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Home / Our therapy areas / Cardiovascular, Renal and Metabolism (CVRM) / Metabolism
Metabolic dysregulation in different organs such as the liver or pancreas can lead to several related conditions with significant impacts to quality of life, morbidity and mortality.1 Evidence shows the underlying disease drivers can act synergistically to increase the risk associated with developing these varied conditions.2
The pathophysiology of metabolic diseases
There are more that 650 million adults living with obesity, a growing global health challenge and a key upstream factor for many cardiovascular, renal and metabolic conditions, like cardiovascular disease, type 2 diabetes and non-alcoholic steatohepatitis.3-6
Metabolic diseases encompass these multiple conditions that result in metabolic dysregulation in different organs and increase the risk of other related comorbidities.1 Understanding the different risk factors and disease drivers, like genetics, and the interplay between them is critical. We believe that one mechanism of action does not deliver a complete solution.
Addressing diabetes and related comorbidities
The global number of people living with diabetes expected to rise to 783 million by 2045 and people with type 2 diabetes have an increased risk of developing several serious life-threatening health problems, lower quality of life and high medical costs7-10. Obesity and insulin resistance are two key drivers in the development of type 2 diabetes and are also connected to development of diseases of the heart and circulation, liver and kidneys.11
Our research is focused on uncovering the underlying mechanisms that link diabetes to comorbidities, especially the main causes of death from the disease, including myocardial infarction and stroke, as well as end organ failure in the heart, liver or kidneys.
Our ambition is to help treat beyond glycated haemoglobin (HbA1c), a measure of blood sugar over time, to prevent early cardiorenal complications and explore the broader metabolic condition, by exploring the use of our best-established therapies in metabolism. Emerging science also suggests significant ‘crosstalk’ between the liver and other organs, and we are identifying promising approaches for reducing liver fat and inflammation which may have implications for alleviating type 2 diabetes, as well as cardiovascular and renal diseases.12 Targeting weight loss and obesity is also a key component of our strategy in metabolism, aiming to address these diverse chronic co-morbidities.
Our approach in NASH
Non-alcoholic steatohepatitis, or NASH, is a liver disease in which a build-up of fat in the liver is followed by inflammation and cell damage.13 It is rapidly becoming a leading cause of chronic liver disease, with an estimated 350 million patients diagnosed by 2030.14,15 People with NASH are also at greater risk of type 2 diabetes and cardiovascular disease.16
NASH is driven by the same lifestyle and dietary factors behind obesity and type-2 diabetes.17 There are strong genetic risk factors now emerging and certain populations are disproportionately affected by it.18-21
The disease has a gradual onset ‒ over years to decades ‒ and the early stages are often clinically silent and overlooked by both patients and clinicians.22,23 This, combined with a lack of precise non-invasive diagnostics, often leads to late, or even missed diagnoses.24,25 Patients that progress to late-stage, fibrotic NASH often require complex, invasive, and expensive surgical interventions such as liver transplant.26
We are tapping into our expertise in metabolism and related comorbidities, uncovering novel biology and investing in cutting-edge technologies to find treatments that address the metabolic, inflammatory, fibrotic, or genetic drivers of NASH. Our aim is to identify the next wave of therapeutics, either alone or in combination that might offer unique benefits for patients.
The impact of liver cirrhosis
Liver cirrhosis is a chronic and progressive condition characterised by the replacement of healthy liver tissue with scar tissue. It is often the result of long-term liver damage caused by various factors, including excessive alcohol consumption, chronic viral hepatitis, fatty liver disease, and certain autoimmune disorders.27-29
Cirrhosis may be compensated in which no clinical complications that affect outcome i.e. decompensation events have occurred.30 The risk for decompensation events is highly associated with degree of portal hypertension (increased blood pressure in the liver). Decompensation events include variceal haemorrhage (bleeding from the gastrointestinal tract), ascites (accumulation of fluid in the abdomen), hepatic encephalopathy (brain dysfunction due to liver failure), or hepatocellular cancer.30-32 Patients with decompensated cirrhosis have had at least one these clinical complications. Of note is that 80-90% of all cases of hepatocellular cancer develop in patients with liver cirrhosis.33,34
While there is no cure for liver cirrhosis, treatment focuses on managing the underlying cause, reducing portal pressure, and alleviating symptoms. Lifestyle changes such as abstaining from alcohol, adopting a healthy diet, and maintaining a healthy weight are crucial. In advanced cases, a liver transplant may be the only option.31
With little options, we are committed to better understanding the condition and researching potential medicines so that individuals with cirrhosis can lead fulfilling lives and minimise the risk of complications.
Our people
Built on an impressive legacy in cardiovascular, renal and metabolic (CVRM) research, we are uniquely positioned to build a healthier and longer future for people with these diseases. Our team of over 1,000 people spans more than 23 functions including early and late R&D, medical and commercial.
Our employees are accomplished and experienced scientists, researchers, clinicians, and healthcare and commercial professionals dedicated to advancing novel science and driving practice change to benefit patients with CVRM diseases.
References
1. American Heart Association [Internet]. What is Metabolic Syndrome? [cited 2023 July 27]. Available from: http://www.heart.org/en/health-topics/metabolic-syndrome/about-metabolic-syndrome
2. National Institutes for Health [Internet]. Common Metabolic Diseases [cited 2023 August 1]. Available from: http://www.nih.gov/research-training/accelerating-medicines-partnership-amp/common-metabolic-diseases#:~:text=A%20growing%20body%20of%20evidence%20suggests%20that%20these,increases%20the
%20likelihood%20of%20developing%20additional%20metabolic%20diseases.
