Efficacy and safety of saxagliptin in combination with insulin in Japanese patients with type 2 diabetes mellitus: a 16-week double-blind randomized controlled trial with a 36-week open-label extension

Background: We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus.

Research design and methods: We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint.

Results: At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference ?0.92% [95% confidence interval ?1.07%, ?0.76%; p < 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups.

Conclusions: Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes.     

Evogliptin: a new dipeptidyl peptidase inhibitor for the treatment of type 2 diabetes

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel, potent oral antihyperglycemic agents that reduce degradation of endogenous glucagon-like peptide 1 (GLP-1) to increase insulin secretion and satiety and decrease glucagon. DPP-4 inhibitors enhance insulin secretion in a glucose-dependent manner, which potentially reduces hypoglycemia risks during monotherapy or combination therapy with other antidiabetic agents. Evogliptin (Suganon^TM) is a new oral DPP-4 inhibitor developed for the treatment of patients with type 2 diabetes inadequately controlled by diet and exercise.

Areas covered: This review summarizes the collected data concerning mechanism of action, clinical efficacy, and safety of evogliptin in improving glycemic control in patients with type 2 diabetes. Additional non-glycemic benefits and safety profiles of evogliptin are also discussed.

Expert opinion: Evogliptin is effective in improving glycosylated hemoglobin (HbA_1c) and fasting plasma glucose without inducing hypoglycemia events, which potentially can improve adherence and prevent complications. It is also found that evogliptin has benefits on insulin secretory and β-cell functions. Based on the current clinical data, evogliptin has a neutral effect on body weight. These attributes contribute to the clinical practice in monotherapy or in combination with other antidiabetic agents.     

The use of insulin in elderly patients with type 2 diabetes mellitus

Introduction: Older patients with diabetes sometimes present comorbidities that increase the risk of other common geriatric syndromes. In such patients, treatment with insulin is usually started when full doses of oral hypoglycemic agents are no longer adequate to achieve acceptable glycemic control.

Areas covered: This article reviews the available literature on the use of insulin in elderly patients with type 2 diabetes. The aims are to gain information on: the benefits and risks of initiating insulin treatment, the efficacy and safety of different types of insulin and the most appropriate initial dosing and titration regimens. Thirteen published trials have evaluated the effects of different insulin regimens in the management of elderly subjects with type 2 diabetes but, given that older people are generally excluded in clinical studies with insulin, only three published reports on subgroup analyses are limited to elderly patients.

Expert opinion: The available literature shows that the addition of insulin to current oral treatments is generally safe and effective in improving metabolic control, with a low risk for hypoglycemia. Further research is needed to better understand the most appropriate insulin regimens necessary to achieve glycemic goals while appropriately addressing the risk of hypoglycemia.     

Oral antidiabetic agents in type 2 diabetes

ABSTRACT

Background: Oral antidiabetic agents differ with regard to mechanisms of action, hemoglobin A_1c-lowering efficacy, safety, and tolerability. Traditional agents consist of those that enhance insulin secretion (i.e., sulfonylureas and glinides), those that enhance insulin sensitivity (i.e., metformin and the thiazolidinediones), and those that inhibit intestinal carbohydrate absorption (i.e., the α?glucosidase inhibitors). New oral agents include the dipeptidyl peptidase-4 (DPP?4) inhibitors, which potentiate the activity of the incretin glucagon-like peptide 1 and enhance glucose-dependent insulin secretion.

Scope: We review the characteristics of the traditional oral agents and these newer additions to the pharma­ceutical armamentarium. Abstracts and original clinical and preclinical reports in the English language were identified for review based on MEDLINE literature searches (1970–2006) and abstract collections from major diabetes meetings.

Conclusions: Traditional oral agents provide significant treatment benefits for diabetic patients, including reduction in risk of microvascular complications. However, most patients with type 2 diabetes do not achieve target glycemic levels with traditional therapies, and these agents are also associated with hypoglycemia, weight gain, and poor tolerability. Oral DPP?4 inhibitors offer the potential for significant improvement in glycemic control without hypoglycemia or weight gain, although long-term durability of glycemic control (>?52 weeks) has not been established.     

