The importance of synthetic drugs for type 2 diabetes drug discovery

Introduction: Type 2 diabetes mellitus (T2DM) is a major metabolic, multi-causal and heterogeneous disorder which causes significant morbidity and mortality with considerable burden to healthcare resources. The number of deaths due to T2DM highlights the insufficiency of the currently available drugs for controlling the disease and its complications and more needs to be done.

Areas covered: This paper reviews the updated pathobiology of T2DM that should be targeted in drug discovery. Further, the article provides discussion on the mechanism of action, side effects and structure of the currently available synthetic drugs. The authors specifically evaluate two newer classes of anti-diabetic agents: dipeptidyl peptidase IV (DPP-4) and sodium-glucose transporter-2 (SGLT2). They also present information on newer synthetic compounds. The article also highlights the key interactions between synthetic compounds and DPP-4 active site residues for rational drug design.

Expert opinion: Numerous anti-hyperglycaemic drugs are currently available but many are limited by their adverse effects. The identification of the 3D structure of DPP-4 has opened new avenues for design, thus aiming to produce drugs that directly exploit the structural characteristics of this binding site. Further, structural- and ligand-based screening techniques have been developed for designing novel DPP-4 and SGLT2 inhibitors. There has also been progress with the design and development of novel T2DM therapeutics including: PPARα/ dual agonists, Sirtuin 1 activators, glycogen phosphorylase inhibitors and protein tyrosine phosphatase 1B inhibitors. Finding new targets and synthesis methods is still essential but it is becoming accepted that no diabetic therapy is ‘best suited' with each patient responding differently.     

Linagliptin,a xanthine-based dipeptidyl peptidase-4 inhibitor with an unusual profile for the treatment of type 2 diabetes

Importance of the field: Type 2 diabetes is a progressive disease for which current treatments are often unsatisfactory with respect to achieving therapeutic goals and unwanted side effects.

Areas covered: Preclinical and clinical studies of linagliptin, a new oral antidiabetic agent, including data presented at Scientific Meetings and peer-reviewed studies published since 2007.

What the reader will gain: This article reviews pharmacokinetic and pharmacodynamic characteristics of linagliptin. Linagliptin belongs to a new chemical class of dipeptidyl pepidase-4 (DPP-4) inhibitors, which comprise xanthine-based compounds. It is a potent, long-acting inhibitor with high selectivity for DPP-4 versus the related enzymes DPP-8 and DPP-9. The drug has modest oral availability in humans, but is absorbed rapidly to inhibit plasma DPP-4 activity by > 80% over 24 h. It is not metabolized appreciably in vivo, but binds extensively to plasma proteins, with elimination occurring primarily in the liver. Linagliptin reduces degradation of the incretin hormone glucagon-like peptide-1 and is associated with reduced fasting and postprandial glucose in preclinical and clinical studies. Limited data from longer duration clinical trials show it improves glycemic control in patients with type 2 diabetes.

Take home message: Linagliptin is a new oral antidiabetic agent associated with minimal risk of hypoglycemia, which holds promise for treatment of type 2 diabetes.     

Safety evaluation of trelagliptin in the treatment of Japanese type 2 diabetes mellitus patients

Introduction: Trelagliptin is a novel, long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM) in japan. The safety and efficacy of trelagliptin has been evaluated in three published clinical trials to date: one phase II and two phase III studies. As trelagliptin only requires dosing once per week, this new agent has the potential to improve compliance and subsequently, glycaemic control, in patients with T2DM.

Areas covered: This article reviews the available safety data for trelagliptin from published clinical trials, and evaluates the published safety profile relative to competitor once-daily and once-weekly DPP-4 inhibitors.

Expert opinion: Clinical trial data to date suggest that trelagliptin is a safe and efficacious medication with a similar safety profile to once-daily DPP-4 inhibitors, and to the once-weekly DPP-4 inhibitor, omarigliptin. Trelagliptin is well tolerated when given alone, and in combination with other anti-diabetic medications. An advantage of trelagliptin over existing once-daily DPP-4 inhibitors is the decrease of dosing frequency, rather than once-daily. No specific, serious adverse events have been reported for trelagliptin in published clinical trials, making it an attractive alternative to other DPP-4 inhibitors.     

