Diabetes mellitus is a common disease with at least 10% of the adult population above the age of 40 years suffering from it and amost twice the number having pre-diabetes in Jammu and Kashmir, according to Prof. Abdul Hamid Zargar, a leading endocrinologist of the country.
This disease is known to the mankind for more than 3000 years ago when the ancient Egyptians described its typical clinical features. The term diabetes means “siphon” and it was coined by the Araetus of Cappodocia, around the time 81-133 AD. A major tourist attraction these days in central Turkey. The word mellitus was later added by Thomas Willis in 1675 after rediscovering the sweetness of urine and blood of these patients, which had been noticed earlier by ancient Indians. Mellitus means “honey sweet” . It was however Dobsom from Britan who confirmed the presence of excessive sugar as the cause of this sweet urine and blood. Claude Bernard (France) established the role of liver in production of glucose from glycogen which is a multi lobular polysaccharide of glucose that serves as a form of energy storage . It was only in 1889 that the central role of pancreas in the causation of diabetes was discovered by two Austrians, Mering and Minkowski. This pivotal discovery led to the isolation of insulin and its clinical use by Fredrick Banting and Charles Best under the directorship of John Macleod at the University of Toranto, Canada. It was then purified with the help of James Collin and insulin became available for succesful treatment of diabetes. Banting and Macleod were honoured for this path breaking achievement and received the Noble Prize in 1923.
The developments to make oral drugs for treating diabetes bore fruit in 1955, when tolbutamide and carbutamide became available and a better and safer preparation metformin then came into existance and is still one of the drugs recommended as the first drug to be used in adult onset diabetes.
Blood glucose cut offs for labelling diabetes.
Fasting Blood Sugar: A blood glucose after overnight fasting is less than 100 mgs/dl. A level of 100 to 125 mgs means Pre-Diabetes and levels more than 126 mgs/dl is the cut off for diagnosing diabetes mellitus.
Random Blood Sugar: Regardless of when you last ate, a level of 200 mg/dL) or higher suggests diabetes, especially if you also have signs and symptoms of diabetes, such as frequent urination and extreme thirst.
Glycosylated Hemoglobin (HbA1C); It means the amount of glucose tagged to the hemoglobin contained in the red blood cells. Less than 5.7% is normal. 5.7 to 6.4% is defined as Pre-Diabetes and more than 6.4% as diabetes. This parameter gives an idea of the last 3 months average sugar values.
Consequences of being a Diabetic:
It is a complex disease, it is actually more aptly described as a group of diseases in which high levels of blood glucose result from defects in insulin secretion, insulin action or both. If it remains undiagnosed it results in hyperglycemia (high blood sugar levels) and is associated with several associated complications. It is very often associated with high blood pressure (Hypertension), High levels of bad cholesterol (LDL cholesterol) and ugly fats (Triglycerides). The result is blockages of the arteries (atherosclerosis or fat depositions) supplying blood to vital organs like the heart, brain and the kidneys and make the patients very prone to get heart attacks, strokes and kidney failure. In addition, diabetes, can independent of atherosclerosis lead to weakness of the heart muscle which is an important cause of heart failure. All types of heart failure (heart failure with reduced ejection fraction (HFref) and Heart failure with preserved ejection fraction (HFpef) are seen often in long standing diabetics
Diabetes and Heart Attacks:
Patients of un-complicated diabetes have a 20 percent risk of getting a heart attack in 10 years. The frequency is much higher if hypertension and high cholesterol levels accompany. Unfortunately, often these heart attacks come silently because the sensation of pain and classical chest discomfort is not felt. This is because of the involvement of the nerves carrying this sensation to brain (neuropathy). The resulting vague — instead of acute— symptoms may be ignored, or passed off as indigestion or stomach upset.
Early diagnosis and learning how to monitor and control the disease are key to avoiding complications down the road. Some experts suggest that the course of this disease can be changed by life style modification coupled with evidence-based drug therapy.
“No More Heart Attacks,” the mission of Gauri Heart Foundation is based upon optimal treatment of diabetes and hypertension in the community.
Drugs For Diabetes and Recent Advances:
What About Insulin?
Although Insulin has been the first and most predictable agent in bringing the sugar levels down, it is not the best agent to reduce the vascular events like heart attacks and strokes. On the other hand, by causing weight gain, hypoglycemia and inflammatory changes leading to high BP, High cholesterol levels, heart failure and irregularities in heart beat can produce higher mortality. No doubt there have been great advances in Insulins and we have today very long-acting insulins and measures to avoid hypoglycemia.
