Two drugs for type 2 diabetes seem to raise risk of acute pancreatitis, study showsBMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f1304 (Published 27 February 2013) Cite this as: BMJ 2013;346:f1304
All rapid responses
There are further Concerns of Prescribing Glucagon-like peptide-1 Analogues:
The prescribing information for Liraglutide (Victoza) also states ‘There is limited experience in patients with mild, moderate or severe hepatic (liver) impairment. Therefore, Victoza should be used with caution in this patient population.’ (1)
With increasingly sedentary lifestyles and changing dietary patterns, the prevalence of obesity and insulin resistance have increased, and non alcoholic fatty liver disease (NAFLD) has become the most common cause of abnormal liver function in many developed countries. (2)
Liver disease is a major cause of morbidity and mortality in sub-Saharan Africa, including Nigeria, due to the high endemicity of viral hepatitis B. (3) Many patients remain undiagnosed and so it is not known what the true prevalences of steatosis and steatohepatitis are and how many people will actually develop liver related morbidity. (4)
The presence of steatosis and particularly the progression of insulin resistance to diabetes mellitus, adversely affect the course of chronic hepatitis C leading to an increase in steatohepatitis and higher annual rates in the progression of fibrosis. (5)(6)(7)(8) This is also prevalent in other countries, including China (9) and India. (10)
A significant concern regarding hepatic function is there are estimated to be around 33 million people living with Human Immunodeficiency Virus (HIV) infection around the world. (11) The immunosuppression resulting from HIV infection is known to lead to more rapid progression of hepatitis C virus related liver pathology. (12) A disease with a particularly high, and often hidden, prevalence around the world. More than 60% of all HIV-infected adults live in Sub-Saharan Africa. (13) In India it is estimated that around 2.4 million people are currently living with HIV. (14)
The high prevalence of hepatic diseases in the developing world, with the prescribing of new diabetes drugs warrants caution. Alcohol consumption represents another concern.
Glucagon-like peptide-1 and Insulin use.
The use of (GLP-1) diabetes drugs combined with insulin represents another concern. Exenatide is sometimes used with insulin in clinical practice in the UK. (15)
The U.S. Food and Drug Administration (FDA) has recently approved (Exenatide) as an add-on therapy to insulin Glargine, with or without metformin and/or a thiazolidinedione (TZD), in conjunction with diet and exercise for adults with T2DM who are not achieving adequate glycaemic control on insulin Glargine alone. (16)
Studies have also been undertaken to evaluate the safety and efficacy of adding the long acting insulin Levemir to treatment with Victoza. (17) Glucagon-like peptide-1 analogues (GLP-1) suppress glucagon release (thus reducing hepatic gluconeogenesis). Epinephrine and glucagon are the counter regulatory factors in nocturnal hypoglycaemia. These hormones are secreted promptly after plasma glucose levels fall, and both induce a rapid increase in endogenous glucose production (to prevent hypoglycaemia). (18)
This would mean mild hypoglycaemia may proceed unnoticed to more advanced and dangerous phases. Diabetics with impaired awareness of hypoglycaemia, in addition to defective counter regulation, may be at the greatest risk of developing severe hypoglycaemia. (19) A phenomenon usually associated with T1DM and insulin therapy.
Further to this concern, studies are now being undertaken on T1DM subjects using Liraglutide (Victoza) as an additional treatment for those on insulin. (20)(21)(22)
Exenatide has also been studied in the US on adolescents (age13-22) with suggestion of therapeutic potential. Further larger studies are planned in combination with insulin. (23)
Normal thyroid function, which is essential for normal growth, development and the regulation of energy metabolism within cells, is dependent on a normally functioning thyroid and liver axis.
It has long been known that the liver is the major site for cholesterol and triglyceride metabolism, and the thyroid hormones play an integral part in hepatic lipid homeostasis. Thyroid hormones increase the expression of LDL receptors on the hepatocytes, (24) and increase the activity of lipid‐lowering liver enzymes, resulting in a reduction in low‐density lipoprotein levels. (25)
Subclinical hypothyroidism is a known risk factor for nephropathy and cardiovascular diseases in T2DM patients. (26)(27)
Abnormalities of thyroid function are seen in chronic liver diseases. Of patients treated with alpha interferon for hepatitis C, 2.5–10% developed thyroid dysfunction, (28) (29) with both thyrotoxicosis (due to acute thyroiditis) and hypothyoidism being observed. (30) Thyroid anomalies have been highlighted in GLP-1 analogue trials. Of liraglutide-treated patients, thyroid neoplasms, increased blood calcitonin and goitres are the most frequently thyroid adverse events and were reported in 0.5%, 1% and 0.8% of patients, respectively. (31)
A complex relationship exists between the thyroid gland and the liver in both health and disease. A multisystem approach to treating patients with diseases affecting either organ is vital to avoid missing subtle but clinically relevant abnormalities. (32) This is important within diabetes care.
