type 2 diabetes and normal glucose tolerance. Interestingly, the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors or glucagon-like peptide-1 receptor agonists was reported to be greater in Asians than in non-Asians. The difference in the treatment responses could be ascribed to a different pathophysiology of type 2 diabetes (lower insulin secretory function and less insulin resistance), lower body mass index, different genetic makeups, preserved incretin effect and different food compositions in East Asians compared with other ethnic groups. Based on the currently available data, incretin-based therapies appear to be safe and well tolerated in East Asians. Nevertheless, continuous pharmacovigilance is required. The characteristics of incretin biology and treatment responses to incretin-based therapies should be considered in developing ethnicity-specific treatment guidelines and making patient-centered decisions for patients with type 2 diabetes.

Pharmacokinetics, safety, and efficacy of DPP-4 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus and renal or hepatic impairment. A systematic review of the literature

Renal or hepatic impairment, often encountered in patients with type 2 diabetes, influences the pharmacokinetics and bioavailability of antihyperglycemic agents. An emerging concern is whether pharmacotherapy with incretin-based agents, the most recent drug classes to be introduced for type 2 diabetes, can be safely used in patients with renal insufficiency or hepatic damage. This literature review examines the results of studies on these novel drug classes, with a view to provide the practitioner with a balanced, evidence-based position when considering incretin-based therapies in patients with type 2 diabetes and impaired kidney or liver function. All currently available dipeptidyl peptidase-4 (DPP-4) inhibitors appear to be appropriate pharmacotherapeutic choices in patients with declining renal function, with linagliptin affording the added advantage of not requiring dose adjustment or periodic monitoring of drug-related kidney function. In contrast, caution is warranted with the use of glucagon-like peptide-1 (GLP-1) receptor agonists in patients with moderate or severe renal impairment. The slightly wider evidence base for liraglutide than for exenatide or lixisenatide is not sufficient to support its use in severe renal impairment. What little evidence there is for incretin-based therapies in hepatic impairment has come from a few past hoc analysis of clinical trials, with most precautions and warnings reflecting the paucity of knowledge about incretin efficacy or safety in this condition.

Efficacy and Safety of Dipeptidyl Peptidase-4 Inhibitors in Combination with Metformin

Use of dipeptidyl peptidase-4 (DPP-4) inhibitors is prevalent for the treatment of type 2 diabetes since they have fewer adverse effects compared with other non-insulin medications currently available; however, as monotherapy, the glycosylated hemoglobin (HbA1c)-lowering power of these agents is moderate. The aim of this article is to evaluate the current literature regarding the safety and efficacy of DPP-4 inhibitors in combination with metformin. A literature search was conducted through MEDLINE (from 1950 to October 2012), PubMed (from 1966 to October 2012), EMBASE (from 1966 to October 2012), and International Pharmaceutical Abstracts (from 1970 to October 2012) using the search terms "sitagliptin," "linagliptin," "alogliptin," "vildagliptin," "saxagliptin," and "metformin." Studies that did not evaluate the DPP-4 inhibitors in combination with metformin and those that were not phase 3, were excluded. Many of the studies evaluated DPP-4 inhibitors in combination with metformin versus glucagon-like peptide-1 (GLP-1) agonists, placebo, DPP-4 inhibitors as monotherapy, thiazolidinediones, and sulfonylureas. The results of these noninferiority trials were that DPP-4 inhibitors as a whole are noninferior to either each other or other agents except for GLP-1 agonists. Also, in superiority studies, GLP-1 agonists proved to have greater HbA1c lowering. In summary, DPP-4 inhibitors play a vital role in the treatment of diabetes. They have relatively limited adverse effects, especially regarding hypoglycemia. DPP-4 inhibitors in combination with metformin are generally well tolerated and are available as combination products to reduce pill burden and enhance compliance. The limitations to DPP-4 inhibitors are the lack of outcomes data and more limited HbA1c lowering than other medications currently approved for the treatment of type 2 diabetes. However, as previously stated, thiazolidinediones, glinides, sulfonylureas, pramlinitide, and GLP-1 agonists are all quite beneficial in HbA1c lowering but are not without major adverse effects. Therefore, DPP-4 inhibitors have a vital role as an oral add-on agent for the treatment of type 2 diabetes.

Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis

The aim of this work was to compare the glucose-lowering efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors between Asian and non-Asian patients with type 2 diabetes. We searched MEDLINE, EMBASE, LILACS, CENTRAL, ClinicalTrials.gov and conference proceedings. Studies were eligible if they were randomised controlled trials with a treatment duration of at least 12weeks, compared a DPP-4 inhibitor with a placebo as either monotherapy or oral combination therapy, had information on ethnicity and HbA1c values and were published or described in English. A systematic review and meta-analysis with a meta-regression analysis was conducted. Among 809 potentially relevant studies, 55 trials were included. A meta-analysis revealed that DPP-4 inhibitors lowered HbA1c to a greater extent in studies with ≥50% Asian participants (weighted mean difference [WMD] -0.92%; 95% CI -1.03, -0.82) than in studies with <50% Asian participants (WMD -0.65%; 95% CI -0.69, -0.60). The between-group difference was -0.26% (95% CI -0.36, -0.17, p < 0.001). The baseline BMI significantly correlated with the HbA1c-lowering efficacy of DPP-4 inhibitors. The RR of achieving the goal of HbA1c <7.0% (53.0mmol/mol) was higher in studies with ≥50% Asian participants (3.4 [95% CI 2.6, 4.7] vs 1.9 [95% CI 1.8, 2.0]). The fasting plasma glucose-lowering efficacy was higher with monotherapy in the Asian-dominant studies, but the postprandial glucose-lowering efficacy and changes in body weight were comparable between the two groups. DPP-4 inhibitors exhibit a better glucose-lowering efficacy in Asians than in other ethnic groups; this requires further investigation to understand the underlying mechanism, particularly in relation to BMI.

Trends in Antidiabetic Prescription Patterns in Japan From 2005 to 2011

There have been few reports concerning the trends in antidiabetic drug use in Japan. In 2009, a dipeptidyl peptidase-4 inhibitor (DPP4I), an antidiabetic with a new mechanism of action, was made available. This study was conducted to analyze the antidiabetic prescription trends in Japan in recent years and the influence of DPP4Is on those trends. We used monthly claims data obtained from a database company. Data from patients 20 years of age or older and who were prescribed antidiabetics were extracted and analyzed. A total of 18,457 patients were prescribed antidiabetics (mean age, 53.6 ± 11.0). The sulfonylurea prescription rate decreased while that of biguanides increased. After the introduction of DPP4Is, use of these agents rapidly increased and the rate further increased one year after DPP4I introduction. DP-P4Is also became the most prescribed antidiabetics for those prescribed antidiabetics for the first time. The decrease in the use of sulfonylureas and the increase in the use of biguanides are in accordance with trends observed in the United States and Europe, and probably reflect Japanese physicians' awareness of cumulating evidence gained from studies such as the UK Prospective Diabetes Study (UKPDS). The rapid increase in the DPP4I prescription rate might be the result of several factors including their safety profiles, which were highlighted in clinical studies published just prior to the drugs becoming available. However, there is little data regarding the efficacy of DPP4Is in reducing diabetes related complications, which should be determined in future studies.

Clinical Characteristics of the Responders to Dipeptidyl Peptidase-4 Inhibitors in Korean Subjects with Type 2 Diabetes

We investigated characteristics associated with the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4i) in Korean patients with type 2 diabetes. We reviewed medical records of 477 patients who had taken sitagliptin or vildagliptin longer than 40 weeks. Response to DPP4i was evaluated with HbA1c change after therapy (ΔHbA1c). The Student's t-test between good responders (GR: ΔHbA1c > 1.0%) and poor responders (PR: ΔHbA1c < 0.5%), a correlation analysis among clinical parameters, and a linear multivariate regression analysis were performed. The mean age was 60 yr, duration of diabetes 11 yr and HbA1c was 8.1%. Baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and creatinine were significantly higher in the GR compared to the PR. Duration of diabetes, FPG, HbA1c, C-peptide and creatinine were significantly correlated with ΔHbA1c. In the multivariate analysis, age (r2 = 0.006), duration of diabetes (r2 = 0.019), HbA1c (r2 = 0.296), and creatinine levels (r2 = 0.024) were independent predictors for the response to DPP4i. Body mass index and insulin resistance were not associated with the response to DPP4i. In conclusion, better response to DPP4i would be expected in Korean patients with type 2 diabetes who have higher baseline HbA1c and creatinine levels with shorter duration of diabetes.

