Linagliptin exacerbates heart failure due to energy deficiency via downregulation of glucose utilization and absorption in a mouse model.

Use of dipeptidyl peptidase-4 (DPP4) inhibitor in some clinical trials might have caused heart failure (HF), leading to increased hospitalizations. The aim of the present study was to determine whether linagliptin has any effect on chronic dilated HF, and its underlying mechanisms. Physiologic and pathologic studies were conducted on heart/muscle-specific manganese superoxide dismutase-deficient mice, which exhibited dilated cardiomyopathy, and were randomized to receive a low dose (1 mg/kg, HF-L group) or high dose (10 mg/kg, HF-H group) mixed with food, or normal food (HF group), for 8 weeks. Linagliptin increased mortality and heart/body weight ratio in mice with HF. Cardiac contractility and fibrosis worsened, whereas hepatic glycogen content and individual carbohydrate consumption decreased significantly in the HF-H group, when compared with the HF control group. Therefore, we performed a complementary experiment by supplementing glucose to the mice treated with high-dose linagliptin (HF-HG group). Adequate glucose supplementation reduced heart/body weight ratio and cardiac fibrosis, and improved cardiac contractility, without changing mortality. Following oral administration of 13C glucose, the respiratory 13C decreased in the HF-H and HF-HG groups, when compared with that in the HF group; the fecal 13C increased, suggesting that linagliptin inhibited glucose absorbance in the intestine. In addition, the expression of GLUT2, a glucose transporter was downregulated in the small intestine. Linagliptin treatment exacerbated HF, which increased mortality, cardiac function, and fibrosis. DPP4 inhibitors might boost cardiac cachexia and exacerbate HF, at least in part, through the modification of glucose utilization and absorption.

Efficacy of Yishen Huashi Granules Combined with Linagliptin Tablets on Blood Glucose and Renal Function in Patients with Type 2 Diabetic Nephropathy.

Objective: To probe into the efficacy of Yishen Huashi granules combined with linagliptin tablets in the treatment of type 2 diabetic nephropathy (DN) and its effect on blood glucose and renal function in patients. Methods: 70 patients with type 2 DN at our hospital between May 2020 and May 2022 were chosen as the research objects and separated into the control group and the research group based on their treatments. With 35 cases in each group, the patients treated with initial therapy and linagliptin tablets were enrolled in the control group, and those who received the above treatments and also Yishen Huashi granules were included in the research group. Their clinical indexes such as blood glucose and renal function were compared with both groups after treatment. Results: After treatment, the research group had remarkably lower fasting blood glucose (FPG), 2 h-postprandial blood glucose (2 h-PBG), and glycosylated hemoglobin A1c (HbA1c) levels than those in the control group (P < 0.05). After treatment, the research group had remarkably lower levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) (P < 0.05) and higher high-density lipoprotein (HDL) levels (P < 0.05) than those in the control group. After treatment, the urinary microalbumin (u-mALB) level was remarkably lower in both groups (P < 0.05) and was distinctly lower in the research group than in the control group (P < 0.05). After treatment, the research group had remarkably lower renal function indexes such as serum creatinine (SCr), blood urea nitrogen (BUN), urinary protein (UPro), and urinary albumin excretion rate (UAER) (P < 0.05) and a higher estimated glomerular filtration rate (eGFR) level (P < 0.05) than those in the control group. The efficacy was evaluated by the traditional Chinese medicine (TCM) syndrome score after treatment. There were no patients in complete remission between both the groups, where slight differences were found in the proportion of significant remission (P > 0.05), with the total effective rate of the research group remarkably higher than that of the control group (P < 0.05). Conclusion: The combination of Yishen Huashi granules and linagliptin tablets can reduce the blood glucose and blood lipid levels in patients with type 2 DN and lower UPro and protect renal function at the same time, which provides a new idea and a method for clinical treatment of type 2 DN with integrated traditional Chinese and Western medicine.

Hepatoprotective effect of linagliptin against liver fibrosis induced by carbon tetrachloride in mice.

