Dipeptidyl Peptidase IV Inhibitors (eg Sitagliptin, Linagliptin, Vildagliptin )in CKD

What is Dipeptidyl Peptidase IV Inhibitors?

Dipeptidyl Peptidase IV Inhibitors are a group of antihyperglycemic or a class of oral hypoglycemic that blocks the enzyme dipeptidyl Peptidase IV that helps to manage diabetes mellitus type-2 which is an increasing risk factor for different kinds of cardiovascular and renal conditions.

Examples of Dipeptidyl Peptidase IV Inhibitors

The following are included in the class of Dipeptidyl Peptidase IV Inhibitors that are approved by the FDA 

• Sitagliptin 
• Saxagliptin
• Linagliptin
• Alogliptin 

However, Sitagliptin is the safest DPP -4 inhibitor known and is also confirmed by FDA for managing type 2 diabetes mellitus. It was the first available DPP-4 inhibitor that came into clinical use. 

What are the functions of Dipeptidyl Peptidase IV Inhibitors? 

• Dipeptidyl Peptidase IV Inhibitors lowers the blood sugar by increasing the levels of insulin hormone after the meals. 
• It also increases the incretin levels that inhibits glucagon release , decreases gastric emptying and therefore decreases blood glucose levels in the body. 
• DPP-4 inhibitor are usually used along with diet and exercise to easily manage blood sugar levels in adults  
• DPP-4 inhibitors are available as single – ingredient products and sometimes, in combination with other diabetes medicines such as metformin. 
• In addition, DPP-4 inhibitors also include some side effects such as inflammation of pancreas and severe joint pains. 

What are the contraindications of DPP-4 inhibitors?

• DPP 4 inhibitors should not be used with type-1 diabetes. 
• Patients should avoid DPP-4 inhibitors in diabetic ketoacidosis. 
• Sitagliptin is usually combined with insulin therapy whereas saxagliptin does not. 

What are the possible side effects of DPP-4 inhibitors?

The possible side effects of DPP-4 inhibitors include:-

• Gastrointestinal problems such as nausea, diarrhoea, and stomach pain. 
• Flu-like symptoms such as headache ,runny nose and sore throat. 
• Certain skin irritations such as painful skin followed by a red or purple rash. 

What are the roles played by Dipeptidyl Peptidase IV Inhibitors in Chronic kidney disorder?

Dipeptidyl Peptidase IV Inhibitors are an effective treatment option for patients with any stage of CKD. It has been studied that patients with diabetes mellitus type-2 have higher risks of Chronic kidney disorder and this situation offers limited therapeutic options. DPP 4 inhibitors are a class of glucose-lowering agents and are known to be very effective in such cases. 

Approximately, 2 million individuals are affected by Chronic kidney disorder. 

• There is an absolute need for treating patients to achieve glucose targets and without the risks of hypoglycaemia. 
• There are lots of management options for such patients to use glucose lowering therapeutic treatments ,in particular the Dipeptidyl Peptidase IV Inhibitors.
• DPP-4 inhibitors prevent the breakdown of GLP-1 as well as glucose dependent insulinotropic peptide, pivotal for glucose regulation in the body. 
• There are currently 4 DPP-4 inhibitors approved by FDA ,also effective at lowering HbA1C in patients aged 60 years and older suffering with moderate to severe kidney insufficiency including ESRD and dialysis. 
• On analysis, patients with moderate to severe CKD demonstrated that DPP-4 inhibitor monotherapy successfully reduced HbA1C and however, was not associated with a risk of increased hypoglycemia or weight gain. No reports showed increase in body weight, incidents of severe adverse events or any mortalities. 
• According to the studies, Dipeptidyl Peptidase IV Inhibitors exhibit Reno protective effects along with antihyperglycemic effects. Multiple logistic regression analysis suggests that DPP-4 inhibitors significantly lowers the estimated glomerular filtration rate decline (20%over 12 months ,odds ratio,0.626, 95% confidence interval).

