Part Ⅰ：Long-Term Dipeptidyl Peptidase 4 Inhibition Worsens Hypertension And Renal And Cardiac Abnormalities in Obese Spontaneously Hypertensive Heart Failure Rats

Contact: Audrey Hu audrey.hu@wecistanche.com

Edwin K.Jackson; Zaichuan Mi; Delbert G.Gillespie; Dongmei Cheng; Stevan P. Tofovic

BACKGROUND: The long-term effects of dipeptidyl peptidase 4 (DPP4) inhibitors on blood pressure and cardiovascular and renal health remain controversial, Herein, we investigated the extended (>182 days) effects of DPP4 inhibition in a model of spontaneous hypertension, heart failure, diabetes melitus, obesity and hyperlipidemia.

METHODS AND RESULTS: Adult obese spontaneously hypertensive heart failure rats (SHHF) were implanted with radio transmitters for measurement of arterial blood pressures. Two weeks later, SHHF were randomized to receive either a DPP4 inhibitor (sitagliptin, 80 mg/kg per day in drinking water) or a placebo. At the end of the radiotelemetry measurements, renal and cardiac function and histology, as well as other relevant biochemical parameters, were assessed. For the first 25 days, mean arterial blood pressures were similar in sitagliptin-treated versus control SHHF; afterward, mean arterial blood pressures increased more in sitagliptin-treated SHHF (P<0.000001). The time-averaged mean arterial blood pressures from day 26 through 182 were 7.2 mm Hg higher in sitagliptin-treated SHHF. Similar changes were observed for systolic (8.6 mm Hg) and diastolic (6.1 mm Hg) blood pressures, and sitagliptin augmented hypertension throughout the light-dark cycle. Long-term sitagliptin treatment also increased kidney weights, renal vascular resistance. the excretion of kidney injury molecule-1 (indicates injury to proximal tubules), renal interstitial fibrosis, glomerulosclerosis, renal vascular hypertrophy, left ventricular dysfunction, right ventricular degeneration, and the ratios of collagen IV/collagen Il and collagen IV/laminin in the right ventricle.

CONCLUSIONS: These findings indicate that, in some genetic backgrounds, long-term DPP4 inhibitor treatment is harmful and identify an animal model to study mechanisms of, and test ways to prevent, DPP4 inhibitor-induced pathological conditions.

Key Words: dipeptidyl peptidase 4 inhibitors, heart damage, hypertension, kidney damages, spontaneously hypertensive heart failure rats

Renal protective effect of Cistanche

Dipeptidyl peptidase 4 (DPP4) inhibitors (DPP4ls; eg, sitagliptin, saxagliptin, and alogliptin) are a widely used class of antidiabetic drugs that increase incretin levels by inhibiting their metabolism by DPP4. Because activation of incretin receptors augments insulin release and suppresses glucagon secretion, DPP4I therapy improves glucose homeostasis.1.2

There is considerable evidence, however, that DPP4s yield suboptimal cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. For example, the SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus [SAVOR]-Thrombolysis in Myocardial Infarction [TIM]53) trial reported that saxagliptin significantly increased hospitalization for heart failure, induced renal abnormalities, and tended to increase all-cause mortality. Although an analysis of the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin vs Standard of Care in Patients with Type 2 Diabetes Melltus and Acute Coronary Syndrome) study concluded that alogliptin does not increase overall hospitalization for heart failure,4 this analysis did reveal a significantly increased rate of hospitalization for heart failure in a sub-group of patients without a history of heart failure who were treated with alogliptin.4 Indeed, a US Food and Drug Administration advisory committee concluded that alogliptin increases hospitalization for heart failure. In line with this conclusion, several observational studies concluded that DPP4Is increase hospitalization for heart failure.5.6A comprehensive meta-analysis involving 54 trials enrolling 74 737 patients noted a near-significant 10.6% increased risk of hospitalization for heart failure in patients taking DPP4ls.7 Moreover, Chen et al concluded that sitagliptin had no cardiovascular benefits, but did increase the risk of recurrent myocardial infarction and coronary revascularization, and the PROLOGUE (Program of Vascular Evaluation under Glucose Control by DPP-4 Inhibitor) study found no evidence that sitagliptin decreases the progression of carotid intima-medial thickness.9 At best, cardio-vascular outcome trials suggest that DPP4ls do not improve cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke.2 This is in stark contrast to glucagon-like peptide-1 receptor agonists (GLP-1RAs), which clearly afford cardiovascular and renal benefits in patients with type 2 diabetes mellitus by directly activating incretin receptors.2