Accurate Diagnosis of Diabetes Type.
The age of onset of T2DM is decreasing in countries such as Sub-Saharan Africa. (33)
The decreasing age for T2DM may also confuse the correct diagnosis of diabetes type. As supported by a recent report from the Royal College of General Practitioners and NHS Diabetes in the UK, (34)
Does the developing world have the facilities and the relevant expertise within this area to overcome these problems? On average, there are 15 times the numbers of doctors and 8 times the number of nurses in Europe compared to Africa. (35) The World Health Organization estimates that the global shortage of trained health care staff exceeds four million. (36) Malawi, for example. has just one doctor per 50,000 people compared to the United States with one per 390 people. (37)
'Type 2 diabetes represents a worldwide significant problem, investigating affordable safe solutions should be a priority not the fast tracking of unaffordable drugs. The BMJ has been conducting a campaign into drug trial truth and transparency. If this was ever needed more, it would be in the diabetes industry. Time for common sense in T2DM care not rapid progression to barely tested drugs. People around the world need to have a working knowledge of how to prevent/manage diabetes and have a good quality of life. The drug centred approach is unsustainable and doesn’t encourage prevention.
(1) Novo nordisk Victoza Reference ID: 2948949 Prescribing Information. Pdf Accessed 28th February 2013
(2) Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol2010;53:372-84
(3) Onyekwere CA, Ogbera AO, Balogun BO. Non-alcoholic fatty liver disease and the metabolic syndrome in an urban hospital serving an African community. Ann Hepatol. 2011 Apr-Jun;10(2):119-24
(4) Quentin M Anstee, Stuart McPherson, Christopher P Day, How big a problem is non-alcoholic fatty liver disease? BMJ 2011; 343:d3897
(5) Fartoux L, Chazouilleres O, Wendum D, Poupon R, Serfaty L. Impact of steatosis on progression of fibrosis in patients with mild hepatitis C. HEPATOLOGY 2005; 41: 82–87.
(6) Adinolfi LE, Gambardeall M, Andreana A, Tripodi MF, Utli R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. HEPATOLOGY 2001; 33: 1358–1364.
(7) Hickman IJ, Powell EE, Prins JB, Clouston AD, Ash S, Purdie DM, et al. In overweight patients with chronic hepatitis C, circulating insulin is associated with hepatic fibrosis: implications for therapy. J Hepatol 2003; 39: 1042–1048.
(8) Global challenges in liver disease †Roger Williams,
Article first published online: 29 AUG 2006 DOI: 10.1002/hep.21347
Copyright © 2006 American Association for the Study of Liver Diseases
(9) Fan JG, Farrell GC Epidemiology of non-alcoholic fatty liver disease in China J Hepatol. 2009 Jan;50(1):204-10.
(10) Duseja A. Non-alcoholic fatty liver disease in India - a lot done, yet more required! Indian J Gastroenterol. 2010 Nov; 29(6):217-25(23) www.who.int/hiv accessed 28th February 2013
(11) www.who.int/hiv accessed 28th February2013
(12) G Antonucci, D Goletti, S Lanini, E Girardi and O Loiacono HIV/HCV co-infection: putting the pieces of the puzzle together Cell Death and Differentiation (2003) 10, S25–S26.
(13) R. Choi, C. Farquhar AIDS, Epidemiology and Surveillance International Encyclopedia of Public Health, 2008, Pages 76-90
(14) UNAIDS (2010) 'UNAIDS report on the global AIDS epidemic
(15) Yoon NM, Cavaghan MK, Brunelle RL, Roach P. Exenatide added to insulin therapy: a retrospective review of clinical practice over two years in an academic endocrinology outpatient setting. Clinical Therapeutics2009;31:1511-23.
(16) Baptist Gallwitz. (2011) Glucagon-like Peptide–1 Analogues for Type 2 Diabetes Mellitus. Drugs 71:13, 1675-1688
(17) Rosenstock J et al. New Type 2 Diabetes Treatment Paradigm: Sequential Addition of Liraglutide to Metformin and then Basal Insulin Detemir. Presented at American Diabetes Association (ADA) June 2011.