3. World Health Organization [Internet]. Obesity and overweight [cited 2023 July 27]. Available from: http://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
4. Powell-Wiley TM, et al. Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. May 25 2021;143(21):e984-e1010.
5. Prasad R, et al. Chronic Kidney Disease: Its Relationship With Obesity. Cureus. Oct 2022;14(10):e30535.
6. American Liver Foundation [Internet]. NASH causes and Risk Factors. [cited 2023 July 27]. Available from: http://liverfoundation.org/liver-diseases/fatty-liver-disease/nonalcoholic-steatohepatitis-nash/nash-causes-risk-factors/
7. International Diabetes Federation [Internet]. IDF Diabetes Atlas 2021. 10th Edition. [cited 2023 July 27]. Available from: http://diabetesatlas.org/atlas/tenth-edition/
8. Mayo Clinic [Internet]. Type 2 diabetes. [cited 2023 July 27] Available from: http://www.mayoclinic.org/diseases-conditions/type-2-diabetes/symptoms-causes/syc-20351193
9. Trikkalinou A, et al. Type 2 diabetes and quality of life. World J Diabetes. Apr 15 2017;8(4):120-129.
10. Centers for Disease Control and Prevention [Internet] How Type 2 Diabetes Affects Your Workforce. [cited 2023 July 27] Available from: http://www.cdc.gov/diabetes/prevention/how-type2-affects-workforce.htm
11. Rhodes C, et al. [Internet] Following the science in the search for a cure. Nature. [cited 2023 July 27] Available from: http://www.nature.com/articles/d42473-021-00264-7
12. Ye DW, et al (2017). Liver-adipose tissue crosstalk: A key player in the pathogenesis of glucolipid metabolic disease. Chinese journal of integrative medicine, 23(6), 410–414.
13. NIH National Institute of Diabetes and Digestive and Kidney Diseases. [Internet] Definitions and facts of NAFLD and NASH [cited 2023 July 27] Available from: http://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/definition-facts
14. Paik JM, et al. Changes in the Global Burden of Chronic Liver Diseases From 2012 to 2017: The Growing Impact of Nonalcoholic Fatty Liver Disease. Hepatology. 2020 Feb 11. [Epub ahead of print]
15. International NASH Day [Internet]. What is International NASH Day? [cited 2023 July 27]. Available from: http://www.international-nash-day.com/
16. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016 Jun;64(6):1388-402.
17. Cheemerla S, Balakrishnan M. Global Epidemiology of Chronic Liver Disease. Clin Liver Dis (Hoboken). May 2021;17(5):365-370.
18. He S, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem. Feb 26 2010;285(9):6706-15.
19. Witzel HR, et al. PNPLA3(I148M) Inhibits Lipolysis by Perilipin-5-Dependent Competition with ATGL. Cells. Dec 24 2022;12(1)
20. Romeo S, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. Dec 2008;40(12):1461-5.
21. Liu YL, et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol. Jul 2014;61(1):75-81.
22. Kawanaka M, et al (2021). Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Cirrhosis Confirmed by Liver Histology after 14 Years. Internal medicine (Tokyo, Japan), 60(9), 1397–1401.
23. NIH National Institute of Diabetes and Digestive and Kidney Diseases.[Internet] Symptoms & Causes of NAFLD & NASH. 2021. [cited 2023 July 27] Available from: http://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/symptoms-causes
24. NIH National Institute of Diabetes and Digestive and Kidney Diseases.[Internet] Diagnosis of NAFLD & NASH. 2021. [cited 2023 July 27] Available from: http://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/diagnosis
25. Cleveland ER, et al. Low Awareness of Nonalcoholic Fatty Liver Disease in a Population-Based Cohort Sample: the CARDIA Study. J Gen Intern Med. 2019 Dec;34(12):2772-2778.
26. Fraile JM, et al (2021). Non-Alcoholic Steatohepatitis (NASH) - A Review of a Crowded Clinical Landscape, Driven by a Complex Disease. Drug design, development and therapy, 15, 3997–4009.
27. Sharma B, John S. [Internet] Hepatic cirrhosis. StatPearls. [cited 2023 July 27]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK482419/
28. NIH National Institute of Diabetes and Digestive and Kidney Diseases [Internet]. Definition & Facts for Cirrhosis. [cited 2023 July 27]. Available from: http://www.niddk.nih.gov/health-information/liver-disease/cirrhosis/definition-facts
29. NIH National Institute of Diabetes and Digestive and Kidney Diseases [Internet]. Symptoms & Causes of Cirrhosis. [cited 2023 July 27]. Available from: http://www.niddk.nih.gov/health-information/liver-disease/cirrhosis/definition-facts
30. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis: Clinical Practice Guidelines. (2018). Journal of Hepatology, 69, 406–460.
31. NIH National Institute of Diabetes and Digestive and Kidney Diseases. [Internet] Treatment for Cirrhosis [cited 2023 July 27] Available from: http://www.niddk.nih.gov/health-information/liver-disease/cirrhosis/treatment
32. Berzigotti A. Advances and challenges in cirrhosis and portal hypertension. BMC Med. Nov 10 2017;15(1):200.
33. Tarao K, et al. Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases—meta‐analytic assessment. Cancer Med. 2019; 8(3): 1054-1065.
34. Li D, et al. Current Treatment Landscape for Advanced Hepatocellular Carcinoma: Patient Outcomes and the Impact on Quality of Life. Cancers (Basel). 2019;11(6):841.
Veeva ID: Z4-56863
Date of preparation: August 2023