Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high levels of blood sugar, either because the body does not produce enough insulin or because cells do not respond to the insulin that is produced.
This high blood sugar produces the classic symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). Diabetes is the fifth most common disease in the world after malaria, tuberculosis, common cold and cancer and is one of the biggest causes of premature illness and death worldwide. It was estimated that approximately four million people died of diabetes in 2010. This is largely due to a 29% increase in the number of deaths due to diabetes in the North America and Caribbean Region.
There are two main types of diabetes. Type 1 diabetes results from the body’s failure to produce insulin and requires manual injection of insulin by the patient. It is also referred to as insulin-dependent diabetes mellitus (IDDM). Type 2 diabetes results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. It was formerly referred to as non-insulin-dependent diabetes mellitus (NIDDM).
“The number of sufferers is expected to grow to 438 million by 2030, corresponding to 7.8% of the adult population“
The number of sufferers is expected to grow to 438 million by 2030, corresponding to 7.8% of the adult population. While the global prevalence of diabetes is 6.4%, prevalence varies widely according to region. It is high in the Western Pacific region at 10.2% of the total adult population but lowest in the African region where it affects 3.8% of the total adult population but is expected to increase fastest in the future. The primary driver of the diabetes epidemic is the rapid epidemiological shift associated with significant changes in lifestyle including changes in dietary patterns and decreased physical activity, leading to a higher prevalence of diabetes in the urban population.
Diabetes is one of the most costly health problems in the world. Healthcare expenditure on diabetes accounted for 11.6% of the total healthcare expenditure worldwide in 2010. Diabetes also imposes large economic burdens in the form of lost productivity and foregone economic growth. The American Diabetes Association estimated that the US economy lost $58 billion, approximately half of the direct healthcare expenditure on diabetes in 2007, because of lost earnings due to lost work days, restricted activity days, lower productivity at work, mortality and permanent disability caused by diabetes.
The main goals of diabetes treatments are to keep blood glucose levels under control and to prevent long-term complications. Diet and exercise, oral hypoglycemic agents, insulin and GLP-1 (glucagon like peptides) agonists are the major options available for the treatment of type 2 diabetes. The treatment options are chosen either individually or in combination depending on stage and severity. Diet and exercise are also critically important as 95% of patients with type 2 diabetes are obese, a major risk factor for the disease. Obese peoples are at five times more risk of diabetes than those who are a normal weight. For this reason, major pharmaceutical companies focus their biomedical research on the monitoring, control, and treatment of diabetes mellitus and its complications. There has been a significant increase in number of players involved in diabetes research over the last five years. Drug makers are also more focused on metabolic disease as it represents one of the largest areas of unmet need in medicine with huge market opportunities and is increasing with the obesity epidemic.
“The American Diabetes Association estimated that the US economy lost $58 billion, approximately half of the direct healthcare expenditure on diabetes“
Currently available treatment options meet desired efficacy levels but the market has unmet needs in terms of safety and patient compliance. This implies that the market is moderately served by the current treatment options and that significant potential exists for new entrants. Glitazones, a type of oral anti-diabetic drug, were found to lead to cardiovascular risks in diabetes patients. In 2000, Rezulin (troglitazone), which treated more than 2 million diabetes patients, was found to cause severe side effects such as liver damage and heart problems. The drug was pulled from the market on March 21, 2000, following a request from the US FDA.
In 2007, Avandia (rosiglitazone), marketed by GlaxoSmithKline, treated more than 6 million diabetic patients and brought in more than $1.8 billion in revenue. However, sales declined sharply after studies discovered that Avandia had been associated with a 40% increase in severe heart risks, congestive heart failure and osteoporosis. According to Sen. Charles Grassley (R-Iowa), approximately 100,000 heart attacks may have been linked to Avandia. Following a review of the data, in September 2010 the European Medicines Agency asked GlaxoSmithkline to withdraw Avandia from the European market and the US FDA asked for it to be used in a restricted class of patients with a new warning. The FDA also issued a black box warning to another TZD class drug Actos (pioglitazone hydrochloride) about the serious risk of adverse cardiovascular events including heart attacks, heart failure and cardiovascular-related deaths. Actos was finally withdrawn from most of the major markets due to its association with an increased risk of bladder cancer. Unmet need also exists in term of insulin delivery systems which currently carry poor patient compliance. Diabetes is a self-managed condition for which the dosage regimen can become confusing, resulting in poor patient compliance and reduced utilization of medication. In addition diabetic patients have to make decisions about their daily diet, lifestyle, exercise and insulin regime in relation to self-monitored blood glucose levels. This means that there is a need for insulin delivery systems that can be customized for a specific individual due to differing insulin speeds and durations of action.
Insulin analogs such as Lantus have been found to have carcinogenic effects. Diabetic patients using insulin analogs were found to contract long-term complications including a risk of cancer. Many insulin analogs act in a similar way to normal human insulin but differ in their biological effect and lead to unknown consequences such as mitogenicity, apoptosis, glucose and lipid metabolism, and protein degradation.
Current competition in the type 2 diabetes market is strong. Many of the older oral hypoglycemic agents which are essentially restricted for use in type 2 diabetics are now available in generic form. In 2010, metfomin, a gold standard treatment for type 2 diabetes, was one of the most prescribed and preferred medications used alone or in combination with other products. The other classes of oral hypoglycemic are also widely available as generic agents, such as sulphonylureas and alpha glycosidase inhibitors. However, there has recently been an increase in the use of combination products as many patients require treatment with multiple drugs. The most popular combinations are those containing metformin such as Actoplus Met, Janumet and Avandamet.
There has also been an increased acceptance of newer agents that target the incretin pathway such as injectable agonists that activate GLP-1 receptors and DPP IV inhibitors that inhibit the peptidase that deactivates GLP-1. This has led to revenue growth in the diabetes market due to better efficacy and safety profiles. Two GLP-1 agonists are currently approved for use: exenatide (Byetta) and liraglutide (Victoza), which are preferred for use in combination with other oral diabetic agents. The patents of some key established molecules are set to expire between 2012 and 2017, including Humalog and Lantus. However, the impact of the patent expiry of these drugs will be offset by the expected launch of new products.
The market in 2010 was led by Actos, Januvia, Byetta and Lantus. Long acting insulin analogues Lantus and Levemir contributed $6.5 billion, with sales from Lantus amounting to $4.9 billion.
There are currently five approved DPP4 inhibitors: Januvia from Merck, Galvus from Novartis, Onglyza from Bristol-Myers Squibb and AstraZeneca, Tradjenta from Boehringer Ingelheim, and Nesina from Takeda, which is only approved in Japan. Of these, Januvia is approved in all major markets and had 2010 sales of approximately $3.2 billion, while in the same year Onglyza had sales of only $152m. Nesina had a minimal impact because it is only approved in the Japanese market. Novartis’ vildagliptin (Galvus, Equa) is approved in Europe and Japan and had 2010 sales of $391m.