1921 marks the year of insulin discovery. Exactly 100 years ago, on the 11th January 1922, Leonard Thompson, a 14-year-old boy, was the first diabetic patient receiving insulin injection, a treatment that saved his life. After 100 years of this revolutionary finding, many drugs on the market have been developed to help the diabetic patients manage their disease, prevent further health problems and improve their quality of life, but unfortunately none of them offers an actual cure. In addition, many regions in the world struggle to access available and affordable treatments.
The Year 2021 was the 100’s years anniversary of insulin discovery. As we are stepping into the New 2022 Year, it is a good opportunity to review what is known and standardly used in the management of diabetes and what are recent development that have marked the 2021 Year in this field.
Key facts about diabetes prevalence
Globally, there are 425 million of people with diabetes, which represent 6% of the world population. According to World Health Organization (WHO), this number is estimated to rise to 570 million by 2030 and to 700 million by 2045. 1 in 2 adults have undiagnosed diabetes and face a great risk of aggravating complications, that would have been prevented by early diagnosis of the disease and treated accordingly. Remarkably, 80 % people with diabetes live in developing countries – 65% of diabetic people living in Africa and 50% in Southeast Asia are undiagnosed due to low screening and those who are diagnosed lack care for extended periods.
Diabetes is a leading cause of death in the world. In 2019, the International Diabetes Federation estimated 4 million of deaths due to the disease and its complicationsIn addition, from 2007 to 2017, four countries having the highest number of death due to diabetes type 2 were developing countries.
The prevalence of diabetes increases with:
- unhealthy diet linked to urbanization, tobacco consumption
- sedentary life, low prevention possibilities
- genetic susceptibility (obesogenic factors)
- ethnicity (early onset of the disease in Asian populations)
- epigenetic factors (predisposing to different health destinies)
What is diabetes and how is it managed?
Diabetes is a very heterogeneous disease, defined as persistent high blood glucose levels or chronic hyperglycemia. The diagnosis consists in measuring fasting and fed blood glucose levels and the glycated hemoglobin, which gives an indication of the 3-month average blood glucose values.
There are two main types of diabetes that can be classified into Type 1 and Type 2 diabetes. In addition, gestational diabetes, a condition that can develop during pregnancy, is rarer, but serious (for more detailed information, please refer to my page about Diabetes) and other types of diabetes, such as monogenic diabetes syndromes.
Basic components of diabetes care include the drugs, taken orally or by means of injection, supplies and equipment for injections and monitoring of blood glucose and education of patients and the support in their every day life with diabetes.
T1 Diabetes Management
T1D represents 10% of cases and is a form of the disease where insulin-producing cells are progressively dying, usually because of an autoimmune reaction developed against those cells, until no insulin source is left (condition called insulin-deficiency). As a result, T1D management mainly focuses on exogenous inputs of insulin, which are mainly based on injectable medications.
There are several forms of insulins developed, the so-called standard short-acting, the rapid-acting, the intermediate acting, the long-acting, and the combination insulins. These insulins are classified in each group according to three main characteristics:
- the length of time the insulin will take to reach the body and start lowering glucose levels
- the time during which the insulin action is the strongest in lowering glucose
- how long the insulin will work in the body and how long it will act to lower blood glucose levels.
On one hand, once injected, the standard short-acting insulin reaches the bloodstream in 30 minutes, has the strongest activity within 2-3 hours after injection, and lasts between 3-6 hours. Therefore, this type of insulin is injected before a meal. On the other hand, the long-acting insulin reaches the bloodstream gradually within several hours after injection, has a stable activity throughout time and lowers glucose levels up to 24 hours. This type of insulin analogue offers a better quality of life to patients, fewer material to buy and fewer opportunities to get stung, while still having a continuous treatment for their condition.
Insulin analogues are the basis of T1D treatment. Nevertheless, a century after its discovery, insulin remains unaffordable and inaccessible (reflecting the steps that it has to go through – production, distribution and pricing, as well as the safety involved in its marketing) for many diabetic children and adults, especially in low- and middle-income countries.
T2 Diabetes Management
T2D represents 90% of cases. This form of the disease develops first after a resistance of the body to circulating insulin and occurs generally in obese individuals. To compensate for insulin resistance, the pancreas, the insulin only reserve, will produce and release more insulin to satisfy the insulin demand resulting from increased nutrient load in the body. This will lead to pancreatic fatigue and a dysfunction in insulin release and will mark the time to prediabetes. The mass of insulin-producing cells will decline, and the disease, if uncontrolled, can lead to serious, life-threatening complications such as cardiovascular diseases, kidney diseases or stroke.
The crucial process in delaying the progression the disease toward these complications is glycemic control. Therefore, T2D drugs are mainly developed to help maintain optimal levels of blood glucose.
The management of the disease is carefully chosen according to several essential factors:
- The specific physiopathology of the patient
- The risks of cardiovascular disease and the status of renal function
- The hypoglycemic risks presented by the treatment
- The influence on the body weight
- The tolerance of the patient toward the treatment
- Sometimes the ethnicity also matters a lot (Asian people are preferably treated with iDPP4 (discussed below)
- Finally, the price and availability of the treatment is an important factor
Biguanides (Metformin is the most used in this class of drugs) work to decrease the glucose de novo production in the liver, or, in other words, how much glucose the liver makes. At the same time, they also increase insulin sensitivity and glucose uptake in organs such as muscles. Metformin can be given as a monotherapy taken orally or comes sometimes in combination with other drugs and is a product that is widely distributed and accessible among all countries.