Combination therapy with metformin plus vildagliptin in type 2 diabetes mellitus

Introduction: Type 2 diabetes mellitus (T2DM) is pathophysiologically characterized by a combination of insulin resistance and beta-cell dysfunction. Consequently, a proper treatment of such a disease should target both of these defects. Dipeptidyl peptidase-4 (DPP-4) inhibitors are among the most recent additions to the therapeutic options for T2DM and are able to increase circulating levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus stimulating glucose-dependent insulin secretion.

Areas covered: This paper provides an overview of the clinical results of combination therapy with metformin and the DPP-4 inhibitor vildagliptin in T2DM patients.

Expert opinion: Vildagliptin–metformin single-tablet combination is indicated for the treatment of T2DM patients not achieving a sufficient glycemic control at their maximally tolerated dose of metformin. Results from clinical trials provide evidence of vildagliptin efficacy administered in addition to metformin, as either first- or second-line treatment. The vildagliptin–metformin association seems to have favorable effects on beta-cell function and is characterized by good safety and tolerability profiles when compared with other antidiabetic agents. Of note, data available suggest that administration of fixed-dose combination products, together with the low incidence of adverse gastrointestinal events, may improve compliance and adherence of patients to therapy, resulting in an improved metabolic control.     

Drug-induced hypoglycaemia in type 2 diabetes

Introduction: Hypoglycaemia is a side effect caused by some therapies for type 2 diabetes, which can cause physical, social and psychological harm. Hypoglycaemia also prevents attainment of treatment goals and satisfactory glycaemic control.

Areas covered: The risk of hypoglycaemia associated with commonly prescribed therapies, including metformin, sulphonylureas, dipeptidyl peptidase-4 enzyme (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists and thiazolidinediones, is reviewed in this paper (insulin-induced hypoglycaemia is not included). Other medications that are frequently co-prescribed in type 2 diabetes are also discussed, including anti-hypertensive drugs, antibiotics and fibrates, along with various important patient-related risk factors.

Expert opinion: Hypoglycaemia is a common and potentially dangerous side effect of some medications used for type 2 diabetes. The risk of hypoglycaemia should always be considered when selecting and implementing a therapy, with a focus on the individual. Future research into new therapies should measure the frequency of hypoglycaemia prospectively and accurately. Hypoglycaemia has been shown to be a potentially life-threatening metabolic stress; therefore therapies that effectively manage diabetes without the risk of hypoglycaemia are likely to be favoured in the future.     

A review of gliptins for 2014

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) occupy an increasing place in the armamentarium of drugs used for the management of hyperglycaemia and offer new opportunities for a personalized medicine in patients with Type 2 diabetes.

Areas covered: An updated review providing an analysis of available recent data with commercialized DPP-4 inhibitors, with a special focus on: differences between the various molecules, novelties regarding their mechanism of action, clinical efficacy in mono- and various combined therapies, comparison with other new therapies, efficacy-safety profile in at risk patients, concern about pancreatic safety, perspectives in cardiovascular prevention and, finally, a selection of remaining unanswered important questions for the clinician.

Expert opinion: DPP-4 inhibitors offer various advantages when compared to other glucose-lowering agents. Despite they have been commercialized since a few years only, available data obtained in randomised controlled trials are of better quality compared to those available with ancient classical glucose-lowering agents, especially in more fragile populations such as elderly people, individuals with renal impairment or at high cardiovascular risk and patients at higher risk of hypoglycaemia. However, there remain uncertainties and controversies that should be resolved by further ongoing large prospective controlled trials and increasing clinical experience combined with a careful post-marketing surveillance.     

Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) occupy a growing place in the armamentarium of drugs used for the management of hyperglycemia in type 2 diabetes, although some safety concerns have been raised in recent years.

