EVOLVING SAFETY CONCERNS ASSOCIATED WITH ANTI-DIABETIC DRUGS

EVOLVING SAFETY CONCERNS ASSOCIATED WITH ANTI-DIABETIC DRUGS

Roma Ghai, Kiran Sharma *, Manisha Prajapati, Ishani Verma, Jaskaran Singh, Harsh Bansal and K. Nagarajan

KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, affiliated to Dr. A.P.J. Abdul Kalam Technical University, Lucknow, Uttar Pradesh, India.

ABSTRACT: Diabetes Mellitus, a chronic metabolic disorder, is prevalent all over the world nowadays. As a result, it is estimated that it can become an epidemic in some parts of the world soon. The number of affected people could be as double as that of the currently affected patients till the next decade. In order to fulfill the increasing demands of newer, safer, and more effective medications for treatment, prevention, diagnosis, and mitigation of this condition, companies all over the world are trying to introduce new medications in the market. Before entering the market, any new drug undergoes several clinical trials and tests to check and ensure its safety and efficacy. All the associated Adverse Drug Reactions are supervised and monitored by Pharmacovigilance Centers. This ensures that the patients receive safe and effective treatment with minimum or no undesired effects. A brief overview of commonly used hypoglycemic agents and their associated ADRs obtained from publishing data is elucidated in this review.

Keywords: Diabetes Mellitus, Adverse Drug Reactions, Insulin, Healthcare, Blood sugar

INTRODUCTION: Diabetes Mellitus (DM) could be explained as a metabolic disorder, in chronic state. It is characterized by increased blood sugar levels, which could lead to serious damage of heart, blood vessels, kidneys, nerves and other vital organs of body. Type 1 diabetes is a type of disease that is autoimmune. The immune system attacks and kills the beta cells (Langerhans islets) of the insulin-producing pancreas. Type 2 diabetes occurs when the cells of body become resistant to insulin and do not metabolize the sugars and thus it builds up in the blood which allows a rise in blood glucose levels.

Gestational diabetes is referred to high blood glucose levels during pregnancy ¹. About 422 million people globally suffer from diabetes, with the majority living in low-and middle-income countries, and 1.6 million deaths per year are directly attributed to diabetes. Over the past few decades, both the number of cases and the incidence of diabetes have been gradually growing.

An internationally accepted goal is to halt the growth in diabetes and obesity by 2025 ². In the world, one out of six people with diabetes is from India. The statistics position the nation among the top 10 countries for people with diabetes, with an estimated 77 million diabetics coming in at number two. China tops the list with over 116 million diabetics ³. Adverse Drug Reactions (ADR) could be explained as undesirable and harmful effects produced by a drug administered in therapeutic concentrations for treatment, mitigation, or diagnosis of any ailment ⁴.

ADR has been recognized as a major limitation in providing health care4.ADRs are responsible for frequent hospital admissions and a major cause of morbidity. In a study done in Indian ambulatory patients, it was pointed out that 3.4-7% of hospitalization was due to ADR ⁵. Before launching a new drug in the market; it undergoes clinical trials and strict surveillance in order to ensure its safety. ADRs, if any, should be reported to monitoring centers and awareness should be developed among patients about them ⁵. ADR reporting prevents the serious adverse effects and aids in instructing healthcare providers for better management of ADRs ⁶. Pharmacovigilance is a branch of science that deals with ADR recognition and their reporting ⁷. Drugs commonly used for the treatment of Diabetes Mellitus are Sulphonylureas (glimepiride, gliclazide etc.), Biguanides (metformin), Alpha- glucosidase Inhibitors (acarbose, voglibose), Phenylalanine analogues/Meglitinides (repaglinide, nateglinide), Dipeptidyl peptidase-4 inhibitors (sitagliptin, teneligliptin, saxagliptin etc.), Sodium-glucose Cotransporter-2 Inhibitors (dapagliflozin, Canagliflozin), Glucagon-like peptide-1agonists (exenatide, lixisenatide, dulaglutide, liraglutide etc.),  Thiazolidinediones (pioglitazone, rosiglitazone) ⁸. Some advancement has resulted in introduction of new anti-diabetic agents. These latest agents are Glucokinase Activator (Piragliatin), Dual PPAR Agonists (Aleglitazar), Monoclonal Antibodies (Otelixizumab, Teplizumab), Dopamine-2 Receptor Agonist (Bromocriptine) ⁹. This review throws an insight on the mechanism of action as well as examples of adverse drug reaction reported, as researched from various journal databases. The review has been compiled after searching journals from Google Scholar, Science Direct, Pubmed, Cochrane Library, etc. The keywords used in surfing the data were Anti-diabetic agents, Hyperglycemia, Diabetes Mellitus, and adverse drug reactions.

