Drug Review - Dipeptidyl peptidase- 4 Inhibitors
Drug review - Dipeptidyl peptidase-4 Inhibitors
Mode of action of DPP-4 inhibitors
Macrovascular and mortality outcomes
Adverse events and precautions
Recommendations for DPP-4-inhibitor use
INTRODUCTION TO INCRETIN-BASED THERAPIES
Incretins are hormones that are secreted into the circulation within minutes of exposure of the gastrointestinal tract lumen to ingested nutrients, resulting in augmentation of insulin release from the pancreatic beta-cells in a glucose-dependent manner.
Two incretins have been identified as having an important role to play in glucose homeostasis. These are glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic peptide (GIP). Both GLP-1 and GIP are responsible for the observed “incretin effect” which is characterised by oral glucose having a greater stimulatory effect on insulin secretion than intravenous glucose.
The net effect of incretin production is to increase insulin-mediated glucose disposal in peripheral tissues and to suppress hepatic glucose production, both of which result in lowering of blood glucose. GLP-1 also suppresses glucagon production and, in pharmacological doses, can delay gastric emptying and reduce food intake. GLP-1 levels are abnormally low in patients with type 2 diabetes mellitus.
Two classes of pharmaceutical agents exploit the beneficial effects of GLP-1 and include the dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists. The DPP-4 inhibitors constitute a relatively new class of agents that enhance the options available for anti-hyperglycaemic therapy and are capable of addressing some of the unmet needs in diabetes.
MODE OF ACTION OF DPP-4 INHIBITORS
Endogenous GLP-1 has a short half-life of one to two minutes, as a result of rapid in-vivo degradation by the enzyme DPP-4. DPP-4 inhibitors are capable of inhibiting the degradation of endogenous GLP-1, thereby therapeutically raising circulating GLP-1 levels. When used alone, DPP-4 inhibitors do not cause hypoglycaemia, because its effects on insulin and glucagon secretion are glucose dependent.
Table I: Comparison of available DPP-4 inhibitors
| DPP-4 inhibitor |
Saxagliptin |
Sitagliptin# |
Vildagliptin* |
| Trade name | Onglyza® | Januvia® | Galvus® |
| Half-life (t ½) | +2.5 hrs | +12 hrs | 1.5-3 hrs |
| Usual Dose | 5 mg once daily | 100 mg once daily | 50 mg once/twice daily* |
| Tablet size | 2.5 mg, 5 mg | 25 mg, 50 mg, 100 mg | 50 mg |
| HbA1c Reduction$ (%) [95% CI] Monotherapy Add-on to Met Add-on to SU Add-on to SU+Met |
~ 0.59 [−0.8 to −0.38] ~ 0.58 [−0.76 to −0.41] ~ 0.72 [−1.22 to −0.22] |
~ 0.78 [−0.95 to −0.62] ~ 0.65 [−0.78 to −0.52] ~ 0.67 [−0.90 to −0.45] ~ 0.89 [−2.41 to 0.63] |
~ 0.6 [−0.80 to −0.40] ~ 0.48 [−0.92 to −0.05] ~ 0.83 [−1.07 to −0.61] ~ 0.76 [−1.01 to −0.51] |
| Liver Metabolism | Liver metabolism Contraindicated in severe hepatic impairment |
Minimal. No dose adjustment with hepatic impairment but caution advised.# |
Contraindicated in moderate to in severe hepatic impairment |
| Renal dose | GFR< 50 ml/min 2.5 mg once daily |
GFR <50 ml/min 50 mg once daily GFR <30 ml/min 25 mg once daily |
GFR <50 ml/min 50 mg once daily |
| Adverse effects | Headache, nasopharyngitis,urinary tract infections | Diarrhoea, nausea, nasopharyngitis | Dizziness, nasopharyngitis |
| SEP at maximum dose | R 256.22 | R 322.10 | R 347.87 |
*Dose is 50 mg once daily when combined with a sulphonylurea; twice daily dosing is needed without sulphonylurea use.
#Despite the lack of hepatic metabolism, use with caution in moderate hepatic impairment and not recommended in severe hepatic impairment.