Dipeptidyl-peptidase inhibitors (example: linagliptin) or iDPP4 are a class of drugs that stop the action of the enzyme dipeptidyl-peptidase DPP4, which degrades the incretin hormones such as glucagon-like peptide 1 (GLP-1). GLP-1 plays a key role in stimulating insulin release from the pancreas and helping decrease the glucose production in the liver. As such, iDPP4 drugs help increase the active form of incretins in the body. They are used either as a single product or can be found in combination with other glucose-lowering medications and are taken orally.
Sulfonylureas (example: tolbutamide, glimepiride) are drugs that act on stimulating insulin release by directly inhibiting potassium-channels present on the surface of insulin-producing cells. These old drugs are often used, very accessible and not costly but induce hypoglycemia (lower blood glucose levels) as a common side-effect and do not favor weight loss. They come in form of a pill.
GLP-1 analogues (example: exenatide, liraglutide) mimic the incretin GLP-1 and bind to the GLP-1 receptor found in intestine cells and insulin-producing cells in the pancreas. These drugs stimulate the health, function and growth of the insulin-producing cells and slow down stomach emptying, decreasing appetite in the patient and eventually body weight. The GLP-1 analogues are injectable drugs, as insulin analogues are, but clinical trials are currently testing the efficiency of a newly developed member of this class coming in oral form (semaglutide).
Thiazolidinediones (example: rosiglitazone) are another class of anti-diabetic drugs. The glucose-lowering mechanism of action of thiazolidinediones works by decreasing the glucose load in the liver and by increasing insulin sensitivity in the adipose (fat) tissue. They are not used in people with risk of heart diseaseThe medications come in form of a pill.
Metformin is the standard of care and the first line in the treatment, but other anti-hyperglycemic medicines can be combined with metformin or assigned sometimes as a monotherapy. If the glycemia is not controlled with these combinations, and insulin is deficient, then insulin injections become the quotidian of the diabetic patients.
Growing issues in the field of diabetes care in low- and middle-income countries
Despite the growing prevalence and increasing mortality due to diabetes in vulnerable regions and low- and middle-income countries (LMICs), access to essential medicines, their availability in local pharmacies and affordability still represent a life struggle for many patients in the world. Issues in diabetes care in these regions include insufficient governmental funds covering diabetes care and type 2 prevention, lack of awareness mostly due to lack of education, weak training of medical staff and healthcare professionals on disease prevention and the last but perhaps the most important, the lack of access to proper diagnosis, treatment, oral medications, and sometimes no access at all to new drugs on the market, such as the iSGLT2, described below (IDF, 2021). In pharmacies, the least-priced medications lay on the shelves, but more recently developed expensive drugs require patients’ high out-of-pocket expenses, due to improper health coverage.
In order to help finding solutions to the global issue that diabetes poses, and improve access and affordability to anti-diabetic drugs and a better diabetes care, the WHO has launched in 2021 the Global Diabetes Compact, and with that, the United Nations have adopted a new Resolution for the call of an urgent coordinated global action to fight against the disease.
The inclusion of anti-diabetic drugs in 2021 WHO’s List of Essential Medicines
The Model List of Essential Medicines was created by WHO in 1977 to include essential medicines that satisfy the priority health care needs of the population. They are selected with regard to disease prevalence, public health relevance, evidence of safety and efficacy and the cost-effectiveness of the drug compared to others (Revised procedure for updating the WHO’s List of essential medicines, WHO, 2001). In 2021, the EML included two classes of anti-diabetic drugs, which marked a progress toward the facilitation to their access and availability, especially in LMICs.
- T1D treatment
Insulin has been on WHO’s EML for both types of diabetes since it was first published in 1977. But not typically for an essential medicine, and despite 100 years full of scientific evidence and medical benefits, too many patients still lack access to proper treatment (According to The Global Diabetes Compact, WHO). In 2021, the long-acting insulin analogue (described above) was fortunately included as an essential medicine in the EML, giving great hope that it will increase the access to this type of drug to everyone in the world.
- T2D treatment
Newcomers included in the EML for diabetes type 2 treatment are the so-called inhibitors of the sodium/glucose-transporter 2 or iSGLT2.
iSGLT2 are a class of medication used to treat T2D. The SGLT2 inhibitors have a unique property. When combined with diet and exercise in adults, they help improve glycemic control by acting on the sodium glucose transporter (type 2) protein that is present in the kidneys. By inhibiting this protein, they prevent the reabsorption of glucose and sodium from the blood and facilitate their excretion in the urine (inducing glycosuria).
During the last years, clinical trials have been widely performed to mainly test the properties of different sub-classes of iSGLT2 (dapagliflozin, empagliflozin and canagliflozin and ertugliflozin). Results from these studies show that these drugs not only decrease blood glucose levels without requiring insulin signaling, but also promote the protection of the cardiorenal system. Therefore, patients with heart failure, cardiovascular disease, or kidney disease, will be preferentially treated with these drugs over others anti-diabetic medications. iSGLT2 are taken orally and combinable forms with other standard anti-diabetic drugs are already developed.
Take home message
Diabetes is a severe and debilitating disease bringing in diabetic people’s life a whole pattern of chronic inabilities and physiological damages. The number of diagnosed diabetic patients is growing every year and official statistics show that worldwide diabetic population (diagnosed and undiagnosed) will reach more than 700 million by 2045. Due to the heterogeneous nature of the disease, the success of diabetes management is variable among the people affected, but also among regions in the world, as anti-diabetic drugs helping improve the quality of life of patients, saving and prolonging their life are not always available, accessible or/and affordable globally. Insulin is the most well known example, as, since 1921, when it was discovered and until now, it still represents one of the medicine that is the most difficult to reach and afford especially in low income countries. It is therefore important to increase awareness of this disease and discuss new solutions that will help improve the access of patients to medicines for fighting against diabetes and protect them against additional health issues, especially in difficult times such as the COVID-19 pandemic, where diabetic patients are more susceptible to develop fatal diabetes complications.