Sitagliptin: A Review of Its Use in Patients with Type 2 Diabetes Mellitus
Sitagliptin (Januvia(®), Xelevia™, Glactiv(®), Tesavel(®)) is an orally administered, potent and highly selective inhibitor of dipeptidyl peptidase-4 (DPP-4) and was the first agent of its class to be approved for use in the management of adults with type 2 diabetes. Numerous randomized placebo- or active comparator-controlled trials have demonstrated the efficacy of sitagliptin in terms of improving glycaemic control in patients with type 2 diabetes, including its use as monotherapy, initial combination therapy (usually with fixed-dose combinations of sitagliptin/metformin), or add-on therapy to metformin or to other antihyperglycaemic drugs, with or without metformin. The primary endpoint of the clinical trials was the reduction from baseline in glycosylated haemoglobin (HbA1c), although sitagliptin also showed beneficial effects for other endpoints, such as the proportion of patients who achieved target HbA1c, and reductions from baseline in fasting plasma glucose (FPG) levels and 2-h postprandial glucose (PPG) levels. Sitagliptin was generally well tolerated in clinical trials, had a low risk of hypoglycaemia (although this depends on background therapy) and had a neutral effect on body weight. Despite concerns regarding a possible increased risk of rare pancreatic adverse events (e.g. pancreatitis) with glucagon-like peptide-1 (GLP-1)-based therapies, such as GLP-1 receptor agonists and DPP-4 inhibitors, no causal association has been found; regulators in Europe recently conducted a review of available data, concluding that there is little evidence that these drugs could cause pancreatic inflammation or pancreatic cancer. A similar review is planned in the USA and postmarketing surveillance will continue. Thus, oral sitagliptin is an effective and generally well tolerated treatment option for the management of patients with type 2 diabetes.
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ABSTRACT: Sodium-Glucose linked transporter 2 (SGLT2) inhibitors are a new family of antidiabetic pharmaceutical agents whose action is based on the inhibition of the glucose reabsorption pathway, resulting in glucosuria and a consequent reduction of the blood glucose levels, in patients with type 2 diabetes mellitus. Apart from lowering both fasting and postprandial blood glucose levels, without causing hypoglycemia, SGLT2 inhibitors have also shown a reduction in body weight and the systolic blood pressure. This review paper explores the renal involvement in glucose homeostasis providing also the latest safety and efficacy data for the European Medicines Agency and U.S. Food and Drug Administration approved SGLT2 inhibitors, looking, finally, into the future of this novel antidiabetic category of pharmaceutical agents.
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ABSTRACT: Aims: This review is aimed at highlighting the potential mitogenic/tumour growth-promoting or antimitogenic/tumour growth-inhibiting effects of the main antihyperglycaemic drug classes. Methods: We review and discuss the most current studies evaluating the association between antidiabetic medications used in clinical practice and malignancies as described so far. Results: Metformin seems to be the only antidiabetic drug to exert protective effects both on monotherapy and also when combined with other oral antidiabetic drugs or insulins in several site-specific cancers. In contrast, several other drug classes may increase cancer risk. Some reason for concern remains regarding sulphonylureas and also the incretin-based therapies regarding pancreas and thyroid cancers and the sodium glucose cotransporter-2 inhibitors as well as pioglitazone regarding bladder cancer. The majority of meta-analyses suggest that there is no evidence for a causal relationship between insulin glargine and elevated cancer risk, although the studies have been controversially discussed. For α-glucosidase inhibitors and glinides, neutral or only few data upon cancer risk exist. Conclusion: Although the molecular mechanisms are not fully understood, a potential risk of mitogenicity and tumour growth promotion cannot be excluded in case of several antidiabetic drug classes. However, more large-scale, randomized, well-designed clinical studies with especially long follow-up time periods are needed to get reliable answers to these safety issues.
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ABSTRACT: The prevalence of chronic kidney disease (CKD) of stages 3-5 (glomerular filtration rate [GFR] <60 mL/min) is about 25-30 % in patients with type 2 diabetes mellitus (T2DM). While most oral antidiabetic agents have limitations in patients with CKD, incretin-based therapies are increasingly used for the management of T2DM. This review analyses (1) the influence of CKD on the pharmacokinetics of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists; and (2) the efficacy/safety profile of these agents in clinical practice when prescribed in patients with both T2DM and CKD. Most DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin) are predominantly excreted by the kidneys. Thereby, pharmacokinetic studies showed that total exposure to the drug is increased in proportion to the decline of GFR, leading to recommendations for appropriate dose reductions according to the severity of CKD. In these conditions, clinical studies reported a good efficacy and safety profile in patients with CKD. In contrast, linagliptin is eliminated by a predominantly hepatobiliary route. As a pharmacokinetic study showed only minimal influence of decreased GFR on total exposure, no dose adjustment of linagliptin is required in the case of CKD. The experience with GLP-1 receptor agonists in patients with CKD is more limited. Exenatide is eliminated by renal mechanisms and should not be given in patients with severe CKD. Liraglutide is not eliminated by the kidney, but it should be used with caution because of the limited experience in patients with CKD. Only limited pharmacokinetic data are also available for lixisenatide, exenatide long-acting release (LAR) and other once-weekly GLP-1 receptor agonists in current development. Several case reports of acute renal failure have been described with GLP-1 receptor agonists, probably triggered by dehydration resulting from gastrointestinal adverse events. However, increasing GLP-1 may also exert favourable renal effects that could contribute to reducing the risk of diabetic nephropathy. In conclusion, the already large reassuring experience with DPP-4 inhibitors in patients with CKD offers new opportunities to the clinician, whereas more caution is required with GLP-1 receptor agonists because of the limited experience in this population.
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