EVOLVING SAFETY CONCERNS ASSOCIATED WITH ANTI-DIABETIC DRUGS
HTML Full TextEVOLVING 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, 13. 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
Name of Drug | ADR detected | Evidence | Age/ Gender | Status |
Glimepiride | Cholestasis &progressive jaundice | Case report | 58/ Male | Glimepiride was discontinued; insulin therapy was started 15 |
Glimepiride | Vasculitis | Case report | 72/ Female | Glimepiride was discontinued. Within 1 week all lesions were healed spontaneously 16 |
Glipizide | Hepatotoxicity | Case report | 71/ Female | Discontinuation of glipizide showed improvement 17 |
Glipizide | Proximal myopathy | Case report | 61/Male | The symptoms of myopathy improved by itself after stopping glipizide 18 |
All Sulphonylureas | Increased risk of Myocardial Infarction and severe hypoglycemia | Cohort Study | 40+/Male & Female | The patients were hospitalized for their symptoms of MI, severe hypoglycemia, ischemic stroke 19 |
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
Name of Drug | ADR detected | Evidence | Age/ Gender | Status |
Metformin | Lactic Acidosis | Case study | 82/Male | Metformin was stopped and treated with dextrose, crystalloids, and bicarbonate intravenously, and urgent hemodialysis was performed 22 |
Metformin | Cholestatic hepatitis | Case report | 68/ Male | Metformin was discontinued 23 |
Metformin | Vitamin B 12 deficiency and Anemia | Phase 3 clinical trial | 25+/ Male & Female | Vitamin B12 was administered to correct the deficiency and continuous monitoring was conducted 24 |
Metformin | Hypersensitivity reaction | Case report
|
59/Female | Metformin was discontinued and patient was prescribed Fexofenadine, Montelukast, Levocetrizine combination to treat the reaction 25 |
Metformin | Gastrointestinal problems (diarrhea, nausea, vomiting, pain abdomen, flatulence, retching, dysgeusia) | Cross-sectional study
|
52.8±11.9 years/ 70 male & 50 female | ADR got removed with the use of extended-release formulation 26 |
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
Name of Drug | ADR detected | Evidence | Age/Gender | Status |
Acarbose | Hepatotoxicity | Case report | 57/ Female | Acarbose was Discontinued 30 |
Voglibose | Hepatic necrosis with cholestasis | Case report | 76/ Female | Voglibose was discontinued 31 |
Voglibose | Severe Dizziness | Case report | 75/ Male | Voglibose was discontinued (dizziness persisted) 32 |
Miglitol | Hallucinations | Case report | 71/ Male | Miglitol was discontinued 33 |
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
Name of Drug | ADR detected | Evidence | Age/ Gender | Status |
Repaglinide | Hypoglycemia | Case Study | 67/ Male | Repaglinide was discontinued 39. |
Repaglinide | Thrombocytopenia | Case report | 71/Male | Discontinuation of repaglinide increase platelet count 40. |
Nateglinide | Leukocytoclastic angiitis | Case Report | 55/ Male | Nateglinide was discontinued and Prednisone was given for management of ADR 41. |
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
Name of Drug | ADR Detected | Evidence | Age/ Gender | Status |
Pioglitazone | Pleural Effusion | Case Report | 76/ Female | Pioglitazone was discontinued 48. |
Pioglitazone | Congestive Heart Faliure and Pulmonary Edema | Case report | 65/ Male | Pioglitazone was discontinued 49. |
Rosiglitazone | Hepatocellular injury | Case report | 61/ Male | Rosiglitazone was discontinued 50. |
Rosiglitazone | Severe electrolyte imbalance and edema | Case report | 49/ Male | Rosiglitazone was discontinued 51. |
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
Name of Drug | ADR detected | Evidence | Age/ Gender | Status |
Vildagliptin | Bullous pemphigoid | Case report | 61/ Male | Vildagliptin was discontinued and bolus insulin was given 57 |
Sitagliptin | Arthralgia | Case report | 56/ Female | Sitagliptin was discontinued 58 |
Sitagliptin | Rheumatoid Arthritis | Case report | 56/ Male | Sitagliptin was discontinued 59 |
Saxagliptin | Acute Pancreatitis | Case report | 85/ Female | Status not specified; Saxagliptin was highly suspected 60 |
Alogliptin | Angioedema | Case report | 67/Male | Alogliptin was stopped and intravenous steroids and antihistamines resolved the problem 61 |
Linagliptin | Blistering and ulceration | Case report | 60/Male | Linagliptin was stopped and intravenous tazocin and teicoplanin was given 62 |
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
Name of Drug | ADR detected | Evidence | Age/ Gender | Status |
Empagliflozin | Diabetic ketoacidosis | Case report | 47/ Male | Empagliflozin was discontinued 67 |
Empagliflozin | Fournier’s gangrene
(Serious infection in genital area) |
Case report | 57/ Male | The patient required two surgical interventions with hyperbaric oxygen therapy and all oral medications were stopped 68 |
Empagliflozin | Cutaneous Polyarteritis Nodosa | Case report | 69/Male | Upon cessation of empagliflozin problem resolved 69 |
Canagliflozin | Genital mycotic infections, UTI, osmotic diuresis, and reduced intravascular volume | Case report | 54/ Male | Patient required insulin infusion (up to 10 units/hr) along with dextrose to prevent hypoglycemia for 72 hours to normalize the anion gap and clear the ketones 70 |
Canagliflozin | Diabetic Ketoacidosis | Case report | 62/Female | Canagliflozin was discontinued and an insulin drip initiated 71 |
Dapagliflozin | Pancreatitis. | Case report | 51/ Male | Dapagliflozin was discontinued 72 |
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
Name of Drug | ADR Detected | Evidence | Age/ Gender | Status |
Liraglutide | Pancreatitis | Case report | 53/ Male | Liraglutide was discontinued 75 |
Exenatide | Systemic Allergic Reaction | Case report | 52/ Male | Exenatide was discontinued 76 |
Abliglutide | Edema | Case report | 35/ Female | Albiglutide was discontinued 77 |
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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Article Information
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747-754
501 KB
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English
IJPSR
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.
kiran.sharma@kiet.edu
22 December 2020
11 June 2021
12 June 2021
10.13040/IJPSR.0975-8232.13(2).747-54
01 February 2022