Comparison of the Efficacy of Dipeptidylpeptidase-4 Inhibitors Between Asian and Non-Asian Populations

아시아인과 비아시아인에서 DPP-4 억제제 효과의 비교 Comparison of the Efficacy of Dipeptidylpeptidase-4 Inhibitors Between Asian and Non-Asian Populations 서울대학교 의과대학 내분비대사내과

Comparative Clinical Pharmacokinetics of Dipeptidyl Peptidase-4 Inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors collectively comprise a presently unique form of disease management for persons with type 2 diabetes mellitus. The aim of this review is to compare the clinical pharmacokinetics of available DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin) for the purpose of identifying potential selection preferences according to individual patient variables and co-morbidities. DPP-4 inhibitors are readily absorbed orally. Following oral ingestion, absorption occurs mainly in the small intestine, with median times to maximum (peak) plasma concentration ranging from 1 to 3 hours. The fraction of each dose absorbed ranges from approximately 30% with linagliptin to 75-87% for all others. Numerical differences in maximum (peak) plasma drug concentrations and areas under the plasma concentration-time curve among the DPP-4 inhibitors vary by an order of magnitude. However, functional capacity measured in terms of glucose-lowering ability remains comparable among all available DPP-4 inhibitors. Distribution of DPP-4 inhibitors is strongly influenced by both lipophilicity and protein binding. Apparent volumes of distribution (V(d)) for most agents range from 70 to 300 L. Linagliptin exhibits a V(d) of more than 1000 L, indicating widespread distribution into tissues. Binding to target proteins in plasma and peripheral tissues exerts a major influence upon broadening linagliptin distribution. DPP-4 inhibitor metabolism is widely variable, with reported terminal half-lives ranging from approximately 3 to more than 200 hours. Complex relationships between rates of receptor binding and dissociation appear to strongly influence the durations of action of those DPP-4 inhibitors with comparatively shorter half-lives. Durations of activity often are not reflective of clearance and, with the exception of vildagliptin which may be administered either once daily in the evening or twice daily, these medications are effective when used with a once-daily dosing schedule. Saxagliptin and, to a lesser extent, sitagliptin are largely metabolized by hepatic cytochrome P450 (CYP) 3A4 and 3A5 isoforms. With the exception of the primary hydroxylated metabolite of saxagliptin, which is 2-fold less potent than its parent molecule, metabolic products of hepatic biotransformation are minimally active and none appreciably contribute to either the therapeutic or the toxic effects of DPP-4 inhibitors. No DPP-4 inhibitor has been shown to inhibit or to induce hepatic CYP-mediated drug metabolism. Accordingly, the number of clinically significant drug-drug interactions associated with these agents is minimal, with only saxagliptin necessitating dose adjustment if administered concurrently with medications that strongly inhibit CYP3A4. Linagliptin undergoes enterohepatic cycling with a large majority (85%) of the absorbed dose eliminated in faeces via biliary excretion. Other DPP-4 inhibitors predominantly undergo renal excretion, with 60-85% of each dose eliminated as unchanged parent compound in the urine. Systematic reviews of clinical trials suggest that the overall efficacy of DPP-4 inhibitors in patients with type 2 diabetes generally is similar. Apart from these generalizations, pharmacokinetic distinctions that potentially influence product selection are tentative. When considered in total, data reviewed in this report suggest that the best overall balance between potency and the clinical pharmacokinetic characteristics of distribution, metabolism and elimination may be observed with linagliptin followed closely by vildagliptin, saxagliptin, sitagliptin and alogliptin.

Predicting efficacy of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: Association of glycated hemoglobin reduction with serum eicosapentaenoic acid and docosahexaenoic acid levels.

This study was initiated to identify clinical and dietary parameters that predict efficacy of dipeptidyl peptidase-4 inhibitors. A total of 72 untreated Japanese patients with type 2 diabetes who received DPP-4 inhibitors (sitagliptin, alogliptin or vildagliptin) for 4 months were examined for changes of glycated hemoglobin (HbA1c) and body mass index (BMI), and self-administered 3-day food records, as well as serum levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). DPP-4 inhibitors significantly reduced HbA1c (before initiation of DPP-4 inhibitors 7.2 ± 0.7%, 4 months after initiation of DPP-4 inhibitors 6.7 ± 0.6% [paired t-test, P < 0.01 vs before]). Multiple regression analysis showed that changes of HbA1c were significantly correlated with baseline HbA1c, as well as estimated intake of fish. Furthermore, changes of HbA1c were significantly correlated with serum levels of EPA (r = -0.624, P < 0.01) and DHA (r = -0.577, P < 0.01). HbA1c reduction by DPP-4 inhibitors is significantly correlated with estimated intake of fish and serum levels of EPA and DHA. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00214.x, 2012).