Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: comparison,efficacy and safety

Introduction: Dipeptidyl peptidase (DPP)-4 inhibitors belong to one class of drugs that have been approved for treatment of type 2 diabetes (T2D) based on the glucose-lowering actions of the gastrointestinal hormone glucagon-like peptide (GLP)-1. Several different compounds are now available, and although their mechanism of action (inhibition of the catalytic activity of DPP-4) is the same, there are fundamental differences between them.

Areas covered: The authors discuss the differences between different DPP-4 inhibitors and review their therapeutic efficacy and key safety data. The literature covered includes original studies and meta-analyses identified in PubMed, recent abstracts presented at major diabetes scientific conferences, and clinical trials registered at ClinicalTrials.gov.

Expert opinion: Although there are some differences in the pharmacokinetic and pharmacodynamic profiles of the different DPP-4 inhibitors, all are small orally active compounds with broadly similar HbA1c-lowering efficacy. They improve glycaemic control in T2D, without increasing the risk of hypoglycaemia or causing weight gain. They can be used as monotherapy or in combination with other anti-diabetic therapies, including insulin, regardless of renal or hepatic function, and are efficacious across the spectrum of patients with T2D, including those with long-standing disease duration. DPP-4 inhibitors may also have beneficial effects beyond glycaemic control, although this remains to be demonstrated in purpose-designed clinical trials.     

Comparison of the antidiabetic effects of linagliptin among groups with a normal renal function and a mild or severe renal impairment – retrospective observation study of Japanese patients with type 2 diabetes mellitus

Objective: The clinical course > 6 months after the initiation of linagliptin in patients with type 2 diabetes was compared among the groups divided by their renal function.

Methods: Two hundred and sixteen Japanese patients with type 2 diabetes treated with 5 mg once daily linagliptin were studied as the treated set. One hundred and forty-five subjects whose medications were not changed during the observation period were investigated as the full analysis set to assess the effectiveness. The subjects were divided into three groups based on an eGFR: eGFR ≥ 60, 59 – 45 and < 45 ml/min/1.73 m². The parameters were analyzed separately in the patients receiving monotherapy and additional therapy of linagliptin.

Results: The HbA1c (NGSP) levels significantly improved in both the patients receiving monotherapy and additional therapy. The changes in the HbA1c levels at 6 months were not significantly different between the groups with an eGFR ≥ 60, 59 – 45 and < 45 ml/min/1.73 m² receiving monotherapy (?1.0, ?0.8 and ?0.8%, respectively). Similarly, those were not significantly different between the different groups receiving additional therapy (?0.6, ?0.5 and ?0.7%, respectively).

Conclusions: Linagliptin is considered to be effective for patients with type 2 diabetes and renal impairment in the present analysis performed at our institution.     

Linagliptin for the treatment of type 2 diabetes mellitus: a drug safety evaluation

Introduction: Established treatments for type 2 diabetes mellitus (T2DM) have side effects that limit their use in specific populations. New therapies with improved safety profiles are needed, especially because of the chronic and progressive nature of T2DM.

Areas covered: This review describes the overall safety and tolerability of linagliptin – a dipeptidyl peptidase-4 inhibitor that improves glycemic control without increasing risk for hypoglycemia and without weight gain. Specifically, the safety of linagliptin is evaluated in difficult-to-treat patients with T2DM, in relation to risk of cardiovascular (CV) events and acute pancreatitis, and in comparison with other antihyperglycemic drugs.

Expert opinion: Linagliptin is generally well tolerated in a broad range of patient populations. It can be used in patients with renal impairment without dose titration and may be a rational alternative treatment in this vulnerable population. Ongoing long-term trials are fully evaluating the CV and renal safety profile of linagliptin.     

DPP-4 inhibitors: focus on safety

Introduction: Dipeptidyl peptidase inhibitors (DPP-4-i) are highly selective inhibitors of the enzyme DPP-4. They act by increasing levels of incretin hormones, which have potent effects on insulin and glucagon release, gastric emptying, and satiety. Our goal is to review the safety issues related to DPP-4-i.

Areas covered: This review is based upon a PubMed search of the literature using keywords alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin, DPP-4-i, glucagon-like polypeptide-1 agonists, as well as extensive personal clinical trial experience with each of these agents. The current DPP-4-i have very different chemical structures. Saxagliptin has significant cytochrome P450 metabolism and carries a risk of drug interactions. Linagliptin has primarily entero-hepatic excretion, a benefit in renally impaired patients. A concern arose related to congestive heart failure in the SAVOR TIMI trial of saxagliptin. Several major cardiac studies are underway, with two concluded. Despite lingering uncertainty related to pancreatitis and pancreatic cancer, large randomized trials have not shown an increased risk with DPP-4-i treatment. Cutaneous adverse effects occur with a low frequency with some of these agents.