Management of Diabetes Mellitus: The categories of Anti-diabetic agents used for management of DM-2 are represented below with examples of Adverse Drug Reactions

Sulphonylureas: Sulphonylureas were discovered in 1942. This class of drugs represents a group of anti-hyperglycemic agents primarily used in the treatment of T1DM.Sulfonylurea increases insulin release by binding to a subunit of potassium ATP-dependent channels known as the sulfonylurea receptor. The frequent side effect identified with sulfonylurea administration is hypoglycemia. Chlorpropamide, tolazamide, and tolbutamide are included in first-generation sulfonylurea, while glipizide and gliclazide are included in second-generation sulfonylurea ¹⁰. Tolbutamide is more likely to cause adverse effects, such as jaundice, compared to second-generation sulfonylureas ¹¹. Glimepiride is a third-generation sulfonylurea approved in 1995 by FDA, long-acting, with hypoglycemic activity. Glimepiride is very potent and has a longer duration of action compared to other generations of sulfonylurea compounds ^{12, 1}3. The first-generation sulphonylureas are no longer used due to associated adverse effects ¹⁴. Although second and third-generation Sulfonylureas are effective and safe comparatively there are certain ADRs associated with them. Some case reports of drugs like Glimepiride, Glipizide, Gliclazidehave been reported in published database, and these examples are given in Table 1.

TABLE 1: ADRS DETECTED ALONG WITH STATUS OF SOME SULPHONYLUREAS CLASS OF DRUGS

Biguanides: Metformin, Phenformin and Buformin compose the biguanide class of anti-diabetic drugs. Metformin and Phenformin were first described in 1957 followed by Buformin in 1958. Owing to the high risk of lactic acidosis in the 1970s, Phenformin and Buformin were removed from the market for clinical use 20. Metformin, approved by the FDA in 1994, is a type 2 diabetes mellitus antidiabetic agent. Blood glucose levels are decreased by decreasing the production of glucose in the liver, decreasing intestinal absorption, and increasing insulin sensitivity. Metformin reduces blood glucose in both basal and postprandial blood ²¹. Some ADR case studies of Metformin have been reported in the published database. So, examples are given in Table 2.

TABLE 2: ADRS DETECTED ALONG WITH STATUS OF SOME BIGUANIDES CLASS OF DRUGS

Alpha-glucosidase Inhibitors: The members of this class were approved during the 1990s; they inhibit the intestinal alpha-glucosidase and alpha-amylase of pancreas by reversible and competitive inhibition ²⁷. The degradation of larger carbohydrates into glucose is stopped and the increase in postprandial blood glucose levels decreases. This results in a smaller and slower increase in blood glucose levels after meals, which is successful during day ²⁸. Members of this class are Acarbose, Miglitol and Voglibose ²⁹. Some case reports of Acarbose, Voglibose and Miglitol have been reported in published database, examples are given in the Table 3.

TABLE 3: ADRS DETECTED ALONG WITH STATUS OF SOME SOME ALPHA-GLUCOSIDASE INHIBITORS CLASS OF DRUGS

Meglitinides: Meglitinides are a class of oral antidiabetic agents approved by US FDA in 1997, which increase the secretion of insulin in the pancreas ³⁴. Because of this, they are often referred to as "insulin secretagogues." In reaction to a meal, insulin secretion is enhanced but does not appear to be intensified during fasting periods. Because meglitinides increase insulin secretion, low blood sugars, i.e. hypoglycemia, can be induced ³⁵. Two analogues are currently available for clinical use, Repaglinide and Nateglinide ³⁶. Repaglinide is absorbed quickly and has a fast onset and short time of action. In the liver, CYP2C8 and CYP3A4 are metabolized, and their metabolites are excreted in the bile. Nateglinide was approved in 2000 and is metabolized by the CYP2C9 isoenzyme cytochrome P450 and, to a lesser degree, by CYP3A4. The parent drug and metabolites are excreted primarily in the urine ^{37, 38}. Some case reports of Repaglinide and Nateglinide have been reported in published database, examples are given in Table 4.

TABLE 4: ADRS DETECTED ALONG WITH STATUS OF SOME MEGLITINIDES CLASS OF DRUGS

Thiazolidinediones: Glycemic management and insulin resistance are supported by thiazolidinediones, also called glitazones. Rosiglitazone and Pioglitazone were approved in 1999 by FDA ^{42, 43}. Although, Rosiglitazone was banned due to increased risk of heart attack and stroke in 2010 ⁴⁴. Pioglitazonewas banned in India in 2013 due to some evidence of associated bladder cancer, but it was revoked after 1.5 months ⁴⁵. Troglitazone is the prototype drug in this class introduced in 1996, but due to its association with idiosyncratic hepatotoxicity, it was removed from the market in March 2000 ⁴⁶. They activate the Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) nuclear receptor, altering the expression of the glucose and lipid homeostasis genes involved. PPARgamma stimulation increases insulin sensitivity through several pathways, such as increased GLUT4 glucose transporter expression, the development of smaller and more insulin-sensitive adipocytes, etc. ⁴⁷ Some case reports of Pioglitazone and Rosiglitazone have been reported in published database, examples are given in the Table 5.

