Treatment in diabetes

“Lifestyle modification is important whether you have type 1, type 2, or don’t have diabetes. Everyone should have 30 minutes of moderate or vigorous exercise daily.”

i. Exercise
ii. Diet
iii. Drugs/Insulin

Medications that increase the insulin output by the pancreas – sulfonylureas and meglitinides.

Sulfonylureas

Sulfonylureas primarily lower blood glucose levels by increasing the release of insulin from the pancreas. Older generations of these drugs include chlorpropamide and tolbutamide, now hardly in use. Newer drugs: 1. Glipizide; 2. Glimiperide.

These drugs are effective in rapidly lowering blood sugar but run the risk of causing hypoglycemia (abnormally low and dangerous levels of blood sugar). In addition, they are sulfa-containing drugs and should be avoided by patients who are allergic to sulfa.

Meglitinides – repaglinide and nateglinide

Meglitinides also work on the pancreas to promote insulin secretion. Unlike the sulfonylureas which last longer in the body, repiglinide(Novonorm)and nateglinide are very short acting, with peak effects within one hour. For this reason, they are given up to three times a day just before meals. Since these drugs also increase circulating insulin levels, they may cause hypoglycemia, but the literature suggests this is less frequent than the hypoglycemia seen with sulfonylureas.

Medications that decrease the amount of glucose produced by the liver

A class of drugs called biguanides has been used for many years in Europe and Canada. In 1994, the FDA approved the use of the biguanide metformin (Glucophage) for the treatment of type 2 diabetes in the U.S.In India it is widely used.It is also told to among Insulin sensitizers. Metformin is unique in its ability to decrease glucose production by the liver. Briefly, because metformin does not increase insulin levels, when used alone, it does not usually cause hypoglycemia. In addition, metformin has an effect whereby it tends to suppress appetite, which may be beneficial in diabetics who tend to be overweight. Metformin may be used by itself or together with other oral drugs or insulin.

It should not be used in patients with kidney impairment and should be used with caution in those with liver impairment.

Medications that increase the sensitivity of cells to insulin

The class of drugs known as thiazolidinediones lowers blood glucose by improving target cell response to insulin (that is, increasing the sensitivity of the cells to insulin).

Troglitazone (Rezulin) was the first of this class in the U.S. Because of severe toxic liver effects, troglitazone has been taken off the market. Sister compounds are now available with a better safety profile. These drugs include pioglitazone and rosiglitazone.

These drugs act by increasing the sensitivity (responsiveness) of cells to insulin. They improve the sensitivity of muscle and fat cells to insulin. These drugs have been effective in lowering blood sugars in patients with type 2 diabetes. It is important to note that it takes up to six weeks to see a drop in blood glucose levels with these drugs and up to 12 weeks to see a maximum benefit.These have been approved as first line therapy in diabetes and for use in combination with other drugs. Both drugs may be used in patients taking other oral drugs as well as those using insulin.

If at any point the liver tests increase to three times the normal upper limit, the drug should be stopped.

The most important contraindications to these medications include any type of liver disease, and heart failure. Fluid retention can be of particular concern in patients with signs or symptoms of heart failure and in those with ejection fractions of less than 40% which indicates poor function of the heart. Some recent studies have suggested an association between pioglitazone and rosiglitazone and untoward cardiac events, for example, heart attacks, though this association is controversial. Regardless of the controversy, it is well established that pioglitazone and rosiglitazone should be avoided in patients with symptomatic heart failure or heart failure.

Another newer concern is an association of treatment with a small increase in the frequency of fractures of the distal long bones of the arms and legs. At present, this does not translate into fractures of the hip and spine, which would be clinically more worrisome. More data is needed to make a definitive statement about cause and effect at this time.

Medications that decrease the absorption of carbohydrates from the intestine

Acarbose, Voglitor

Before being absorbed into the bloodstream, carbohydrates must be broken down into smaller sugar particles, such as glucose, by enzymes in the small intestine. One of the enzymes involved in breaking down carbohydrates is called alpha glucosidase. By inhibiting this enzyme, carbohydrates are not broken down as efficiently and glucose absorption is delayed.

As a single agent, Acarbose or Voglitor is not as effective as the other medications for diabetes. It is currently used alone or in combination with a sulfonylurea.

Because of its mechanism of action, Precose has significant gastrointestinal side effects. Abdominal pain ,diarrhoea and gas are common and are seen in up to 75% of patients taking Precose.

