Table of Contents
Outline of the Pharmacological Treatment
The various classes of drugs which are available for the treatment of diabetes mellitus include:
- Dipeptidyl peptidase IV inhibitors
- Alpha glucosidase inhibitors
Each class of drugs has its own pros and cons and is valuable in their own ways and would be discussed in detail under separate subheadings. These classes of drugs are generally classified on the basis of insulin. One group of drug is the insulin secretagogues, which function by increasing the secretion of insulin. Another is the insulin sensitizers, which function by means of increasing the sensitivity to the insulin which is already present.
Although the general consensus is to initially try with the lifestyle modification for the person, the studies have shown the beneficial effect of the early initiation of the pharmacotherapy.
Classification and mechanism of action of biguanides
This class of drugs comes under insulin sensitizers. The most important drug under this class is metformin.
The mechanism of action of metformin is by decreasing the production of glucose in the liver (gluconeogenesis) and decreasing the absorption of glucose from the intestine and by increasing the sensitivity of the insulin. The increase in the sensitivity is achieved by increasing the peripheral utilisation and uptake of glucose. The proposed mechanism of action for the decrease in insulin resistance is by increasing the AMPK signaling.
Despite being one of the most effective drugs in the treatment of diabetes, the drawback of metformin is the requirement of the beta cell function for its effect to occur. The progressive beta cell failure causes its effectiveness to reach a plateau phase.
Pros & cons and main indication of biguanides
Metformin is one of the preferred drugs for monotherapy in the treatment of diabetes mellitus and it is recommended by the guidelines of American Diabetes Association. But caution needs to be undertaken to look out for the contraindication of giving metformin (will be listed below). Metformin is also preferred in combination therapy.
This group is very effective in overweight and obese, because it has beneficial effects on the low density lipoprotein level of the body and also decreases the triglyceride concentration. The advantage of the group of drugs is there is no weight gain problem and along with that there occurs decreased risk of hypoglycemia.
Though the observational data have shown a reduction in the incidence of cancer with the usage of metformin, the same results did not arise with the meta-analysis of the randomised control trials.
In the UKPDS and other trials, metformin has shown to have a reduction in the cardiovascular events.
Adverse and side effects related to biguanides
The main disadvantage of biguanides is the gastrointestinal side effects.
There is increased risk of lactic acidosis; though rare, it has a very high case fatality rate. That’s why this drug is contraindicated in patients with:
Acute and chronic heart failure
Pulmonary decompensation in the acute phase.
As there is elevated chances of developing lactic acidosis, the administration of metformin is contraindicated.
The drug causes increased risk of vitamin B12 deficiency. Vitamin B12 is required for the normal nerve functions and deficiency of the same leads to neuropathy. The risk of neuropathy precedes that of megaloblastic anaemia.
In one of the meta-analyses, it was demonstrated that the combination of metformin and glibenclamide is associated with increased Charlson comorbidity index and increased in the mortality when compared with other insulin secretagogues.
Classification and mechanism of action of sulfonylurea
This group of drugs are typically called insulin secretagogues because their function is to increase the secretion of insulin by means of inhibiting the potassium ATP channel of the beta cells of the pancreas. So it is natural to understand that it requires effective functioning of the beta cells of the pancreas for its action to occur.
There occur two generations of agents in this class of drugs. The most prominent drugs in the first generation are tolbutamide and chlorpropamide. In the second generation, the most prominent drugs are glipizide, glibenclamide, glimepiride, and gliclazide.
Pros & cons and main indication of sulfonylurea
One of the advantages of this group of drugs is the low cost of treatment along with that it also attains a rapid reduction in the fasting plasma glucose level. The drug is mainly targeted in patients who are recently diagnosed with diabetes mellitus especially in the initial span of 5 years.
The treatment with sulfonylurea has been reported to be associated with a decline in the function of the beta cells, which occurs progressively over the period of time in a linear fashion. This might end up in beta cell failure.
Adverse and side effects related to sulfonylurea
The main disadvantage of this group of drugs is the problem of weight gain (this is due to the anabolic effect of the increase in the insulin concentration with this class of drugs) and along with that increased risk of hypoglycemia (due to the insulin release even when the glucose level is normal).
The hypoglycemia general manifests as sweating along with giddiness and if not properly corrected would lead to unconsciousness.
Classification and mechanism of action of meglitinide
The group of drugs under this class includes repaglinide and nateglinide. They also causes increase in the production of the insulin and are specially referred to as short acting secretagogues.
Their mechanism of actions is also by means of inhibiting the potassium channels and thereby causing the secretion of insulin( the inhibition of potassium channels causes the influx of the calcium which is followed by calcium-dependent insulin release). Their binding site is different from those of the sulfonylurea class of agents.
Pros & cons and main indication of meglitinide
They typically help in maintaining the postprandial blood glucose especially after taking a meal. One more advantage of this class of drugs is its short-acting nature and that the dosing can be easily adjusted according to the meals.
Adverse and side effects related to meglitinide
As common to all secretagogues, the risk of hypoglycemia and also weight gain occurs (the mechanism of both the side effects is almost similar to that of sulphonylurea).
Classification and mechanism of action of thiazolidinedione
This class of drug belongs to the insulin sensitizer family, which includes pioglitazone and rosiglitazone.
The mechanism by which it reduces the insulin resistance is by a novel mechanism of activating the Peroxisome Proliferator Activated Receptors Gamma(PPAR-Gamma) variety in the fat and the muscle cells. By means of activating this receptor, it increases the glucose uptake into these, thereby reducing the glucose level from the blood. PPAR Gamma specifically regulate the storage of the fatty acid and the metabolism of glucose.
