Saxagliptin for the treatment of type 2 diabetes mellitus: Focus on recent studies

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycemic control without causing weight gain or increasing hypoglycemic risk in patients with type 2 diabetes (T2DM). The efficacy and tolerability of saxagliptin, a once-daily DPP-4 inhibitor, administered as monotherapy, as add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione, and as initial combination therapy with metformin, was demonstrated in pivotal 24-week clinical trials. Additional information about the clinical profile of saxagliptin was recently obtained from extension studies, head-to-head clinical trials, and post-hoc analyses. In extension studies, the efficacy and tolerability of add-on saxagliptin and initial saxagliptin-plus-metformin therapy were maintained for up to 102 weeks. Saxagliptin plus metformin was shown to be non-inferior to glipizide plus metformin in lowering glycated hemoglobin from base-line, with reduced body-weight and lower hypoglycemic risk. Post-hoc analyses indicate that the clinical benefits of saxagliptin extend across demographic subgroups and special populations. A meta-analysis found no evidence for increased cardiovascular risk in T2DM patients exposed to saxagliptin for > 1 year. On the basis of this clinical profile, saxagliptin is an attractive option for initial and add-on therapy for T2DM patients with inadequate glycemic control.     

Clarifying the role of incretin-based therapies in the treatment of type 2 diabetes mellitus

BackgroundGlucose homeostasis is the result of a complex interaction of a spectrum of hormones, including insulin, glucagon, amylin, and the incretins. Incretins are released by enteroendocrine cells in the intestine in response to a meal. Incretin dysfunction, along with a number of other defects, has been implicated in contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). Therapies that restore incretin activity may reduce the pathophysiologic consequences of diabetes.ObjectivesThe aim of this article was to review incretin physiology and studies of incretin therapy with glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors that were developed to specifically address the blunted incretin response in patients with T2DM.MethodsRelevant English-language publications between 1995 and 2010 were identified through a search of the MEDLINE and EMBASE databases using the search terms incretin, type 2 diabetes mellitus, GLP-1, glucose-dependent insulinotropic polypeptide, and DPP-4. Review articles and preclinical and clinical trials that described relevant details of the epidemiology of diabetes and incretin physiology in health and in T2DM were selected for review and inclusion. Clinical trials were used to describe the clinical efficacy and safety of the GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM. An occasional systematic review article and/or meta-analysis summarizing numerous clinical trials of a particular agent was selected for summarizing key data.ResultsPharmacologic modulation of incretin pathophysiology by GLP-1 receptor agonists and DPP-4 inhibitors significantly improved glycemic control, benefited β-cell function, improved dyslipidemia, and lowered the risk of hypoglycemia compared with insulin and sulfonylureas. Unlike the DPP-4 inhibitors, GLP-1 receptor agonist therapy also produced weight loss, an important consideration given the close association among T2DM, overweight/obesity, and cardiovascular disease. The most common adverse events with GLP-1 receptor agonist therapy included nausea (28%–44%), vomiting (13%–17%), and diarrhea (11%–17%), which generally reduced in incidence and severity with continued therapy. The tolerability profile of the DPP-4 inhibitors was very good, with the incidence of adverse events similar to that of placebo. There was a suggestion of an increased incidence of nasopharyngitis versus placebo (5%–6% vs 3%–4%) with sitagliptin and urinary tract infection (6.8% vs 6.1% with placebo) and headache with saxagliptin (6.5% vs 5.9% with placebo).ConclusionThe 2 incretin drug classes provided effective and consistent glycemic control with a good tolerability profile. These agents might also improve long-term β-cell function and either reduce body weight or be weight neutral. Their role in the therapeutic armamentarium of T2DM is evolving as their potential strengths and weaknesses become better defined.     

Complementing Insulin Therapy to Achieve Glycemic Control

Introduction

Most patients with type 2 diabetes mellitus (T2DM) will need incrementally more complex therapeutic regimens to control hyperglycemia as the disease progresses. Insulin is very effective in reducing hyperglycemia and may improve β-cell function in patients with T2DM. However, insulin therapy is associated with weight gain and increased risk of hypoglycemia. Adding other antidiabetes medications to insulin can improve glycemic control and potentially lower the required insulin dose, resulting in less weight gain and lower risk for hypoglycemia. This article summarizes the advantages and disadvantages of different classes of commonly used antidiabetes agents, with emphasis on newer classes, for use as add-on therapy to insulin in patients with T2DM inadequately controlled on insulin therapy.