Expert opinion: DPP-4-i are an additional choice in the group of anti-hyperglycemics. Their principal advantage is a low incidence of hypoglycemia, making these agents desirable in patients such as the elderly and those with cardiac disease. Several large trials have hinted at less cardiac risk with DPP-4-i than with sulfonylureas. The CAROLINA Trial comparing linagliptin and glimepiride may provide a conclusive answer to this question.     

Fixed-dose combination of empagliflozin and linagliptin for the treatment of patients with type 2 diabetes mellitus: A systematic review and meta-analysis

The present meta-analysis evaluated the efficacy and safety of empagliflozin + linagliptin combination compared with either monotherapy [n=6 randomized controlled trials; 2857 adults with type 2 diabetes (T2DM) on diet + exercise ± metformin; 39.7% women; mean age: 54.6–59.9 years]. The combination of empagliflozin 10 mg + linagliptin 5 mg led to significantly greater reductions in glycated haemoglobin (HbA1c) compared with either drug alone over 24 weeks: weighted mean difference [WMD; −0.72%, 95% confidence interval (CI): −1.04, −0.40], and fasting plasma glucose (−1.60 mmol/L 95% CI: −2.21, −1.00). Similar results were observed when empagliflozin 25 mg + linagliptin 5 mg was compared with linagliptin 5 mg monotherapy or with empagliflozin 10 or 25 mg monotherapy. Patients with T2DM treated with the drug combination had more than three times higher likelihood of achieving HbA1c <7% than those on either monotherapy. Weight reduction was significantly greater in the combination group only when compared with linagliptin monotherapy. Safety profile was similar between combination treatment and monotherapies. Overall, the empagliflozin + linagliptin combination had superior efficacy and similar safety in achieving euglycaemia compared with either monotherapy. This combination, administered once daily, has the potential to reduce regimen complexity, enhance adherence and improve outcomes in clinical practice.     

Pharmacokinetic drug evaluation of empagliflozin plus linagliptin for the treatment of type 2 diabetes

Introduction: Type 2 diabetes mellitus has become a growing epidemic and therefore efficient treatment strategies that target its management are needed. The treatment of diabetic patients often requires the combination of antidiabetic drug classes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) block glucose reabsorption in the proximal renal tubules. Dipeptidyl peptidase-4 inhibitors (DPP-4i) improve glucose metabolism by blocking the enzyme that degrades incretins leading to increased insulin secretion.

Areas covered: The aim of the review is to present the available data on pharmacokinetic properties/pharmacodynamics, metabolic and cardiovascular effects of empagliflozin plus linagliptin combination.

Expert opinion: Both empagliflozin and linagliptin have established safety and efficacy in the treatment of diabetes. Available data demonstrate the absence of pharmacological interactions when the two drugs are given together. The complementary mechanisms of action would be expected to provide additive benefits on carbohydrate metabolism variables, but the results from clinical trials have shown that the empagliflozin/linagliptin combination provides only mild improvements of glycated hemoglobin compared with either monotherapy. However, the single-tablet formulation of empagliflozin/linagliptin is expected to provide better compliance and thus improved glycaemic control coupled with a favourable safety profile. Thus, the fixed-dose combination of empagliflozin/linagliptin has the capacity to both effectively and safely manage diabetic patients.     

SGLT2 inhibitor/DPP-4 inhibitor combination therapy – complementary mechanisms of action for management of type 2 diabetes mellitus

Type 2 diabetes mellitus is a progressive disease with multiple underlying pathophysiologic defects. Monotherapy alone cannot maintain glycemic control and leads to treatment failure. Ideally, a combination of glucose-lowering agents should have complementary mechanisms of action that address multiple pathophysiologic pathways, can be used at all stages of the disease, and be generally well tolerated with no increased risk of hypoglycemia, cardiovascular events, or weight gain. The combination should also provide conveniences for patients, such as oral dosing, single-pill formulations, and once-daily administration, potentially translating to improved adherence. Two classes of glucose-lowering agents that meet these criteria are the sodium glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. This article reviews the rationale for combination therapy with these agents, and evidence from clinical trials with empagliflozin and linagliptin or dapagliflozin and saxagliptin in the management of type 2 diabetes mellitus. Both combinations have been approved as single-pill formulations.     

Current perspectives in treatment of angina pectoris

Intravenous immunoglobulin is an important method of treating idiopathic thrombocytopenic purpura, especially when a rapid platelet response is desired. Dr Besa explains how to use this therapy in acute and chronic purpura in both children and adults. He also describes the four preparations available and discusses efficacy, cost, and safety.