Cistanche acteoside for kidney health

A better understanding of why DPP4ls underperform, relative to GLP-1RAs, with regard to improving cardiovascular and renal outcomes in patients with type 2 diabetes mellitus may reveal important clues as to causes of, and treatments for, cardiovascular and kidney diseases and may suggest ways to improve outcomes with DPP4I therapy. What is needed to achieve these goals is a reliable animal model in which DPP4ls enhance glycemic control yet worsen cardiac and renal outcomes. By using such an animal model, it may be possible to clarify the following:(1) which biochemical systems activated by DPP4ls neutralize the beneficial cardiovascular and renal effects of DPP4ls in patients; (2) which patients would benefit most from DPP4I therapy; and (3) what co-therapies could be combined with DPP4ls to improve patient outcomes.

Unfortunately, in stark contrast to diabetic patients, animal models of diabetes mellitus are overwhelming and consistently show markedly improved renal and cardiovascular outcomes with DPP4I therapy.10-22 However, our recent work demonstrates context-dependent effects of long-term treatment with sitagliptin on blood pressure in animal models. In this regard, we observed that sitagliptin increases arterial blood pressure in spontaneously hypertensive rats (SHR), has little effect on blood pressure in normotensive Wistar-Kyoto rats (WKY), and is antihypertensive in rats with a polygenetically driven version of the metabolic syndrome (Zucker diabetic Sprague-Dawley rats).23 Because these studies used the same drug, same dose, and same experimental design, yet yielded qualitatively different effects on blood pressure, we concluded that the effects of DPP4ls are context dependent.24

Renal effects of herb cistanche

The fact that sitagliptin worsens hypertension in SHR, but does not adversely affect blood pressure in WKY or Zucker diabetic Sprague-Dawley rats, motivated the present study to investigate the "extended" long-term effects of sitagliptin in obese spontaneously hypertensive heart failure rats (SHHF). Because obese SHHF has an SHR genetic background, they should be sensitive to the adverse effects of DPP4ls. Moreover, because SHHF has a phenotype that includes the metabolic syndrome (obesity, diabetes mellitus, dyslipidemia, and hypertension) and cardiac and renal pathological features and dysfunction,25 they should be more sensitive to the negative cardiovascular and renal effects of DPP4ls and should better model the demographics of patients often prescribed DPP4ls. Therefore, we hypothesized that this animal model may be ideal for revealing the negative effects of DPP4ls. The current study shows unequivocally that, in the appropriate genetic background (context), the extended administration of DPP4ls increases blood pressure and worsens cardiac and renal structure and function. These findings have implications for the current use of DPP4Is and suggest that obese SHHF may be a useful preclinical model for achieving a better understanding of the pharmacological features of DPP4ls. This better understanding may, in turn, improve treatment paradigms with DPP4ls and identify novel targets for drugs aimed at preventing and treating cardiovascular and renal diseases.

Cistanche supplements for renal health

Note： The traditional Chinese medicinal herb cistanche (also known as the "dragon herb" and "desert ginseng"), grows only in the arid and warm deserts. As one of the nine immortal herbs, Cistanche (cistanche tubulosa/cistanche deserticola/desertliving cistanche/cistanche salsa)contents with rich effective ingredients such as echinacoside, acteoside, total phenylethanoid glycosides, flavonoids, polysaccharides, etc. these effective ingredients made cistanche a precious nourishing herb and food material for people's immunity, internal organs, and brain cells and neurons, etc. The modern pharmacological studies have confirmed the following effects of cistanche(benefits of cistanche): improve immunity; improve sexual function and kidney function; anti-fatigue; anti-aging; improve memory; anti-Parkinson's disease; anti-Alzheimer's disease; antioxidation; ease-constipation; anti-inflammatory; promote bone growth, whitening skin; protect liver; etc.