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.     

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.     

Omarigliptin for the treatment of type 2 diabetes mellitus

Introduction: The estimated global prevalence of diabetes mellitus for adults aged 20-70 in 2015 was 415 million with approximately 90% of diagnosed cases being Type 2 diabetes mellitus (T2DM). Improvements in lifestyle and effective therapies are key to management but due to the progressive nature of T2DM, pharmacotherapy is typically required. Whilst the initial therapy will usually be with metformin, thereafter treatment should be individualised, with consideration of several different second line options. These include the dipeptidyl peptidase-4 (DPP-4) inhibitors, of which omarigliptin is the second once weekly version.

Areas covered: The paper summarises key pharmoacodynamic and pharmacokinetic features and reviews the efficacy and safety trial data of omarigliptin, a once-weekly DPP-4 inhibitor.

Expert opinion: Omarigliptin results in a significant improvement in glycaemia with an effective once weekly pharmacokinetic profile and low risk of drug-drug interactions. It has equivalent efficacy to existing once daily DPP-4 inhibitors and shares a similar side effect profile. It is weight neutral with a significantly lower risk of hypoglycaemia compared with sulphonylureas. Adherence to prescribed medication is poor in patients with T2DM. Once weekly omarigliptin is a welcomed addition to the therapeutic armoury but whether it will improve compliance remains to be seen.     

Combination therapy in type 2 diabetes mellitus: adding linagliptin to a stable regimen of metformin and a sulfonylurea

Linagliptin, the most recently approved drug of the dipeptidyl peptidase-4 (DPP-4) inhibitor class, is an oral agent used to improve glycemic control in type 2 diabetes mellitus (T2DM). By inhibiting the DPP-4 enzyme, these drugs slow the inactivation of the endogenous incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), in turn reducing blood glucose levels in a glucose-dependent manner. As well as significantly reducing glycosylated hemoglobin, the class has a good safety profile, with a low incidence of hypoglycemia, and is not associated with weight gain. From a practical point of view, they also have simple regimens, generally with once-daily oral administration, and can be used as monotherapy or in combination with other anti-diabetic drugs. Owens and colleagues have reported a 6-month study of linagliptin add-on therapy in patients who were receiving a stable regimen of metformin and a sulfonylurea, but needed additional glycemic control. Linagliptin was associated with significant improvement in glycemic control and was well-tolerated by patients, indicating that it provides a valuable option for a large number of patients with T2DM, especially for those who would prefer to add an oral therapy to a current regimen.     

艾塞那肽治疗2型糖尿病临床观察

目的观察艾塞那肽治疗2型糖尿病(T2DM)的临床效果。方法对2型糖尿病患者19例予艾塞那肽治疗。治疗前后比较糖化血红蛋白(HbA1c)、空腹血糖(FBG)、餐后2h血糖(2h PG)、总胆固醇(TC)、三酰甘油(TG)、体质量、空腹C肽及餐后2h C肽水平,并观察其不良反应。结果治疗3个月后患者HbA1c、FBG、2h PG、TG、TC和体质量均显著下降(P<0.01),空腹C肽、餐后2h C肽均显著增加(P<0.01)。其中出现恶心等轻度胃肠道反应5例,低血糖发生率为5.3%。结论艾塞那肽可持续有效控制T2DM患者的血糖,降低患者体质量,改善B细胞功能,且低血糖风险低,值得推广应用。     

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.     

二甲双胍血糖控制不佳的2型糖尿病患者联合应用沙格列汀或吡格列酮疗效观察

目的 探讨二甲双胍血糖控制不佳的2型糖尿病患者联合沙格列汀或吡格列酮的疗效。方法 选择2015年1月至2016年1月安徽医科大第二附属医院内分泌门诊符合入选条件的2型糖尿病患者70例,随机被分为两组,观察组35例采用沙格列汀+二甲双胍治疗,对照组35例患者采用吡格列酮+二甲双胍治疗,观察两组治疗前后的空腹血糖（FPG）、餐后2 h血糖（2 hPG）、糖化血红蛋白（HbA1c）、空腹血清胰岛素水平、胰岛素抵抗指数（HOMA-IR）、体质指数（BMI）等。结果 与治疗前比较,治疗16周后观察组、对照组患者的FPG、餐后 2 hPG与HbA1c明显降低,HOMA-IR改善,差异有统计学意义（P<0.05）;但两组间差异无统计学意义（P>0.05）。与治疗前比较,治疗16周后观察组BMI无明显变化,差异无统计学意义（P>0.05）,对照组患者BMI明显上升,差异有统计学意义（P<0.05）,两组间差异有统计学意义（P<0.05）。结论 沙格列汀或吡格列酮联合二甲双胍可有效控制2型糖尿病患者血糖、改善胰岛素敏感性,沙格列汀不增加体质量且不良反应小,联合二甲双胍治疗是一种安全可靠的治疗方法。     