(18) PE Cryer, L Axelrod, AB Grossman Evaluation and management of adult hypoglyceamic disorders: an Endocrine Society Clinical Practice Guideline Journal of Clinical Endocrinology and metabolism. 2009 vol. 94 no. 3 709-728 009
(19) Hypoglycaemia in diabetes: Common, often unrecognized Ilan Gabriely, Md Harry Shamoon, Md Cleveland Clinic Journal Of Medicine Volume 71 • Number 4 April 2004
(20) A. Varanasi, N. Bellini, D. Rawal, M. Vora, A. Makdissi, S. Dhindsa, A. Chaudhuri, P. Dandona. Liraglutide as Additional Treatment in Type 1 Diabetes. European Journal of Endocrinology, 2011; DOI: 10.1530/EJE-11-0330
(21) Kielgast U, Krarup T, Holst JJ, Madsbad S. Four weeks of treatment with liraglutide reduces insulin dose without loss of glycaemic control in type 1 diabetic patients with and without residual beta-cell function. Diabetes Care. 2011 Jul; 34(7):1463-8. Epub 2011 May 18.
(22) Deiss D, Diederich S, Kordonouri O. Dtsch Med Wochenschr.Successful treatment with liraglutide in type 1 diabetes and MODY. 2011 May; 136(21):1116-20. Epub 2011 May 17
(23) Raman VS, Mason KJ, Rodriguez LM, Hassan K, Yu X, Bomgaars L, Heptulla RA. The role of adjunctive exenatide therapy in paediatric type 1 diabetes. Diabetes Care. 2010 Jun;33(6):1294-6. Epub 2010 Mar 23.
(24) Ness GC, Lopez D, Chambers CM, Newsome WP, Cornelius P, Long CA, Harwood HJ, Jr. Effects of L‐triiodothyronine and the thyromimetic L‐94901 on serum lipoprotein levels and hepatic low‐density lipoprotein receptor, 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase, and apo A‐I gene expression. Biochem Pharmacol 1998; 56:121–9.
(25) Ness GC, Lopez D. Transcriptional regulation of rat hepatic low‐density lipoprotein receptor and cholesterol 7 alpha hydroxylase by thyroid hormone. Arch Biochem Biophys1995; 323:404–8.
(26) Hage M, Zantout MS, Azar ST Thyroid disorders and diabetes mellitus. J Thyroid Res. 2011;2011:439463. Epub 2011 Jul 12
(27) Chen HS, Wu TE, Jap TS, Lu RA, Wang ML, Chen RL, Lin HD. Subclinical hypothyroidism is a risk factor for nephropathy and cardiovascular diseases in Type 2 diabetic patients. Diabet Med. 2007 Dec;24(12):1336-44.
(28) Benelhadj S, Marcellin P, Castelnau C, Colas‐Linhart N, Benhamou JP, Erlinger S, Bok B. Incidence of dysthyroidism during interferon therapy in chronic hepatitis C. Horm Res 1997; 48:209–14.
(29) Shimizu Y, Joho S, Watanabe A. Hepatic injury after interferon‐alpha therapy for chronic hepatitis C. Ann Intern Med1994; 121:723.
(30) Fonseca V, Thomas M, Dusheiko G. Thyrotropin receptor antibodies following treatment with recombinant alpha‐interferon in patients with hepatitis. Acta Endocrinol (Copenh)1991; 125:491–3.
(31) www.ema.europa.eu/docs/en_GB/.../WC500050017.pdf accessed 28th February 2013
(32) R. Malik and H. Hodgson QJM The relationship between the thyroid gland and the liver (2002) 95 (9): 559-569.
