Balancing the sweetness

Balancing the sweetness

Though there is no permanent cure for diabetes, advancements in the treatments have made life more bearable for patients. Sachin Jagdale analyses

In recent years, there has been an explosive increase in the prevalence of diabetes mellitus (type 2 diabetes, formerly called non-insulin-dependent diabetes mellitus (NIDDM), or adult-onset diabetes) which may be rightly called a new-age pandemic. This increase is predominantly related to unhealthy lifestyle practices and a resultant surge in obesity. This has even led to the coining of a new term ‘diabesity’, as a description for diabetes caused by excessive weight; the condition of having both diabetes and excessive weight.

The long term metabolic consequences of prolonged and uncontrolled hyperglycemia; including accelerated atherosclerosis, chronic kidney disease, neuropathy and retinopathy, pose an enormous burden not only in patients with diabetes mellitus but also on the public health system and the government. This is also because diabetes is a relentlessly progressive disease for which there is currently no permanent cure. Improvements in our understanding of the pathogenesis of diabetes and in the therapy areas of diabetes are critical to meeting this health care challenge till we find a cure to this disease. Today there are safe and convenient therapeutic modalities available, vide a host of oral anti diabetic drugs, much improved varieties of insulins and few non insulin injectables for adequate control.

Adequate control has been defined by various scientific bodies like American Diabetes Association, American Association of Clinical Endocrinologists, World Health Organization and others, as attaining blood glucose levels as close to normal as possible. The specific target levels recommended are; fasting blood glucose < 110, 2hr post meal glucose < 140 and HbA1c < 6.5-7.0 percent. Until recently, achieving these figures and thereby control was far removed from reality. This occurred because neither oral drugs like sulfonylureas, biguanides, thiazolidinedione, alpha glucosidase inhibitors, nor the newly available treatment modalities like exenatide and DPP 4 inhibitors (sitagliptin) were efficient in maintaining blood glucose control, due to progressive nature of the disease. Also their effectiveness in terms of glycemic control is limited and their doses cannot be increased without resulting in intolerable side effects compared to that of insulin which is a natural hormone and has unlimited capacity of reducing blood glucose levels.

Insulin, benefits and limitations

“The National Control Programme on Diabetes, Cardiovascular Disease and Stroke (NPDCS) launched by the Government should help the government to play a
significant role in the control of diabetes in the country”

– Dr V Mohan Chairman and Chief Diabetologist

Dr Mohan’s Diabetes Specialties Centre

“Insulin remains the backbone of diabetes treatment. However, the fact that it is to be given by an injection is not acceptable to a few patients. Weight gain and hypgolycemia (low blood sugar levels) may be disturbing to a few”

– Dr P S Lamba Endocrinologist

Wockhardt Hospitals, Mumbai

“Doses of insulin have to be adjusted depending upon the blood sugar levels. Hence monitoring of blood glucose on daily basis is often a must”

– Dr Phulrenu Chauhan Consultant Endocrinology Department,

P D Hinduja Hospital, Mumbai

The discovery of insulins in the 1920’s was a turning point in the history of diabetes. The earlier animal insulins had paved the way for the introduction of human insulins. While human insulins were an advancement over the earlier conventional forms and millions worldwide have benefited by their use, they have their own shortcomings. These preparations do not match up to the normal insulin secretion profile, as after injection patients need to wait for 30-60 minutes before their meals. Also snacking is at times needed to counter the in-between meal hypoglycemic episodes, as human insulins act for a longer time than required. This compromises the patient’s quality of life significantly. Dr P S Lamba, Endocrinologist, Wockhardt Hospitals, Mumbai, says “Insulin remains the backbone of diabetes treatment. However, the fact that it is to be given by an injection is not acceptable to a few patients. Weight gain and hypgolycemia (low blood sugar) may be disturbing to a few.”

