Transforming the therapeutic scene: the story of diabetes drug discovery

Dr Abd Tahrani, Clinician Scientist at the University of Birmingham’s Institute of Metabolism and Systems Research, writes for BHP on the history of drug discovery in Type 2 diabetes; including modern non-pharmacological (lifestyle) interventions. 

 

 

This week marks Diabetes UK’s annual Diabetes Week, with the aim of raising awareness about diabetes mellitus and tackling the stigma felt by many patients with diabetes.

Diabetes is very common globally and is a public health challenge in the UK. In England the estimated prevalence of diabetes in 2017 was 8.5%, up from 6% in 2012/2013, with 44.1% of people with diabetes from women and 20.7% from minority ethnic origin. Hence, preventing Type 2 diabetes is a public health priority.

About Type 2 diabetes

Type 2 diabetes results from complex interactions between genetic and environmental factors that lead, via multiple and complex mechanisms, to insulin resistance (i.e. the cells become less responsive to insulin secreted from the pancreas) and reduction in the ability of the pancreas to secrete enough insulin to overcome the insulin resistance.

Prior to the development of Type 2 diabetes, patients might have blood glucose levels higher than normal but below the cut off level for diabetes; this is termed pre-diabetes. In pre-diabetes the pancreas is usually able to secrete enough insulin to overcome the insulin resistance and keep the blood glucose levels below the threshold for Type 2 diabetes. However, over time, the insulin secretion is lessened and at one point it becomes inadequate to control glucose levels and Type 2 diabetes ensues. This time spent in pre-diabetes offers an opportunity to prevent or delay the development of Type 2 diabetes.

Obesity, family history, short sleep and physical inactivity are the major risk factors for the development of Type 2 diabetes. Several randomised controlled trials showed that lifestyle interventions (based on increased physical activity and reduced calorie intake) are effective in reducing the risk of developing Type 2 diabetes in patients with pre-diabetes by about 40%. More recently, the long-term follow-up of these trials showed that lifestyle interventions continued to reduce the risk of developing Type 2 diabetes and cardiovascular disease even 30 years after the end of the trial, showing long term beneficial effects of lifestyle interventions. As a result the NHS launched its landmark NHS Diabetes Prevention Programme in 2016.

The impact of Type 2 diabetes

The personal, economical and societal burden of diabetes is significant as people with diabetes are at increased risk of a wide range of complications, including: cardiovascular disease (heart attacks, strokes, heart failure etc); chronic kidney disease (kidney failure) that could lead to dialysis; retinopathy (eye disease) that could lead to blindness; neuropathy (nerve damage) that could lead to painful symptoms; and foot problems that could result in ulcers and amputations. This results in significant economic burden too, as Type 2 diabetes treatment accounts for just under 9% of the annual NHS budget (around £8.8 billion a year). Hence, treating and reducing the burden of diabetes is a health care priority in the UK. Despite these severe consequences, however, diabetes complications are preventable by ensuring good glycaemic and blood pressure control, lowering the “bad” cholesterol levels, losing weight and improve physical activity levels. Over the last 20 years there has been a significant decline in the incidence of heart attacks, strokes, renal failure and amputations due to the improvement in controlling glucose, blood pressure and lipids levels.

Image from Diabetes UK – visit https://www.diabetes.co.uk/body/ to find out how diabetes can affect multiple areas and systems of the body
Drug discovery for diabetes

Our understanding of the pathogenesis of Type 2 diabetes has evolved significantly over the past two decades, leading to the development of new therapies and treatment. In the 1950s, only two classes of drugs were available – sulphonylureas and biguanides (i.e. metformin). It took us to the late 1990s to have three new classes of medications at the time: meglitinides, alpha-glucosidase inhibitors, and thiazolidinediones. Then, in the mid-2000s, two new classes became available: glucagon-like peptide 1 receptor agonists (GLP-1 RA) and Dipeptidyl-peptidase -4  inhibitors (DPP-4i) with the latest class arriving in 2012 (Sodium-glucose cotransporter -2 (SGLT-2) inhibitors).

GLP-1 RAs initially developed as injectable drugs that are administered daily, followed by weekly formulations which are now available in clinical practice.

Self-administered injections are the most commonly known form of diabetes treatment

These later developments, with classes launched from 2005 (particularly GLP-1 and SGLT-2 inhibitors), transformed the therapeutic scene in patients with Type 2 diabetes. These newer agents have major advantages over older agents, as they have powerful glucose-lowering properties yet do not increase the risk of hypoglycaemia (low glucose levels), and result in significant weight loss while sulphonylureas and insulin are associated with weight gain and hypoglycaemia. Additionally, metformin (which is currently established as the first line treatment for patients with Type 2 diabetes) is weight neutral and does not increase the risk of hypoglycaemia. Furthermore, some of the GLP-1 RAs and SGLT-2i were shown in several trials to reduce the risk of developing cardiovascular disease (heart attacks, heart failure), diabetes-related kidney disease and renal failure, which improved our ability to further reduce the burden of Type 2 diabetes beyond just improving glucose levels.

The development of these newer classes did not stop at their impressive favourable impact on heart and kidney disease; newer data from the American Diabetes Association meeting 2019 in San Francisco has shown the development of oral GLP-1 RAs (rather than the currently available injectable format) which seems to be as effective as the injectable format and newer agents achieving greater weight losses that was not possible with older medications (such as 13% weight loss).

Lifestyle interventions

Another important development in the field of Type 2 diabetes management is the emergence of effective non-pharmacological (i.e. non drug based) treatments. A recent trial showed that lifestyle interventions based on the use of very low energy diets (VLED) resulted in diabetes remission (i.e. the glucose levels maintained at a level below the diabetes threshold without the use of any glucose lowering agent) in about 50% of patients after one year, and in about 1/3 of patients  after two years. Also, weight loss (bariatric/ metabolic) surgery showed that significant sustained long term (20 years) weight loss can be achieved and type 2 diabetes can be put into remission in the majority of patients (diabetes remission occurs in 80% within the first year after surgery but reduced gradually thereafter).

As a result, we now have a wide range of pharmacological and non-pharmacological treatment approaches to treat patients with Type 2 diabetes, allowing clinicians and patients to reach mutual agreement about the best treatment approaches in order to personalise therapeutic approaches. However, despite these advances in the management of Type 2 diabetes, the achievement of the three treatment targets (glucose, blood pressure and lipids) occurred only in 40% of patients in England in 2017/2018. This suggests that the above-mentioned advances in the treatment options have not reached patients yet and this is likely to reflect complexities and economic circumstances in the NHS, as these treatment options are not cheap.

Looking towards the future, we are likely to have more effective treatments that are able to reduce glucose levels, reduce weight and protect patients’ hearts and kidneys; but the health care system will face the challenge of adapting to make these new treatments available and used widely.


By Dr Abd Tahrani

a.a.tahrani@bham.ac.uk

  • Clinician Scientist, IMSR, UoB
  • Consultant Endocrinologist, UHB
  • Lead for Translational Research in Centre for Endocrinology Diabetes and Metabolism (CEDAM), BHP
  • Lead for Weight Management Research and Diabetic Neuropathy Services, UHB.