Areas covered: An updated review providing an analysis of available safety data (meta-analyses, randomized controlled trials, observational cohort and case–control studies and pharmacovigilance reports) with five commercialized DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin). A special focus is given to overall safety profile; pancreatic adverse events (AEs) (acute pancreatitis, pancreatic cancer); overall cardiovascular safety (myocardial infarction and stroke); congestive heart failure concern and finally, safety in special populations (elderly, renal impairment).

Expert opinion: The good tolerance/safety profile of DPP-4 inhibitors has been largely confirmed, including in more fragile populations (elderly, renal impairment) with almost no increased risk of infection or gastrointestinal AEs, no weight gain and a minimal risk of hypoglycemia. Although an increased risk of acute pancreatitis and pancreatic cancer was suspected, the complete set of available data appears reassuring so far. Cardiovascular safety of DPP-4 inhibitors has been proven but an unexpected increased risk of heart failure has been reported which should be confirmed in ongoing trials and better understood. Further postmarketing surveillance is recommended.     

Factors associated with the discontinuation of dipeptidyl peptidase-4 inhibitors (DPP-4is) after initiation of insulin

Abstract

Objective: Type 2 diabetes (T2D) is a prevalent health problem. Oral agents, with the exception of metformin, are often discontinued with the initiation of insulin. The objective was to understand the proportion of patients discontinuing dipeptidyl peptidase-4 inhibitors (DPP-4is) and the reasons for the decision to discontinue.

Methods: A retrospective study using a health claims database investigated discontinuation of DPP-4i in adult patients on a dual therapy of metformin and DPP-4i who initiated insulin (n?=?3391). An online survey administered to 406 physicians in the US examined reasons for discontinuation. Physicians surveyed included endocrinologists (34.5%), general practitioners (32.5%), internal medicine specialists (30.5%), and diabetologists (2.5%), treating a monthly average of 154 patients.

Results: Among patients treated with metformin and DPP-4is who were newly prescribed insulin, 33.3 and 57.3% discontinued DPP-4i therapy within 3 and 12?months, respectively. Patients who discontinued DPP-4i therapy had higher out-of-pocket costs and a greater proportion of renal and liver disease. Top 3 responses for discontinuation included adverse events/tolerability issues (58.9%), lack of efficacy/treatment goals not being met (55.4%) and additional cost of DPP-4i with insulin (48.5%). Top 3 responses for continuing DPP-4i included meeting treatment goals (70.7%), using a lower dose of insulin (65.3%) and good tolerability (48.0%). Physician characteristics, such as physician specialty, age, gender and location impacted to some extent the reasons for treatment decisions.

Conclusions: A large proportion of patients discontinue DPP-4is in the real world when initiating insulin. The impact of physician characteristics in treatment decisions highlights the need for enhanced physician training and support as new clinical data emerges and therapy options are available.     

An update on DPP-4 inhibitors in the management of type 2 diabetes

Introduction: DPP-4 inhibitors are a class of compounds used for the treatment of type 2 diabetes. The drugs inhibit the degradation of GLP-1, thus amplifying the incretin effect. They have moderate glycemic efficacy, a low propensity of causing hypoglycaemia and are weight neutral. The drugs are often used as second line therapy after metformin.

Areas covered: This review summarizes the available compounds in the market and discusses the novel compounds that are currently under development. Several large cardiovascular outcome trials with some of the compounds have been completed, and their results and implications are considered. Fixed dose combination pills are currently the main focus of research and the contribution of these to the care of patients with diabetes is further discussed.

Expert opinion: The DPP-4 inhibitors have been a successful class in drug development for diabetes. Taken orally and available as fixed dose combinations with metformin or with SGLT-2 inhibitors, they have reached a large market share of over 7 billion dollars. Other than retagliptin, it does not appear that any additional compound will be launched soon. Currently, the main focus is on the development of additional fixed dose combinations with SGLT-2 inhibitors, but the success of these combinations remains to be seen.     

Network meta-analysis of liraglutide versus dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes in Japanese patients

Aims: To determine the comparative efficacy and safety of liraglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors as antidiabetics for Japanese patients with uncontrolled type 2 diabetes (T2DM).