According to Dr V Mohan, Chairman and Chief Diabetologist, Dr Mohan’s Diabetes Specialties Centre, despite insulin being a life saving drug there are some limitations of its use. He says, “Till today, insulin has to be given as an injection and it needs to be refrigerated and therefore needs cold storage which is not available in many places.” He adds, “Even given these limitations, insulin still remains a life saving drug and should be considered for all people with diabetes who need these treatments.” Dr Phulrenu Chauhan, Consultant, Endocrinology Department, P D Hinduja Hospital, Mumbai, points out one of the most crucial complication in the administration of insulin. She says, “Doses of insulin have to be adjusted depending upon the blood sugar levels. Hence monitoring of blood glucose on daily basis is often a must.” Role of Insulin analogues

The introduction of recombinant DNA (rDNA) technology in 1980s certainly improved the profile of human insulins, but the search for an ideal insulin continued. The advent of modern insulins (also known as designer insulins/insulin analogues) was a breakthrough and just the right step in this direction.

The development of modern insulins (insulin analogues) resulted from slight modifications in the structure of insulin molecule using the same r-DNA technology. Insulin analogues are classified into rapid acting, long acting and pre-mixed varieties. Rapid acting analogues such as insulin aspart are quickly absorbed into the blood stream, have a greater peak and shorter duration of action than conventional insulins. These are designed for controlling prandial glucose excursions. Basal insulin analogues like insulin detemir mimic the slow and steady background secretion of insulin throughout a 24 hour period and have a desirable flat, peakless profile. Premixed analogues such as Novomix-30 have a combination of a rapid-acting analogue for prandial needs together with the protaminated part of the same analogue, for providing basal insulin levels. Hence with premixed analogues, patients have the same product for both the postprandial and basal insulin needs. Modern insulins provide flexibility in dosing and improved glycaemic control with the desired convenience to the patient. The insulin regimens with modern insulins can now be tailored to meet the individual needs of each patient. They have reduced risk of hypoglycaemic events, cause less weight gain (as with Levemir), are easy to administer and offer a greater predictability. There are various regimens available for modern insulins. The regimen choice needs a consideration of several factors like type of diabetes, glycemic status, patient compliance and physician’s choice among others.

Delivery devices

Complementing the advantages of modern insulin and as a measure of convenience to patients, there emerged a great leap in the technology of insulin delivery devices with the introduction of insulin pens. The traditional insulin injection process was time-consuming, cumbersome, inconvenient, painful and used to cause significant dosing errors. However, insulin pens available today, such as Novopen-3 and Flexpen address these drawbacks offering substantial improvements in convenience, freedom, accuracy and flexibility for people with diabetes. This has also found patient acceptance due to the availability of very fine and virtually painless needles. Furthermore, physicians find that their efforts for early insulinisation are more rewarded with the use of these technology intensive pen devices and this may hold the key to better long-term outcomes.

Though there are discoveries and advanced therapies for diabetes management, these may not necessarily accessible to all diabetes patients. Reasons may vary from place to place. Sometimes advanced therapies are not available in that particular region. Poverty could also prevent a needy patient from availing of diabetic treatment. This problem is prominent particularly in developing nations. Lamba rightly says, “Though all the advanced treatments are available cost remains the problem.”

Incredible Incretins

Another relatively recent development in the treatment of type 2 diabetes has been the concept of “Incretins”. These are hormones in the body that are released from the intestines. The two important incretins are: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1). These augment glucose-dependent insulin secretion from the pancreatic beta cells and differentially stimulate insulin secretion. GIP has little effect whereas GLP-1 significantly augments glucose-dependent insulin secretion. But if these hormones are administered exogenouslym they are degraded very fast resulting in their short duration of action. To circumvent this problem synthetic incretin-mimetic agents were synthesised, namely exenatide and liraglutide. Exenatide needs to be administered twice daily as subcutaneous injections. Intractable vomiting, nausea and diarrhoea are the adverse effects associated with this therapy. Recently, few incidences of pancreatitis have been reported in patients using this drug. Liraglutide is a long-acting GLP-1 analogue currently under phase III clinical trials, which holds a promising once daily dosing requirement and a unique weight loss advantage. Acting on the similar pathway, dipeptidyl peptidase-4 (DPP-IV) inhibitors like sitagliptin and vildagliptin have been developed which inhibit DPP-IV enzyme that degrades the incretin hormones, thereby increasing their duration of action. Efficacy of these inhibitors is a major limitation.

