Dipeptidyl Peptidase IV (DPP IV) Inhibitors


Article Author:
Srinivasa Venkata Siva Kumar Kasina


Article Editor:
Krishna Baradhi


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Updated:
6/24/2019 11:33:33 AM

Indications

DPP-4 inhibitors, known as gliptins, are a class of oral diabetic medications approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus in adults.

DPP-4 inhibitors which have been approved by the FDA include sitagliptin, saxagliptin, linagliptin, and alogliptin. Vildagliptin has approval from the European Medicines Agency (EMA), but not by the FDA.

These drugs act through incretin hormones, which are gut hormones responsible for glucose homeostasis after oral intake of food.

Apart from antihyperglycemic effects, this class of drugs possesses antihypertensive effects, anti-inflammatory effects, antiapoptotic effects and immunomodulatory effect on heart, kidneys and blood vessels independent of the incretin pathway.[1] Some studies have shown that due to all these benefits this class of drugs could also be used in kidney and liver transplant recipients with new-onset diabetes after transplantation (NODAT).[1]

They can be used as monotherapy or add-on therapy with metformin,[2][3][4] sulfonylureas,[5] thiazolidinediones,[6][7] or insulin.[8]

Mechanism of Action

DPP-4 is a ubiquitous enzyme that acts on incretin hormones, mainly GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide) which maintain glucose homeostasis by increasing insulin secretion and decreasing glucagon secretion.[9]

GLP-1 is a hormone secreted by enteroendocrine L cells of the small intestine which lowers blood glucose through stimulation of insulin secretion, reduction in glucagon concentrations and delay in gastric emptying.[10] It has a half-life of fewer than 2 minutes.[11]

GIP is a hormone secreted in the stomach and proximal small intestine by neuroendocrine K-cells. Its half-life is approximately 7 minutes in healthy individuals and 5 minutes in individuals with type 2 diabetes.[11]

These incretins get released within minutes of food intake, and DPP-4 degrades these hormones immediately owing to their short half-life.

DPP-4 inhibitors by inhibiting DPP-4 enzyme increase the levels of GLP-1 and GIP which in turn increase beta cell insulin secretion in the pancreas, thereby reducing postprandial and fasting hyperglycemia.[9]

Administration

All the DPP-4 inhibitors are administered orally, once daily, before or after meals.

A study of oral and intravenous administration of sitagliptin in healthy individuals resulted in 87% oral bioavailability.[10]

Adverse Effects

Gliptins are associated with a low incidence of adverse events including hypoglycemia and also have weight-neutral effects. However, the risk of hypoglycemia increases when used in conjunction with sulfonylureas.[12]

The most common side effects noticed with the DPP-4 inhibitors sitagliptin and saxagliptin are upper respiratory tract infection, nasopharyngitis, headache, urinary tract infection, arthralgia.[10]

There are also reports of hypersensitivity reactions such as anaphylaxis and angioedema in the prescribing information of most DPP-4 inhibitors.[13] Sitagliptin was also associated with Stevens-Johnson syndrome in postmarketing reports[10].

Reports of acute pancreatitis including fatal and non-fatal hemorrhagic or necrotizing variants have correlations with the use of sitagliptin, vildagliptin, and saxagliptin in postmarketing data.[13] However, a causal relationship remains unproven with the use of gliptins and pancreatitis.[14]

There also has been a case series published in Japan of four patients who had acquired hemophilia A with use of DPP-4 inhibitors.[15]

DPP-4 inhibitors (alogliptin, sitagliptin, saxagliptin, linagliptin) did not show an increased risk of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke when compared to placebo in patients with type 2 diabetes,[16][17][18] although saxagliptin had an association with an increased rate of hospitalization for heart failure.[19]

Contraindications

Contraindications to gliptins include type 1 diabetes and diabetic ketoacidosis.

Sitagliptin is contraindicated in individuals who are sensitive to the drug or its components. Caution is necessary when using gliptins in patients with a history of pancreatitis; it would be reasonable to discontinue these drugs if pancreatitis is suspected.[10]

Dose adjustments are necessary for patients with renal insufficiency taking sitagliptin and saxagliptin as these drugs undergo renal excretion; failure to adjust the dose could increase the chance of hypoglycemia.[10]

Monitoring

DPP-4 inhibitors have minimal to no interactions with other drugs because of their pharmacokinetic properties, the exception being saxagliptin. Saxagliptin is metabolized to its active form by CYP3A4/5, hence the levels of drug and its active metabolite might be modified when administered along with drugs affecting CYP3A4/5 isoforms such as ketoconazole, diltiazem (inhibitors of CYP3A4/5) or rifampicin (inducer of CYP3A4/5). Dose adjustments of saxagliptin may be necessary for such instances.[20]

The package insert of sitagliptin mentions about close monitoring when using in conjunction with digoxin as the former causes a small increase (11%) in the area under the curve (AUC) and plasma Cmax (18%) of digoxin. However, dose adjustment is not a recommendation.

