Diabetes and its complications
Diabetes mellitus (DM) is a group of chronic metabolic disorders that result in hyperglycemia from a variety of causes. The condition occurs when the secretion and/or utilization of insulin, a vital hormone composed of 51 amino acids, is impaired. Beta cells in the pancreas are responsible for producing and releasing insulin into the bloodstream, which then travels to target cells located in various tissues and organs throughout the body. After binding to specific receptors, insulin triggers the metabolic effects of intracellular substances. Its primary role is to facilitate the storage of glycogen once it enters cells and the conversion of glucose into energy. In addition, insulin is essential for the metabolism of proteins and fats. Abnormalities in any part of this process can lead to diabetes[1].
Diabetes is a complex disease resulting from the combined influence of genetic and environmental factors. Regardless of its root cause, the natural course of diabetes involves several stages. Initially, diabetes-related pathophysiological changes, such as autoimmune antibody positivity, insulin resistance, and pancreatic β-cell dysfunction may be present for an extended period of time while the patient still exhibits normal glucose tolerance. As the disease progresses, impaired glucose regulation (IGR), which is indicated by impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), emerges as an intermediate metabolic state between normal glucose homeostasis and diabetic hyperglycemia. Finally, the disease culminates in diabetes. Long-term metabolic disorders of carbohydrates, as well as fat, protein, water, and electrolytes, can cause systemic damage, leading to chronic progressive lesions, hypofunction, and failure of tissues and organs such as the eyes, kidneys, nerves, heart, and blood vessels. Severe acute metabolic disturbances may occur under certain conditions or stress, such as diabetic ketoacidosis (DKA) or hypertonic hyperglycemic syndrome[2].
Currently, the classification system for diabetes mellitus proposed by the World Health Organization (WHO) Expert Committee includes type 1 diabetes, type 2 diabetes, other specific types of diabetes that have well-defined etiologies, and gestational diabetes. Two main types of diabetes are described below:
Type 1 diabetes
Type 1 diabetes mellitus (TIDM) is the most common form of diabetes in children, although it can occur at any age and is not preventable. Insulin is essential for survival in type 1 diabetes. The primary cause of type 1 diabetes is autoimmunity, in which the immune system attacks the insulin-producing beta cells in the pancreas, resulting in little or no insulin production by the body. To maintain a healthy blood glucose levels, individuals with type 1 diabetes must self-administer daily insulin injections. With proper daily insulin therapy, regular blood glucose monitoring, education and support, individuals with type 1 diabetes can lead healthy lives and delay or prevent many of the complications associated with the disease. Managing insulin use, monitoring blood glucose levels, engaging in physical activity, and maintaining a healthy diet during childhood and adolescence can be challenging, and financial difficulties can exacerbate the situation, leading to disability and premature death due to the accumulation of ketones in the body that cause DKA. Poor metabolic control can also lead to stunted growth and early onset of vascular complications. Symptoms of type 1 diabetes include excessive thirst, frequent urination, hyperphagia, lack of energy, and lethargy. Unfortunately, the diagnosis of type 1 diabetes is sometimes delayed until the patient is hospitalized for DKA, which can be fatal[3].
Type 1 diabetes progresses through a series of stages, which are as follows:
1. In the early stages of type 1 diabetes, the individual may have no clinical abnormalities but has a genetic predisposition to the disease.
2. Following a trigger, such as a viral infection, TIDM initiates a chronic autoimmune process that results in the destruction of a small number of beta cells. This process may be continuous or intermittent and is often accompanied by the regeneration of beta cells.
3. Abnormalities in the immune system, such as the presence of detectable antibodies against various islet cells, may be observed.
4. The number of β-cells begins to decline, but normal glucose tolerance can still be maintained.
5. When β-cell damage reaches a certain level (usually only 10-20% of β-cells remain in children and adolescents, while in adults, up to 40% of β-cells remain at the onset of the disease), insulin secretion is insufficient and reduced glucose tolerance or clinical diabetes develops, requiring treatment with exogenous insulin;
6. Almost complete loss of cells and dependence on exogenous insulin for life support[2].
Type 2 diabetes
Type 2 diabetes mellitus (T2DM), which can be prevented, delayed, and reversed, is the most common form of diabetes worldwide, accounting for over 90% of cases. The prevalence of the disease has increased due to an aging population, economic development, urbanization leading to sedentary lifestyles, unhealthy diets promoting obesity, and the effectiveness of treatment leading to longer survival rates. In some countries, the incidence of T2DM has increased in children who are overweight or obese. It's possible that between one-third and fifty percent of people with T2DM remain undiagnosed, and if they remain undiagnosed, they may experience complications such as heart disease, stroke, vision loss or poorly healing lower extremity ulcers before they are first diagnosed.
