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Linagliptin; Uses, Dosage, Side Effects, Drug Interactions

Linagliptin is a Dipeptidyl Peptidase 4 Inhibitor. The mechanism of action of linagliptin is as a Dipeptidyl Peptidase 4 Inhibitor.Linagliptin is a potent, orally bioavailable dihydropurinedione-based inhibitor of dipeptidyl peptidase 4 (DPP-4), with hypoglycemic activity. The inhibition of DPP-4 by linagliptin appears to be longer lasting than that by some other DPP-4 inhibitors tested.

Linagliptin is a DPP-4 inhibitor developed by Boehringer Ingelheim for the treatment of type II diabetes [Wikipedia]. Two pharmacological characteristics that sets linagliptin apart from other DPP-4 inhibitors is that it has a non-linear pharmacokinetic profile and is not primarily eliminated by the renal system. FDA approved on May 2, 2011. In comparison, sitagliptin, saxagliptin, and vildagliptin have an IC50 of 19, 50, and 62 nM respectively. A dose of 2.5 and 5 mg reduces the activity of DPP-4 by 72.7% and 86.1% from baseline respectively in healthy male subjects. In diabetes patients, a dose of 5 and 10 mg inhibits >90% of DPP-4. Linagliptin is also selectively inhibited DPP-4 as indicated by the lack of DPP-8 or DPP-9 inhibition at therapeutic exposures in vitro.

Mechanism of Action of Linagliptin

Linagliptin belongs to a class of drugs called DPP-4 inhibitors. DPP-4 inhibitors prevent the hormone incretin from being degraded, allowing insulin to be released from the pancreatic beta cells. While incretin remains in the blood stream, the pancreas is stimulated to produce more insulin. Meanwhile, glucagon release from the pancreas is staggered, preventing glucose level increase. In other words, linagliptin, along with diet and exercise, can help the body produce more insulin and lower blood glucose. Managing blood sugar can mean a lower HbA_1c, an index for glycemia control that theoretically correlates with glucose level in the blood.

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Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta-cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, resulting in a reduction in hepatic glucose output.

Indications of Linagliptin

Type 2 Diabetes Mellitus
The drug can effectively reduce blood sugar
Linagliptin is used for the management of type 2 diabetes mellitus.
Trajenta is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control as monotherapy
when metformin is inappropriate due to intolerance or contraindicated due to renal impairment.
Combination therapy in combination with other medicinal products for the treatment of diabetes, including insulin, when these do not provide adequate glycaemic control.

Contra-Indications of Linagliptin

Low blood sugar
Pituitary hormone deficiency
Decreased Function of the Adrenal Gland
Inadequate Vitamin B12
Excess Body Acid
Extreme Loss of Body Water
Habit of Drinking Too Much Alcohol
Alcohol Intoxication
Heart Attack
Suddenly serious symptoms of heart failure
Liver Problems
Recent operation
Fever
Shock
Severe Vomiting
Severe Diarrhea
Serious Lack of Oxygen in the Blood
Weakened Patient
Injury
Sepsis Syndrome
X-Ray Study with Intravenous Iodine Contrast Agent
Chronic kidney disease stage 3B (moderate)
Chronic kidney disease stage 4 (severe)
Chronic kidney disease stage 5 (failure)
Kidney disease with a likely reduction in kidney function
Pancreatitis

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Dosage of Linagliptin

Strengths: 5 mg

Diabetes Type 2

Recommended dose: 5 mg orally once a day

Side Effects of Linagliptin

Most common

physical weakness (asthenia)
diarrhea
gas (flatulence)
symptoms of weakness, muscle pain (myalgia)
upper respiratory tract infection
low blood sugar (hypoglycemia)
abdominal pain (GI complaints), lactic acidosis (rare)
low blood levels of vitamin B-12
nausea,vomiting
chest discomfort
chills, dizziness
bloating/abdominal distention
constipation
heartburn

More common

Abdominal or stomach discomfort
cough or hoarseness
decreased appetite
diarrhea
fast or shallow breathing
fever or chills
general feeling of discomfort
lower back or side pain
muscle pain or cramping
painful or difficult urination

Less common

Abnormal stools
bad, unusual, or unpleasant (after) taste
change in taste
difficulty with moving
discoloration of the fingernails or toenails
flu-like symptoms
joint pain
rash
runny nose
sneezing
stuffy nose
swollen joints

Drug Interactions of Linagliptin

Linagliptin may interact with following drugs, supplements & may decrease the efficacy of the drug

angiotensin-converting enzyme inhibitors (ACEIs; captopril, enarapril,ramipril)
alcohol
antipsychotic medications (e.g., chlorpromazine, haloperidol, olanzapine,
birth control pills
bupropion
atorvastatin
atypical antipsychotics (e.g., aripiprazole, clozapine, olanzapine; quetiapine, risperidone)
“azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
barbiturates (e.g., pentobarbital, phenobarbital)
crizotinib
cyclosporine
cyproterone
dabrafenib
corticosteroids (e.g., dexamethasone, prednisone)
diabetic drugs (e.g., glyburide, insulin, repaglinide, sitagliptin)
diuretics (e.g., furosemide, hydrochlorothiazide)
HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir)
phenytoin
quinolone antibiotics (e.g., levofloxacin, moxifloxacin)
selective serotonin reuptake inhibitors (SSRIs; citalopram, fluoxetine, sertraline paroxetine,
trimethoprim
vancomycin
verapamil
warfarin

Pregnancy & Lactation of Linagliptin

FDA Pregnancy Category B

Pregnancy

This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.

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Lactation

It is not known if linagliptin passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.