Methods and materials: We searched for randomized controlled trials (RCTs) evaluating outcomes among Japanese adults with uncontrolled T2DM and including liraglutide or DPP-4 inhibitors up to August 2016. We extracted data on trial and patient characteristics, and the following outcomes: HbA1c, weight, patients meeting HbA1c <7%, patients experiencing hypoglycemic events, microalbuminuria, estimated glomerular filtration rate (eGFR) and creatinine. We synthesized data using network meta-analyses (NMA) using a Bayesian framework. Continuous outcomes were modeled using normal likelihoods and an identity link, while dichotomous outcomes were modeled using a binomial likelihood and a logit link.

Results: The systematic literature review yielded 39 publications pertaining to 38 trials. A total of 27 trials (5032 patients) reported change in HbA1c at 12 weeks and at 24 weeks 9 trials (2091 patients). All treatments showed statistically significant reductions in HbA1c relative to placebo at 12 and 24 weeks. Liraglutide 0.9?mg was statistically superior to all DPP-4 interventions (vildagliptin, sitagliptin, linagliptin, alogliptin, teneligliptin, trelagliptin and omarigliptin) at 12 weeks and 24 weeks among those reporting. Treatments were not statistically differentiable with respect to weight change and risk of hypoglycemia. Finally, no comparisons of eGFR and microalbuminuria were conducted, as this data was reported in too few trials to conduct analyses.

Limitations: Some important outcomes were limited by poor reporting (eGFR and microalbuminuria) or low event rates (hypoglycemia). The follow-up time was relatively short. Clinically, the 24 week time point is more important as it demonstrates more sustained results.

Conclusions: Our research suggests that liraglutide 0.9?mg offers a more efficacious treatment option for T2DM than the DPP-4 inhibitors among adult Japanese patients and that it is a viable option for this population.     

Linagliptin,a dipeptidyl peptidase-4 inhibitor with a unique pharmacological profile,and efficacy in a broad range of patients with type 2 diabetes

Introduction: Increasing population age, obesity and physical inactivity mean that type 2 diabetes mellitus (T2DM) is increasingly common. Current treatments may be limited by adverse events, drug–drug interactions or contraindication/need for dose adjustment in patients with renal impairment.

Areas covered: This paper reviews studies that evaluate the pharmacokinetics, pharmacodynamics and clinical efficacy and safety of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, recently approved in the US, Japan and Europe for the treatment of T2DM.

Expert opinion: Oral linagliptin, 5 mg once daily, is an effective, well-tolerated DPP-4 inhibitor, suitable for use in a wide range of patients with T2DM. It is weight-neutral, without increasing the risk of hypoglycemia, and can be administered either alone or in combination with other diabetes treatments. It has a unique pharmacological profile within its class and, unlike other DPP-4 inhibitors, linagliptin does not require dose adjustment in patients with renal impairment.     

Medically minimising the impact of hypoglycaemia in type 2 diabetes: a review

Introduction: Some therapies for type 2 diabetes (T2DM) are limited by hypoglycaemia, and this underestimated side effect carries an associated morbidity and financial burden. Large trials that have examined strict glycaemic control and cardiovascular outcomes in T2DM have highlighted the potential harm of exposure to hypoglycaemia in people with coronary heart disease.

Areas covered: The responses to, and the morbidity associated with, hypoglycaemia in T2DM are discussed with identification of people most at risk of severe hypoglycaemia. The evidence base for non-pharmacological strategies and the risks of hypoglycaemia associated with various treatment modalities are examined. This review provides the clinician with a rational approach to the selection of different anti-diabetes drugs to minimize the risk of hypoglycaemia.

Expert opinion: When managing T2DM, insulin and insulin secretagogues should be used judiciously and glycaemic targets individualized to avoid hypoglycaemia. Incretin mimetics present a lower risk of hypoglycaemia with similar efficacy as traditional agents in treating hyperglycaemia. The potential relationship between hypoglycaemia and precipitation of acute cardiovascular events is a highly topical area of research and may help determine what glycaemic targets are appropriate in people with T2DM.     