Combination therapy with saxagliptin and dapagliflozin for the treatment of type 2 diabetes

Introduction: Sodium glucose co-transporter 2 (SGLT2) inhibitors such as dapagliflozin and dipeptidyl peptidase-4 (DPP-4) inhibitors such as saxagliptin have the potential to confer significant benefits in glycemic control without the risk of weight gain and hypoglycemia, which may be associated with other medications used to treat type 2 diabetes.

Areas covered: This review examines the current available literature on the combination of saxagliptin and dapagliflozin as a treatment option, which is likely to be available as a fixed-dose combination in 2016. We reviewed the available published literature along with recently published abstracts examining the combination of these agents in relation to glycemic control, weight and blood pressure reduction, and adverse effects.

Expert opinion: To date, the limited literature suggests that the combination of saxagliptin and dapagliflozin is associated with significant improvements in glycated haemoglobin, fasting and postprandial glucose levels with few adverse effects. The combination appears to be well tolerated with low rates of hypoglycemia, urinary tract, and genital infections. Combination therapy may also be associated with improved beta-cell function and enhanced insulin clearance in addition to their established underlying mechanisms of action. Further publications of ongoing trials and abstracts should further support its clinical role.     

Metformin + saxagliptin for type 2 diabetes

INTRODUCTION: Metformin is considered as the first-line drug therapy for the management of type 2 diabetes. Dipeptidyl peptidase-4 (DPP-4) inhibitors, by promoting insulin secretion and reducing glucagon secretion in a glucose-dependent manner, offer new opportunities for oral therapy after failure of metformin. AREAS COVERED: An updated review of the literature demonstrates that saxagliptin, a DPP-4 inhibitor, and metformin may be administered together, separately or in fixed-dose combination (FDC), either as saxagliptin added to metformin or as initial combination in drug-naive patients. Both compounds exert complementary pharmacodynamic actions leading to better improvement in blood glucose control (fasting plasma glucose, postprandial glucose, HbA1c) than either compound separately. Adding saxagliptin to metformin monthotherapy results in a consistent, sustained and safe reduction in HbA1c levels. Tolerance is excellent without hypoglycemia or weight gain. EXPERT OPINION: The combination saxaglitpin plus metformin may be used as first-line or second-line therapy in the management of type 2 diabetes, especially as a valuable alternative to the classical metformin-sulfonylurea combination.     

Vildagliptin: the evidence for its place in the treatment of type 2 diabetes mellitus

Introduction:

Type 2 diabetes is increasing in prevalence worldwide and is a leading cause of morbidity and mortality, mainly due to the development of complications. Vildagliptin is an inhibitor of dipeptidyl peptidase 4 (DPP-4), a new class of oral antidiabetic agents.

Aims:

To evaluate the role of vildagliptin in the management of type 2 diabetes.

Evidence review:

Clear evidence shows that vildagliptin improves glycemic control (measured by glycosylated hemoglobin and blood glucose levels) more than placebo in adults with type 2 diabetes, either as monotherapy or in combination with metformin. Vildagliptin is as effective as pioglitazone and rosiglitazone, and slightly less effective than metformin, although better tolerated. Further glycemic control is achieved when adding vildagliptin to metformin, pioglitazone, or glimepride. There is evidence that vildagliptin improves beta-cell function and insulin sensitivity. Vildagliptin does not appear to be associated with weight gain or with a higher risk of hypoglycemia than placebo or other commonly used oral antidiabetic agents. Economic evidence is currently lacking.

Place in therapy:

Vildagliptin improves glycemic control with little if any weight gain or hypoglycemia in adult patients with type 2 diabetes when given alone or in combination with metformin, thiazolidinediones, or sulfonylureas. Since many diabetic patients require combination therapy, the complementary mechanism of action of vildagliptin and other commonly prescribed antidiabetic drugs represents an important new therapeutic option in diabetes management.     