Although not fully understood, the development of type 2 diabetes is strongly associated with factors such as overweight, obesity, increasing age, race, and family history[3]. The primary characteristic of the disease is a progressive insulin deficiency accompanied by insulin resistance. In the early stages of insulin resistance, compensatory increases in insulin secretion by β-cells help to maintain normal blood glucose levels. However, as the β-cells become unable to secrete enough insulin to compensate for insulin resistance, the disease may progress to impaired glucose regulation (IGR) and diabetes mellitus. Many patients require oral hypoglycemic agents, such as metformin or combination drugs, to achieve optimal glycemic control. As β-cell insulin secretion progressively declines, insulin may be required to control hyperglycemia, but not to sustain life. However, as the disease progresses, a significant proportion of patients may require insulin to control blood glucose and sustain life[2].
In addition to blood glucose levels, it is important to control blood pressure (BP)and low-density lipoprotein cholesterol (LDL-c levels) in individuals with T2DM. Regular evaluation of the management of these risk factors, at least once a year, are necessary. Early detection of diabetic complications such as kidney disease, retinopathy, neuropathy, peripheral artery disease, and foot ulcers is critical and preventive treatment should be initiated to prevent their development. With regular checkups, good lifestyle management, and medication as needed, people with T2DM can live long and healthy lives[3].
Diabetes complications
References：
Diabetes epidemiology
Diabetes in adults
Type 2 diabetes mellitus (T2DM) accounts for the majority of adult diabetes cases. According to the latest data from the 10th edition of the International Diabetes Federation (IDF) Global Diabetes Atlas, approximately one in ten people worldwide, or 537 million adults, are expected to have diabetes in 2021. The total number is expected to reach 643 million by 2030; and 783 million by 2045, an increase of 46% from 2021 (see Figure 1). The prevalence of diabetes is lowest among people aged 20-24 years (2.2%) and highest among people aged 75-79 years (24.0%), with the prevalence expected to increase to 24.7% by 2045. As the global population ages, the proportion of people with diabetes over the age of 60 is also expected to increase.
Figure 1 Global diabetes population and prevalence rate
In addition, approximately 240 million adults worldwide have undiagnosed diabetes, meaning that 1 in 2 people with diabetes are unaware of their condition. In addition, there are 541 million adults worldwide with impaired glucose tolerance (IGT) and 319 million adults with impaired fasting glucose (IFG)[1].
In 2021, the number of adult men with diabetes is 17.7 million, higher than the number of women with diabetes (10.2% vs. 10.8%). The prevalence of diabetes is higher in urban areas than in rural areas (12.1% vs. 8.3%), and it is projected that the prevalence of diabetes in urban areas is projected to increase to 13.9% by 2045 due to global urbanization and the population aging. The countries with the highest number of adults with diabetes are China, India, and Pakistan, with 141 million, 74 million, and 33 million people affected, respectively. Pakistan has the highest rate of diabetes with a prevalence of 30.8%. The lowest relative prevalence of adult diabetes in Africa (5.3%) may be related to lower levels of urbanization and incidence of overweight and obesity[1].
However, the increase in diabetes prevalence does not necessarily indicate an increase in the risk of developing the disease; it could be the result of improved medical care and longer life expectancy. Therefore, it is important to consider the incidence of new cases of diabetes in addition to prevalence. However, studies on the incidence of T2DM are limited. Some research suggests that the incidence of T2DM may be declining or stabilizing in several high-income countries, which may be due to the successful implementation of prevention strategies, diabetes screening, and the adoption of glycated hemoglobin as a diagnostic tool for the disease, among other factors[2].