$Weighted mean difference at usual dose1
SEP - single exit price2
Table adapted from Chen et al3
PHARMACOLOGY
Table I above compares the pharmacological properties of the three DPP-4 inhibitors that are available in South Africa. All of the DPP-4 inhibitors are dosed once daily with the exception that vildagliptin is dosed twice daily when not combined with a sulphonylurea.
There are three DPP-4 inhibitors currently registered in South Africa and these drugs are all administered orally, once or twice daily. They have differing pharmacokinetic profiles but appear to have similar efficacy, and will reduce HbA1C modestly, by approximately 0.5-1.1% compared to placebo. Their main advantages are weight neutrality and the relatively low propensity for hypoglycaemia.
There have been no microvascular outcome studies with DPP-4 inhibitor therapy.
MACROVASCULAR AND THE MORTALITY OUTCOMES
Three studies (SAVOR-TIMI 53, EXAMINE and TECOS) using DPP- 4 inhibitors were designed to assess cardiovascular outcomes using these newer agents.4,5,6 All three studies revealed no increased cardiovascular risk and mortality rates were not elevated. However, an increased rate of hospitalisation for cardiac failure was significant in the SAVOR -TIMI 53 trial with saxagliptin, but this finding remains unexplained and merits further evaluation.5
Results from the CAROLINA and CARMELINA trials using linagliptin, are expected in 2018 and may provide more insight into the long-term outcomes associated with these agents. In the meantime, saxagliptin should not be prescribed in patients with, or at high risk for heart failure (e.g. severe coronary disease, known to have elevated pro-BNP).
ADVERSE EVENTS AND PRECAUTIONS
The DPP-4 inhibitors are usually well tolerated.
Infrequent: Infrequently reported side-effects in clinical trials include upper respiratory infection, nasopharyngitis and headache.
Rare: Rare cases of pancreatitis have been reported in adverse event databases raising concerns about safety but observational studies have been inconclusive. Furthermore, recently published results from three large randomised controlled trials using saxagliptin, alogliptin and sitagliptin (SAVOR-TIMI 53, EXAMINE and TECOS respectively), have individually not shown an increased risk of pancreatitis.4,5,6
A meta-analysis of the trials suggests a statistically significant risk of pancreatitis, however the absolute risk is small. DPP-4 inhibitors are contraindicated a history of a serious hypersensitivity reaction to DPP-4 inhibitors, a history of acute, chronic or recurring pancreatitis, and those with pancreatic cancer.
RECOMMENDATIONS FOR DPP-4 INHIBITOR USE
DPP-4 inhibitors can be employed as monotherapy in patients intolerant of metformin or where metformin use is undesirable. DPP-4 inhibitors can be used in combination with metformin as second-line agents, with a low risk of hypoglycaemia and weight neutrality being advantageous. Some DPP-4 inhibitors are approved for addition as third-line therapy after metformin and sulphonylurea or pioglitazone.
They may be preferred in situations when the risk of hypoglycaemia or its consequences are too high, or when tolerability/adverse event risk limits the use of other treatment options. Some DPP-4 inhibitors are also available in fixed-dose combination tablets with standard-release metformin; these are dosed twice daily. The lower pill burden of a fixed-dose combination without the risk of hypoglycaemia, may improve adherence and facilitate targeting a lower HbA1C safely.
Author: Imran Paruk
Editor: Aslam Amod
References
- Craddy P, Palin H-J, Johnson KI. Comparative Effectiveness of Dipeptidylpeptidase-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison. Diabetes Ther. 2014;5(1):1-41. doi:10.1007/ s13300-014-0061-3.
- South African Medicine Price Registery. Database Of Medicine Prices 14th March 2017. http://www.mpr.gov.za/Publish/ViewDocument.aspx?DocumentPublicatio nId=3285. Accessed March 20, 2017.
- Chen X-W, He Z-X, Zhou Z-W, et al. Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus. Clin Exp Pharmacol Physiol. 2015;42(10):999-1024. doi:10.1111/1440-1681.12455.
- Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373(3):232-242. doi:10.1056/ NEJMoa1501352.
- Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. N Engl J Med. 2013;369(14):1317-1326. doi:10.1056/NEJMoa1307684.
- Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327- 1335. doi:10.1056/NEJMoa1305889.