ASK DIS: DPP-4 inhibitors in T2DM

Monday, August 3, 2015

Overview

The treatment of type 2 diabetes mellitus (T2DM) has included the use of metformin and sulfonylurea (SU) as first-line anti-diabetic therapies world over since years.
This remains, despite the knowledge that the combination results in a progressive decline in [beta]-cell function and by 3 years up to 50% of diabetic patients can require an additional pharmacological agent to maintain the glycosylated hemoglobin (HbA1c) <7.0% (UKPDS).
The oral DPP-4 inhibitors are new incretin-based therapies for treatment of type 2 diabetes.
Gliptins represent a novel class of agents that improve beta cell health and suppress glucagon, resulting in improved post-prandial and fasting hyperglycemia.
They function by augmenting the incretin system (GLP-1 and GIP) preventing their metabolism by dipeptidyl peptidase-4 (DPP-4).
Not only are they efficacious but also safe (weight neutral) and do not cause significant hypoglycemia, making it a unique class of drugs.
This new class of anti-diabetic agents seems like they have revolutionized the treatment of diabetes.
Although various DPP-4 inhibitors have different pharmacokineic and pharmodynamic profiles, they are remarkably similar with regards anti-hyperglycemic properties with a very safe adverse effect profile (weight neutral without causing hypoglycemia).

According to CPG on Management of DM 4^th Edition, 2009:

It lowers HbA1c by 0.5 – 0.8%, its efficacy improves when used at higher HbA1c baselines.
It can be combined with cumulative efficacy with other OAD agents e.g. metformin, TZDs,
Data comparing it with glipizide suggest equivalent glycaemic efficacy.
Other benefits include is the minimal risk of hypoglycaemia and weight neutrality.
It is excreted unchanged by the kidneys and a reduction of dose is recommended with renal impairment (25mg to 50mg).
It is generally well tolerated.

Dosing of Sitagliptin and Saxagliptin

Saxagliptin : 2.5 mg to 5 mg OD

Safety and Efficacy

The three gliptins (vildagliptin, sitagliptin, saxagliptin) showed almost similar glycemic control and incidence of adverse events.
However, for FBG control, saxagliptin demonstrated superiority to sitagliptin, while, inferiority to vildagliptin.
Sitagliptin and saxagliptin result in similar modest HbA1c reductions and do not increase the risk of hypoglycaemia unless combined with other therapies.
Their role in the long-term treatment of type 2 diabetes remains unclear given the lack of long-term data on efficacy, harms and health outcomes.
When compared to metformin, SU (glimerperide, glipizisde), thiazolidinediones (rosiglitazone, pioglitazone), and alfa-glucosidase inhibitors (voglibose), the use of gliptin has shown to be equally efficacious and non-inferior.
When compared to SU the incidence of hypoglycemia was near negligible with the added advantage of being weight neutral.
A meta-analysis comparing the efficacy of sitagliptin versus vildagliptin showed that the overall HbA1c reduction was ~0.74% and 0.73%, respectively. The glycemic outcomes were better if the initial HbA1c was higher >9% versus <8%.
A recent meta-analysis suggested that using a gliptin (vildagliptin, sitagliptin, saxagliptin or alogliptin) in patients with T2DM was associated with a greater proportion of patients achieving their HbA1c goal of <7%, without any weight gain or hypoglycemia.

References:

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