Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD) progression in experimental diabetic nephropathy in a glucose-independent manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. Animals were allocated to 1 of 4 groups: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus linagliptin; and 5/6 nephrectomy plus telmisartan. Interstitial fibrosis was significantly decreased by 48% with linagliptin but a non-significant 24% with telmisartan versus placebo. The urine albumin-to-creatinine ratio was significantly decreased by 66% with linagliptin and 92% with telmisartan versus placebo. Blood pressure was significantly lowered by telmisartan, but it was not affected by linagliptin. As shown by mass spectrometry, the number of altered peptide signals for linagliptin in plasma was 552 and 320 in the kidney. For telmisartan, there were 108 peptide changes in plasma and 363 in the kidney versus placebo. Linagliptin up-regulated peptides derived from collagen type I, apolipoprotein C1, and heterogeneous nuclear ribonucleoproteins A2/B1, a potential downstream target of atrial natriuretic peptide, whereas telmisartan up-regulated angiotensin II. A second study was conducted to confirm these findings in 5/6 nephrectomy wild-type and genetically deficient DPP-4 rats treated with linagliptin or placebo. Linagliptin therapy in wild-type rats was as effective as DPP-4 genetic deficiency in terms of albuminuria reduction. Thus, linagliptin showed comparable efficacy to telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. However, the underlying pathways seem to be different.

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Diabetic nephropathy is one of the most frequent, devastating and costly complications of diabetes. The available therapeutic approaches are limited. Dipeptidyl peptidase type 4 (DPP-4) inhibitors represent a new class of glucose-lowering drugs that might also have reno-protective properties. DPP-4 exists in two forms: a plasma membranebound form and a soluble form, and can exert many biological actions mainly through its peptidase activity and interaction with extracellular matrix components. The kidneys have the highest DPP-4 expression level in mammalians. DPP-4 expression and urinary activity are up-regulated in diabetic nephropathy, highlighting its role as a potential target to manage diabetic nephropathy. Preclinical animal studies and some clinical data suggest that DPP-4 inhibitors decrease the progression of diabetic nephropathy in a blood pressure-and glucose-independent manner. Many studies reported that these reno-protective effects could be due to increased half-life of DPP-4 substrates such as glucagon-like peptide-1 (GLP-1) and stromal derived factor-1 alpha (SDF-1a). However, the underlying mechanisms are far from being completely understood and clearly need further investigations.

Aim: ACE2 is the receptor for SARS-CoV-2. Animal studies suggest that RAAS blockers might increase the expression of ACE2 and potentially increase the risk of SARS-Cov-2 infection. Methods and Results: The effect of ACE inhibitor (ACEi) treatment on the pneumonia incidence in non-COVID-19 patients (25 studies, 330,780 patients) was associated with a 26% reduction of pneumonia risk (OR: 0.74, p<0.001). Pneumonia related death cases in ACEi treated non-COVID-19 patients were reduced by 27% (OR: 0.73, p=0.004). However, ARB treatment (10 studies, 275,621 non-COVID-19 patients) did not alter pneumonia risk in patients. Pneumonia related death cases in ARBs treated non-COVID-19 patients was analysed only in one study and was significantly reduced (OR, 0.47; 95% CI, 0.30 to 0.72). Results from 11 studies (8.4 million patients) showed that the risk of getting infected with the SARS-CoV-2 virus was reduced by 13% (OR: 0.87, p=0.014) in patients treated with ACEi, whereas analysis from 10 studies (8.4 million patients) treated with ARBs showed no effect (OR, 0.92, p=0.354). Results from 34 studies in 67,644 COVID-19 patients showed that RAAS blockade reduces all-cause mortality by 24% (OR=0.76, p=0.04). Conclusion: ACEi reduces the risk of getting infected with the SARS-CoV-2 virus. Blocking the RAAS may decrease all cause mortality in COVID-19 patients. ACE inhibitors do reduce the risk of non-COVID pneumonia. All cause mortality due to non-COVID pneumonia is reduced by ACEi and potentially by ARBs.