Current Drug Safety - Volume 16, Issue 2, 2021

Diabetes mellitus (DM) has already affected one in every eleven person in the global population, and the dis-ease prevalence continues to increase because of the obesity pandemic. Even with the availability of a multitude of antidi-abetic medications for optimal glycaemic control, cardiovascular morbidity and mortality were not largely altered until re-cently when newer antidiabetic drugs such as glucagon-like peptide-1 receptor analogues (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors were introduced. Cardiovascular safety of antidiabetic drugs has also been a hot topic for global scientific debate after the US Food and Drug Administration (FDA) enforced restrictions on Rosiglita-zone in 2010 with the suspicion of increased mortality and myocardial events (with subsequent uplift of the ban on the drug in 2013 following the emergence of additional evidence on safety). After this debate, all antidiabetic should go through rigorous safety checks with cardiovascular outcome trials (CVOTs). Recent CVOTs with GLP-1RAs and SGLT2 inhibitors have revealed markedly positive outcomes that have changed the landscape of diabetes management across the world. Thus, the therapeutic algorithm for optimal management of DM should consider not only the glycaemic control ef-ficacy of the individual antidiabetic agent but also the cardiovascular safety and modifications in other anticipated long-term DM complication profiles. Therefore, it is imperative to critically appraise the efficacy and cardiovascular safety of all antidiabetic drugs to improve the scientific practice of our diabetes care globally. This issue, “Efficacy and cardiovas-cular safety of antidiabetic medications,” provides readers the back-up of up to date evidence.

Alpha Glucosidase Inhibitors (AGIs) are a group of drugs which act on the gastrointestinal tract and help in reducing fasting and postprandial hyperglycemia by reducing the absorption of carbohydrates. This group comprises Acarbose, Miglitol and Voglibose. They are available on the market for almost three decades now. When used as monotherapy, Glycated Haemoglobin (HbA1c) reduction can be as high as 0.77%, which is predominantly noted in the Eastern Asian population and those on a high carbohydrate diet. There is a more pronounced reduction in HbA1c in those who present with higher baseline values. Despite not showing a significant cardiovascular benefit with regards to mortality and morbidity, they have proven to be a safe class of drugs which can be used in patients not tolerating various other anti-diabetic agents due to their local site of action and poor systemic absorption. Though they are available worldwide, AGIs are used more often in the Far East and South Asia. They have shown benefits in reducing the development of diabetes when used in those with impaired glucose tolerance or pre-diabetes. They have been shown to improve postprandial hyperglycemia, which in itself is an independent risk factor for cardiovascular morbidity. These have proven their safety from both cardiovascular and non-cardiovascular perspectives and can be combined with any class of anti-diabetic agents. They are not favoured in most of the current Western Guidelines due to their modest HbA1c reduction, neutrality with cardiovascular benefit as well as their significant gastrointestinal side effect profile.

A large proportion of persons with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) do not reach the glycosylated haemoglobin (HbA1c) target of < 7% (53 mmol/- mol), with an increasing proportion of them being overweight or obese. In both T1DM and T2DM, there is accelerated gastric emptying and postprandial hyperglucagonemia. Furthermore, insulin therapy itself is associated with risk of hypoglycemia and weight-gain both of which are barriers to achieving good control. Medications which can achieve significant HbA1c and weight reduction associated with an ability to delay gastric emptying and suppress the glucagon secretion with minimal/ no hypoglycemia are of particular interest as an adjuvant to insulin. A synthetic amylin analogue, pramlintide is a drug with above mentioned properties. Other medications with similar properties are glucagon-like peptide-1 receptor agonists (GLP-1 RAs). In this article, we will review the efficacy of pramlintide when given with insulin in improving HbA1c, weight, and cognition with- /without GLP-1 RAs as well as its cardiovascular (CV) safety.

There is a universal agreement that when lifestyle modifications are inadequate to control the hyperglycemia, metformin should be considered the first line of pharmacological therapy. However, when metformin monotherapy fails, there is no consensus as to which drug should be added. Many new classes of drugs that are currently available including DPP-4 inhibitors, GLP-1 agonists and SGLT-2 inhibitors have undergone cardiovascular outcome trials which had been made mandatory by the regulatory authority and thereby established their cardiovascular safety or at least neutrality. Though sulfonylureas are one of the widely prescribed drugs both in developed and developing countries and have proven their efficacy for glycemic control and prevention of microvascular complications, there is considerable uncertainty about its cardiovascular safety which has been going on for nearly five decades. In this review, we will critically analyze the efficacy and cardiovascular safety of sulphonylureas, based on the latest available literature to clarify their role in our day-to-day clinical practice.