The safety of gliptins : updated data in 2018

Introduction: Dipeptidyl peptidase-4 inhibitors (DPP-4is) are generally considered as glucose-lowering agents with a safe profile in type 2 diabetes.

Areas covered: An updated review of recent safety data from randomised controlled trials, observational studies, meta-analyses, pharmacovigilance reports regarding alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin, with a special focus on risks of hypoglycemia, pancreatitis and pancreatic cancer, major cardiovascular events, hospitalisation for heart failure and other new safety issues, such as bone fractures and arthralgia. The safety of DPP-4i use in special populations, elderly patients, patients with renal impairment, liver disease or heart failure, will also be discussed.

Expert opinion: The good tolerance/safety profile of DPP-4is has been largely confirmed, including in more fragile populations, with no gastrointestinal adverse effects and a minimal risk of hypoglycemia. DPP-4is appear to be associated with a small increased incidence of acute pancreatitis in placebo-controlled trials, although most observational studies are reassuring. Most recent studies with DPP-4is do not confirm the increased risk of hospitalisation for heart failure reported with saxagliptin in SAVOR-TIMI 53, but further post-marketing surveillance is still recommended. New adverse events have been reported such as arthralgia, yet a causal relationship remains unclear.     

Evolving concepts of type 2 diabetes management with oral medications: new approaches to an old disease

ABSTRACT

Background: Type 2 diabetes is often accompanied by co-morbid conditions such as hypertension and dyslipidemia, which, coupled with persistent hyperglycemia, result in significant macrovascular and microvascular complications. Type 2 diabetes treatments focus primarily on controlling hyperglycemia, hypertension, and dyslipidemia to stabilize the disease and minimize complications. Despite treatment, control of hyperglycemia and the conditions associated with type 2 diabetes are suboptimal in the majority of patients. Research efforts have concentrated on the development of new therapies for type 2 diabetes, including agents that could be used both as monotherapy and in combination with established oral antidiabetic agents to improve glycemic control and reduce the disease burden on patients.

Objective: To review published literature on oral agents in development for type 2 diabetes, with a focus on their mechanism of action and impact on concomitant risk factors.

Methods: After identifying oral agents in late-stage development for type 2 diabetes using the R&D Insight database, a literature review was conducted through PubMed for studies (preferably randomized, controlled trials) on dipeptidyl peptidase-IV inhibitors, CB₁ cannabinoid receptor blockers, and bile acid sequestrants. Where limited published data were available, abstracts from recent major conferences were searched. Other emerging therapies targeting pathways involved in modifying insulin resistance, glycogenolysis, and gluconeogenesis are also discussed.

Conclusions: A variety of novel therapies for type 2 diabetes are in development, which will provide patients and diabetes care providers more choices for the management of this disease. Importantly, many of these treatments offer the potential to significantly improve multiple metabolic parameters.     

Ertugliflozin as a monotherapy for the treatment of type 2 diabetes

ABSTRACT

Introduction: Sodium-dependent glucose transporter 2 (SGLT2) inhibitors are novel, potent oral anti-diabetic agents in a β-cell function-independent manner, inhibiting SGLT2-mediated renal glucose reabsorption and thus increasing urinary glucose excretion. Ertugliflozin (Steglatro^TM) is a new oral SGLT2 inhibitor for the treatment of patients with type 2 diabetes mellitus (T2DM) as a monotherapy or in combination with other anti-diabetic agents.

Areas covered: This review summarizes the collected data concerning the pharmacokinetics, clinical efficacy, as well as safety and tolerability profiles of ertugliflozin given as a monotherapy for the management of T2DM.

Expert opinion: Good glycemic control is crucial to the management of T2DM, and accordingly, anti-diabetic agents with various anti-hyperglycemic mechanisms are developed one after another. Based on the available clinical trials of ertugliflozin as a monotherapy for T2DM, it could be found that ertugliflozin effectively improves the glycemic control, body weight and blood pressure of patients with a low risk of hypoglycemia. It is also found that ertugliflozin moderately reduces their blood pressure, which is beneficial for decreasing the risk of cardiovascular disease. These attributes show the good potential of ertugliflozin as an adjunct treatment to diet and exercise for improving glycemic control in patients with T2DM.     

Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin

Abstract

Objective:

To evaluate efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes (T2D) with inadequate glycemic control on insulin alone or combined with metformin.     

Treatment of the patient with diabetes: importance of maintaining target HbA1c levels

SUMMARY

Objective: To review clinical trial evidence supporting treatment of patients to a near-normal HbA_1c target level and outline therapeutic strategies that optimize glycemic control.

Research design and methods: The current MEDLINE database and bibliographies were searched for literature relevant to diabetic complications, glycemic control, and the intensive management of diabetes mellitus.

Results: Two randomized trials, the Diabetes Control and Complications Trial and the UK Prospective Diabetes Study (UKPDS), provided evidence that intensive glycemic control obtained with either intensive insulin or oral therapy effectively slowed the onset and progression of diabetic retinopathy, nephropathy, and neuropathy in patients with type 1 and type 2 diabetes. An epidemiologic analysis of the UKPDS results showed a significant correlation between glycemic control and microvascular and cardiovascular disease risk and mortality rates.

Conclusions: The results of clinical trials confirm that stringent levels of glycemic control can be attained through the use of intensive multiple-injection insulin regimens (administration of insulin 3 or more times daily by injection or an external pump with dosage adjustments as needed), oral monotherapy or combination therapy, or a combination of insulin and oral therapy. The expanded choices for oral agents and the availability of insulin analogs now provide physicians with the tools to tailor therapy to prevent or delay the devastating complications of diabetes. Indeed, newer insulin analogs, both short-acting (insulin lispro, insulin aspart) and long-acting (insulin glargine), are an important part of a treatment strategy to circumvent diabetes complications and overcome the shortcomings of conventional insulin preparations.     

Insulin and GLP-1 analog combinations in type 2 diabetes mellitus: a critical review

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral antidiabetic drugs (OADs). The potential for combined use with insulin has garnered increasing attention due to the potential to reduce side effects associated with insulin therapy and improve glycemic control.

Areas covered: We reviewed published and other publicly released data from controlled and uncontrolled studies that included subjects treated with insulin/GLP-1 analog combination therapy. The currently available guidance for clinical practice when combining insulin and GLP-1 analogs was also summarized.

Expert opinion: Limited data currently available from placebo-controlled trials support the use of exenatide twice daily or liraglutide once daily in combination with basal insulin and metformin in subjects with type 2 diabetes unable to attain treatment goals. Several randomized controlled trials are currently studying combinations of insulin with various GLP-1 analogs. Additional guidance on the clinical use of these combinations will likely be forthcoming once these studies are reported. Insulin/GLP-1 analog combinations will require optimization of blood glucose monitoring strategies and delivery systems to decrease the risk of administration errors and reduce the potential complexity of these regimens.     

Investigational insulin secretagogues for type 2 diabetes

Introduction: Insulin secretory defects are a key feature in the pathophysiology of type 2 diabetes (T2D). Classical insulin-secreting agents such as sulfonlyureas stimulate insulin secretion independent of glucose and cause hypoglycemia. Despite the advantages offered by incretin-based therapies, there is still a medical need for developing new insulin secretagogues for treating T2D.

Area covered: This article discusses: the new advances in the field of incretin-based therapies, glucokinase (GK) activators, free fatty acid receptor (FFAR) or G protein-coupled receptor (GPR) agonists (GPR40, GPR119, GPR120), imeglimin and some other insulin secretagogues with diverse mechanisms of action still in preclinical development.

Expert opinion: New insulin secretagogues should offer major advantages over sulfonylureas and gliptins. The challenge is to avoid uncontrolled insulin secretion and minimize the risk of hypoglycemia, to protect cells from progressive loss of mass and function for a better durability of glucose control, and to offer a good safety profile. Numerous approaches are in development. However, it is too early to decide whether one new pharmacological class will emerge as a clinically useful insulin secretagogue in the near feature.     