New medications that affect glycemic control

Pramlintide [Symlin] – Not available in India

It is the first in a new class of injectable, anti-hyperglycemic medications for use in patients with type 2 or type 1 diabetes treated with insulin. Pramlintide, is a synthetic analog of human amylin, a naturally occurring neuroendocrine hormone synthesized by pancreatic beta cells that helps control glucose control after meals. Amylin, similar to insulin, is absent or deficient in patients with diabetes. When used with insulin, this compound can improve glycemic control and has additional benefits that cannot be realized with insulin alone.

Byetta (exenatide)

Byetta is the first in a new class of drugs for the treatment of type 2 diabetes called incretin mimetics.it a new medication on the market that has it’s origins in an interesting place–the Gila monster’s saliva. Scientists studying this small lizard noted it could go a long time without eating.They found a substance in it’s saliva that slowed stomach emptying, thus making the lizard feel fuller longer.

This substance was similar in nature to a gut hormone found in humans known as GLP-1. GLP-1 is broken down in the body by an enzyme called DPP-IV. So, if you could make a substance like GLP-1 that was not so easy to breakdown, this would have potential benefit; thus, the studies began. Ultimately, after modifying this hormone, exenatide (with the trade name Byetta) was developed. Byetta has been shown to have many of the same effects on sugar regulation as GLP-1, so it mimics the body’s natural physiology for self-regulating blood sugar. Namely, it slows the release of glucose from the liver, slows stomach emptying thereby regulating delivery of nutrients to the intestine for absorption, and works centrally in the brain to regulate hunger.

Just like Symlin, Byetta is given by injection, but it is given twice a day (usually before breakfast and dinner meals). It comes in a disposable pen form and is available in two doses.

A longer acting from of Byetta is currently being considered for approval by the FDA. This would allow for the same benefits (and side effects) without need for such frequent injections.

DPP-IV inhibitors: Sitagliptin [Januvia], Vidagliptin [Galvos]

The latest drugs called DPP IV inhibitors are now available in India.They do just that, that is, they inhibit this enzyme from breaking down GLP-1. This allows GLP-1 already in the blood to circulate longer. There are a number of companies working on this class of drug and the FDA just approved the first drug in this class made by Merck and called januvia. Januvia can be used in combination with certain other medications and must be dose adjusted in patients with poor kidney function.

Januvia is also available in combination with Metformin as Janumet.

Vidagliptin is avaiable as 50mg tab with trade name Galvos.

SGLT2 Inhibitors:

A New Mechanism for Treating Type 2 Diabetes Mellitus

In recent years, it has become clear that the kidneys play a key role in the overall handling of blood glucose in the body. In “normal” individuals, the kidneys continuously filter a large volume of glucose through the glomerulus (approximately 180 g/day) and actively reabsorb nearly all of this glucose.

In people with type 2 diabetes mellitus who have hyperglycemia, more glucose is filtered than reabsorbed, helping to sustain the hyperglycemia of diabetes. A protein called sodium-glucose cotransporter 2 (SGLT2) plays an important role in the kidneys and is responsible for most renal glucose reabsorption in people with type 2 diabetes mellitus. Retention of excess glucose by this pathway contributes to persistent hyperglycemia

It is now known that suppressing the activity of SGLT2 in the body inhibits renal glucose reabsorption, thereby increasing the excretion of excess glucose from the body and assisting in the reduction of hyperglycemia. SGLT2 inhibitors do not stimulate insulin secretion and therefore are expected to be associated with a low risk for hypoglycemia. In addition, there is the potential for clinically significant weight loss, and, as mentioned above, reduced hepatic glucose production and amelioration of glucotoxicity.

The first phase 3 data for dapagliflozin, an investigational SGLT2 inhibitor, were presented during the European Association for the Study of Diabetes (EASD) 45th Annual Meeting; September 29-October 2, 2009; Vienna, Austria. After 24 weeks, results from this phase 3 clinical study demonstrated that dapagliflozin, when added to metformin in people with type 2 diabetes mellitus inadequately controlled with metformin alone, resulted in significant mean reductions in the primary endpoint, A1c, and in the secondary endpoint, fasting plasma glucose.

The study also evaluated the potential impact of dapagliflozin on weight loss and demonstrated that individuals receiving dapagliflozin had statistically greater mean reductions in body weight compared with individuals taking placebo. Dapagliflozin, currently under joint development as a once-daily agent, is a potential first-in-class oral SGLT2 inhibitor designed for treating type 2 diabetes mellitus.