Dipeptidyl peptidase-4 (DPP-4) inhibitors or gliptins belong to the class of incretin mimetics. These drugs have been available on the market for the management of type 2 diabetes mellitus (T2DM) for over a decade. Sitagliptin, linagliptin, vildagliptin, saxagliptin and alogliptin are widely available globally, whilst anagliptin, gemigliptin and teneliptin are used mainly in the Asian countries. The glycemic control conferred by DPP-4 inhibitors varies among individual molecules with an average reduction of glycated hemoglobin (HbA1c) ranging between –0.5 to –1.0% with monotherapy. Additive effects on HbA1c reduction may result from combination therapy with other antidiabetics. Weak evidence from various studies suggests that DPP-4 inhibitors may be useful in treating nonalcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS). DPP-4 inhibitors safety is not established in pregnancy, and there is only meagre evidence of its use in T2DM among children. In line with the United States Food and Drug Administration (US FDA) recommendations, sitagliptin, linagliptin, saxagliptin and alogliptin have undergone rigorous cardiovascular outcome trials (CVOTs) in recent years, and the safety data for vildagliptin is available through retrospective analysis of various studies in meta-analysis. Small clinical trial, and meta-analysis based data are available for the CV safety of other DPP-4 inhibitors. In general, the CVOTs and other safety data do not reveal serious warning signals except for saxagliptin (higher risk of hospitalization from heart failure [hHF]), although there is no robust data on the risk of hHF among patients with moderate to severe HF at baseline treated with other DPP-4 inhibitors. This review critically appraises the efficacy and cardiovascular safety of DPP-4 inhibitors to empower clinicians to use this class of antidiabetic medications judiciously.

Metformin has been the cornerstone of the medical management of type 2 diabetes mellitus (T2DM) for over 6 decades now since its first-ever discovery. Although there were initial concerns about its efficacy and safety, increasing evidence over the years proved it to be very effective and safe. It has stood the test of time, proving to be much safer than other drugs in the same class and garnering robust evidence in cardiovascular safety. In patients with T2DM, metformin lowers mean glycated hemoglobin (HbA1c) levels by 1.1–1.2% as monotherapy, by 0.6–0.83% as an add- on therapy to insulin, and by 0.9- 0.95% as add-on therapy to other oral agents. Recently its use has also been explored for unlicensed indications other than diabetes, including but not limited to obesity, polycystic ovarian syndrome (PCOS), and type 1 diabetes. Metformin is also currently under investigation for its role as a cancer adjuvant therapy. We aim to provide a comprehensive review of the available evidence for the safety and efficacy of metformin.

Patients with diabetes continued to exhibit a high risk for cardiovascular and renal events despite achieving satisfactory glycemic, blood pressure and lipid targets. Studies evaluating new diabetes medications focused on cardiovascular events, largely overlooking heart failure (HF). The latter has recently been recognised as a major cause of morbidity and mortality in patients with diabetes mellitus. There had been an unmet need for drugs with cardiovascular (including HF) and renal protection, with an expectation that an ideal diabetic drug should improve these endpoints. Moreover, an ideal drug should have weight reducing benefits. Recently published outcome trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) can reduce cardiovascular and renal events, together with statistically significant weight reduction. As a result, many recently published international guidelines have recommended SGLT2 inhibitors and GLP-1RAs in patients with diabetes and pre-existing cardiovascular disease (CVD). In this review, we will critically analyse the efficacy and cardiovascular (CV) safety of SGLT2 inhibitors, based on the available literature to help position them in the clinical decision process.

Glucagon-like peptide- 1 receptor analogs (GLP-1RAs) are incretin mimetics with potent glucose-dependent insulinotropic action that translates to glycemic control in people with type- -2 diabetes mellitus (T2DM). These agents potentially have the ability to stimulate proliferation or prevent apoptosis of pancreatic β-cells, induce weight-loss and provide vascular benefits in patients with T2DM. Newer GLP-1RA, semaglutide has shown a robust reduction in HbA1c up to 1.5 - 1.8%. However, individual differences exist between the different GLP-1RAs, in terms of efficacy, pharmacokinetics, tolerability, and vascular protection. The potential of vascular protection offered by newer anti-diabetic agents has generated a lot of excitement in the field of diabetes, and to a large extent, is now driving treatment decisions. So far, six cardiovascular outcome trials of GLP-1 RAs have been published, analyzing lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), long-acting exenatide (EXSCEL), dulaglutide (REWIND), and oral semaglutide (PIONEER 6) with a follow-up duration of 2-4 years. LEADER, REWIND and SUSTAIN-6 trials have demonstrated a reduction in rates of major adverse cardiovascular events with active GLP-1 RA treatment, but ELIXA, PIONEER 6 and EXSCEL, have been neutral. In this review, we discuss the available evidence from randomized controlled trials (RCTs) analyzing the cardiovascular effects of various GLP-1 RAs with the aim of comparing individual drugs. We have also summarized the general aspects of GLP-1RAs that can be applied in clinical practice.