Similar results were obtained by Cox proportional hazards regression analysis (hazard ratio,0.707;959%CI). This analysis suggests that DPP-4 inhibitors suppress the decrease of estimated glomerular filtration rate in patients with Diabetes Mellitus with a renoprotective effect. 

• DPP-4 inhibitors enhance the function of endogenous incretins by particularly inhibiting incretin – degrading enzyme DPP-4. Incretins are actually the gut hormones secreted after foods. 
• DPP-4 inhibitor is an ubiquitous protein with an exopeptidase activity existing in cell membrane and in soluble forms. Also, the kidneys contain the highest levels of DPP-4 which is known to be increased in nephropathy. 
• Of all the DPP 4 inhibitors , Linagliptin is the most potent inhibitor that has the highest affinity for these proteins with the largest volume of distributions. These properties of Linagliptin allow it to penetrate kidney tissues and tightly bind to resident DPP-4 inhibitors.
• In the animal models of kidney disease or renal failures, Linagliptin explicit various renoprotective effects such as well that includes reducing albuminuria, glomerulosclerosis, and tubulointerstitial  fibrosis and independent of changes in glucagon like peptide-1(GLP-1 ) as well as the glucose levels.
• On a closer look to the molecular level, Linagliptin prevents the profibrotic endothelial to mesenchymal transition by disrupting the interaction between membrane bound DPP-4 and integrin beta1 that usually enhances signalling by transforming the growth factor beta-1 and vascular endothelial growth factor receptor. 
• Linagliptin is also known to increase stromal cells derived factor -1 levels, ameliorated endothelial dysfunction and the displayed unique antioxidant effects. 
• Linagliptin is the only drug to be excreted predominantly by non renal pathways and does not require adjustments in dose for the respective Chronic kidney disorder . On the contrary, Sitagliptin , Saxagliptin ,alogliptin and vildagliptin are mainly excreted by the kidneys itself which necessitates certain adjustments in dose for renal impaired patients. 

Other facts about Dipeptidyl peptidase 4 inhibitors 

• DPP 4 is also known as CD26 and glycoprotein gp110 .
• The catalytic activity of DPP-4 states that it removes the N-terminal dipeptide from peptides containing proline or alanine in the second position of the chain. 
• Soluble DPP-4 is also found in the blood and almost other body fluids and is thought to have arisen from the shedding of membrane forms. 
• It was discovered 50 years ago. 
•  It is a Multifunctional protein and was first characterized as a T-cell differentiation antigen(CD26). 
• It is involved in various protein-protein interactions, also including association with adenosine deaminase in most of the tissues and with the HIV envelope glycoprotein gp120 on T lymphocytes. 
• DPP-4 is present throughout the body but its levels vary widely between different organs . However, the highest amounts of DPP-4 activity per gram of tissue are found in kidneys. 

Sitagliptin in Chronic Kidney Disease 

• Sitagliptin was first approved by the FDA and is a potent and highly selective Dipeptidyl peptidase 4 inhibitor. Sitagliptin is effective and does not affect the closely related enzymes such as DPP-8 or DPP-9 at therapeutic concentrations.
• It is an oral antidiabetic drug with a recommendation of 100mg as a dose per day or it varies in different situations. Also, Sitagliptin reflects 87% of bioavailability and a reversible fraction bound to plasma proteins of 38% with a half life of around 12.4 hours. 
• Sitagliptin holds minimal hepatic metabolism mainly by cytochrome P4503A4  ,while its excretion is done to 70%-80% by the kidney in its unchanged form with a renal clearance of approximately 350mL/min. 

Dosages of Sitagliptin in Chronic kidney disorder.

Dosage forms and strengths of Sitagliptin-

Tablet-

• 25mg
• 50mg
• 100mg

Dosage modifications 

Renal impairment 

• eGFR>_ 45 to <90mL/min / 1.74m^2. No dosage adjustment required.
• eGFR 30 to<45mL/min/ 1.73m^2: 50 mg PO q Day required.
• eGFR <30mL/min /1.73 m^2 ; 25 mg POq Day recommended.
• End stage renal disease demanding haemodialysis or peritoneal dialysis ; 25 MG POq Day regardless of the timings of dialysis. 