Methods

A PubMed search from July 1, 2003 to April 15, 2013 for peer-reviewed clinical and review articles relevant to insulin combination or add-on therapy in T2DM was conducted. Search terms included “insulin combination therapy,” “add-on therapy diabetes,” “dipeptidyl peptidase-4 (DPP-4) inhibitors,” “glucagon-like peptide-1 (GLP-1) receptor agonist,” “sodium-glucose cotransporter 2 (SGLT2) inhibitors”, “insulin metformin,” “insulin sulfonylurea,” and “insulin thiazolidinedione.” Bibliographies from retrieved articles were also searched for relevant articles. Study design, clinical relevance, and effect on insulin combination therapy were analyzed.

Results

Therapies used as add-on to insulin include agents associated with weight gain (thiazolidinediones and sulfonylureas) and/or hypoglycemia (sulfonylureas), which, therefore, may exacerbate risks already present with insulin. GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when added to insulin and have a low propensity for hypoglycemia and cause no change (DPP-4 inhibitors) or a reduction (GLP-1 receptor agonists, SGLT2 inhibitors) in body weight.

Conclusion

GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when combined with insulin. They also have low propensity for weight gain and hypoglycemia and so may be preferred treatment options for insulin combination when compared with traditional therapies.     

Dapagliflozin combination therapy in type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a progressive disease, and most patients ultimately require two or more antidiabetes drugs in addition to lifestyle changes to achieve and maintain glycemic control. Current consensus statements and guidelines recommend metformin as first-line pharmacotherapy for the treatment of T2DM in most patients. When glycemic control cannot be maintained with metformin alone, the sequential, stepwise addition of other agents is recommended. Agents such as thiazolidinediones or sulfonylureas have typically been added to metformin therapy. Although effective in reducing glycated hemoglobin, these drugs are often associated with adverse effects, most notably weight gain, and in the case of sulfonylureas, hypoglycemia. Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, are the newest class of antidiabetes drugs approved for the treatment of T2DM. Dapagliflozin effectively improves glycemic control by increasing the renal excretion of excess glucose. In clinical trials, dapagliflozin has been well tolerated and has additional benefits of weight loss, low risk of hypoglycemia and reduction in blood pressure. This review discusses the clinical evidence and rationale for the use of dapagliflozin as add-on therapy in T2DM. The results suggest that dapagliflozin add-on therapy is a promising new treatment option for a wide range of patients with T2DM. Results from an ongoing cardiovascular outcomes trial are needed to establish the long-term safety of dapagliflozin.     

Clinical use of dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in combination therapy for type 2 diabetes mellitus

Objective. To review the efficacy, safety, and tolerability of combination treatment regimens including a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or sodium-glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes mellitus (T2DM). Methods. Clinical trials of combination therapies including a DPP-4 and/or SGLT2 inhibitor were identified through a PubMed database search. To be included, studies had to have a primary end point of change from baseline to ≥24 weeks in glycated hemoglobin, include ≥1 other oral antidiabetic drug (OAD), and have randomized more than 200 patients. Results were limited to medications approved by the US Food and Drug Administration at the time of the search (March 2015). Results. A total of 1534 articles for the DPP-4 inhibitor class and 434 articles for the SGLT2 inhibitor class were retrieved from PubMed. Of these, 33 articles from the DPP-4 inhibitor class and 24 articles from the SGLT2 inhibitor class were included for review. In each study, the addition of a DPP-4 or SGLT2 inhibitor as a second or third agent resulted in improved glycemic control versus comparator arms. Reductions in weight or lack of weight gain were consistently observed, as were low rates of hypoglycemic events, particularly when the combination regimen also included metformin. Overall, the pattern of adverse events observed in combination treatment groups was consistent with the known effects of the individual agents. Conclusion. Combination treatment with a DPP-4 and/or SGLT2 inhibitor is an efficacious option for patients with T2DM starting pharmacological therapy, or for patients who have received treatment but require additional glycemic control. Study findings indicate that the underlying mechanisms of action of DPP-4 inhibitors and SGLT2 inhibitors complement a variety of OADs.     