In addition, remogliflozin etabonate has been identified to be a potent and highly selective SGLT2 inhibitor. Orally administered remogliflozin etabonate has been found to increase urinary excretion of glucose in both mice and rats. Through this action, remogliflozin etabonate inhibits the increase in plasma glucose after glucose loading without stimulating insulin secretion in normal rats, suggesting that remogliflozin etabonate may be a new and useful drug for the treatment of diabetes.

Combination medications – These days combination therapy is being used.

Treatment of diabetes with insulin

It the mainstay of treatment for patients with type 1 diabetes. Insulin is also important in type 2 diabetes when blood glucose levels cannot be controlled by diet, weight loss, exercise, and oral medications.

Ideally, insulin should be administered in a manner that mimics the natural pattern of insulin secretion by a healthy pancreas; however, the complex pattern of insulin secretion by the pancreas is difficult to duplicate. Still, adequate blood glucose control can be achieved with careful attention to diet, regular exercise, home blood glucose monitoring, and multiple insulin injections throughout the day.

In the past, the insulin was being derived from animal sources, particularly cows and pigs. Not only was there a problem with enough supply of insulin to meet the demand, but beef and pork insulin also had specific problems. Human insulin is now widely used.

Insulin now comes in a variety of preparations that differ in the amount of time following injection until they begin to work and the duration of their action.

Different methods of delivering insulin

Not only is the variety of insulin preparations growing, so are the methods for administering insulin.

Pre-filled Insulin Pens

In the past, insulin was available only in an injectable form that involved carrying syringes (which a few decades ago were made of glass and required sterilization), needles, vials of insulin, and alcohol swabs. Needless to say, patients often found it difficult to take multiple shots each day, and, as a result, good blood sugar control was often compromised. Many pharmaceutical companies are now offering discreet and convenient methods of delivering insulin.

Both Novo Nordisk and Lily have an insulin pen delivery system. This system is similar to an ink cartridge in a fountain pen. A small pen-sized device holds an insulin cartridge (usually containing 300 units). Cartridges are available in the most widely used insulin formulations, such as those listed in the table above. The amount of insulin to be injected is dialed in by turning the bottom of the pen until the required number of units is seen in the dose-viewing window. The tip of the pen consists of a needle that is replaced with each injection. A release mechanism allows the needle to penetrate just under the skin and deliver the required amount of insulin. The cartridges and needles are disposed of when finished and new ones simply are inserted. In many cases, the entire pen is disposed of. These insulin delivery devices are less cumbersome than traditional methods.

Insulin pump

The most recently available advance in insulin delivery is the insulin pump. I An insulin pump is composed of a pump reservoir similar to that of an insulin cartridge, a battery-operated pump, and a computer chip that allows the user to control the exact amount of insulin being delivered.

Currently, pumps on the market are about the size of a pager or beeper. The pump is attached to a thin plastic tube (an infusion set) that has a cannula (like a needle but soft) at the end through which insulin passes. This cannula is inserted under the skin, usually on the abdomen. The cannula is changed every two days. The tubing can be disconnected from the pump while showering or swimming.

The pump is used for continuous insulin delivery, 24 hours a day. The amount of insulin is programmed and is administered at a constant rate (basal rate). The insulin pump allows for the user to program many different basal rates to allow for this variation in lifestyle. In addition, the user can program the pump to deliver additional insulin during meals to cover the excess demands for insulin caused by the ingestion of carbohydrates with the meal.

Probably the most exciting innovation in pump technology is the ability to use the pump in tandem with newer glucose sensing technology. Glucose sensors have improved dramatically in the last few years, and are an option for patients to gain further insight into their patterns of glucose response to tailor a more individual treatment regimen.

The newest generation of sensors allows for a real time glucose value to be given to the patient. The implantable sensor communicates wirelessly with a pager-sized device that has a screen. The device is kept in proximity to the sensor to allow for transfer of data, however, it can be a few feet away and still receive transmitted information. Depending on the model, the screen displays the blood glucose reading, a thread of readings over time, and a potential rate of change in the glucose values. The sensors can be programmed to produce a “beep” if blood sugars are in a range that is selected as too high or too low. Some can provide a warning beep if the drop in blood sugar is occurring too quickly.

Inhaled Insulin

It has been almost withdrawn from the market

Inhaled insulin, marketed by Pfizer in 2006, was approved by the FDA. This inhaled form of insulin is called Exubera.The insulin is packaged in dry blister packs that are inserted into an inhalation device. This device lances the powder packs allowing the insulin to enter a chamber that has a mouth piece through which the user can inhale the insulin. Exubera has a peak of action similar to Humalog (rapid acting), and a duration of action similar to regular insulin (short acting). It can be combined with oral medication in patients with type 2 diabetes or used alone. In patients with type 1 diabetes the insulin should be combined with a longer acting basal insulin such as glargine.