Limitation

Not recommended with diagnosis in patients with a history of pancreatitis.

Adverse effects of using Sitagliptin

• Constipation
• Vomiting
• Headache
• Back pain.
• Pruritus

Vildagliptin in chronic kidney disease 

• Vildagliptin is major used as an effective treatment option for chronic kidney disease as it is rapidly absorbed orally active, potent, selective and reversible DPP 4 inhibitor, effective and is well tolerated in T2DM patients as well taken either as monotherapy or in combination with other OADs.
• The main route for the elimination of  Vildagliptin is hydrolysis by our tissues or organs with around 25% of the drug excreted unchanged by the kidneys from the body. Also, DPP -enzyme contributes to the formation of a major metabolite LAY51 that preferably suggests that  Vildagliptin is a known substrate for DPP 4.
• Kidneys play a partial role in the elimination of Vildagliptin. It has been seen that there is no significant alteration in Vildagliptin pharmacokinetics in patients with mild renal impairment (eGFR <_80 and >50 ml/min/1.73m^2) , so it does not require dose adjustment.
• The pharmacodynamics of Vildagliptin shows that a single dose of 10 to 400 milligram of Vildagliptin includes greater than 90% inhibition of DPP four activity between 0.5 and 4.5 hours post dose.
• Vildagliptin is one of the doctors’ favourite options for chronic kidney patients. When Vildagliptin treatment continues for approximately 24 weeks, it significantly not only decreases proteinuria and albuminuria but also improves GFR glomerular filtration rate, thereby reducing kidney injury. However, these results are likely dependent upon the doses. Also, vildagliptin is more effective in decreasing Hb A1C.
• In some other animal models, it has also been noticed that Vildagliptin was even able to prevent decreasing myogenic construction of intra renal arteries, thereby reducing glomerular sclerosis. Vildagliptin is also able to decrease tubular necrosis by the inhibition of apoptosis signalling in the renal proximal epithelial cells.
• Another reason to choose Vildagliptin is that Vildagliptin is a well tolerated treatment option in 169 drug naïve  elderly patients with T2DM, 50% of whom is having at least mild renal impairment that is global filtration must be between 50 and 80ML per minute 1.73 meters square.
• Vildagliptin also shows improvements in some cardio renal parameters. However, no major differences were noticed in hepatic pancreatic and skin adverse events in patients when treated with vildagliptin.
• The patients who are on haemodialysis received a daily dosage of 50 milligram  Vildagliptin.
• Vildagliptin has the largest amount of data in patients with moderate to severe renal functions and demonstrates a good clinical profile in terms of efficacy and safety.

Dose and strength of Vildagliptin tablet

• 25 milligram
• 50 milligram
• 100 milligram.

That adjustment of Vildagliptin in patients with renal impairment

• When eGFR/min is 60-89 , the recommended dose of Vildagliptin is maximally daily doses 100 milligram.
• When eGFR per minute is 45 to 59 the maximal daily dose of Vildagliptin  is 50 milligram.
• When eGFR permanent is in the range of 30 or below 30 the daily dose of Vildagliptin recommended is 50 milligram and in severe cases the adjustment in dose is done by the physician.

Limitations of Vildagliptin

• Sometimes, the gliptin causes serious dizziness or fatigue. It is also recommended that one should not drive vehicles or operate heavy machinery’s while or after taking Vildagliptin.
• Vildagliptin is mainly contraindicated in patients with severe hepatic disorders type one diabetes and diabetic ketoacidosis.

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Conclusion

Sitagliptin was the first DPP-4 inhibitor that came into clinical practice being licensed in 2006. It has also proved helpful and effective in triple therapy. An additional feature of maintaining low risks of hypoglycemia and its weight-neutral properties makes it a recommended choice as compared to other drugs such as sulfonylurea or thiazolidinedione in various aspects. 

The major portion of Sitagliptin is excreted unchanged following glomerular filtration.