Dipeptidyl peptidase-4 inhibitor use in patients with type 2 diabetes and cardiovascular disease or risk factors

Objectives: Management of cardiovascular (CV) risk is an essential aspect of diabetes care, and acceptable CV risk is a requirement for antidiabetes medications. Dipeptidyl peptidase-4 (DPP-4) inhibitors effectively reduce glycated hemoglobin, with a low risk of hypoglycemia and weight gain. The purpose of this review is to discuss the use of DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2DM) and CV disease or risk factors. Methods: A PubMed search (January 2013–June 2015) was conducted to identify prospective trials, meta-analyses, pooled analyses and cohort studies evaluating CV outcomes with DPP-4 inhibitors. Results: Meta-analyses, pooled analyses and retrospective cohort studies in patients with T2DM suggest no increased CV risk and possible CV benefit compared with some antidiabetes medications. The three published, long-term, prospective, randomized, double-blind CV outcomes trials in patients with CV disease or risk factors found no increased rate of major CV events in patients treated with alogliptin, saxagliptin or sitagliptin versus placebo as add-on to standard-of-care. However, the analysis of the components of the secondary end point of the saxagliptin study showed an increased number of hospitalizations for heart failure (HF) in treated patients versus placebo. A post hoc analysis of the alogliptin study showed no increase in HF hospitalization in treated patients with a history of HF versus placebo, but did show an increase in alogliptin-treated patients with no baseline HF history. Sitagliptin showed no increased risk for HF hospitalization versus placebo in the overall cohort. Two CV outcomes trials for linagliptin are ongoing. Conclusion: The majority of available data from CV outcomes trials suggest a neutral effect of DPP-4 inhibitors on major CV events.     

Vildagliptin: clinical trials programme in monotherapy and combination therapy for type 2 diabetes

As part of an extensive clinical development programme in patients with type 2 diabetes (T2DM), vildagliptin 50 mg once daily and twice daily, and 100 mg once daily have been assessed in placebo-controlled and, more importantly, in head-to-head active-comparator monotherapy trials over a wide range of baseline HbA1c levels and in a large number of elderly patients. Notable findings in individual trials included: comparable HbA1c lowering over 24 weeks with 100 mg once daily or 50 mg twice daily; efficacy comparable to rosiglitazone with reduced risk of weight gain and oedema over 24 weeks; and durable glycaemic control for up to 2 years with a reduced frequency of gastrointestinal adverse events compared with metformin. Pooled monotherapy data indicate that vildagliptin 100 mg daily produces consistent and clinically meaningful reductions in HbA1c across a range of initial HbA1c levels, in patients with lower and greater body mass index, and in younger and older patients. To date, the safety/tolerability profile seems comparable to placebo with neutral effects on body weight and lipid profiles, and minimal risk of hypoglycaemia. A preliminary study in subjects with impaired glucose tolerance showed that vildagliptin 50 mg once daily enhanced islet cell function, reduced glycaemic excursions and was very well tolerated, paving the way for a future trial in diabetes prevention. Vildagliptin has also been extensively studied in multiple clinical scenarios as add-on combination therapy in patients with inadequate glycaemic control on metformin, thiazolidinedione, sulfonylurea and insulin treatment, and has consistently been shown to improve glycaemic control with good tolerability and low risk for hypoglycaemia. In a trial in patients receiving metformin, the addition of vildagliptin 50 mg twice daily resulted in a 1.1% reduction in HbA1c at 24 weeks. Compared with add-on pioglitazone 30 mg daily in patients inadequately controlled with ongoing metformin therapy, vildagliptin 50 mg twice daily reduced HbA1c by 0.9% vs. 1.0% and was not associated with weight gain (+0.3 kg vs. +1.9 kg) over 24 weeks. Most notably, vildagliptin plus pioglitazone as initial combination therapy in drug-naive patients resulted in robust HbA1c reductions of 1.9% from baseline. In patients receiving stable insulin therapy, vildagliptin 50 mg twice daily improved glycaemic control and was associated with a significant reduction in hypoglycaemic episodes over 24 weeks. Vildagliptin shows considerable promise as a partner for metformin and other commonly used oral antidiabetic agents, and may well play an important role in combination with insulin therapy to further improve glycaemic control.     

Impact of EMPA-REG OUTCOME® on the management of type 2 diabetes mellitus: a review for primary care physicians

Cardiovascular (CV) disease is the leading cause of death in patients with type 2 diabetes mellitus (T2DM). Most published trials of glucose-lowering agents have shown no significant CV benefit or increased risk of death or heart failure, with the exception of metformin. Three novel classes of glucose-lowering agents, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium glucose cotransporter 2 (SGLT2) inhibitors, have been approved by the U.S. Food and Drug Administration for the treatment of T2DM in the United States and have also been available in other parts of the world in the past decade. Of the SGLT2 inhibitors, empagliflozin has demonstrated a CV benefit in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME®) while trials with other SGLT2 inhibitors are still ongoing. Empagliflozin has also provided possible renal protective benefit in those with mild-to-moderate renal impairment. The mechanisms behind the benefits seen with empagliflozin are likely multifactorial. Empagliflozin is the reasonable choice for add-on therapy in patients with long-standing T2DM who are at high CV risk as demonstrated in the EMPA-REG OUTCOME® study.     

