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.