Diabetes is a leading cause of premature mortality, with 6.7 million individuals between the ages of 20 and 79 worldwide expected to die from diabetes or its complications in 2021. That's an average of one death every five seconds. Approximately 1.4 million people in China die from diabetes each year, making it the country with the highest number of diabetes-related deaths in the world. The United States ranks second, with 700,000 deaths, followed by India, Pakistan, and Japan with 600,000, 400,000, and 200,000 deaths, respectively. The countries with the highest proportion of diabetes-related fatalities were Singapore, Pakistan, and Israel, all with a rate of 29%. Pakistan had the highest proportion of diabetes-related deaths in individuals under 60 years old, with a rate of 35.5%[1].
The economic costs associated with diabetes are staggering, estimated to be at least ＄966 billion in 2021. By 2030, these costs are projected to increase to ＄1.03 trillion, and by 2045, they are expected to reach ＄1.05 trillion. The United States, China, and Brazil bear the largest burden of these costs (＄379.5 billion, ＄165.3 billion, and＄42.9 billion, respectively). Notably, nearly 81% of people with diabetes worldwide live in low- and middle-income countries. Additionally, 87.5% of people with undiagnosed diabetes live in these countries. The countries with the most undiagnosed cases are China, India, and Pakistan, with approximately 72.8 million, 39.4 million, and 14.3 million people, respectively[1].
For adult-onset type 1 diabetes mellitus (T1DM), the prevalence is greater than 30 per 100,000 in regions of Northern Europe and East Africa, but less than 1 per 100,000 in China, and is higher in males than in females. Althoufh T1DM is generally thought to occur in childhood and adolescence, there is no clear association between the prevalence of T1DM and age at onset. The incidence of adult-onset T1DM does not appear to decrease with age. Most studies of the prevalence of T1DM in adults are based on clinical diagnosis or the need for insulin therapy within 12 months of a physician's diagnosis of T1DM. The true incidence of T1DM in adults may be underestimated because of the absence of classic symptoms such as ketoacidosis in some cases, the lack of common biomarkers, the slow progression of the disease, and delays in initiating insulin therapy in some people with T1DM, which may lead to misdiagnosis of T2DM[1].
Diabetes in children and adolescents
T1DM is the most common form of diabetes in children and adolescents in most countries, although type 2 and monogenic diabetes can also occur. For T1DM, insulin therapy is critical to survival, and either multiple daily injections or the use of an insulin pump is required to maintain proper glycemic control. Successful insulin therapy requires regular blood glucose monitoring, comprehensive diabetes education, and the support of competent healthcare professionals. The increasing incidence and decreasing mortality of T1DM in many countries has led to an annual increase in the number of new (incidence) and existing (prevalence) T1DM patients. Globally, there are an estimated 1.21 million children and adolescents under the age of 20 with T1DM, and approximately 150,000 young people under the age of 20 are diagnosed each year. India has the highest prevalence of T1DM in children under the age of 20, at approximately 2.4%. The prevalence in the United States, Brazil, Algeria, and China is about 1.8%, 0.89%, 0.65%, and 0.61%, respectively. India also has the highest rate of T1DM in children under the age of 20, at 22.9%, followed by the United States (15.7%), Brazil (9.23%), and China (5.6%)[1].
T2DM is rare in children before puberty, but its incidence has been increasing over time, possibly due to hormonal changes and insulin resistance during adolescence. It is more common in girls than in boys. Additionally, factors such as race and other individual characteristics may affect the incidence and prevalence of T2DM in young individuals. Young individuals with T2DM exhibit unique physiological and phenotypic characteristics. Compared to adults with the same disease, they tend to have a poorer glycemic control, higher rates of metformin monotherapy failure, and a more rapid decline in β-cell function. In addition, individuals with T2DM are more likely to develop other cardiometabolic risk factors, such as hypertension, elevated triglycerides, and central obesity, than those with T1DM. In addition, the prevalence of certain microvascular complications has been found to be two to three times higher in patients with T2DM of the same age[1].
References：
Insulins
Over the past century, the study of insulin has undergone three generations of development since Banting and Macleod's successful isolation of active insulin from dogs in 1921[1][2][3]. The first generation of insulin products, derived from animal sources such as pig and bovine pancreas, were structurally different from human insulin and resulted in a high incidence of allergic reactions upon injection. To address this issue, further research led to the development of subsequent generations of insulin. In 1978, Genentech produced the world's first second-generation insulin: recombinant human insulin, using recombinant DNA technology. It has an identical structure to that of human insulin and it is divided into short-acting and intermediate-acting insulins based on the duration of its action. Short-acting insulin has an onset of action of 30-60 minutes, a peak action of 2-4 hours, and a duration of 6-8 hours. It is injected subcutaneously about 30 minutes before meals to control postprandial glucose levels and is also used to control transient hyperglycemia. Biosynthetic human insulin (Novolin®R) and mixed protamine zinc recombinant human insulin (Humulin®R) are representative of the second-generation of insulins. Intermediate-acting insulin has an onset of action of 2-4 hours, a peak action of 4-10 hours, and a duration of 10-16 hours. It has an effect close to that of basal insulin. Compared with first-generation insulins, second-generation insulins have improved glucose-lowering effects and are associated with fewer systemic and local allergic reactions after injection.