The current study aimed to investigate linagliptin for its potential role in the prevention of liver fibrosis progression. Balb-C mice were randomly allocated into five groups (10 each): (i) control; (ii) mice were injected intraperitoneally with 50 µL carbon tetrachloride (CCl4) in corn oil in a dose of 0.6 µL/g three times per week for four weeks; (iii) linagliptin was administered orally in a daily dose of 10 mg/kg simultaneously with CCl4; (iv) silymarin was administered orally in a daily dose of 200 mg/kg concomitantly with CCl4; and (v) only linagliptin was administered. Hepatic injury was manifested in the CCl4 group by elevation of biochemical parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP)), and hepatic fibrosis was evident histopathologically by increased METAVIR score and immunostaining expression of alpha-smooth muscle actin (α-SMA), as well as increased liver tissue oxidative stress parameters, transforming growth factor-ß1 (TGF-ß1), and mammalian target of rapamycin (mTOR). Linagliptin was able to stop the progression of liver fibrosis, evident histopathologically with reduced METAVIR score and α-SMA expression. The possible mechanism may be via suppression of oxidative stress, TGF-ß1, and mTOR, which was associated with improvement of serum biochemical parameters ALT and AST. In conclusion, linagliptin might help to protect the liver against persistent injury-related consequences.

SGLT2 inhibitor/DPP-4 inhibitor combination therapy - complementary mechanisms of action for management of type 2 diabetes mellitus.

Type 2 diabetes mellitus is a progressive disease with multiple underlying pathophysiologic defects. Monotherapy alone cannot maintain glycemic control and leads to treatment failure. Ideally, a combination of glucose-lowering agents should have complementary mechanisms of action that address multiple pathophysiologic pathways, can be used at all stages of the disease, and be generally well tolerated with no increased risk of hypoglycemia, cardiovascular events, or weight gain. The combination should also provide conveniences for patients, such as oral dosing, single-pill formulations, and once-daily administration, potentially translating to improved adherence. Two classes of glucose-lowering agents that meet these criteria are the sodium glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. This article reviews the rationale for combination therapy with these agents, and evidence from clinical trials with empagliflozin and linagliptin or dapagliflozin and saxagliptin in the management of type 2 diabetes mellitus. Both combinations have been approved as single-pill formulations.

A Hamster Model of Diet-Induced Obesity for Preclinical Evaluation of Anti-Obesity, Anti-Diabetic and Lipid Modulating Agents.

AIM: Unlike rats and mice, hamsters develop hypercholesterolemia, and hypertriglyceridemia when fed a cholesterol-rich diet. Because hyperlipidemia is a hallmark of human obesity, we aimed to develop and characterize a novel diet-induced obesity (DIO) and hypercholesterolemia Golden Syrian hamster model. METHODS AND RESULTS: Hamsters fed a highly palatable fat- and sugar-rich diet (HPFS) for 12 weeks showed significant body weight gain, body fat accumulation and impaired glucose tolerance. Cholesterol supplementation to the diet evoked additional hypercholesterolemia. Chronic treatment with the GLP-1 analogue, liraglutide (0.2 mg/kg, SC, BID, 27 days), normalized body weight and glucose tolerance, and lowered blood lipids in the DIO-hamster. The dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin (3.0 mg/kg, PO, QD) also improved glucose tolerance. Treatment with peptide YY3-36 (PYY3-36, 1.0 mg/kg/day) or neuromedin U (NMU, 1.5 mg/kg/day), continuously infused via a subcutaneous osmotic minipump for 14 days, reduced body weight and energy intake and changed food preference from HPFS diet towards chow. Co-treatment with liraglutide and PYY3-36 evoked a pronounced synergistic decrease in body weight and food intake with no lower plateau established. Treatment with the cholesterol uptake inhibitor ezetimibe (10 mg/kg, PO, QD) for 14 days lowered plasma total cholesterol with a more marked reduction of LDL levels, as compared to HDL, indicating additional sensitivity to cholesterol modulating drugs in the hyperlipidemic DIO-hamster. In conclusion, the features of combined obesity, impaired glucose tolerance and hypercholesterolemia in the DIO-hamster make this animal model useful for preclinical evaluation of novel anti-obesity, anti-diabetic and lipid modulating agents.