Pros & cons and main indication of thiazolidinedione
This class of drugs is targeted in overweight, obese and insulin resistant patients.
It is also used in combination therapy along with biguanide. Since it is an insulin sensitising therapy, there is a low risk of causing hypoglycemia.
There are some reported beneficial effects in the lipid level with this drug (though the drug has been reported and confirmed for cardiovascular morbidity).
Adverse and side effects related to thiazolidinedione
This class of drugs also have the disadvantage of causing weight gain. In addition to this, it also has the increased risk of causing heart failure (especially rosiglitazone).
In one of the meta-analyses it was shown that the odds ratio of myocardial infarction and death is greater with rosiglitazone as compared to that of the control.
Though the drug is advocated for the persons with obesity and increased resistance, this drug has the side effect of causing an increase in the LDL cholesterol and triglycerides level and has reported to be linked with risk of causing bladder cancer.
Alpha Glucosidase Inhibitor
Classification and mechanism of action of alpha glucosidase inhibitor
The drugs under this category include acarbose, voglibose, and miglitol. Alpha glucosidase is an enzyme which is present in the intestine and is responsible for the digestion of carbohydrates. This digestion of carbohydrates is required for the absorption of glucose in the intestine.
These drugs act by means of inhibiting the enzyme alpha glucosidase. The inhibition of the digestion of carbohydrates causes reduced absorption of glucose, which in turn results in the reduction and the blood glucose level.
Pros & cons and main indication of alpha glucosidase inhibitor
This group of drugs is mainly used along with other drugs in combination therapy. As compared with sulfonylurea, this is not associated with weight gain.
Adverse and side effects related to alpha glucosidase inhibitor
In addition to being expensive, the drug has risk of causing GI disturbances and is the least effective drug among the oral hypoglycemics in lowering the HBa1c levels.
(The level of HB a1c is the indirect prediction of the control of glucose over a range of months).
One more thing which makes this group of drug into disfavour is the presence of the side effects like flatulence and bloating. This causes discomfort to the person and also embraces the surrounding persons.
Gliptins, or DPP-4 inhibitors
This class of drugs are called gliptins and function by inhibiting the DPP-4 enzyme. Some of the drugs under this category are sitagliptin, vildagliptin, saxagliptin, linagliptin.
Incretin enzyme, which consists of GLP-1 and GIP, stimulates glucagon release. Glucagon increases the blood glucose level. By inactivating that enzyme, the release of glucagon is inhibited.
In addition to this, it also decreases the gastric emptying time (so literally there will be less time for the absorption of the glucose thus reducing the blood glucose level).
GLP-1 receptor agonists
This group of drugs is similar in structure to GLP-1 but was modified to resist breakdown by the enzyme DPP-4. The drugs under this category include exenatide and liraglutide.
These drugs are given subcutanelously because they are not orally active.
Unlike sulfonylureas, incretin-based therapies stimulate insulin secretion only when there is a glucose “trigger”, and when the levels of glucose in blood is normal, the insulin secretion is not increased. Therefore, this group of drugs does not cause hypoglycemia.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are considered a new promising class of oral hypoglycemic medications because of their therapeutic effect without causing hypoglycemia and causing weight loss. Secondly, this is an insulin independent mechanism of action and thus would be effective even in case of low reserve of the pancreatic beta cell.
Dapagliflozin, canagliflozin, and empagliflozin are the drugs that fall under the category.
Mechanism of action of SGLT2 inhibitors
The urine glucose is routinely excreted in very small amount and most of the glucose is reabsorbed. This reabsorption is done by the sodium glucose cotransporter, which is located at the proximal renal tubules of the nephrons present in the kidney. The kidney has a set threshold, until which the glucose will be completely absorbed. When the filter glucose level exceeds the threshold, the glucose is excreted in the urine.
This group of drugs act by blocking the sodium glucose cotransporter (more specifically on the SGLT2 located in the S1 and S2 segment of the proximal renal tubules, located along the brush border of the epithelial cells) and inhibiting the reabsorption of glucose. In addition, the renal threshold is also reduced hence shifting the kidney to excrete glucose even at the lower level of glucose in the filtered fluid.
Adverse and side effects related to SGLT2 inhibitors
Due to the excretion of glucose in the urine as part of the mechanism, there occurs increase in the risk of fungal infection of the urinary tract (Vulvovaginal Candidiasis), increase in frequency of urination, and increase in the potassium concentration in the blood (hyperkalemia).
One of the serious adverse effects is acute kidney injury in patients who are treated with canagliflozin and dapagliflozin, Therefore, the drug should be avoided in patients with predisposing factors for acute kidney injury and appropriate dose adjustments need to be made in renal impairment patients.
There is an increased risk of venous thromboembolism and hemoconcentration consequent to the volume depletion, which occurs with these group of drugs.
Combination of Oral Hypoglycemic Drugs
Combination therapy is preferred when the blood glucose level of the patient is not typically controlled by treating with a single monotherapy agent.
Some of the recognised combination therapies administered to the patient include:
- Biguanide plus sulfonylurea
- Biguanide plus alpha glucosidase inhibitors
- Biguanide plus thiazolidinediones
- Biguanide plus meglitinide.
In addition to the double combination therapy, in uncontrolled patients even the triple combination therapy can be given. Some of the recognised combinations include:
- Biguanide plus sulfonylurea plus thiazolidinediones
- Biguanide plus sulfonylurea plus alpha glucosidase inhibitors.
An alternative option in the physician hands is the addition of insulin into the treatment regimen of the patients who are not controlled with a single agent or the dual therapy.
The details about the various insulin regimen and their pros and cons have been discussed in detail in the alternate topic.