Monday, August 3, 2015

DPP-4 inhibitors in T2DM

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 4th 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: 

CPG Management On Type 2 Diabetes Mellitus (4th Edition) 2009
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3193779/
http://www.nps.org.au/publications/health-professional/nps-radar/2011/july-2011/gliptins
http://www.ncbi.nlm.nih.gov/pubmed/22098472
http://www.uptodate.com/contents/diabetes-mellitus-type-2-treatment-beyond-the-basics

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