The side effect profile of inhaled insulin is similar to other insulins, and the user must be aware of hypoglycemia. In addition, since the insulin is absorbed through the lungs, there was initial concern regarding lung function.

Exubera is not to be used in regular or intermittent smokers and patients requiring very small doses of insulin. Nevertheless, in the right population, this is a great option. Unfortunately, acceptance of Exubera was poor over the year or so it was available since it’s launch in 2006. in October 2007, the company Pfizer decided not to sell the product anymore.Intranasal, Transdermal

Other routes for the delivery of insulin have also been tried. Intranasal insulin delivery was thought to be promising. However, this method was associated with poor absorption and nasal irritation. Transdermal insulin (skin patch delivery) has also yielded disappointing results to date. Insulin in pill form is also not yet effective since the digestive enzymes in the gut break it down.

Shreya Life Sciences launches first buccal insulin spray in India

The Oral-Recosulin is an ultra rapid prandial glucose regulator, which will reach the onset of action within five to 10 minutes of intake and will last for duration of 120 to 150 minutes. The product is developed with the RapidMist technology of Generex in insulin delivery, which will be marketed by the US-based company under the brand name Oral-lyn.

Rapid Mist Diabetes Management System:

This technology utilizes the formation of micro fine thin membranes or micelles to encapsulate and protect insulin molecule. The system introduces fine particle aerosol at high velocity ( 100 miles per hour) into the patient’s breath. The mouth deposition is dramatically increased compared with conventional technology. This oral aerosol formulation is rapidly absorbed through the buccal mucosal lining and in the oropharynx region. It provides the plasma insulin levels necessary to control post prandial glucose rise in diabetic patients.

This novel, pain free, oral insulin formulation has a critical series of attributes:

i. Rapid absorption.
ii. Simple (user- friendly) administration technique.
iii. Precise dosing control.
iv. Bolus delivery of Drug.

A simplified means for prandial insulin delivery, such as that offered by this technique, will significantly reduce key complication by allowing increased patient compliance for consistent drug administration in order to regulate the patient’s blood glucose levels.

Dosage and Administration

Puff of Oral-Recosulin delivers 10 units of regular insulin. Approximately 1 unit of regular insulin is absorbed into systemic circulation of patient after taking 1 puff of Oral-Recosulin.

The patient should be relaxed and breathing normally. The mouthpiece of the device placed in mouth at the end of normal exhalation. The patient sprays Oral-Recosulin into the mouth. Patient is asked to hold breath for 5 second (by counting slowly to 5). This procedure is repeated until correct numbers of puffs are administered.

Unique features of Oral-Recosulin: Oral-Recosulin has been shown to be fast, flexible safe and simple. Most important it well accepted by both patient well as doctors.

Benefits are:

i. Needle Free, Pain Free therapy.
ii. Rapid Insulin Absorption.
iii. Short duration of action.
iv. Higher Patient Compliance.
v. Better Quality of Life.
vi. No risk of hypoglycemia.

Cost: In Indian market 2 cansters are available in Rs. 2300.

Pancreas transplantation

Ultimately, the goal in the management of type 1 diabetes is to provide insulin therapy in a manner that mimics the natural pancreas. Perhaps the closest therapy available at this time is a transplant of the pancreas. Several approaches to pancreatic transplantation are currently being studied, including the whole pancreas and isolated islet cells (these groups of cells contain beta cells that are responsible for insulin production). Most patients undergo pancreatic transplantation at the time of kidney transplantation for diabetic kidney disease.

Transplantation is not without risk. Both the surgery itself and the immunosupression that must occur afterward pose significant risks to the patient. For these reasons, the kidney and pancreas are usually transplanted at the same time. At present, there is disagreement about whole pancreas transplantation in patients not currently requiring kidney transplantation.

The issue of whether the benefits outweigh the risks in these patients is under debate. There is also a chance that diabetes will occur in the transplanted pancreas. Selectively transplanting islet cells is an interesting alternative to whole pancreas transplantation. However, the concern over rejection remains.

Attempts to disguise the islet cells in tissues that the body won’t reject (for example, by surrounding the islet cells by the patient’s own cells and then implanting them) are underway. In addition, researchers are exploring artificial barriers that can surround the islet cells, provide protection against rejection, and still allow insulin to enter the bloodstream.