Renal function requires monitoring after initiating therapy with either sitagliptin or saxagliptin in addition to glycemic control.[10]

Toxicity

Clinical trials showed no adverse drug reactions using very high doses of saxagliptin, alogliptin, linagliptin. However, high doses of sitagliptin were associated with an 8.0-millisecond mean increase in QTc in controlled clinical trials as labeled by the FDA. In case of overdose, hemodialysis removes approximately 13% of sitagliptin and approximately 23% of saxagliptin but did not affect alogliptin or linagliptin.

Enhancing Healthcare Team Outcomes

A multidisciplinary approach is critical in controlling diabetes and its complications. It requires providers (primary care physician, endocrinologist, ophthalmologist, podiatrist), pharmacist, nurse practitioners, dieticians, and diabetes educator nurses to come together as a comprehensive team in providing care. Literature indicates that such a collaborative effect can improve diabetic management, lower the risk of chronic disease complications. [Level V]

Health care providers can emphasize the importance of metabolic control and other cardiovascular risk factors, promote healthy lifestyle practices including physical activity and healthful eating, and explain the benefits of comprehensive team care.

Diabetes educators and dieticians provide education to the patient in improving patient's weight loss and A1c values with ideal diet and nutrition.

Pharmacists can collaborate with patients and their physicians to improve clinical measures, lower health care costs and making sure that the drugs are in an affordable range to the patient by communicating with patient's insurance companies.

Recognizing danger signs of foot and eye problems and referral to an appropriate provider can be done by any member of the comprehensive team. Various health care providers achieve referral for regular screening.

Specialist providers such as podiatrists, ophthalmologists can help reduce lower extremity amputation rates in foot care clinics, prevent blindness respectively.

National Diabetes Education Program (NDEP), a federally sponsored initiative of National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) is committed to work with public and private partners in preventing or delaying the onset of type 2 diabetes, promoting early diagnosis, improve treatment and outcomes for people with diabetes. It also offers resources to help healthcare professionals implement collaborative, multidisciplinary diabetes team care in a variety of settings.


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Dipeptidyl Peptidase IV (DPP IV) Inhibitors - Questions

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A 50-year-old male with a history of diabetes mellitus, hypertension, atrial fibrillation comes to the clinic for routine follow up. He is on metformin 1000 mg daily, saxagliptin 5 mg daily for diabetes control. Hemoglobin A1c is within the normal range. He was seen by a cardiologist recently and started on diltiazem 240 mg daily for atrial fibrillation. Other medications are amlodipine and a statin. What is the next best step in his medication management?



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A 60-year-old male with diabetes, hypertension, chronic kidney disease comes to the clinic for a follow-up visit. He was started on a new oral hypoglycemic agent which acts by inhibiting DPP-4 enzyme at the last visit. He regularly checks blood sugars at home and are within the normal range. What are the most common side effects of this new drug?



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A 65-year-old female was diagnosed with type 2 diabetes ten years ago. She is on glyburide and metformin. The hemoglobin A1c has been in the normal range for the past three years. However, she lost her father ten months ago leading to her neglecting her diabetes care. She was not compliant with diet, medications, or exercise. When she presented at the last clinic visit, you went over the importance of diet and exercise in controlling diabetes. Today, she comes to the clinic for follow up visit. She reports compliance with diet and exercise and has never missed any doses. This was confirmed by her daughter who accompanied her. The hemoglobin A1c remained above goal at this visit. It is decided to add a third oral drug for diabetes. A few days later, the daughter calls saying that her mother was admitted to hospital for recurrent hypoglycemic episodes. What is the mechanism of action of the third drug that was most likely added to her regimen?



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A 40-year-old obese female with a history of recently diagnosed type 2 diabetes presents to your clinic 3 months after starting metformin therapy. She reports compliance with metformin and is taking the highest dose tolerated. HbA1c level checked today is 7.5%. She has no significant cardiovascular disease. Her labs show serum creatinine of 0.9 mg/dl. What is the mechanism of action of next best medication to add to her current regimen?



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A 43-year-old female with diabetes who was recently started on a new oral antidiabetic medication two months ago presents to the emergency department with a chief complaint of abdominal pain, nausea, and vomiting. Labs revealed normal bicarbonate, normal serum creatinine, elevated lipase, and normal beta-hydroxybutyrate. Which of the most accurately identifies the most likely diagnosis and the offending agent?



