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  • Becky McCall - United Kingdom & Bob Kirsch - United States

Landmark discoveries with staggering impact

As long ago as 550 BC, Chinese philosopher Confucius told us to “study the past if you would define the future.” In that spirit FORESIGHT Global Health takes a look at how specific medicines for treating non-communicable diseases (NCDs) have evolutionised the prospects and care of people diagnosed with an NCD. Understanding this evolution in medical knowledge shows what research can achieve—and what it can aspire to next.

In the annals of medical history, 2021 will go down as the year in which a rapidly developed series of vaccines prevented the loss of millions of lives at the hands of covid-19. The year also marks the centenary of the discovery of insulin. Just as covid-19 vaccines were the result of revolutionary re- cent developments in mRNA technology, insulin was also borne out of advanced technical expertise, the isolation of insulin-producing islet cells, an achievement that since 1921 has made diabetes a disease to be managed, not a death sentence for millions.

The impact of landmark discoveries in medical science can be staggering. Insulin has extended the lifespan of people diagnosed with type 1 diabetes from a typical one to two years before its discovery to around 80 years today, while covid-19 vaccines are preventing serious disease and death in millions by protecting them from the virus.

The development of insulin became a model for the treatment of other non-communicable diseases (NCDs), showing the way to self-management for people living with chronic conditions, observes Carsten Timmermann who lectures in the history of science, technology, medicine and medical humanities at the University of Manchester in England. In much the same way, angiotensin-converting enzyme (ACE) inhibitors and inhalers have made it easier for those with hypertension and respiratory conditions such as asthma to live more comfortably with their conditions. Now, the newest generation of cancer medicines are aiming at the previously elusive goal of making cancer a chronic condition rather than a killer.

It is this level of progress that has made the past century so remarkable, Timmermann says. “You turn something acute and life-threatening into something chronic that you manage.”

Life changing drugs

The World Health Organization (WHO) singles out four of the most prevalent NCDs worldwide for particular focus—cardiovascular disease, diabetes, respiratory diseases, and cancer. Alone, these four kill around 41 million people every year, according to WHO. Without the medicines developed to prevent and treat them, however, the number of dead would be significantly higher.

Four classes of medicine epitomise the advances in NCD treatment: heart drugs such as ACE-inhibitors, diabetes therapies like insulin, respiratory drugs like salbutamol, and anti-cancer drugs such as methotrexate. All four of the NCDs for which these drugs were developed were life-limiting a century ago. Now, with proper treatment, many of those with these conditions can hope for a normal life span.

Specific medicines have been transformative for those living with the most common NCDs and development and application of them has led to better understanding of disease aetiology and risk factors. It has also contributed to the continued improvement of global health infrastructure and served to light the way for better global management of NCDs. The steady progress has rested on a series of building blocks, from the comparatively rudimentary ability to use an organ extract to manufacture insulin to the more advanced understanding of cell biology and reproduction that ultimately led to the development of cancer treatments.

Portrait of a pathfinder

The one-hundred-year anniversary of the discovery of insulin marks a story of what was, what is, and what may be possible for people with diabetes. It is a serious illness with several co-morbidities such as heart disease, stroke, and kidney disease; it can damages sight and nerves. In 2016, an estimated 1.6 million deaths globally were directly caused by diabetes. The disease lies behind almost half of all deaths before the age of 70 attributable to high blood glucose levels.

The innovations of the past century in NCD treatments have made it possible to live with rather than die from chronic diseases

Diabetes medication is based on two fundamental players: insulin and metformin. Metformin reduces the body’s own production of glucose and makes its use of insulin more efficient. Widespread use of metformin started in the late-1950s, half a century after the discovery of insulin. By around 1980, animal insulin was being replaced with human insulin and since the beginning of the current century an array of insulin analogues have appeared. “There are efforts to increase production, demand, and quality assurance of generic biosimilars,” says Gene Bukhman, a medical anthropologist and cardiologist at Brigham and Women’s Hospital in Boston in the US, who heads the global programme in non-communicable disease and social change at Harvard Medical School.