Current treatments and strategies for type 2 diabetes: can we do better with GLP-1 receptor agonists?

Abstract Diet, lifestyle modification, and pharmacotherapy with metformin are appropriate initial treatments for many patients with type 2 diabetes (T2DM). However, most individuals do not maintain glycemic control with metformin alone. Addition of other oral antidiabetes drugs (OADs), including sulfonylurea, meglitinide, or thiazolidinedione, is often the next step. Newer options, including incretin-based glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, offer important benefits as monotherapies or in combination with OADs, with low risk for hypoglycemia. Reductions in glycated hemoglobin (A1C) have been reported among patients treated with GLP-1 RAs (exenatide, -0.8 to -1.1%; liraglutide, -0.8 to -1.6%), as has weight loss (exenatide, -1.6 to -3.1 kg; liraglutide, -1.6 to -3.2 kg). GLP-1 RAs also stimulate β-cell responses and have positive effects on cardiovascular risk factors often present in patients with T2DM. The most common adverse events associated with GLP-1 RAs are nausea, which diminishes over time, and hypoglycemia (when used in combination with a sulfonylurea). A large number of trials demonstrated benefits of GLP-1 RAs, suggesting they could provide suitable treatment options for patients with T2DM.     

Saxagliptin: a new DPP-4 inhibitor for the treatment of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic with increasing impact on individuals and healthcare providers. Available treatments (such as metformin, sulfonylureas, glitazones, and insulin) have proven unsatisfactory in producing a long-lasting impact on glycemic control. In addition, most of these treatments have undesirable side effects such as weight gain and hypoglycemia. As a result, exploring new treatment targets and new therapies is mandatory in order to treat this condition. The incretin pathway, in particular glucagon-like peptide (GLP-1), plays an important pathological role in the development of T2DM, and treatments targeting the incretin system have recently become available. These can mainly be divided into two broad categories; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase-4 (DPP-4; the enzyme responsible for rapid inactivation of incretins) inhibitors (sitagliptin, vildagliptin). Saxagliptin is a novel DPP-4 inhibitor that has recently completed phase 3 studies. Saxagliptin is a potent and specific inhibitor of DPP-4 (in comparison with other dipeptidyl peptidase enzymes) that is given once daily. Current data suggest that saxagliptin as monotherapy or in combination with metformin, glyburide, or a glitazone results in significant reductions in fasting and postprandial plasma glucose and hemoglobin A_1c (HbA_1c). Saxagliptin is well tolerated and does not increase hypoglycemia compared with the placebo, and is probably weight neutral. Saxagliptin will be a new effective drug in the currently available variety of antidiabetic medications for patients with T2DM.     

Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy

The dipeptidyl peptidase 4 (DPP-4) inhibitors comprise a promising new class of agent for the management of type 2 diabetes. They possess a range of physiological effects associated with improved glycemic control including stimulation of glucose-dependent insulin secretion and suppression of glucagon secretion, and lower blood glucose levels through different, but potentially complementary, mechanisms to standard oral therapies. Linagliptin is the latest DPP-4 inhibitor to complete pivotal phase 3 trials. The data show that linagliptin provides significant, clinically meaningful and sustained improvements in glycemic control, with an incidence of adverse events similar to placebo and an excellent tolerability profile. In addition, linagliptin has been shown to be weight neutral and, importantly, there was no increased risk of hypoglycemia attributed to linagliptin use in monotherapy or combination therapy with metformin or pioglitazone. A unique characteristic of linagliptin that differentiates it from other members of the class is its primarily nonrenal route of excretion. The linagliptin phase 3 program included several hundred patients with type 2 diabetes and different stages of renal disease and the data suggest that the drug would not need dose adjustment, regardless of the degree of renal impairment. There is a particular need for safe and effective therapeutic agents that can be used when renal function declines. Linagliptin has recently been approved by the US Food and Drug Administration and may find a place in therapy as a treatment option for the significant number of patients in whom metformin and the other DPP-4 inhibitors are either contraindicated or require dose adjustment because of moderate to severe renal impairment.     