Short-term cost-effectiveness of insulin detemir and insulin aspart in people with type 1 diabetes who are prone to recurrent severe hypoglycemia

Objective: Based on the data of the HypoAna trial (ClinicalTrials.gov NCT00346996), a short-term cost–effectiveness analysis was conducted comparing an all insulin analogue regimen with an all human insulin regimen in people with type 1 diabetes who are prone to recurrent severe hypoglycemia.

Methods: Clinical data from the HypoAna trial and Danish cost data related to the treatment of severe hypoglycemia were used to populate a 1-year cost–effectiveness analysis. Hypoglycemia quality-of-life data were based on previously published utility values, used to calculate the quality-adjusted life-years (QALYs) gained. Sensitivity analyses were conducted to test the robustness of the analysis. The main outcome measure was the incremental cost–effectiveness ratio (ICER).

Results: The insulin analogue regimen was associated with greater total costs compared with the human insulin regimen (20,418 DKK [1972 GBP] vs. 18,558 DKK [1793 GBP], respectively), primarily driven by the difference in insulin costs. Total costs for corrective actions for hypoglycemic events, however, were lower in the insulin analogue group (927 DKK [89 GBP]) compared with the human insulin group (1311 DKK [127 GBP]), primarily due to a lower event rate. QALYs were higher with insulin analogues vs. human insulin (difference 0.0672). The resulting ICER was 27,685 DKK (2674 GBP) per QALY gained, which is well below the generally accepted cost–effectiveness threshold.

Conclusions: The analysis shows that treating people with type 1 diabetes who are prone to recurrent severe hypoglycemia with an insulin analogue regimen is cost-effective compared with a human insulin regimen.     

A review of the effects of antihyperglycaemic agents on body weight: the potential of incretin targeted therapies

ABSTRACT

Background: Current American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) treatment guidelines recommend metformin (which does not promote weight gain) as the first-line antihyperglycaemic drug for patients with type 2 diabetes. However, when metformin fails, the recommended add-on treatment options (sulphonylureas, glitazones and basal insulin) can lead to significant weight gain. This article reviews the effect on body weight of current treatments for type 2 diabetes and discusses the potential impact of weight gain in this patient group.

Scope: MEDLINE searches were performed to evaluate the prevalence and impact of changes in body weight in type 2 diabetes (articles published between January 1966 and August 2006) and the effects of sulphonylureas, glitazones, insulin, dipeptidyl peptidase?4 (DPP?4) inhibitors and incretin analogs on body weight in these patients (search between January 2004 and September 2006).

Findings: Weight gain in general affects not only the physiological capability of patients with diabetes to achieve glycaemic control, but also their psychological well-being, quality of life and persistence with antihyperglycaemic treatment. Excess body weight and obesity in patients with diabetes are also associated with increased healthcare resource utilisation. Development of obesity is also associated with increased cardiovascular risk, although a link between drug-induced weight gain per se and increased cardiovascular risk has not been established. Initial clinical trial experience with the new oral DPP?4 inhibitors such as sitagliptin and vildagliptin suggests that these agents are weight-neutral, while providing improved glycaemic control when added to metformin.

Conclusions: Because currently available add-on treatments can cause weight gain, physicians initiating add-on therapy in patients who can no longer achieve glycaemic control with metformin are faced with the problem of improving glycaemic control while causing weight gain. Initial clinical trial experience with oral DPP?4 inhibitors such as sitagliptin and vildagliptin suggest that these agents may represent an important oral treatment option for weight-neutral, glycaemic control when added to metformin. The new oral DPP?4 inhibitors, therefore, represent a potentially important addition to the oral treatment options currently available for the management of type 2 diabetes mellitus. Long-term clinical trials are now required to evaluate the relative risk/benefit profile of these drugs compared with the established antihyperglycaemic drug classes.     