The association of health literacy with illness perceptions,medication beliefs,and medication adherence among individuals with type 2 diabetes

Background

Beliefs in medications and illness perceptions is associated with medication adherence among individuals with diabetes and several adherence interventions focus on patients' beliefs in medicines and illnesses. Though health literacy is important in medication adherence, the relationship between health literacy and medication adherence remains inconclusive; thus raising the question as to whether health literacy has an amplifying or reducing effect on the relationship between beliefs and adherence.

A holistic conceptual framework model to describe medication adherence in and guide interventions in diabetes mellitus

Background

Nonadherence to medications in patients with diabetes, which results in poor treatment outcomes and increased healthcare costs, is commonly reported globally. Factors associated with medication adherence have also been widely studied. However, a clear and comprehensive, disease-specific conceptual framework model that captures all possible factors has not been established.

The potential role of vildagliptin in the management and prevention of type 2 diabetes mellitus

Proper control of blood sugar in type 2 diabetes mellitus (T2DM) is not adequate till now in spite of use of well-planned dosage regimens containing oral hypoglycemic agents/insulin or both. Recently, the role of 'incretins,' particularly that of glucagon-like peptide-1 (GLP-1) in glucose homeostasis has been firmly established. The peptide (GLP-1) increases insulin secretion while decreasing that of glucagon in response to rise in plasma glucose in addition to delay of gastric emptying time, reduction of appetite, preservation of beta-cell function, and increase in beta-cell mass all of which will contribute toward lowering of blood sugar in T2DM. But the peptide hormone cannot be used orally as such because of its very short plasma half-life (2 min) and chemical nature, which needs continuous i.v. infusion or repeated s.c. or i.v. injections at short intervals. Hence, to prolong the duration of action of endogenous GLP-1, compounds have been synthesized which inhibit the enzyme dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for metabolic degradation of GLP-1. One such compound is vildagliptin. In this article, an attempt has been made to compile some of the established recent advances in the therapeutic utility of vildagliptin along with a discussion about the physiological role of endogenous GLP-1 and its metabolism by DPP-4.     

Targeting the pathophysiology of type 2 diabetes: rationale for combination therapy with pioglitazone and exenatide

ABSTRACT

Objective: The objectives of this article are to review the pathophysiology of type 2 diabetes mellitus (T2DM), present the rationale for a pathophysiologically based treatment approach for patients with T2DM and discuss the role of the therapeutic combination of pioglitazone and exenatide in the management of T2DM.

Methods: References were identified from searches of the PubMed database that were conducted in May 2007, October 2007 and March 2008 and updates to product labeling that occurred between May 2007 and December 2007. Information was selected for inclusion on the basis of its relevance to the pathophysiology of T2DM or the clinical use of thiazolidinediones or exenatide. Discussion of other anti-diabetic treatment strategies is not included.

Results: T2DM results from a combination of insulin resistance and beta-cell dysfunction. The combination of a thiazolidinedione and an incretin mimetic offers a combination of characteristics (e.g., glycemic control, reduced insulin resistance, decreased weight, potential cardiovascular benefits, beta-cell preservation) that addresses many of the pathophysiologic underpinnings of T2DM. A recent small placebo-controlled study assessed the effects of exenatide used with a thiazolidinedione (TZD; pioglitazone or rosiglitazone) with or without metformin. Exenatide demonstrated a greater incidence of glycosylated hemoglobin (HbA_1c) <?7%; greater reductions in fasting blood glucose, postprandial plasma glucose and body weight; and improved beta-cell function versus the TZD/placebo group. However, exenatide was associated with a high dropout rate, and the 16-week duration of treatment in this study precluded evaluation of the long-term effects of the exenatide/pioglitazone combination. Furthermore, exenatide/pioglitazone has not been compared with any other anti-diabetic combination in a head-to-head clinical study.