Initial Combination with Linagliptin and Metformin in Newly Diagnosed Type 2 Diabetes and Severe Hyperglycemia

Making appropriate treatment decisions for patients newly diagnosed with type 2 diabetes mellitus (T2DM) and severe hyperglycemia (glycated hemoglobin [HbA1c] >10% or fasting plasma glucose ≥250 mg/dL) presents a formidable challenge to primary care physicians. Extreme defects in insulin secretion make it unlikely that these patients will achieve glycemic targets with metformin monotherapy. Additionally, uncontrolled hyperglycemia is associated with an increased risk of short-term acute complications, such as hyperosmolar coma, and long-term complications affecting the micro- and macrovasculature. Thus, severely hyperglycemic patients require prompt, intensive treatment to re-establish glycemic control. Current guidelines indicate that either initial insulin therapy or initial combination therapy with metformin plus non-insulin drug(s) are the treatments of choice for these challenging-to-treat patients. This mini-review examines the clinical evidence supporting these two treatment options, with particular reference to the findings of a phase 3 study of treatment with an initial combination of metformin plus the dipeptidyl peptidase-4 inhibitor, linagliptin. Intensive insulin therapy can induce sustained euglycemia and improve beta-cell function in newly diagnosed patients. However, insulin use is associated with an increased risk of adverse events, such as hypoglycemia and weight gain. These potentially serious side effects cause concern among patients and physicians, and are a major barrier to initiating and maintaining adherence to insulin treatment. In the phase 3 study, open-label treatment of severely hyperglycemic patients (HbA1c ≥11.0%) with linagliptin plus metformin resulted in a mean change in HbA1c of ?3.7% ± 1.7%. This combination therapy was generally well tolerated with most adverse events being of mild or moderate intensity; asymptomatic hypoglycemia was reported by just 1 of 66 (1.5%) patients. These findings provide evidence in support of linagliptin plus metformin as a well-tolerated and effective treatment alternative to insulin for new-onset patients with T2DM and severe hyperglycemia.     

Glycemic control of type 2 diabetes mellitus across stages of renal impairment: information for primary care providers

Chronic kidney disease (CKD) is a frequent complication of type 2 diabetes mellitus (T2DM) and elevates individuals’ risk for cardiovascular disease, the leading cause of morbidity and mortality in T2DM. Achieving and maintaining tight glycemic control is key to preventing development or progression of CKD; however, improving glycemic control may be limited by effects of renal impairment on the efficacy and safety of T2DM treatments, necessitating dosing adjustments and careful evaluation of contraindications. Understanding the treatment considerations specific to each class of T2DM medication is important in individualizing therapy and improving glycemic, renal, and cardiovascular outcomes.

Traditional glucose-lowering treatments include insulin, metformin, sulfonylureas, meglitinides, and thiazolidinediones. Each of these agents exhibits altered pharmacokinetics in patients with renal impairment except for the thiazolidinediones, which are metabolized by the liver and do not accumulate appreciably in patients with renal impairment. Newer glucose-lowering treatments include GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors. Of these, only the DPP-4 inhibitor linagliptin can be used across all stages of renal impairment without dosing restrictions or concerns regarding dose escalation, and all SGLT2 inhibitors are contraindicated when eGFR <45 mL/min/1.73m². Several of the newer treatments have also been investigated for effects on renal and cardiovascular outcomes, demonstrating potential benefits of the GLP-1 agonists liraglutide and semaglutide, as well as the SGLT2 inhibitors canagliflozin and empagliflozin, in reducing risk for some adverse renal and cardiovascular events. In addition, some DPP-4 inhibitors have been shown to reduce albuminuria, an indicator of glomerular dysfunction. Consideration of this information is useful in informing optimal management strategies for patients with T2DM and concomitant CKD. More clinical data from future and ongoing clinical trials, including data regarding potential renal and cardiovascular benefits, will be important in clarifying the safety and efficacy profiles of each of these agents in patients with CKD.     

Current treatments and strategies for type 2 diabetes: Can we do better with GLP-1 receptor agonists?

Abstract

Diet, lifestyle modification, and pharmacotherapy with metformin are appropriate initial treatments for many patients with type 2 diabetes (T2DM). However, most individuals do not maintain glycemic control with metformin alone. Addition of other oral antidiabetes drugs (OADs), including sulfonylurea, meglitinide, or thiazolidinedione, is often the next step. Newer options, including incretin-based glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, offer important benefits as monotherapies or in combination with OADs, with low risk for hypoglycemia. Reductions in glycated hemoglobin (A1C) have been reported among patients treated with GLP-1 RAs (exenatide, ?0.8 to ?1.1%; liraglutide, ?0.8 to ?1.6%), as has weight loss (exenatide, ?1.6 to ?3.1 kg; liraglutide, ?1.6 to ?3.2 kg). GLP-1 RAs also stimulate β-cell responses and have positive effects on cardiovascular risk factors often present in patients with T2DM. The most common adverse events associated with GLP-1 RAs are nausea, which diminishes over time, and hypoglycemia (when used in combination with a sulfonylurea). A large number of trials demonstrated benefits of GLP-1 RAs, suggesting they could provide suitable treatment options for patients with T2DM.     