(33) Alberti KG, Zimmet P & Shaw J. International Diabetes Federation:A consensus on type 2 diabetes prevention. Diabetic Medicine. 24,451–463. 2007
(34) Royal College of General Practitioners and NHS Diabetes. Coding, classification and diagnosis of diabetes 2011. www.diabetes.nhs.uk/our_work_areas/classification_of_diabetes
(35) World Health Organization (2007), 'World Health Statistics 2007'
(36) WHO (2010) 'HIV/AIDS Programme Highlights 2008-09'
(37) UNAIDS (2008) 'Report on the global AIDS epidemic
Competing interests: No competing interests
Diabetes consultants Kilvert and Rayman eloquently described the crisis in diabetes care in England alone as being catastrophic. (1) This sorry state of affairs also reflects the poor management of this crisis from a global perspective. Extreme poverty in developing countries also leads to inability to access vital basic medicines, including insulin. (2)
Concerns have again been raised over glucagon-like peptide-1 (GLP1) based treatment for type 2 diabetes (T2DM). There is a hefty price to be paid by those who have been diagnosed with T2DM. What sort of ‘care’ has been developed over the past 20 years in particular? Type 2 diabetes is a lifestyle disease which for the majority of people is highly preventable and very manageable - if effective education was available, which sadly it is not. T2DM has been gradually transformed into a massive cash cow for the food and drug industry. Over the last few years the disease has been portrayed, mostly by stealth, as irreversible. The real Holy Grail for the drug industry is finding a drug to ‘cure’ obesity. The line between obesity and T2DM is being blurred - probably in the attempt to kill two birds with one stone. Glucagon-like peptide-1 drugs were originally introduced as a third line therapy for diabetes T2DM. Where was the adequate provision for the first and second therapies?
It was considered that pharmacological solutions could be found to treat T2DM. However, concerns over drugs such as Rosiglitazone (Avandia) which caused adverse cardiovascular events have raised serious doubt. (3) Are new drugs being pushed through without adequate evidence of efficacy?
Concerns have previously been raised over the new Glucagon-like peptide-1 (GLP-1) diabetes drugs. A letter by Dr Yudkin et al in the British Medical Journal highlighted the point that ‘All drugs have many effects, and we cannot infer how a drug affects patient risk on the basis of how it modifies a single biomarker. In other words, ‘we currently have no idea whether their use is beneficial or harmful in relation to the outcomes that matter most to people with diabetes’.
It was further concluded ‘Even if we were to argue that larger, longer studies of a 1% reduction in HbA1c might have reached significance, the numbers needed to treat would be so large that with Exenatide (Byetta®) it would cost £1.13m to prevent one case of blindness, and £2.60m to prevent one case of renal failure. The costs with Liraglutide (Victoza®) would be 15% higher. (4) (5) The predisposition of these populations makes the developing world vulnerable to pharmaceutical treatments which may not be suitable for their needs. They are also unaffordable. The access to unbiased factual information on healthy diet and lifestyle is another concern. Many people diagnosed with diabetes may also suffer social stigma and not be able to earn a living due to disability - a dire situation. Drug interventions which offer hope would seem an attractive option.
There are other serious side-effects associated with GLP-1 analogues: The aforementioned pancreatitis- which may be severe and lead to death, the risk of thyroid tumours, adverse renal effects, cardiovascular risk is unknown. It is also not recommended as a first-line therapy for patients inadequately controlled on diet and exercise.
Despite the cost and limited safety data, the Glucagon-like peptide-1 Liraglutide and Exenatide are being promoted and used in the developing world, (6) (7) where the peak occurrence of T2DM is between the ages of 20 and 44, (encompassing the reproductive age group) already 40 years lower than the peak age of occurrence in high income countries. The highest diabetes (T2DM) prevalence is in people of Indian origin, followed by native Africans. (8)(9)(10)(11)
In the UK, Exenatide (GLP-1) is not recommended in pregnancy due to fetal abnormalities in animal trials and not recommended during breast feeding. However, in the USA the Food and Drug Administration (FDA) state ‘Exenatide (Byetta) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. A decision should be made whether to discontinue nursing or discontinue the drug, taking into account these potential risks against the glycaemic benefits to the lactating woman. The prescribing directory MIMS (UK) recommends ensuring adequate contraception in women of child-bearing potential during and for 3 months after stopping Exenatide (Byetta) and Exenatide (Bydureon). The same recommendation is not extended to Liraglutide.(Victoza, Nova Nordisk) (12)
Concerning the prescribing of Liraglutide the FDA (USA) state Victoza should be used during pregnancy: ‘Only if the potential benefit justifies the potential risk to the fetus - a decision should be made whether to discontinue nursing or to discontinue Victoza, taking into account the importance of the drug to the mother’. (13)
The medicalisation of pregnancy or of women of child bearing age with barely tested drugs, known to cause fetal harm in animal experiments, should ring alarm bells in the worldwide medical fraternity. The importance of a safe pregnancy and the importance of breast feeding, particularly in the developing world, cannot be understated. If a pregnancy suffers any adverse events, will this be judged to be caused by drug interactions, Diabetes or a natural event? The limited safety profile of the GLP-1 analogues warrants urgent action to protect this population group.
