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Archive for January, 2013

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.

Avandia compensation claims in the UK

30 Jan, 13 | by Dr Dean Jenkins

The Guardian is today running with a story about the difference in compensation claims for families in the UK and US whose relatives may have suffered harm from rosiglitazone (Avandia) which was a drug for Type 2 Diabetes until its license was revoked in 2010.

http://www.guardian.co.uk/business/2013/jan/29/glaxosmithkline-legal-fight-uk-diabetesGlaxoSmithKlines-Avandia--007

“The manufacturer, GlaxoSmithKline, has admitted concealing data about the damaging side-effects of the drug, and there is evidence of the drug’s harmful effects. But, despite this, GSK is not prepared to settle claims in the UK without a court fight.

The history of drug litigation in the UK suggests that families might not easily get  compensation.”

Rosiglitazone seemed to be a useful drug in Type 2 diabetes which worked very well in only a small proportion of people with Type 2 diabetes. In others it increased the risk of fluid retention, heart failure and myocardial infarction. GSK hid the data and it took a meta-analysis of published data from the FDA and GSK itself to highlight the risk [1]. In 2012 the company paid a multi-billion dollar fine for Avandia and several other drugs which some have suggested could be written off as a business cost.

How court cases are settled in the UK and US obviously differ but it is hard to explain that to families who feel they are affected when there has been such international corporate wrongdoing. Expect to see more news of the ongoing Avandia saga for some time yet.

1. Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. New England Journal of Medicine 2007;356(24):2457–2471. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa072761

Diabulimia – what’s in a name?

25 Jan, 13 | by Dr Dean Jenkins

The charity DWED (Diabetes with Eating Disorders) is “campaigning to have omitting insulin to lose weight officially recognised as a mental illness“.

http://www.bbc.co.uk/newsbeat/20988655

Image of a roseIt is alarming that as many as 30% of adolescent Type 1 females may have altered their insulin doses to lose weight [1]. Reducing insulin causes glucose to rise, many calories are ‘excreted’ in the urine and there is a risk of ketosis and dehydration. In the longer term the poor control increases the risk of microvascular complications of diabetes. Adding binge-eating with vomiting or anorexia to this insulin manipulation makes for a dangerous venture in weight control.

A patient perspective case report [2] gives a good account of how a young person with diabetes started using insulin manipulation and vomiting to control her weight after diagnosis:

“I developed a fear that my weight would continue increasing and never stop. I began cutting back on my insulin to lose a few pounds. When I moved away to college, I started using insulin manipulation again to lose weight. This time, my body was more fragile. One night, I was nauseated, throwing up, and on the verge of diabetic ketoacidosis. I realized I no longer needed to wait until my blood sugar became dangerously high to throw up; I could just make myself do it. It was then that I came to believe that, between insulin manipulation and bulimia, I had found the perfect ‘diet’.”

Giving some ‘condition’ a name is a very useful way of increasing its recognition. The more academic and descriptive ‘disordered eating behaviour in people with type 1 diabetes’ is nowhere near as succinct as the combination of two terms ‘diabetes’ and ‘bulimia’ into a single word ‘diabulimia’. What is in a name? What matters most is what something is, not what it is called.

Is there sufficient reason for labelling this condition as a mental illness? For those that have an eating disorder there is already a classification system and an evidence base for management [3]. I think the additional manipulation of insulin does not necessarily represent another diagnosis; instead, it should be a marker of increased risk and urgency for management under existing guidelines.

 

1. Rydall AC, Rodin GM, Olmsted MP, Devenyi RG, Daneman D. Disordered Eating Behavior and Microvascular Complications in Young Women with Insulin-Dependent Diabetes Mellitus. New England Journal of Medicine 1997;336(26):1849–1854. Available from: http://www.nejm.org/doi/full/10.1056/NEJM199706263362601

2. A battle to overcome ‘diabulimia’. Am Fam Physician 2009 Feb;79(4):263; discussion 263.

3. NICE Eating disorders (CG9): Core interventions in the treatment and management of anorexia nervosa, bulimia nervosa and related eating disorders. 2004. http://www.nice.org.uk/cg009

New formula suggested for BMI

24 Jan, 13 | by Dr Dean Jenkins

In 1832, whilst trying to define ‘normal’, Adolphe Quetelet, Belgian polymath, defined an index – the Quetelet Index – which later became known as the Body Mass Index (BMI) and is used as an indicator of obesity which has become recognised as an important marker of early mortality. [1] Typical BMI chart

The formula is well known to us though rather cumbersome to calculate. It is weight in kilograms divided by the square of height in metres. We are all familiar with the swathes of colour that map out underweight, normal, overweight and obese. We may very well say to people in our clinics that ‘according to your BMI you seem to be obese!’.

However, there is a problem with the index in that it doesn’t quite catch the nature of obesity and human growth. Those who tend to be below average height score slightly lower on this index than perhaps they should. The opposite is true of people who are taller than average. Clearly we can’t change our height but when certain recommendations [2] have explicit levels of BMI we need to be sure it is representing what we feel it should. The problem is mainly to do with the power that the height is raised to and Quetelet seems to have recognised that too (though he wasn’t so concerned with obesity). Babies seem to require a power of 3 to correctly recognise their growth in all dimensions and children would probably benefit from a figure of 2 since they grow more vertically. Adults fall in between and 2.5 seems to fit better.

So, Professor Nick Trefethen of Oxford University, made all these points and has suggested a refined formula following a letter to The Economist where he said:

“millions of short people think they are thinner than they are, and millions of tall people think they are fatter”

His formula is:

BMI = 1.3*weight(kg)/height(m)2.5

In the diabetes literature there is concern over the suitability of BMI in those with short-stature [3] and its usefulness when compared with other measures [4].

So, will you be using the new (slightly more cumbersome) formula in your clinic?

 

1. Garabed Eknoyan. Adolphe Quetelet (1796–1874)—the average man and indices of obesity.  Nephrol. Dial. Transplant. (2008) 23 (1): 47-51. doi: 10.1093/ndt/gfm517

2. NICE Clinical Guideline 43. Obesity. http://www.nice.org.uk/cg43

3. Lara-Esqueda A, Aguilar-Salinas CA, Velazquez-Monroy O, Gómez-Pérez FJ, Rosas-Peralta M, Mehta R, Tapia-Conyer R. The body mass index is a less-sensitive tool for detecting cases with obesity-associated co-morbidities in short stature subjects. Int J Obes Relat Metab Disord. 2004 Nov;28(11):1443-50.

4. Lee CM, Huxley RR, Wildman RP, Woodward M. Indices of abdominal obesity are better discriminators of cardiovascular risk factors than BMI: a meta-analysis. J Clin Epidemiol. 2008 Jul;61(7):646-53. doi: 10.1016/j.jclinepi.2007.08.012.

Welcome!

8 Jan, 13 | by Dr Dean Jenkins

Welcome to the BMJ Group Diabetes Blog which has now launched!

This Blog will be maintained by a team of writers mostly made up of the faculty of the Postgraduate Diploma in Diabetes programme run by BMJ Learning and validated by the University of Leicester.

We hope to bring comments and opinions about diabetes, the different perspectives, latest scientific discoveries, reports of conferences, and the views of people with diabetes.

Looking forward to a much wider discussion and hoping to share some of the enthusiasm and advocacy for diabetes that we see on the Diploma programme.

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