Cardiovascular Safety of Incretin-Based Therapies in Type 2 Diabetes: Systematic Review of Integrated Analyses and Randomized Controlled Trials

Introduction

Regulatory requirements mandate that new drugs for treatment of patients with type 2 diabetes mellitus (T2DM), such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, are evaluated to show that they do not increase cardiovascular (CV) risk.

Methods

A systematic review was undertaken to evaluate the association between DPP-4 inhibitor and GLP-1 receptor agonist use and major adverse cardiac events (MACE). The National Institutes of Health Medline database was searched for pooled analyses, meta-analyses, and randomized controlled trials (RCTs) of DPP-4 inhibitors and GLP-1 receptor agonists that included CV endpoints.

Results

Thirty-six articles met the inclusion criteria encompassing 11 pooled analyses, 17 meta-analyses, and eight RCTs (including secondary analyses). Over the short term (up to 4 years), patients with T2DM exposed to a DPP-4 inhibitor or GLP-1 receptor agonist were not at increased risk for MACE (or its component endpoints) compared with those who received comparator agents. Two meta-analyses showed a significant reduction in the incidence of MACE associated with DPP-4 inhibitor therapy as a drug class, but this beneficial effect was not observed in other meta-analyses that included large RCT CV outcome studies. In four RCTs that evaluated alogliptin, saxagliptin, sitagliptin, or lixisenatide, there was no overall increased risk for MACE relative to placebo in T2DM patients at high risk for CV events or with established CV disease, although there was an increased rate of hospitalization for heart failure associated with saxagliptin. A fifth RCT showed that liraglutide reduced MACE risk by 13% versus placebo.

Conclusion

Overall, incretin therapy does not appear to increase risk for MACE in the short term.

     

Treatment of elderly patients with type 2 diabetes mellitus: a systematic review of the benefits and risks of dipeptidyl peptidase-4 inhibitors

Background: Achievement of glycemic control in elderly patients with type 2 diabetes mellitus (DM) is complicated by many factors.Objective: The aim of this article was to systematically review evidence on the effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors (ie, lowering of glycosylated hemoglobin [HbA_1c]), the risk of hypoglycemia associated with these agents, and the effects of these agents on body weight in elderly patients with type 2 DM.Methods: The PubMed and Biosis databases were searched for reports of clinical trials and meeting presentations (eg, abstracts, posters) published in English between January 1, 2000, and October 25, 2009, that included elderly patients with type 2 DM who were treated with sitagliptin, saxagliptin, vildagliptin, alogliptin, BI-1356, DSP-7238, or PF-734200. Pharmacokinetic and pharmacodynamic studies were excluded from the review, as were studies that did not specifically provide quantitative clinical data on glycemic parameters or specifically list patients aged ≥65 years.Results: Eighty-five articles and 5 presentations were identified in the search; of those, 18 articles and 3 presentations were included in the review. These publications described studies of DPP-4 inhibitors administered as monotherapy or in combination with metformin, a thiazolidinedione, glimepiride, glibenclamide, or insulin. Quantitative data indicated that, in these elderly patients (generally defined as ≥65 years of age) with type 2 DM, DPP-4 inhibitors were associated with significant HbA_1c reductions that ranged from ~0.7% (baseline HbA_1c = 7.8%; P < 0.001) to 1.2% (baseline HbA_1c = 8.3%; P < 0.05). Additional studies that did not quantify the number of elderly patients (as would a subanalysis), but did specify that elderly patients were included and that patient age did not influence the results, were incorporated in this review to support the quantitative results. No significant differences were noted in the HbA_1c-lowering effects of these agents between elderly and younger patients. Less information about the incidence of hypoglycemia or weight gain in elderly patients was reported, but the available results suggested that the risk of hypoglycemia with DPP-4 inhibitors was not significantly different from that with placebo (sitagliptin 50 or 100 mg/d [0%] vs placebo [0%]; saxagliptin 5 mg/d [6.3%] vs placebo [8.0%]; vildagliptin 100 mg/d [2.32 events per patient-year] vs placebo [2.64 events per patient-year]; alogliptin 12.5 mg/d [8.0%] vs placebo [10.5%]) and that these agents were weight neutral (change, ≤0.9 kg).Conclusions: For elderly patients with type 2 DM, reductions in HbA_1c after treatment with a DPP-4 inhibitor were not significantly different from those in younger patients. Use of DPP-4 inhibitors in these studies was associated with a low risk of hypoglycemia, and these agents were weight neutral.     

The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone

OBJECTIVE

This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone.

