The search for safer, better diabetes medication

According to the International Diabetes Federation (IDF), an estimated 371 million people worldwide have been diagnosed with type 1 and type 2 diabetes (T2D), and with this expected to increase by 50 per cent over the next 20 years, the anti-diabetic therapy area is a hot area of research. T2D is the most common type, accounting for an estimated 90 per cent of all diabetes cases.

November 14 is World Diabetes Day and education and prevention being the theme for the past five years, it is only to be expected that pharmaceutical companies go into overdrive, announcing patient awareness campaigns, collaborations and the like.

China may have more diabetic patients but India is inching closer each day to becoming the diabetes capital of the world. Given the high rate of cases which go undiagnosed, the scenario is indeed worrying. An Abnormality Report put together by Indus Health Plus, which is involved in preventive healthcare check-ups, has shown rapid increase in numbers of diabetic across major cities in India as compared to any other disease. The report, based on findings from July 2012 to May 2013, also highlights the increasing trend of diabetes among females and youth. (BOX: Cities under siege)

Cities under siege

An Abnormality Report put together by Indus Health Plus, which is involved in preventive healthcare check-ups, has shown rapid increase in numbers of diabetics across major cities in India as compared to any other disease. The report, based on findings from July 2012 to May 2013, also highlights the increasing trend of diabetes among females and youth. 1. Delhi 18 per cent increase amongst men observed in diabetic cases, there was whooping increase of 39 per cent in females Delhites are evidently seen to have a sweet tooth. They also consume high amount of oil/ghee/butter in various cooked eatables. This has evidently increased the numbers of obesity, hypertension therefore giving a rise in the numbers of diabetes 2. Mumbai In Mumbai, sugar levels were found to be high surprisingly amongst youth, especially between the age group of 25-35 years of age. 32 per cent of these were detected with diabetes A lot of stress is borne by population in the age bracket of 28-40 years age. This lot is mainly those from the MNC and IT industry with less physical activity as per their work portfolio. With 65 per cent of women detected as diabetic, almost more than 50 per cent of those were working. There were men from the age bracket of 40-60s who were seen at a higher risk 3. Pune In Pune too, those in the age bracket of 30-40 were observed to be living at higher risk levels of diabetes. Even those from the age bracket of 20-30s were observed to have increased by 21 per cent cases of diabetes Younger women in the age bracket of 30-35 have been observed to have having extra junk and sweet stuff that has also elevated the chances of diabetes in them 4. Hyderabad Increase in diabetes among women by 15 per cent Polished rice, carbohydrates, coconut and urban trends is a major cause of diabetes 5. Bangalore Clear increase noticed in the age group of 25-30 years both in male and female. While 40 per cent of the cases are because of genetic, 60 per cent of the detections are because of change in their lifestyle It was also observed during doctor consultation that not just middle age group population but also 40 per cent of the young Bangloreans ( 25-45 years) did not know the after effects of diabetes and the need to get test done.

Challenging collection of risk factors

The treatment of diabetes is particularly challenging due to the collection of risk factors associated with it, and this is the main driver for research on better treatment options. Clinicians require different treatments and different combinations of treatments to focus on the different factors impacting diabetes at different stages of the condition as the disease progresses. The 49th Annual Meeting of the European Association for the Study of Diabetes (EASD) in Barcelona in September saw a number of pharmaceutical companies present research on promising investigational molecules.

At a pre conference media briefing, Boehringer Ingelheim and Eli Lilly presented data on empagliflozin, an investigational compound as well as safety data on as Trajenta (linagliptin), a once-daily tablet that is used along with diet and exercise to improve glycaemic control in adults with T2D. Boehringer Ingelheim’s Trajenta has reportedly had a successful run in the the year since its launch globally and in India, and bagged two award: ‘Marketing Excellence’ by OPPI & ‘Pharmaceutical Brand of the Year’ (New launch) by Frost & Sullivan.

Protecting the heart …

Experts stress that diabetes increases the risk of other diseases. For instance, cardiovascular events rank as the major cause of death in patients with diabetes, accounting for more than 50 per cent of all diabetes fatalities. Professor Mark Kearney, Professor of Cardiovascular and Diabetes Research, British Heart Foundation, University of Leeds, UK stressed that diabetes accelerates multiple aspects of heart failure.

A practising cardiologist with an interest in heart failure and diabetes, he gave chilling examples from his practice to demonstrate the impact of diabetes. The risk of heart attack is less than five per cent in a non-diabetic but increases to 15 per cent in a diabetic. Even if diabetic patients survive a heart attack, they are left with left ventricular damage. Focussing on the diagnosis and treatment of modern day diabetic patients, he stressed the need for life style changes but also the need for new therapies and delivery modes.