TABLE 5: ADRS DETECTED ALONG WITH STATUS OF SOME THIAZOLIDINEDIONE CLASS OF DRUGS

DPP-4 Inhibitors: DPP-4 inhibitors also known as gliptins, are a class of oral diabetic medicines approved for the treatment of type 2 diabetes mellitus in adults by the Food and Drug Administration (FDA) in 2006 ⁵². Sitagliptin, Saxagliptin, Linagliptin, currently followed by Alogliptin approved in 2013 by FDA, compose this category of anti-diabetic agents ⁵³. The approval of Vildagliptin is from the European Medicines Agency (EMA), but not from the FDA ⁵⁴.  DPP-4 inhibitors increase the concentrations of active incretin hormones, GLP-1, and glucose-dependent insulinotropic polypeptides (secreted by enteroendocrine L and K cells, substrates for DPP-4). This results in an enhanced response of β-cells to prevailing glucose levels and in the suppression of glucagon secretion ⁵⁵. All agents in this class, alone or in conjunction with other hypoglycemic agents, are used in conjunction with diet and exercise ⁵⁶. However, case reports of agents of this class have been reported in the published database; examples are given in Table 6.

TABLE 6: ADRS DETECTED ALONG WITH STATUS OF SOME DPP-4 INHIBITORS CLASS OF DRUGS

SGLT2 Inhibitors: Sodium-glucose co-transporter 2 (SGLT2) inhibitors, also known as Gliflozin, are a new class of diabetic drugs indicated for the treatment of type 2 diabetes. The first member of this class, Canagliflozin was approved in 2013 ⁶³. They are also found to have cardiac advantages in patients with diabetes and are being studied for possible use in type 1 diabetes. They act by reducing the absorption of glucose through the kidneys so that excess glucose is excreted by urination.SGLT2 is a protein in humans that makes it easier to reabsorb glucose in the kidney. SGLT2 inhibitors block the reabsorption of glucose by the kidney, increase glucose excretion and decrease blood glucose levels ⁶⁴. Currently, the Food and Drug Administration (FDA) has approved three SGLT2 selective inhibitors for mono, dual, and triple therapy: canagliflozin (2013), dapagliflozin (2014), and empagliflozin (2014) ⁶⁵. In January 2020, the FDA approved an extended-release combination product containing empagliflozin, metformin, and linagliptin ⁶⁶. The case reports of agents of this class have been reported in published database, examples are given in Table 7.

TABLE 7: ADRS DETECTED ALONG WITH STATUS OF SOME SGLT2 INHIBITORS CLASS OF DRUGS

Glucagon-like Peptide- 1 Receptor Agonist: For the treatment of type 2 diabetes mellitus in adults, GLP-1 agonists were approved by FDA in 2019 ⁷³. Exenatide, Lixisenatide, Liraglutide, Albiglutide, Dulaglutide, and Semaglutide are the agents in this class. It has been shown that these agents decrease HbA1C (by 0.8-1.6 percent), body weight (by 1-3 kg), blood pressure, and lipids. GLP-1 receptor agonists are associated with a low risk of hypoglycemia and the most common adverse effects are linked to the GI tract ⁷⁴. However, case reports of agents of this class have been reported in the published database; examples are given in Table 8.

TABLE 8: ADRS DETECTED ALONG WITH STATUS OF SOME GLUCAGON-LIKE PEPTIDE- 1 RECEPTOR AGONIST CLASS OF DRUGS

CONCLUSION: With the introduction of new oral anti-diabetic medications in the market, the need for ADR monitoring is extremely important in order to maintain safety and efficacy throughout the treatment. Though the recently approved classes, GLP-1 agonists and SGLT-2 inhibitors, have proved to be beneficial, they also have the potential to cause ADRs like pancreatitis, edema, allergic reactions and ketoacidosis, Fournier’s gangrene, mycotic infections, respectively.

The older classes, such as Thiazolidinediones, were associated with life-threatening conditions like Hepatocellular injury and heart failure, hence were withdrawn from the market permanently. In other categories, the most reported ADRs were hepatotoxicity, pancreatitis, electrolyte imbalance, arthritis, etc. This brings us to the conclusion that active and effective ADR monitoring is necessary, followed by its awareness among healthcare profession.

ACKNOWLEDGEMENT: Authors are highly grateful to the Director, Dr. (Col.) A. Garg and Joint Director, Dr. Manoj Goel, KIET Group of Institutions, for their motivation and all-round support.

CONFLICTS OF INTEREST: The authors declare no conflict of interest, financial or otherwise.

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    How to cite this article:

    Ghai R, Sharma K, Prajapati M, Verma I, Singh J, Bansal H and Nagarajan K: Evolving safety concerns associated with anti-diabetic drugs. Int J Pharm Sci & Res 2022; 13(2): 747-54. doi: 10.13040/IJPSR.0975-8232.13(2).747-54.

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