RESEARCH DESIGN AND METHODS

This was a randomized, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily) or placebo plus a stable dose of metformin (1,500–2,500 mg) in 743 patients (A1C ≥7.0 and ≤10.0%). Efficacy analyses were performed using an ANCOVA model using last observation carried forward methodology on primary (A1C) and secondary (fasting plasma glucose [FPG] and postprandial glucose [PPG] area under the curve [AUC]) end points.

RESULTS

Saxagliptin (2.5, 5, and 10 mg) plus metformin demonstrated statistically significant adjusted mean decreases from baseline to week 24 versus placebo in A1C (−0.59, −0.69, and −0.58 vs. +0.13%; all P < 0.0001), FPG (−14.31, −22.03, and −20.50 vs. +1.24 mg/dl; all P < 0.0001), and PPG AUC (−8,891, −9,586, and −8,137 vs. −3,291 mg · min/dl; all P < 0.0001). More than twice as many patients achieved A1C <7.0% with 2.5, 5, and 10 mg saxagliptin versus placebo (37, 44, and 44 vs. 17%; all P < 0.0001). β-Cell function and postprandial C-peptide, insulin, and glucagon AUCs improved in all saxagliptin treatment groups at week 24. Incidence of hypoglycemic adverse events and weight reductions were similar to those with placebo.

CONCLUSIONS

Saxagliptin once daily added to metformin therapy was generally well tolerated and led to statistically significant improvements in glycemic indexes versus placebo added to metformin in patients with type 2 diabetes inadequately controlled with metformin alone.Saxagliptin is a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor, specifically designed for extended inhibition of the DPP-4 enzyme (1,2). DPP-4 rapidly cleaves and inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (1). GLP-1 and GIP regulate blood glucose homeostasis by stimulation of glucose-dependent insulin secretion (3). GLP-1 also delays gastric emptying and inhibits glucagon secretion (3,4). In rodents, GLP-1 has been shown to stimulate β-cell growth and differentiation and inhibit β-cell apoptosis (5). Such an approach is needed because the majority of patients with type 2 diabetes fail to achieve recommended glycemic targets with existing therapies, owing to safety and tolerability issues and loss of efficacy over time (6).Metformin is the most widely prescribed first-line agent for the management of type 2 diabetes and is standard first-line pharmacotherapy, along with diet and exercise (7). Mechanistically, metformin reduces hepatic glucose production and improves insulin sensitivity (8); however, metformin alone is frequently insufficient to maintain glycemic goals in the face of progressive β-cell failure and increasing insulin resistance (9). Consequently, many patients require multiple oral antihyperglycemic agents (9,10). Metformin works through pathways complementary to saxagliptin, and the combination of saxagliptin with metformin may improve glycemic control (11,12). Studies of other DPP-4 inhibitors in combination with metformin over 24 weeks have demonstrated increased efficacy versus placebo (13–15). The safety and efficacy of saxagliptin monotherapy in treatment-naive patients were established previously in a 12-week study across a dose range of 2.5 to 40 mg/day. Significant A1C reductions were demonstrated in all active treatment groups with maximal A1C efficacy observed with 5 mg saxagliptin. A test for log-linear trend across the treatment groups did not demonstrate a statistically significant dose response after 12 weeks of treatment. The overall frequency of adverse events was comparable across all treatment groups and placebo and did not appear to be dose related (16). The current trial (CV181-014) examined the efficacy and safety of saxagliptin in combination with metformin administered for up to 24 weeks in patients with type 2 diabetes inadequately controlled with metformin alone.     

Fixed-Dose Combination of Canagliflozin and Metformin for the Treatment of Type 2 Diabetes: An Overview