Meglitinides are a group of oral hypoglycemic medications currently approved for the treatment of type 2 diabetes mellitus (T2DM). Two meglitinide molecules, Repaglinide and Nateglinide, are presently in use. Repaglinide is preferred because of its superior glycemic efficacy. They have modest efficacy with a mean decrement of glycosylated haemoglobin (HbA1c) ranging between -0.2 to -1.50% with individual therapy. Additional HbA1c reduction can occur with combination therapy with other oral hypoglycemics. This class of drugs is effective in controlling postprandial hyperglycemia with minimal risk of hypoglycemia. It is also useful in patients with variable meal timings, especially in the elderly, and in patients with renal failure. There are a dearth of long-term studies on meglitinides to assess cardiovascular outcomes or mortality in T2DM, although the Nateglinide and Valsartan in Impaired Glucose ToleranceOutcomes Research (NAVIGATOR) study showed no difference between Nateglinide and placebo with regard to the core composite cardiovascular outcomes. Based on a PubMed literature search using key words: ‘meglitinides’, ‘repaglinide’, ‘nateglinide’, ‘HbA1c’, ‘glycated haemoglobin’, ‘cardiovascular safety’, ‘cardiovascular events’, ‘cardiovascular outcome trials’, ‘type 2 diabetes mellitus’ and heart failure, and combining the search terms using Boolean operators ‘AND’, ‘OR’ and ‘NOT’ as needed we compiled current evidence for use of these oral hypoglycemic agents in clinical use. This article is an attempt to review the efficacy and cardiovascular (CV) safety of Meglitinides to help clinicians to use this class of oral hypoglycaemic agents prudently.

Insulin is a lifesaving drug for patients with type 1 diabetes mellitus. Many type 2 diabetes mellitus patients will eventually require insulin. The rapid-acting and long-acting insulin analogues (RAIAs and LAIAs) have a pharmacological profile that closely mimics normal human physiology when compared to Neutral Protamine Hagedorn (NPH) insulin and regular human insulin, respectively. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) were found to have a proven cardiovascular safety. They are preferred over insulin in many recent guidelines. Fixed-ratio combinations of GLP-1RAs and insulin are also recommended when either of these molecules fail to achieve glycaemic control. Despite decades of experience in using insulin, there is a debate among the scientific community over the safety of exogenous insulin, especially regarding their cardiovascular safety and the risk of cancer. There is also an ongoing debate regarding the safety, even though two long-acting insulin analogues (glargine and degludec) have proven their cardiovascular non-inferiority. Drugs with proven safety are often preferred in patients with pre-existing cardiovascular disease or at high risk of cardiovascular disease. In this review we will critically analyse efficacy and safety issues related to insulin molecules to help in clinical decision making.

Type 2 diabetes mellitus (T2DM) is characterized by a progressive beta cell dysfunction in the setting of peripheral insulin resistance. Insulin resistance in subjects with type 2 diabetes and metabolic syndrome is primarily caused by an ectopic fat accumulation in the liver and skeletal muscle. Insulin sensitizers are particularly important in the management of T2DM. Though thiazolidinediones (TZDs) are principally insulin sensitizers, they possess an ability to preserve pancreatic β-cell function and thereby exhibit durable glycemic control. Cardiovascular outcome trials (CVOTs) have shown that Glucagon-like-peptide 1 receptor agonists (GLP-1 RAs) and sodium glucose transporter-2 inhibitors (SGLT2i) have proven cardiovascular safety. In this era of CVOTs, drugs with proven cardiovascular (CV) safety are often preferred in patients with preexisting cardiovascular disease or at risk of cardiovascular disease. In this review, we will describe the three available drugs belonging to the TZD family, with special emphasis on their efficacy and CV safety.