… and the kidneys

Besides cardiovascular events, kidney disease is another common complication of diabetic patients. Dipeptidyl peptidase-4 (DPP-4) inhibitors like Trajenta (linagliptin), have become the mainstay of treatment, according to Prof Cliff Bailey, Professor of Clinical Sciences, Aston University, UK. DPP-4 inhibitors work by enhancing the secretion of incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) thus increasing insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels.

Impairment of renal functions becomes even more of an issue with elderly patients and ongoing studies have tried to collect safety data in this patient group. Boehringer Ingelheim and Eli Lilly presented results from a post-hoc analysis of pooled data from seven clinical trials including 1,293 people with T2D aged 65 years or older which showed linagliptin was well tolerated including in the elderly with normal renal function to severe renal impairment. The overall incidence of adverse events was similar for linagliptin compared to placebo.

The new kid on the block

Terming diabetes as the epidemic of the 21st century, Prof. Bernard Zinman, Director, Leadership Sinai Centre for Diabetes, Canada worries that it will “bankrupt the health systems of countries if we do not do something about it.”

T2D is clinical described as a dysregulation of glucose homeostasis characterised by persistent hyperglycaemia (high blood glucose levels over a long time), impaired ß-cell function (reduced ability of the pancreas to produce insulin) and insulin resistance (secreted insulin is less effective at lowering blood glucose in the body). Even though there are many treatments available for patients with T2D to reduce their blood glucose, many do not achieve their glycaemic goals. This may partly be due to side effects of medication such as weight gain, hypoglycaemia and gastrointestinal effects.

Zinman explains that an important part of the biological evolution of man was the reabsorption of sugar in the kidneys, as the human body was programmed to conserve calories. But this survival tactic that helped our ancestors store nutrition in preparation for times when food might not be in plenty, creates a problem for TD2 patients as the reabsorbed glucose is re-circulated into the blood stream and results in high blood glucose levels (hyperglycaemia) as well as weight gain.

Virtually all of the filtered glucose is reabsorbed by sodium glucose cotransporters (SGLTs) in the kidney. Since SGLT2 inhibition targets glucose directly and works independently of ß-cell function, this class of drugs has become the subject of study as a probable important clinical addition to the treatment regimen for people with T2D and their physicians.

The use of SGLT2 inhibitors to increase elimination of glucose in the urine thus represented a unique way of turning a symptom of the disease (ie: increased glucose in the urine) into the treatment.

Other drugs in the SGLT2 inhibitors class include canagliflozin, dapagliflozin, empagliflozin and ipragliflozin. In November 2012, AstraZeneca and Bristol-Myers Squibb’s Forxiga/dapagliflozin was approved by the European Commission for the treatment of T2D in the European Union (EU) while in March this year, Johnson & Johnson’s Invokana/ canagliflozin got US FDA approval for the treatment of T2D diabetes.

Empagliflozin, one of the members of the SGLT2 group of compounds, is one of three research compounds under the Boehringer Ingelheim and Eli Lilly alliance for diabetes. At EASD, the two companies presented results from a new analysis of pooled efficacy data from four Phase 3 trials of empagliflozin showing improved glycaemic parameters, body weight and blood pressure, in adults with T2D. The Phase 3 trial has enrolled more than 14,500 patients and comprises more than 10 multinational clinical trials.

Also under investigation is the effect on the risk of hypoglycaemia and urinary tract and genital infections as the Phase 2 and 3 studies threw up key safety points related to an increase in adverse events related to genital infections; a similar rate of adverse events related to urinary tract infections compared to placebo; and a similar hypoglycaemic event rate compared to placebo in studies without sulphonylurea and insulin background therapy, according to a press release from the companies.

On the sidelines of the media briefing, Dr Thomas Seck, Associate Therapeutic Area Head, responsible for Medical Affairs at the metabolism department at Boehringer Ingelheim confirmed that India is included in the Phase 2 and 3 studies of empagliflozin. He indicated that around 30-40 per cent of patients in these studies are from Asia and of this, a majority are from India.

Efficacy profiles of empagliflozin are somewhat similar and there might be differences in safety but it is difficult to make any conclusions with the data collected so far, says Seck.

Basal insulin, the third compound in the BI-Lilly alliance, is currently in phase 3 and Seck indicated that the company hopes to be able to submit data to regulatory agencies by next year.

Education the key

But treating diabetes needs a multipronged approach beyond research labs. (See report: Complexity of managing Type 2 diabetes is currently underestimated, reveals survey) The online survey showed that though managing T2D is complex, 90 per cent of physicians polled agreed that both healthcare practitioners and patients could gain from additional medical information and patient support materials. Education and awareness would seem to be as vital as the medicines themselves.

viveka.r@expressindia.com