Glycemic/metabolic responses to identical meal tolerance tests at breakfast,lunch and dinner in Japanese patients with type 2 diabetes mellitus treated with a dipeptidyl peptidase-4 inhibitor and the effects of adding a mitiglinide/voglibose fixed-dose combination

Background: The effects of the mitiglinide/voglibose fixed-dose combination on postprandial glycemic/metabolic responses in patients with type 2 diabetes mellitus (T2DM) treated with dipeptidyl peptidase-4 (DPP-4) inhibitors are unknown.

Methods: Twelve T2DM patients treated with a DPP-4 inhibitor underwent identical meal tolerance tests (MTTs) at breakfast, lunch and dinner, before and 2 – 3 weeks after treatment with a fixed-dose combination of mitiglinide 10 mg and voglibose 0.2 mg (combination). Patients were randomized in a cross-over fashion to administer the combination either three-times-daily before each meal or twice-daily before breakfast and dinner. Glycemic/metabolic responses were evaluated at 0, 30, 60 and 120 min in each MTT.

Results: Three-times-daily administration of the combination significantly suppressed postprandial hyperglycemia after each meal, particularly after lunch and dinner. Active glucagon-like peptide-1 levels increased significantly after each meal, as did early-phase insulin secretion without excessive insulin secretion. Postprandial hyperglycemia after lunch was significantly greater after twice-daily than three-times-daily administration, but there were no clinically relevant differences in other metabolic responses.

Conclusion: This study revealed that adding the mitiglinide/voglibose combination to a DPP-4 inhibitor elicited additive improvements in postprandial glycemic/metabolic responses assessed using MTTs at breakfast, lunch and dinner with identical meal compositions.     

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.     

Vildagliptin in the treatment of type 2 diabetes mellitus

Introduction: Inhibition of dipeptidyl peptidase IV (DPP-4) augments glucose-dependent insulin release and is a new approach to the treatment of type 2 diabetes (T2DM). Vildagliptin is a new DPP-4 inhibitor approved in many countries for the treatment of T2DM. This review provides an overview of vildagliptin with emphasis on its pharmacology and clinical effectiveness.

Areas covered: Results of preclinical and several Phase II and III studies from 2004 – 2010 are discussed.

Expert opinion: Vildagliptin acts to inhibit the breakdown of glucagon-like peptide (GLP)-1, which in turn enhances the beta-cell response to glucose and inhibits glucagon secretion. It is an effective agent alone or in combination in patients with T2DM, resulting in modest improvements in HbA1c usually in the 0.5 – 1% range. Advantages include weight neutrality and a lesser incidence of hypoglycemia. Concerns remain regarding its use in renal disease and potential complications seen in animal models.     

Real-world evaluation of glycemic control among patients with type 2 diabetes mellitus treated with canagliflozin versus dipeptidyl peptidase-4 inhibitors

Objective To evaluate glycemic control among patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin (CANA) vs. dipeptidyl peptidase-4 (DPP-4) inhibitors.

Methods Using integrated claims and lab data from a US health plan of commercial and Medicare Advantage enrollees, this matched-control cohort study assessed adult T2DM patients receiving treatment with CANA or DPP-4 inhibitors (1 April 2013–31 December 2013). Cohorts were chosen hierarchically; the first pharmacy claim for CANA was identified as the index date; then the first pharmacy claim for a DPP-4 inhibitor was identified and index date set. Eligible patients had 6 months of continuous health plan enrollment before the index date (baseline) and 9 months after (follow-up) and no evidence of index drug in baseline. Patients were matched 1:1 using propensity score matching. Changes in glycated hemoglobin (HbA1c) and percentages of patients with HbA1c <8% and <7% during the follow-up were evaluated.