After the 1990s, with the progress of genetic engineering technology, the third generation of insulins- insulin analogs, were developed by modifying the structure of insulin or changing its physicochemical properties. With lower immunogenicity and improved safety, they have gradually become the preferred insulins for diabetes treatment. Third-generation insulins are classified as ultra-rapid-acting, rapid-acting, and long-acting insulin analogs. (Ultra)-rapid-acting insulin analogs are primarily used for postprandial glycemic control and the treatment of transient hyperglycemia. They have a rapid onset of action, with rapid-acting insulin analogs acting within 10-15 minutes and ultra-rapid-acting insulin analogs acting within 2-4 minutes. Their peak effect lasts for 1-2 hours, and their duration is 3-5 hours. The representatives of ultra-rapid-acting products are insulin aspart (Fiasp®) and insulin lispro-aabc (Lyumjev®), and the representatives of rapid-acting products are insulin aspart (Rapilin®, NovoRapid®) and insulin lispro (Prandilin®, Humalog®). Long-acting insulin analogs serve as basal insulin and are typically administered 1-2 times per day. These types of insulin have an onset of action of 2-4 hours and produce a steady drug concentration in the body after injection, with no noticeable peak effect, that lasts for 16-42 hours. Representative drugs include glargine insulin (Basalin®, Lantus®) and insulin degludec (Tresiba®)[4].
Figure 1 Three generations of insulins
Figure 2 History of insulin development
With an in-depth understanding of diabetes, the treatment of diabetes is evolving to better simulate physiological insulin secretion and action. More comprehensive insulin therapy is required according to the glycemic control goals of diabetic patients. In terms of controlling the range of blood glucose fluctuations, insulin therapy should attempt to mimic basal and mealtime physiologic insulin secretion and take into account fasting and postprandial glucose. Therefore, premixed formulations of basal and mealtime insulin have become increasingly popular as a safer, more convenient, and more physiological approach to diabetes treatment. There are two types of premixed insulin available in China: premixed human insulin and premixed insulin analogs[5].
Premixed human insulin consists of the recombination of human insulin (short-acting) and protamine zinc recombinant human insulin (intermediate-acting) in specific proportions to produce short- and intermediate-acting insulin preparations. On the other hand, premixed insulin analogs are produced by combining rapid-acting insulin analogs such as insulin lispro or insulin aspart with protamine zinc recombinant rapid-acting insulin analogs or long-acting insulin analogs in specific ratios[5].
Individualized insulin therapy for Chinese diabetic patients must take into account their dietary habits, which are characterized by a high consumption of high glycemic index rice and flour products as staple foods for all three meals, resulting in a greater glycemic impact compared to Europeans. In addition, due to genetic factors and other differences, Chinese people have greater glycemic effects than Europeans even when consuming the same amount of the same grains[6]. Therefore, considering the dietary habits and glycemic variability characteristics, Chinese diabetic patients are more suitable for insulin regimens that can cover both fasting and postprandial glucose. The dual insulin formulation, which requires only one injection and can simulate close to physiological insulin secretion, significantly reduces the number of injections and offers convenient treatment, good patient compliance, and a high treatment achievement rate compared with the typical basal-bolus regimen.
The characteristics of the above-premixed formulations are detailed in Table 3.
Table 3 Classification of marketed premixed insulins
Insulin analogs currently dominate the insulin market due to their superior safety profile and lower potential to induce an immune response. Rapid-acting, short-acting, and intermediate-acting insulins are primarily used to regulate postprandial blood glucose, while long-acting insulins are used to regulate basal blood glucose. Premixed insulins can control both basal and postprandial blood glucose levels. Table 4 shows the long-acting basal insulins currently available on the market, including glargine insulin, insulin detemir, and insulin degludec. Evaluate forecasts that global sales of glargine insulin (Lantus®), insulin detemir (Levemir®), and insulin degludec (Tresiba®) will be＄2.953 billion, ＄0.904 billion, and ＄1.549 billion, respectively, in 2021. Furthermore, the diabetes market is expected to reach ＄66 billion by 2026.