A relatively recent and significant development for those with diabetes includes wearable continuous glucose monitors as an option to finger-prick tests multiple times a day. Even more recent and exciting are closed-loop systems, which are the nearest thing to an artificial pancreas in that glucose is monitored automatically and an insulin pump is worn on the body to administer medication to meet real-time demand.

Diabetes technology has come a long way in a century. At the same time, affordability of insulin as well as the availability of equipment used to test glucose levels or administer insulin remain key issues for those living with the disease, also in a country as developed as the US.

A silent killer for centuries

Hypertension is particularly challenging because it is an asymptomatic, silent killer and often remains hidden until caught during monitoring or evidenced in a hypertension-associated disease such as heart failure or stroke. Undiscovered and untreated, hypertension significantly increases the risk of developing cardiovascular, brain, and kidney diseases.

High blood pressure is a worldwide problem, but the greatest increases in the absolute burden of hypertension are currently being seen in East Asia and the Pacific, Latin America and the Caribbean, South Asia, and Sub-Saharan Africa. The Global Burden of Disease Study for 2019 estimates that about ten million deaths were attributable that year to high blood pressure, mostly in low-and-middle-income countries (LMICs). “Only about a third of people with hypertension are receiving pharmacological treatment and only one in ten have their blood pressure appropriately controlled, in LMICs,” points out Pablo Perel at the World Heart Federation.

Elevated blood pressure has been a major public health challenge and cause of premature death for thousands of years. The Chinese referred to it as “hard pulse” disease in 2600 BC and the Ebers Papyrus from 1550 BC testifies to the ancient Egyptians describing the relationship between palpated pulse and the development of heart and brain afflictions. Even so, outside the medical profession high blood pressure was not widely recognised until 1945 when US President Franklin D. Roosevelt reported a severe occipital headache and died with a recorded blood pressure of 300/190 (normal is considered to be less than 120/80 mmHg).

Perel observes that progress in hypertension medication in the past five decades has been remarkable and that there is now a wide portfolio of cost-effective and safe pharmacological options with which to treat people. “The evidence is supported by a large number of outcome-based randomised clinical trials. There is strong evidence that a 10 mmHg reduction in systolic blood pressure, which measures the pressure in arteries when the heartbeats, or a 5 mmHg reduction in diastolic blood pressure, which measures arterial pressure when the heart is resting between beats, is associated with substantial reductions in all major cardiovascular events and mortality,” he states.

A disease with strong environmental links

An upside of covid-19 lockdowns in cities has been the reduction in outdoor air pollution, largely due to less human activity on the roads and in the air. The link between air pollution and lung diseases is well established, with more evidence of it provided in a 2020 survey by the British Lung Foundation. Over the spring lockdown, the charity found that one in six people in the UK with lung conditions had experienced better health, with the number increasing to one in five for children. Asthma sufferers reported the most benefit, with one in four showing improvement in their condition.

In 2017, close to 545 million people in the world were classified with a chronic respiratory disease, representing a near 40% increase since 1990 and ac- counting for 3.9 million deaths according to the Global Burden of Diseases. A wide range of conditions fall into this category, including chronic obstructive pulmonary disease, asthma, bronchiectasis, tuberculosis, pneumonias, and undefined interstitial lung diseases.

Environmental and social determinants like clean air and poverty reduction are fundamental to im- proving chronic respiratory diseases, but medicines, including inhalers and nebulisers, can ease suffering once the damage is done.

Of all the NCDs, chronic respiratory diseases illustrate most clearly the direct interaction between the human body, the environment, and the economic interests bound up in polluting the air, from the money made from fossil fuel exploitation and toxic chemical processes to savings made on worker protection. While the air is free, what is circulated within it from human activity may prove to be extremely costly for the planet.

Advances in cancer cures and care

Cancer is the second leading cause of death globally, after cardiovascular conditions, with tobacco use responsible for approximately 25% of cancer deaths, according to WHO. Comprehensive cancer treatment is available in more than 90% of high-income countries, but in fewer than 15% of low-income countries.

Even in high-income countries, many knowledgeable physicians as recently as the 1950s doubted that medicines could be used to cure cancer. Back then the mainstays of cancer treatment were surgery and radiation. During the 1960s and early 1970s, after chemotherapy successes had been achieved with cancers of the blood and the lymph system, questions remained about its potential to contribute to the cure of advanced solid tumour cancers.