Results The matched CANA and DPP-4 inhibitor cohorts (53.2% treated with sitagliptin) included 2766 patients each (mean age: 55.7 years). Among patients with baseline and follow-up HbA1c results, mean baseline HbA1c values were similar, 8.62% and 8.57% (p?=?0.615) for the CANA (n?=?729) and DPP-4 inhibitor (n?=?710) cohorts, respectively. Change in HbA1c was greater among patients in the CANA cohort than for those in the DPP-4 inhibitor cohort (?0.92% vs. ?0.63%, p?<?0.001), and also among the subset of patients with baseline HbA1c ≥7% (-1.07% [n?=?624] vs. ?0.79% [n?=?603], p?=?0.004). During follow-up, greater percentages of the CANA cohort relative to the DPP-4 inhibitor cohort achieved HbA1c of <8% (66.0% vs. 58.6%, p?=?0.004) and <7% (35.4% vs. 29.9%, p?=?0.022).

Limitations This study was observational and residual confounding remains a possibility.

Conclusions In this real-world study of patients with T2DM, CANA use was associated with greater HbA1c reduction and higher percentages of patients attaining HbA1c goals than those treated with DPP-4 inhibitors.     

The safety of DPP-4 inhibitor and SGLT2 inhibitor combination therapies

Introduction: Type 2 diabetes (T2D), a multifactorial and chronic disease, requires in an elevated percentage of patients the association of several antidiabetic drugs to achieve optimal glycemic control. Dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium–glucose cotransporter inhibitors (SGLT2i) are new classes of oral antidiabetic drugs developed over the last years.

Areas covered: This paper summarizes the safety of DPP-4i and SGLT2i combination therapies. Relevant studies were identified through searches in PubMed.

Expert opinion: DPP4i and SGLT2i are antidiabetic drugs that lower blood glucose without causing hypoglycaemia or weight increase. More importantly, cardiovascular trials have clearly demonstrated the cardiovascular safety of DPP4i and a reduction in cardiovascular events with SGLT2i (empagliflozin and canagliflozin). Therefore, the association of both therapeutic groups could be an attractive option to achieve optimal blood glucose control in T2D because of their complementary mechanism of action. Clinical trials evaluating the combination of SGLT2i and DPP4i show that the co-administration of these drugs in fixed-dose combinations in comparison to separate tablets does not carry additional safety concerns that each individual drug, but increases therapeutic effects. Therefore, this antidiabetic combination is a safe and effective therapy for patients with T2D.     

Cardiovascular effects of anti-diabetes drugs

ABSTRACT

Introduction: Cardiovascular disease remains the major contributor to morbidity and mortality in diabetes. From the need to reduce cardiovascular risk in diabetes and to ensure that such risk is not exacerbated by drug treatments, governmental regulators and drug manufacturers have focused on clinical trials evaluating cardiovascular outcomes.

Areas covered: Findings from mechanistic and clinical trials of biguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose co-transporter 2 (SGLT-2) inhibitors will be reviewed. These drug classes will be compared within the context of available cardiovascular outcomes data. Clinical implications of new study regulations will be examined.

Expert opinion: Recent cardiovascular studies provide a more comprehensive evaluation of specific anti-diabetes therapy in individuals with high cardiovascular risk. Long-term effects of anti-hyperglycemic agents in patients with lower cardiovascular risk are still speculative. Historical data supports continued use of metformin as a first-line agent. DPP-4 inhibitors and GLP-1 receptor agonists appear to have neutral effects on cardiovascular outcomes. The significantly decreased cardiovascular risk associated with empagliflozin SGLT-2 inhibitor therapy is impressive and may change how practitioners prescribe add-on therapy to metformin.     

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

ABSTRACT

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors such as alogliptin are becoming more widely established as treatment options for patients with type 2 diabetes (T2DM) because of their ability to improve glycemic control without increasing the risk of hypoglycemia or weight gain. New therapies with improved safety profiles are needed, especially because of the chronic and progressive nature of T2DM.

Areas covered: In this article, the overall safety and tolerability of alogliptin are evaluated based upon a review of the literature. In particular, adverse events (AEs) that have been of interest for the DPP-4 class of drugs, such as the risk of major cardiovascular (CV) events and acute pancreatitis, will be investigated in detail.

Expert opinion: Alogliptin is generally well-tolerated in a broad range of patient populations including different ethnic groups and the elderly. In the pivotal EXAMINE clinical trial, alogliptin was found not to be associated with an increased risk of major CV events or acute pancreatitis/pancreatic cancer.