Lixisenatide as add-on to insulin glargine for the treatment of type 2 diabetes mellitus

Introduction: As type 2 diabetes mellitus (T2DM) advances, patients receiving basal insulin will eventually require another agent on top of their current regimen in order to achieve glycemic control. One such agent that can be administered in combination with basal insulin is the glucagon-like peptide-1 receptor agonist (GLP-1 RA) lixisenatide. GLP-1 RAs, such as lixisenatide, and basal insulin offer complementary mechanisms of action in their ability to provide glycemic control, thus providing a strong rationale for using them in combination with each other for the treatment of T2DM.

Areas covered: The current data available on the use of lixisenatide added to basal insulin for the management of T2DM is reviewed.

Expert opinion: Lixisenatide as add-on to basal insulin provides overall glycemic control as well as offering a number of other treatment benefits, such as a reduction in both body weight and the risk of hypoglycemia. Therefore, when basal insulin becomes inadequate in managing T2DM, lixisenatide should be considered as an add-on agent to help patients achieve glycemic targets with a low risk of hypoglycemic events.     

A multicenter,epidemiological study of the treatment patterns,comorbidities and hypoglycemia events of patients with type 2 diabetes and moderate or severe chronic kidney disease – the ‘LEARN’ study

Objective Management of patients with type 2 diabetes (T2DM) and stage 3 to 5 chronic kidney disease (CKD) is challenging. The aim of the ‘LEARN’ study was to describe treatment patterns employed in this population and to record comorbidities, glycemic control and hypoglycemia episodes in routine clinical practice in Greece.

Research design and methods ‘LEARN’ was a non-interventional, multicenter, cross-sectional study conducted in Greece between 15 February 2013 and 4 July 2013. A total of 120 adult patients were enrolled from four hospital sites in different geographic regions of Greece.

Results Participants had a mean age of 69.1?±?10.3 years and a male:female ratio of 2:1. Nearly all patients (99.2%) suffered from at least one comorbidity, with hypertension (95.8%) and hyperlipidemia/dyslipidemia (78.3%) being the most prevalent. Of the overall study population, 57.5% was managed with insulin therapy only, 30.8% with oral antidiabetics only and 11.7% with a combination of insulin and oral antidiabetics. The overall rate of glycemic control, defined as glycated hemoglobin (HbA_1c)?≤?7.0% during the most recent assessment, was 55.0%. This rate was significantly higher among those receiving oral antidiabetics only (73.0%) compared to insulin only (47.8%) or a combination of both types of treatment (42.9%) (p?=?0.03). Moreover, patients receiving oral antidiabetics only had experienced fewer hypoglycemia episodes over the last 7 days prior to the study visit (0.1?±?0.4) compared to patients receiving insulin only (0.9?±?1.7) (p?=?0.03).

Conclusions Although this is an observational study, it seems that oral antidiabetic therapy might be advantageous for heavily burdened T2DM patients with moderate or severe CKD in terms of glycemic control and hypoglycemia episodes. More data preferably from randomized trials is needed in order to validate this hypothesis.     

Treatment options for paediatric diabetes

Importance of the field: Diabetes mellitus is the most common endocrine disease in childhood. The global incidence of diabetes emphasizes the health, social and financial magnitude of this disease and the importance of optimizing disease management and prevention.

Areas covered in this review: This article reviews the treatments options for type 1 and 2 diabetes in children, focusing on insulin regimens and new alternative therapies.

What the reader will gain: The treatment goals for children with diabetes mellitus are to achieve normal development with prevention of complications. Insulin is the primary medication in the treatment of type 1 diabetes. New therapeutic options and prevention strategies (cellular therapies, immunomodulation and vaccination) aim to preserve residual beta-cell function. There are limited data about the effectiveness and safety of treatment strategies for type 2 diabetes. Many oral agents are approved only for use in adults and have not been yet studied in children.

Take-home message: Therapy regimens should be adapted to the lifestyle of individual patients to achieve optimal blood glucose control. The replacement of beta-cells, preservation of the residual beta-cell function and investigation of additional oral treatment options, present a hope for a cure.