Table 4 Comparative information of marketed long-acting basal insulins
References：
Biosimilar medicines
What is a biosimilar medicine?
A biosimilar medicine is developed to be highly similar to an existing biological medicine (known as the “reference medicine”) for which the patent has expired and exclusivity has been lost. Biosimilars have been shown to have equivalent efficacy and comparable safety, purity/quality, and immunogenicity. Therefore, physicians and patients can expect the same clinical outcome[1][2][3][4][5][6][7].
“Biosimilar” is a regulatory term that should be used only with reference to biologics that have been approved in highly regulated markets, such as Europe, Australia, Japan, Canada, and the United States, that meet strict criteria of quality and comparability to their respective reference biologics[7].
A biosimilar is approved based on the demonstration that it has no meaningful differences from the reference medicine for: quality/purity; safety; efficacy/potency; immunogenicity.
By definition, a biosimilar is required to have an identical protein (i.e., amino acid sequence and 3D structure), the same route of administration, and the same strength as the reference medicine. In addition, a biosimilar is highly similar to the reference medicine in terms of analytical and functional properties, pharmacokinetics, pharmacodynamics, purity, as well as clinical efficacy, safety, and immunogenicity, based on the results of comprehensive comparability studies[1][2].
Since the approval of the first biosimilar in 2006, biosimilar medicines have been used successfully in clinical practice in Europe and other parts of the world and they are already making an impact in terms of cost savings and patient access[1][5][8][9].
Why do we need biosimilar medicines – what are the benefits?
Why do we need biosimilar medicines – what are the benefits？
The growing demand for biologics, combined with historically limited competition, continue to strain healthcare budgets and limit patient access. Biosimilar medicines may offer benefits at all levels of the healthcare system:
Physician benefit:
Introduction of biosimilar medicines drives competition, helping to stimulate research and development into next-generation biologics, resulting in increased choice for healthcare professionals in how they treat their patients[10][11].
Patient benefit:
The availability of biosimilars has often enabled changes in policies that make biosimilars or their reference medicines available to broader patient populations or perhaps earlier in a treatment cycle, which can often lead to better clinical outcomes[9][11][12][13][14][15][16][17].
Cost savings generated by biosimilar medicines can be used to make more therapies available that otherwise would not have been covered. For example, in the Canadian province of British Columbia, the savings obtained from switching patients from reference biologics to biosimilars have been used to pay for some diabetes medications that were not previously covered by provincial health plans[18].
In some British hospitals, the savings obtained by using biosimilars have been used to hire more nurses, enhancing patient care. This process is called “gainsharing”[11][19].
Payer benefit:
The introduction of biosimilar medicines stimulates price competition between marketed biologic medicines, which is predicted to save healthcare systems up to €98 billion in the next five years across the EU and US[9].
Can physicians use a biosimilar with the same confidence as the reference medicine?
Yes. Approved biosimilar medicines are high-quality medicines that match their reference medicine in terms of safety, quality and efficacy[5][25].
When considering product and manufacturing process quality, health authorities apply the same high standards to all biological medicines, whether they are reference biologics or biosimilars. In addition to national recommendations, the International Conference on Harmonization has issued multiple guidance documents that apply to manufacturing process quality and product quality[1][20][21][22].
In highly regulated markets, like Europe, Australia, Japan, Canada, and the US, a biosimilar is approved only if it has demonstrated comparability to the reference medicine in terms of quality/purity, safety, and efficacy/potency. This comparibility is determined through an extensive and iterative process, based on the strict guidelines set by the regulatory authorities. Regulators such as the EMA (EU), TGA (Australia), PMDA (Japan), Health Canada, and the FDA (US) will only approve a biosimilar medicine if the respective company provides information convincingly demonstrating that no clinically meaningful differences exist between the biosimilar and the reference medicine[23][24][25][26][27][28].
References：
[25] Schneider CK. Biosimilars in rheumatology: the wind of change. Ann Rheum Dis. 2013;72:315-8.
WC500176768.pdf; accessed Oct 24, 2017