Conclusions: Dual effects on insulin sensitivity (TZD) and insulin secretion (exenatide) make the TZD/exenatide combination a rational treatment option for patients who do not attain glycemic control with a single agent. Studies undertaken to evaluate the effects on cardiovascular outcomes and the potential for prevention of T2DM with impaired glucose tolerance may reveal additional advantages of this combination approach.     

Efficacy and safety of saxagliptin in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials

As a new oral hypoglycemic agent, saxagliptin belongs to the class of dipeptidyl peptidase-4 (DPP-4) inhibitors. However, it remains inconclusive whether saxagliptin is associated with increased risk of adverse events (AE) and efficacy as add-on treatment. Therefore, we performed an up-to-date meta-analysis to compare the efficacy and safety of saxagliptin with placebo and other oral hypoglycemic agents in adult patients with type 2 diabetes mellitus (T₂DM). Randomized clinical trials (RCTs) comparing saxagliptin with comparators were retrieved by selecting articles from Pubmed, Embase, Cochrane Library and Clinical Trials Registry Platform up to Oct. 2013. Weighted mean difference (WMD) was used to analyze the effect of hypoglycemic agents on HbA1c, weight and fasting plasma glucose (FPG). While the patients who achieved HbA1c<7.0% and had AE were analyzed as relative risks (RR).A total of 18 articles from 16 RCTs and one clinic trial from the WHO International Clinical Trials Registry Platform met the included criterion. Clinically significant decrease from baseline HbA1c compared with placebo was certified for 2.5 mg/day saxagliptin (WMD = –0.45%, 95%CI, –0.48% to –0.42%) and 5 mg/d saxagliptin (WMD = –0.52%, 95%CI, –0.60% to –0.44%). Saxagliptin as add-on therapy was superior to thiazolidinediones, up-titrated glyburide, up-titrated metformin or metformin monotherapy in achieving HbA1c<7.0%. Treatment with saxagliptin had negligible effect on weight, and it was considered weight neutral. Saxagliptin treatment did not increase the risk of hypoglycemia (RR = 1.28, 95% CI 0.72 to 2.27, P = 0.40) and serious adverse experiences (RR = 1.25, 95% CI 0.94 to 1.66, P = 0.13). No statistically significant differences were observed between saxagliptin and comparators in terms of the risk of infections.The present study showed that saxagliptinwas effective in improving glycaemic control in T₂DM with a low risk of hypoglycaemia and incidence of infections in either monotherapy or add-on treatment. This founding should be further certified by large-sample size and good-designed RCT.     

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.     

Effectiveness of a pharmacist-led structured group-based intervention in improving medication adherence and glycaemic control among type 2 diabetes mellitus patients: A randomized controlled trial

BackgroundA pharmacist-led structured group-based intervention (MEDIHEALTH) was formulated to improve medication adherence among Malay type 2 diabetes mellitus (T2DM) patients in the Malaysian state of Sarawak.ObjectivesThe objective of this study was to examine the effectiveness of MEDIHEALTH and its mechanism of impact for improving medication adherence and the glycated haemoglobin (HbA1c) level.MethodsA two group and parallel randomised controlled trial with a twelve months follow-up period was conducted at two primary health clinics in Malaysia that were surrounded by Malay communities. Malay T2DM patients whose HbA1c was >7% and total score on the Self-Efficacy for Appropriate Medication Use Scale (SEAMS) was <26 were recruited and parallelly randomised to the MEDIHEALTH or usual care (control) groups. The extended theory of planned behaviour was employed to test the mechanism of impact. Repeated measure analysis of variance was used to assess the difference in the estimated marginal mean of the SEAMS scores and HbA1c level between the intervention and control groups at different times.ResultsA total of 142 participants were recruited and randomised; three from the intervention group and eight from the control group withdrew before receiving any treatment. Hence, 68 participants in the intervention group and 63 in the control group were included for analyses. The MEDIHEALTH group had a significantly greater increase in the SEAMS score compared to the control group (p < 0.001) at one, three, six and twelve months post-intervention. There was also a significantly greater reduction in HbA1c in the MEDIHEALTH compared to the control group at one, three, six and twelve months post-intervention (p < 0.001). These improvements were mediated by enhancements in perceived behavioural control and knowledge about medications.ConclusionsThe MEDIHEALTH may improve medication adherence and glycaemic control among Malay T2DM patients.