Pramlintide, a synthetic analog of amylin (ß-cell hormone), modulates postprandial glucose levels and inhibits glucagon production. It might be associated with some weight loss but the major limiting factors are the parenteral route of administration, the need to take injections before each meal, a limited capacity to decrease hyperglycemia and side effects like nausea, vomiting, and anorexia. Also the long term safety has not yet been established. Though weight loss has been seen with this drug, some of it might result from gastrointestinal disturbances.

Government’s role

According to Lamba, government can increase public awareness through media and is of paramount importance. Exercise, proper dietary habits and life style modifications in healthy young Indians will not only prevent diabetes but also other metabolic diseases (heart attacks). Prevention of childood obesity is of paramount importance as this is the harbinger of adult metabolic disease. Primary health centers, government and muncipal hospitals and free dispensaries should be the places where these efforts should be targeted.

V Mohan says, “The Government. can offer subsidised treatment and also free insulin for low income groups. Government can conduct screening camps in rural areas free of cost as most of them are not aware of diabetes and its complications, as 70 percent of India’s population lives in rural areas. The National Control Programme on Diabetes, Cardiovascular Disease and Stroke (NPDCS) launched by the Government should help the government to play a significant role in the control of diabetes in the country.”

More to offer

Developing a treatment strategy for patients with diabetes is not only to control hyperglycemia, as there may be a co-existing complex metabolic cardiovascular syndrome including either hypertension, dyslipidemia, obesity, clotting abnormalities or micro-albuminuria, and could even include accelerated atherosclerosis. Therefore, management of these concomitant conditions becomes essential, along with addressing the primary goal of tight glycaemic control.

Of late, a number of other experimental approaches which have been tried in the field of diabetes care are: intraperitoneal delivery devices, closed-loop artificial pancreas, islet cell and pancreatic transplantation and gene therapy. Attempts have also been made to administer insulin by oral, nasal, rectal or inhalation routes. Even subcutaneous implantation of pellets has been tried The most promising of these alternatives is the inhalation route, aimed at absorption through the pulmonary mucosa. Although oral delivery of insulin would be more convenient for patients and would provide higher relative concentrations of insulin in the portal circulation, attempts to increase intestinal absorption of the hormone have met with only limited success. Efforts have focused on protection of insulin by encapsulation or incorporation into liposomes. But many of these approaches are still experimental.

In developing a cure for diabetes, pancreatic transplantation and gene therapy are provocative approaches to insulin replacement. Segmental pancreatic transplantation has been employed successfully; however, the surgery is technically complex and is usually considered in patients with advanced disease and complications. A person with diabetes will benefit from pancreatic transplantation. It will help to produce complete insulin independence. In the year 1966 the first successful pancreas transplantation in conjunction with simultaneous kidney transplantation was done by Richard Lillehei, University of Minnesota. Till two decades back , the procedure was considered experimental however, now it is a widely accepted therapeutic modality, with virtually all insurance carriers covering the procedure making it lot easier for patients who are not financially capable of availing such procedures. The pancreas comes from a cadaveric organ donor.

Till we succeed in the development of a practical cure, there remains a need to manage diabetes as a whole, taking cognisance of important issues like the quality of life of patients. While conventional modalities focused only on reducing glucose levels, advanced therapy options such as modern insulins along with improved delivery devices provide for a more holistic treatment approach, which includes improving the quality of life for patients with diabetes.