Metformin is recommended as a first-line therapy for patients with type 2 diabetes mellitus (T2DM). However, many patients do not achieve glycemic goals with metformin monotherapy and require subsequent combination therapy with other antihyperglycemic agents (AHAs). For newly diagnosed patients with high blood glucose, initial combination therapy may be required to achieve glycemic control. The American Association for Clinical Endocrinologists algorithm for the treatment of T2DM recommends metformin plus a sodium glucose co-transporter 2 (SGLT2) inhibitor as the first oral combination in patients who present with HbA1c ≥7.5%. Canagliflozin, an SGLT2 inhibitor, lowers the renal threshold for glucose and increases urinary glucose excretion leading to a mild osmotic diuresis and a net caloric loss. The effect of canagliflozin is insulin-independent and complementary to other AHAs, including metformin. A fixed-dose combination (FDC) of canagliflozin and metformin is also available with variable dosing, which may be attractive to some patients owing to the potential for reduced pill burden and costs. This article reviews the efficacy and safety of canagliflozin in combination with metformin based on data from the canagliflozin phase 3 clinical program. As initial combination therapy in drug-naïve patients or as dual therapy with metformin or triple therapy in combination with metformin and other AHAs, canagliflozin 100 and 300 mg improved glycemic control and provided reductions in body weight and systolic blood pressure that were sustained for up to 104 weeks. Canagliflozin was generally well tolerated across studies in combination with metformin. An increased incidence of adverse events (AEs) related to the mechanism of SGLT2 inhibition (i.e., genital mycotic infections, urinary tract infections, osmotic diuresis-related AEs) was observed with canagliflozin. Canagliflozin was associated with a low incidence of hypoglycemia when not used in conjunction with AHAs associated with hypoglycemia (i.e., insulin or sulfonylurea). Together, these results support the use of a canagliflozin and metformin FDC as a treatment approach for a broad range of patients with T2DM. Funding: Janssen Scientific Affairs, LLC.     

Safety and Tolerability of Linagliptin in Patients With Type 2 Diabetes: A Comprehensive Pooled Analysis of 22 Placebo-controlled Studies

Purpose

Dipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of linagliptin.

Methods

Safety data for once-daily linagliptin 5 mg (1 study of linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase I–III, placebo-controlled clinical trials of ≤102 weeks’ duration. Assessments of pooled data included incidence of patient-reported adverse events (AEs).

Findings

Data from 7400 patients (linagliptin, 4810; placebo, 2590) were pooled. Most patients (58.4%) had T2DM diagnosis for >5 years; approximately 75% were receiving ≥1 type of background therapy in addition to linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for linagliptin- and placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 linagliptin-treated patients (<0.1%) and 1 placebo-treated patient (<0.1%). The occurrence of cardiac disorder AEs was similar in linagliptin- and placebo-treated patients (3.2% [n = 153] and 3.3% [n = 83], respectively); the incidence of heart failure AEs for linagliptin- and placebo-treated patients was 0.2% (n = 11) and 0.3% (n = 7), respectively. Overall, linagliptin was weight neutral. Occurrence of investigator-defined hypoglycemic AEs was low for both linagliptin and placebo (11.5% vs 14.0%). In patients receiving concomitant sulfonylurea therapy, investigator-defined hypoglycemic AEs were more frequent with linagliptin versus placebo (22.1% [238/1079] vs 14.5% [61/421], respectively). Subgroup analyses showed similar frequencies of AEs for linagliptin- and placebo-treated patients across different age groups and renal function levels.

Implications

This updated and expanded pooled, post hoc analysis of 22 placebo-controlled trials of linagliptin 5 mg daily supports previous findings of the acceptable overall safety/tolerability profile of linagliptin when administered to a broad range of patients with T2DM. Linagliptin-treated patients demonstrated a low overall risk of hypoglycemia (risk increased by concomitant sulfonylurea therapy). As with all pooled analyses, this study is limited by the use of data from different studies, and the relatively short duration of some included studies, although use of individual patient data from consistently designed trials should minimize methodological differences between trials. Results from ongoing clinical trials will provide additional insight into the long-term safety/tolerability of linagliptin.     

Use of dipeptidyl peptidase-4 inhibitors for the treatment of patients with type 2 diabetes mellitus and chronic kidney disease

Choices of antidiabetic agents for patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) are limited. Available data suggest that the use of dipeptidyl peptidase-4 (DPP-4) inhibitors may be safe in patients at various stages of renal insufficiency. However, except for linagliptin, dosage adjustment is necessary. The efficacy of DPP-4 inhibitors in patients with renal insufficiency is generally similar to that of the general population with T2DM, with reductions in mean glycated hemoglobin (HbA1c) levels of 0.7% to 1.0% compared with baseline, and 0.4% to 0.7% compared with placebo. The frequency of moderate hypoglycemia is 21% to 80% higher with DPP-4 inhibitors compared with placebo, but the frequency of severe hypoglycemia is similar to that with placebo. The use of DPP-4 inhibitors in patients with renal insufficiency is associated with a slight weight loss of < 1 kg. Dipeptidyl peptidase-4 inhibitors may be used as monotherapy in patients with CKD and HbA1c levels < 8.5% as an alternative to insulin, glipizide, or pioglitazone. They can also be used as add-on therapy to glipizide and/or pioglitazone in patients with HbA1c levels < 9%, but studies are needed to evaluate these combinations in patients with renal insufficiency. Long-term and large-scale clinical trials are underway to better determine the safety and efficacy of DPP-4 inhibitors in patients with T2DM with and without CKD.