For these reasons Insulin injections should be reserved for Type I diabetes where the pancreas does not produce any insulin because of genetic problems or destruction of the pancreas by auto-immune or viral disorders in childhood and those adults where in spite of oral drugs sugar levels remain un acceptably high.
For adult onset or maturity onset diabetes there is usually a reduction in the production of insulin or the utilization by the body tissues becomes faulty. These patients respond very well to oral drugs. The best and the most often used agent of first choice is Metformin which acts by making the body more sensitive to insulin, reduces the release of glucose from liver and decreases the absorption of sugar from gut. It continues to be the drug of first choice for type 2 diabetes and can reduce the HbA1c by up to 2%. There are now several group of oral drugs available; Sulfonyl urea’s were also amongst the first widely used oral anti-hyperglycemic medications. They triggerinsulin release from pancreas. several types of these pills have been marketed which include, glibenclamide, glimepiride and gliclazide which are the second-generation sulfonyl urea’s. They are more effective than first-generation drugs and have fewer side-effects. These agents however may cause weight gain. There is also a group of non-sulfonyl urea’s called Meglitinides (Repaglinide etc.)which also produce more insulin from pancreas and reduce HbA1c modestly by 0.5 to 1%.
Another group of drugs Dipeptidyl peptidase-4 inhibitors(Sitagliptin, linagliptin, vildagliptin etc) are also often used, they also reduce glucose levels by increasing the levels of glucagon like peptide levels. These however can cause increase in body weight and need to be used with caution in patients with heart failure.
Recent Spectacular Advances in Drug Treatment:
SGLT2 (sodium-glucose co-transporter 2) inhibitors.
SGLT2 blockers are the only molecules that lead to removal of excess sugar from the body and this novel mechanism of action confers additional benefits of weight loss and blood pressure reduction, not seen with any other class of anti-diabetics. Three agents are available from this group. Empagliflozin (Jardiance and Gibtulio), Canagliflozin (Invokana, Sulisent and Prominad) and Dapagliflozin (Forxiga and several other generics). All three agents have positive data in this regard. This is heartening for patients with diabetes as well as the doctors treating them, as these agents now gives them an option to reduce risk of heart failure along with controlling blood sugar. The trial also shows that the drug improves kidney function. Available evidence with large clinical studies shows that SGLT2 inhibitors should be preferred as an add-on therapy for all type 2 diabetes patients who fail to achieve targets on metformin or who have uncontrolled diabetes at the time of diagnosis to reduce future heart and kidney related complications. Patients’ hearts will be at an advantage if SGLT2 inhibitors are started early, before disease advances and not just as a 3rd or 4th line of treatment.Only precaution is that patients with urinary and genital infections have to avoid these agents during active infection phase.
Recently this group of drugs has been found to be very useful in the treatment of heart failure including in non-diabetic patients.
GLP1 Analogues: This group of agents are extremely useful in diabetic, over weight patients who have had previous heart attack or a stroke. These are to be administered by an injection either daily (Liraglutide) or once a week (Semaglutide and Dulaglutide). They act on several target sites in the body and convincingly reduce recurrences of such events in addition to reducing weight. An oral agent Semaglutide (Rybelsus) tablet has been released in the USA and Europe and should be available by the end of this year in India also.
Other Measures: Regular exercise, quitting smoking, Weight reduction, keeping cholesterol levels very low, Blood pressure control to targets is extremely important for the holistic management of diabetic patients.
Take Home Message:
Diabetes is a disease as old as human civilization with a number of landmark researches which have brought us to this stage, where we are much better off in diagnosis and management. Improvements in the life style management coupled with very effective oral drugs besides newer Insulins have improved the outcomes remarkably. The revolutionary drugs like SGLT2 inhibitors have markedly reduced the chance of heart failure and resultant hospitalizations, weight gain and death. Agents belonging to the group of GLP1 analogues have helped in reducing the occurrence of vascular events like heart attacks and strokes besides weight reduction. It is now possible to improve the longevity of patients of diabetes with a good quality of life. These new group of drugs should be used more often than are being used presently.
Prof Upendra Kaul is Founder Director Gauri Kaul Foundation. A recipient of Dr B C Roy Award and Padma Shri