Linagliptin – An Incretin-Based Therapy for Type 2 Diabetes Mellitus

It is estimated that 346 million people worldwide have diabetes. Of this figure, Type 2 Diabetes Mellitus (T2DM) comprises 90% of people with diabetes. T2DM is associated with chronic microvascular and macrovascular complications and management is further complicated in special patient populations such as in those with Chronic Kidney Disease (CKD).

When determining appropriate therapies for T2DM in patients with CKD, individualisation of treatment is necessary and should take into account comorbidities, the history of hypoglycaemia, hypoglycaemia (un)awareness, patient education, motivation, adherence, age, life expectancy, and other medications. Drug therapies often require dose modification, or are not suitable in patients with severe renal impairment as drug clearance is reduced, leading to prolonged exposure to the drug or its metabolites. Other challenges are the adverse effects, particularly hypoglycaemia, and effects on weight, from traditional oral anti-diabetic therapies.

Metformin, a biguanide oral hypoglycaemic, is considered first-line treatment of T2DM, however its use is limited in patients with CKD (particularly moderate to severe CKD) as the plasma half-life is prolonged and renal clearance is reduced, resulting in an increased risk of accumulation and lactic acidosis.

A greater understanding of glucose homeostasis and its role in T2DM novel drug therapies, and in particular the incretin-based therapies, provides further options for prescribers. Linagliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor approved for the treatment of T2DM, does not require dose reduction in renal impairment, and as such may be a valuable addition in the renally impaired population.

Linagliptin (Tradjenta^®, Boehringer Ingelheim Pharmaceuticals) is a competitive, reversible inhibitor of the DPP-4 enzyme which is involved in the degradation of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1).

In humans, eating promotes the secretion of gastrointestinal hormones involved in gut motility, gastric acid and pancreatic enzyme secretion, as well as the stimulation of insulin secretion. GLP-1 is found in the enteroendocrine L cells of the distal ileum and colon, and is secreted upon the ingestion of food. It promotes satiety, reduces appetite, reduces gastric emptying, inhibits glucagon secretion, enhances glucose-dependent insulin secretion by the ß-cells of the pancreas, and promotes ß-cell proliferation.

In addition, GLP-1 may lower postprandial hyperlipidaemia through inhibiting intestinal lipoprotein secretion, and may offer cardioprotection. DPP-4 inhibitors essentially reduce the breakdown of the incretin hormones, in particular GLP-1, thus enhancing glucose-dependent insulin secretion and inhibiting glucagon release. In patients with T2DM, the insulinotropic response to GLP-1 (compared with that of GIP) is preserved, and is the reason for the interest in developing agents targeting GLP-1.

Linagliptin’s oral bioavailability of 30% is not affected by the presence of food. It is extensively protein bound (70%) in a concentration dependent manner, is rapidly absorbed and displays non-linear pharmacokinetics. Its long terminal half-life allows for once daily dosing and it is not extensively metabolised.

What sets linagliptin apart from others in its class is that most DPP-4 inhibitors are eliminated via the kidneys. In the case of linagliptin, elimination is predominantly via the hepatic biliary route, with approximately 85% eliminated in the faeces, and as such does not require dose adjustment in patients with renal impairment.

Linagliptin does not induce or inhibit the cytochrome P450 (CYP) isoenzymes, however it is a P-glycoprotein (P-gp) substrate, and inhibitors or inducers of P-gp may theoretically affect linagliptin’s plasma kinetics. In vivo clinical data has not shown any clinically relevant effects on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin or oral contraceptives. There is a low potential for drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter.

Linagliptin is generally well tolerated and, as with the other drugs in its class is reported to have a lower potential for hypoglycaemia and is also weight neutral. Traditional oral hypoglycaemics such as the insulin secretagogues (e.g. sulphonylureas) promote insulin secretion and so hypoglycaemia and weight gain can occur. There is a negligible risk of hypoglycaemia with the DPP-4 inhibitors because GLP-1 is released in a glucose-dependent manner, and in circumstances where there are low levels of plasma glucose the pharmacological effect is reduced.

Hypoglycaemia is more frequent when used in combination with a sulphonylurea, in the elderly, and renally impaired populations, so caution should be exercised when co-prescribing in these patients. Overall, linagliptin is safe and well tolerated.

In a study by Del Prato et al, linaglipton 5mg was given for 24 weeks to patients with T2DM who were either treatment naïve or had previously been treated with one oral anti-diabetic drug. Treatment with linagliptin resulted in a placebo-corrected change in HbA1c from baseline of -0.69% (p<0.0001). Treatment with linagliptin also resulted in a greater reduction of fasting plasma glucose (adjusted mean change -1.3mmol/L; p<0.0001) and 2 hour postprandial glucose (adjusted mean change -3.2mmol/L; p<0.0001) when compared with placebo. Overall the study found that monotherapy with linagliptin when compared with placebo improved glycaemic control.

Taskinen et al showed that the addition of linagliptin to metformin resulted in a placebo-controlled reduction of 0.64% in HbA1c, 1.2mmol/L in fasting plasma glucose levels and 3.7mmol/L in the two hour postprandial concentrations. This study also found that there was an improvement in the measures of ß-cell function.

Gomis et al compared the effect of linagliptin with placebo when administered once a day for 24 weeks in combination with pioglitazone and found that the combination reduced HbA1c by a further 0.5% (1.1% combination therapy, 0.6% for monotherapy with pioglitazone). Fasting plasma glucose levels were greater in the linagliptin and pioglitazone group (-1.8mmol/L) when compared with the pioglitazone only group (-1.0mmol/L). An enhancement in ß-cell function was also seen.

Owens et al evaluated the use of linagliptin in combination with metformin and a sulphonylurea for 24 weeks. The rationale for this investigation was to look at the use of an agent with a complementary mechanism of action to further control blood glucose levels. It was found that at the end of the 24 weeks, the linagliptin placebo-corrected HbA1c adjusted mean change from baseline was -0.62% (p<0.0001). Linagliptin also produced a greater adjusted mean change in fasting plasma glucose when compared with placebo (-0.7mmol/L; p<0.0001), and an improvement in markers of ß-cell function. There was an increase in hypoglycaemia seen in the linagliptin group; however the paper states that this increase is consistent with other studies using a DPP-4 inhibitor with a sulphonylurea.

Linagliptin is a novel DPP-4 inhibitor administered at a dose of 5mg once daily. By inhibiting DPP-4 enzyme degradation of GLP-1, the result is the enhancement of glucose-dependent insulin secretion and the inhibition of the release of glucagon. It displays non-linear pharmacokinetics, is highly protein bound, and has a long terminal half-life. Its lack of renal elimination gives it an advantage, especially in patients with severe renal impairment. It has limited drug-drug interactions which also makes it a favourable addition for patients with multiple comorbidities, such as those with T2DM and CKD, who require polypharmacy.

Linagliptin appears to be well tolerated and its lower risk of hypoglycaemia and weight neutrality makes it favourable in the treatment of T2DM. It has been demonstrated as being effective clinically as both monotherapy and in combination with other oral hypoglycaemics, and has also demonstrated improvement in ß-cell function.