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Incretins

Gliptins – where are we now?

30 Jan, 13 | by sghosal

Insulin resistance and beta cell dysfunction has traditionally been held responsible for the development and progression of diabetes. However, with time we have identified many more pathophysiological defects popularly termed “The Ominous octet” [1]. One of the most important determinants of post-meal hyperglycemia is the pattern of insulin secretion with the first phase (0-10 minutes after an intravenous glucose challenge) playing a very important part [2]. In type 2 diabetes this response is blunted resulting in post-meal hyperglycemia [2].

Alogliptin molecular structure

Alogliptin

 

GLP-1 is a gut hormone, which has an influence on the pancreatic beta cells influencing the first phase insulin release as well as the alpha cells reducing release of glucagon [3]. In type 2 diabetes GLP-1 activity is blunted resulting in hyperglycemia [3]. Systemic GLP-1 has a very short half life (t½ ~ 1-2 min) being degraded by the enzyme Dipeptidyl peptidase-4 (DPP-4) [4]. Gliptins are agents, which inhibits the enzyme DPP-4 thereby increasing the circulatory time of GLP-1 and hence restoring its actions.

We have come a long way in managing hyperglycemia. Yet the goal of reducing CVD outcomes remains elusive. Although the follow-up data from two landmark trials (UKPDS 10-year follow up & DCCT/EDIC) demonstrated CVD outcomes benefit, it was not documented in the trial period per se. [5,6]. It took 23 years in DCCT & 20 years in UKPDS to demonstrate cardiovascular benefits of tight glycemic control. Later on other randomized trials (ACCORD, ADVANCE & VADT)  failed to demonstrate a reduction in CV events in spite of stringent A1C control [7]. Increased incidence of hypoglycemia and weight gain was the two major barriers not only in achieving the stringent glucose targets but also nullifying the CVD benefits.

This is where the incretins (Gliptins & GLP-1 analogs) comes into the picture. The advantages with these agents are the glucose-dependent release of insulin negating the hypoglycemic episodes and also weight loss with GLP-1 analogs & weight neutrality with DPP-4 inhibitors. Recent data suggests when a DPP-4 inhibitor is added to metformin its A1C reducing capacity is equivalent to that of a sulfonylurea [8]. As a result achieving the new composite target in diabetes (A1C reduction without hypoglycemia and weight gain) looks more attractive with a combination including the incretins [9]. In addition to the advantages enlisted above the renal and hepatic safety profile also makes gliptins an attractive choice. Since the introduction of sitagliptin in 2006  and subsequently vildagliptin in 2008 (EU) there has been a lot of changes noticeable not only in the prescribing pattern of the physicians but also the guidelines and recommendations. Saxagliptin was the next to get FDA approval [10] followed by linagliptin and adding to the recent list is Alogliptin, which has received FDA approval this year. Linagliptin can be used in full dose at any stage of renal impairment adding to the already existing list of advantages with DPP-4 inhibitors.

Alogliptin’s FDA approval was put up as a FDA news release on the 25th of January 2013 [11]. Three formulations were given approval – Nesina (alogliptin), Kazano (alogliptin & metformin hydrochloride),and Oseni (alogliptin & pioglitazone). As monotherapy the A1C reduction from baseline was 0.4-0.6%, an additional 1.1% with Kazano & 0.4-0.9% with Oseni (10). However dose alteration is probably required in moderate (50% dose reduction) & severe (25% dose reduction) CKD in line with most gliptins except linagliptin [11].

A few questions:

  • What does alogliptin add to the existing anti-hyperglycemic armamentarium? Is it just another gliptin or does it have something more to offer? Alogliptin has the highest DPP-4 selectivity versus DPP-8,9 & fibroblast activator protein [11] the clinical significance of which is still unknown [12].
  • The other noticeable fact about this new drug is that it got approval (the first of its kind) in all 3 formulations – monotherapy as well as in combination with metformin & pioglitazone. With all the recent controversies surrounding pioglitazone how popular is Oseni going to be?

 

1. Ralph A. DeFronzo. From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus. Diabetes 2009;58: 773-795.

2. Del Prato S and Tiengo A. The importance of first-phase insulin secretion: implications for the therapy of type 2 diabetes mellitus. Diabetes Metab Res Rev 2001; 17(3): 164-74.

3. Garber A.J. Incretin Effects on ß-Cell Function, Replication, and Mass. Diabetes Care 2011; 34(Suppl 2): S258-S263.

4. Andre´ J Scheen. A review of gliptins in 2011. Expert Opin. Pharmacother. 2012; 13(1):81-99.

5. Rury R. Holman, Sanjoy K. Paul, M. Angelyn Bethel, et al. 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Engl J Med 2008; 359:1577-89.

6. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes. N Engl J Med 2005; 353:2643-53.

7. Faramarz Ismail-Beigi, Etie Moghissi, Margaret Tiktin, et al. Individualizing Glycemic Targets in Type 2 Diabetes Mellitus: Implications of Recent Clinical Trials. Ann Intern Med. 2011; 154:554-559.

8. M. A. Nauck, G. Meininger, D. Sheng, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes, Obesity and Metabolism, 2007; 9: 194–205.

9. Bernard Zinman, Wolfgang E. Schmidt, Alan Moses, et al. Achieving a clinically relevant composite outcome of an HbA1c of <7% without weight gain or hypoglycaemia in type 2 diabetes: a meta-analysis of the liraglutide clinical trial programme. Diabetes Obes Metab. 2012; 14(1): 77-82.

10. FDA News Release. FDA approves new drug treatment for type 2 diabetes. 2009. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm174780.htm

11. FDA News Release. FDA approves three new drug treatments for type 2 diabetes. 2013. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm336942.htm [Accessed on:28th January 2013]

12. C. F. Deacon. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes, Obesity and Metabolism, 2011; 13: 7–18.

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