(1) Kilvert A Rayman G. The crisis in diabetes care in England BMJ 2012;345:e5446
(2)The prickly problem of access to insulin. Deborah Cohen BMJ 2011;343:d5782
(3) Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med2007;356:2457-71.
(4) Yudkin JS, Richter B, Gale EAM. Intensified glucose lowering in type 2 diabetes: time for a reappraisal. Diabetologia2010;53:2079-85.
(5) John S Yudkin, Richard Lehman, Harlan M Krumholz, Glucagon-like peptide-1 drugs. Use of GLP-1 analogues needs great caution BMJ 2011; 342:d1478
(6) Novo Nordisk Feature
issuu.com/tnt-multimedia/docs/sa-mag-novo-nordisk-feature accessed 28th February 2013.
(7) Holst JJ, Gromada J. Incretin therapy: a new treatment modality in the fight against the worldwide diabetes epidemic. Drug Trends. SA Journal of Diabetes & Vascular Disease 2009;6(2):83-84.
(8) Levitt NS, Steyn K, Lambert EV, et al. Modifiable risk factors for type 2 diabetes mellitus in a peri-urban community in South Africa. Diabetic Medicine. 16, 946–50. 1999
(9) Omar MA, Seedat MA, Dyer RB, et al. South African Indians show a high prevalence of NIDDM and bimodality in plasma glucose distribution patterns. Diabetes Care. 17, 70–74. 1994
(10) Ramaiya KL, Swai ABM, McLarty DG, et al. Impaired glucose tolerance and diabetes mellitus in Hindu Indian immigrants in Dar es Salaam. Diabetic Medicine. 8, 738–44. 1991
(11) McLarty DG, Swai AB, Kitange HM, et al. Prevalence of diabetes and impaired glucose tolerance in rural Tanzania. The Lancet. Volume 335, Issue 8690, Pages 661 – 662 (1990)
(12) MIMS.co.uk/diabetes/oral and parenteral hypoglycaemics accessed 28th February 2013. Oral and parenteral hypoglycaemics – Mims www.mims.co.uk
(13) Victoza REMS - Food and Drug Administration
www.fda.gov/.../PostmarketDrugSafetyInformationforPatientsandPro Novo nordisk Victoza Reference ID: 2948949 prescribing Information. Pdf Accessed 28th February 2013
Competing interests: No competing interests
Recent reports that around ten per cent of the NHS’s budget is being spent on the treatment and prevention of diabetes http://www.bbc.co.uk/news/health-21584598, highlights the need for an integrated healthcare model to improve the way in which patients with long term conditions such as diabetes are managed.
With seven million people in the UK currently at high risk of diabetes and three million already being treated for the incurable condition, it’s imperative that any avoidable costs often brought about through secondary complications are prevented. It is estimated that 4/5ths of the cost to the NHS is due to avertable complications such as kidney failure, heart disease, amputation and blindness.
This is where health coaching can make a huge difference. For individuals diagnosed with a particular long-term condition, health coaching - where registered nurses help the patient manage their condition by providing mentoring and support via two-way phone calls - is emerging as a powerful platform to nurture informed patients and help them overcome fears, embarrassment and better manage their long-term conditions.
With the security and anonymity of liaising with a trusted nurse, patients are more likely to mention that they have noticed a difference in their vision or a frequent need to urinate. Using the correct, non-directive, terminology, the health coach can then suggest whether the patient needs to report it to their GP which could ultimately provide the necessary spur a patient needs to help early diagnosis and improved chances of recovery.
Health coaching has been shown to motivate patients towards a readiness to change unhelpful thinking patterns. It can facilitate patients’ confidence and skills in self-management, and help them prepare for consultations, particularly in this instance by providing them with the confidence to know they would not be wasting the doctor’s time, proactively consider treatment options and encourage behavioural change. Moreover, with patients conscious that consultation time with their GP is limited, health coaching provides a valuable opportunity for individuals to discuss the longer-term management and implications of their condition with a trained health practitioner – providing that ongoing support patients need as they seek to adapt their lifestyles.
It is essential that integrated support tools and services such as health coaching form part of the way in which healthcare is provided, to best support individuals and their long term conditions, avoiding unnecessary complications and achieving cost savings.
CEO, Totally Health
Competing interests: No competing interests