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Dipeptidyl Peptidase IV (DPP IV) Inhibitors - References

References

Pathak R,Bridgeman MB, Dipeptidyl Peptidase-4 (DPP-4) Inhibitors In the Management of Diabetes. P     [PubMed]
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Lim SW,Jin JZ,Jin L,Jin J,Li C, Role of dipeptidyl peptidase-4 inhibitors in new-onset diabetes after transplantation. The Korean journal of internal medicine. 2015 Nov;     [PubMed]
Charbonnel B,Karasik A,Liu J,Wu M,Meininger G, Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes care. 2006 Dec;     [PubMed]
Bosi E,Camisasca RP,Collober C,Rochotte E,Garber AJ, Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes care. 2007 Apr;     [PubMed]
DeFronzo RA,Hissa MN,Garber AJ,Luiz Gross J,Yuyan Duan R,Ravichandran S,Chen RS, The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes care. 2009 Sep;     [PubMed]
Salvo F,Moore N,Arnaud M,Robinson P,Raschi E,De Ponti F,Bégaud B,Pariente A, Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis. BMJ (Clinical research ed.). 2016 May 3;     [PubMed]
Hermansen K,Kipnes M,Luo E,Fanurik D,Khatami H,Stein P, Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes, obesity     [PubMed]
Rosenstock J,Brazg R,Andryuk PJ,Lu K,Stein P, Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clinical therapeutics. 2006 Oct;     [PubMed]
Garber AJ,Schweizer A,Baron MA,Rochotte E,Dejager S, Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes, obesity     [PubMed]
Fonseca V,Schweizer A,Albrecht D,Baron MA,Chang I,Dejager S, Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007 Jun;     [PubMed]
Capuano A,Sportiello L,Maiorino MI,Rossi F,Giugliano D,Esposito K, Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy--focus on alogliptin. Drug design, development and therapy. 2013;     [PubMed]
Karagiannis T,Boura P,Tsapas A, Safety of dipeptidyl peptidase 4 inhibitors: a perspective review. Therapeutic advances in drug safety. 2014 Jun;     [PubMed]
Montilla S,Marchesini G,Sammarco A,Trotta MP,Siviero PD,Tomino C,Melchiorri D,Pani L, Drug utilization, safety, and effectiveness of exenatide, sitagliptin, and vildagliptin for type 2 diabetes in the real world: data from the Italian AIFA Anti-diabetics Monitoring Registry. Nutrition, metabolism, and cardiovascular diseases : NMCD. 2014 Dec;     [PubMed]
Yamasaki S,Kadowaki M,Jiromaru T,Takase K,Iwasaki H, Acquired Hemophilia A Associated with Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Type 2 Diabetes Mellitus: A Single-Center Case Series in Japan. Diabetes therapy : research, treatment and education of diabetes and related disorders. 2019 Mar 29;     [PubMed]
Green JB,Bethel MA,Armstrong PW,Buse JB,Engel SS,Garg J,Josse R,Kaufman KD,Koglin J,Korn S,Lachin JM,McGuire DK,Pencina MJ,Standl E,Stein PP,Suryawanshi S,Van de Werf F,Peterson ED,Holman RR, Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. The New England journal of medicine. 2015 Jul 16;     [PubMed]
Rosenstock J,Perkovic V,Johansen OE,Cooper ME,Kahn SE,Marx N,Alexander JH,Pencina M,Toto RD,Wanner C,Zinman B,Woerle HJ,Baanstra D,Pfarr E,Schnaidt S,Meinicke T,George JT,von Eynatten M,McGuire DK, Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial. JAMA. 2019 Jan 1;     [PubMed]
White WB,Cannon CP,Heller SR,Nissen SE,Bergenstal RM,Bakris GL,Perez AT,Fleck PR,Mehta CR,Kupfer S,Wilson C,Cushman WC,Zannad F, Alogliptin after acute coronary syndrome in patients with type 2 diabetes. The New England journal of medicine. 2013 Oct 3;     [PubMed]
Scirica BM,Bhatt DL,Braunwald E,Steg PG,Davidson J,Hirshberg B,Ohman P,Frederich R,Wiviott SD,Hoffman EB,Cavender MA,Udell JA,Desai NR,Mosenzon O,McGuire DK,Ray KK,Leiter LA,Raz I, Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. The New England journal of medicine. 2013 Oct 3;     [PubMed]
Scheen AJ, Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions. Clinical pharmacokinetics. 2010 Sep;     [PubMed]

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