But new findings steadily emerged, sometimes along unexpected paths. During World War II an accidental spill of sulphur mustards on troops in Bari Harbour, Italy, led to findings that nitrogen mustard could achieve cancer regression. The realisation spawned the discovery of cyclophosphamide, a medicine still used in the treatment of cancers of the blood, lymph, breast, and nerves.

Another advance propelled by WWII came from investigations into antibiotics used to treat wound infections, which led to the development of anti-tumour antibiotics, types of medicine still used for breast, lung, gastric, ovarian, thyroid, lymphomas, multiple myeloma, sarcoma, and paediatric cancers.

Development of the right kind of health system is at least as important as development of the right drugs

Nutritional research started prior to WWII found that a substance present in green leafy vegetables folate affected bone marrow. Subsequent research on folate antagonists resulted in development of the chemotherapy and immunosuppressant, methotrexate. The substance is still used in the treatment of leukaemia, lymphoma, breast cancer, lung cancer, head and neck cancer, and bone cancer. In the mid-1950s, research on the cells of cancer of the liver in rats led to the synthesis of fluoropyrimidine 5-fluorouracil, known as 5-FU, currently used in the treatment of cancers of the breast, colon, rectum, stomach, and pancreas.

Recent advances now allow cancer treatment to include both chemotherapy and personalised medicine (also called precision medicine). Today’s innovative treatments are designed according to the specific genetic make-up of the individual’s tumour and evidence suggests these more targeted treatments are less likely to produce severe side effects. While chemotherapy agents may be given to large numbers of patients with a certain type of cancer, in personalised medicine the drug selection is tailored to the patient; not all patients with any one type of cancer, such as lung cancer or breast cancer, are given all of the same medicines.

Accessibility and affordability

A new medical revolution is required to build equal access to treatment and a healthcare infrastructure that is all-inclusive. While medical innovation has progressed apace, healthcare systems have often failed to reflect and respond to the distribution of the burden of disease, or societal and environmental factors, that would allow for revolutionary medicines to be accessible to all, including vaccines.

The innovations of the past century in NCD treatments have made it possible to live with rather than die from chronic diseases. These lifesaving advances, however, have introduced two challenges that policymakers must resolve. First, the escalating cost of medicines makes them unaffordable or unavailable to many citizens of low-and-middle-income countries. Second, the current health infrastructure is not yet designed to support people with NCDs in management of their conditions over many years.

Most of the main innovative medicines developed for NCDs have generic equivalents, but with limited dissemination. “Massive populations are suffering and dying because they are not properly diagnosed and treated and are not able to afford these same medications,” says Harvard Medical School’s Bukhman. “It’s a great injustice that, as a world, we should really remedy as quickly as possible.”

With medical solutions becoming more complex, the associated risks of failure are higher, resulting in skyrocketing demand for investment in medicine development. The introduction of blockbuster treatments that could serve huge populations during the second half of the last century, from antibiotics to the growing field of oncology medicine, caused the transition of the pharmaceutical industry from smaller companies to big pharmaceutical giants, Timmermann notes.

The technology involved to develop the newest generation of medicines has made research and development of them increasingly expensive, contributing to the consolidation within the industry. An era of more individualised medical treatment, dominated increasingly by biotechnology, is likely to accelerate the rate of advance, but the difficulty of producing generic biotech drugs making it harder for health systems to hold down costs, he adds.

One of the key lessons of the past century’s medical discoveries is that those living with chronic conditions cannot benefit from new treatments in isolation. A robust system is needed for supervision of people under treatment for NCDs and to help them to manage their own conditions. Development of the right kind of health system is at least as important as development of the right drugs.

“A pill is easy to administer, but for chronic conditions, it is not just a question of a pill, but of referral networks, monitoring and a whole infrastructure of care,” Timmermann says. The infrastructure needed to diagnose and apply the right interventions at the right time seems to be missing, he says. •

TEXT Bob Kirsch & Becky McCall — MAIN ILLUSTRATION Luke Best



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