Differences in lipid metabolism between anagliptin and sitagliptin in patients with type 2 diabetes on statin therapy: a secondary analysis of the REASON trial

Chihara, Atsuko; Tanaka, Atsushi; Morimoto, Takeshi; Sakuma, Mio; Shimabukuro, Michio; Nomiyama, Takashi; Arasaki, Osamu; Ueda, Shinichiro; Node, Koichi

doi:10.1186/s12933-019-0965-3

Cited by 12 publications

(5 citation statements)

References 28 publications

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“…In a human study using a small number of drug-naïve patients with type 2 diabetes and LDL-C > 120 mg/dL (n = 30), anagliptin significantly decreased a cholesterol synthesis marker, lathosterol, without affecting cholesterol absorption markers including campesterol, sitosterol and cholestanol [45]. Furthermore, a previous sub-analysis using data from the REASON trial demonstrated that anagliptin reduced LDL-C level by suppressing excess cholesterol synthesis even when it was used in combination with statin therapy [46]. Taken together, these findings suggest that anagliptin exerts a hepatoprotective effect beyond its glycemic-lowering action.…”

Section: Possible Mechanisms Of Reduction In Fabp4 Concentration By Anagliptinmentioning

confidence: 92%

Treatment with anagliptin, a DPP-4 inhibitor, decreases FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular disease who are receiving statin therapy

Furuhashi

Sakuma

Morimoto

et al. 2020

Cardiovasc Diabetol

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Background Fatty acid-binding protein 4 (FABP4) acts as a novel adipokine, and elevated FABP4 concentration is associated with obesity, insulin resistance and atherosclerosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of antidiabetic drugs, have distinct structures among the drugs, possibly leading to a drug class effect and each drug effect. Sitagliptin, a DPP-4 inhibitor, has been reported to decrease FABP4 concentration in drug-naïve and sulfonylurea-treated patients with type 2 diabetes mellitus. Anagliptin, another DPP-4 inhibitor, was shown to decrease low-density lipoprotein cholesterol (LDL-C) level to a greater extent than that by sitagliptin in the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. Aim and methods As a sub-analysis study using data obtained from the REASON trial, we investigated the effects of treatment with anagliptin (n = 148, male/female: 89/59) and treatment with sitagliptin (n = 159, male/female: 93/66) for 52 weeks on FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular events who were receiving statin therapy. Results The DPP-4 inhibitor had been administered in 82% of the patients in the anagliptin group and 81% of the patients in sitagliptin group prior to randomization. Serum FABP4 level was significantly decreased by 7.9% by treatment with anagliptin (P = 0.049) and was not significantly decreased by treatment with sitagliptin (P = 0.660). Change in FABP4 level was independently associated with basal FABP4 level and changes in waist circumference and creatinine after adjustment of age, sex and the treatment group. Conclusion Anagliptin decreases serum FABP4 concentration independent of change in hemoglobin A1c or LDL-C in patients with type 2 diabetes mellitus and dyslipidemia who are on statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. Registered January 5, 2015, https://clinicaltrials.gov/ct2/show/NCT02330406

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Section: Possible Mechanisms Of Reduction In Fabp4 Concentration By Anagliptinmentioning

confidence: 92%

Treatment with anagliptin, a DPP-4 inhibitor, decreases FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular disease who are receiving statin therapy

Furuhashi

Sakuma

Morimoto

et al. 2020

Cardiovasc Diabetol

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“…Most of the study patients 2 (SREBP2) in the liver 30) and inhibits absorption of cholesterol in the small intestine 31) . In human studies, it has been shown that inhibition of cholesterol synthesis 32) and suppression of excess cholesterol synthesis 33) are possible mechanisms for LDL-C reduction by anagliptin. On the other hand, the precise mechanisms by which anagliptin, but not sitagliptin, suppresses an excess increase in circulating PCSK9 level in patients receiving statin therapy are unclear.…”

Section: Correlation and Multivariable Linear Regression Analyses Formentioning

confidence: 99%

“…It has been reported that circulating PCSK9 has a diurnal rhythm synchronous with cholesterol synthesis marker lathosterol 34) . Inhibition of cholesterol synthesis 32) and suppression of excess cholesterol synthesis 33) by anagliptin may be linked to reduced PCSK9 levels. In addition, statin therapy is significantly associated with a compensatory increase in plasma PCSK9 concentration 24) .…”

Section: Correlation and Multivariable Linear Regression Analyses Formentioning

confidence: 99%

Differential Effects of DPP-4 Inhibitors, Anagliptin and Sitagliptin, on PCSK9 Levels in Patients with Type 2 Diabetes Mellitus who are Receiving Statin Therapy

Furuhashi

Sakuma

Morimoto

et al. 2022

JAT

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Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial. Methods: PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin ( n =122) or sitagliptin ( n =128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization. Results: Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL, P =0.01), but not anagliptin (233±97 vs. 250±106 ng/mL, P =0.07). Conclusions: PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.

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“…Both sitagliptin and anagliptin are being evaluated in clinical trials for their potential in the regulation of lipid metabolism and CVD in T2DM patients ( Table 2 ). Anagliptin has been shown to decrease LDL-C triglycerides, total cholesterol, and non-HDL-C levels in a mechanism independent from its hypoglycemic effects [ 59 ]. Other gliptins increase adiponectin levels and reduce intestinal cholesterol absorption [ 18 ].…”

Section: Therapies Based On the Incretin Systemmentioning

confidence: 99%

Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia

Aguilar-Ballester

Hurtado-Genovés

Taberner-Cortés

et al. 2021

IJMS

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Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.

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Differences in lipid metabolism between anagliptin and sitagliptin in patients with type 2 diabetes on statin therapy: a secondary analysis of the REASON trial

Cited by 12 publications

References 28 publications

Treatment with anagliptin, a DPP-4 inhibitor, decreases FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular disease who are receiving statin therapy

Treatment with anagliptin, a DPP-4 inhibitor, decreases FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular disease who are receiving statin therapy

Differential Effects of DPP-4 Inhibitors, Anagliptin and Sitagliptin, on PCSK9 Levels in Patients with Type 2 Diabetes Mellitus who are Receiving Statin Therapy

Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia

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