Rosiglitazone plus metformin: combination therapy for Type 2 diabetes

Type 2 diabetes is a common disease associated with an increased risk of long-term complications, in particular cardiovascular disease. Intervention trials have provided evidence that strict metabolic control can substantially reduce the burden of the disease. However, in order to accomplish this, the pathogenetic defects must be tackled by appropriate therapy. Insulin resistance is a common defect in these patients and it is even more severe in those who are obese. Insulin resistance not only contributes to impaired glucose homeostasis, but also to the development of dyslipidaemia, hypertension, inflammatory response and endothelial dysfunction, thus exacerbating the cardiovascular risk. Improvement of insulin sensitivity can be obtained with metformin and thiazolidinediones. These drugs act through different mechanisms with metformin exerting a prevalent effect on the liver and glitazones improving insulin sensitivity in peripheral tissue. Because of different mechanisms, the association of the two compounds is likely to result in an additive effect. Clinical trials available indicate that the combination of the two drugs results in greater improvement in plasma glucose concentration and HbA_1c as compared to single therapy, without increasing the occurrence of specific side effects. More recently, the two compounds have been associated in the same tablet, thus providing the opportunity for a more convienient treatment that may encourage patient compliance and, at the same time, provide a tool to assess whether a more aggressive intervention on insulin resistance may produce favourable effects on the cardiovascular risk.     

离子对RP-HPLC法同时测定复方盐酸二甲双胍缓释片中盐酸二甲双胍和马来酸罗格列酮的含量

目的建立复方盐酸二甲双胍缓释片中盐酸二甲双胍和马来酸罗格列酮的含量测定方法。方法色谱柱为DiamonsilTMC18,流动相为10 mmol.L-1KH2PO4和5 mmol.L-1SDS的水溶液(磷酸调pH为3.5)-乙腈(体积比为51∶49),流速为1.0 mL.min-1,检测波长0~5 min为260 nm,5 min之后变为245 nm。以外标法计算复方盐酸二甲双胍缓释片中盐酸二甲双胍和马来酸罗格列酮的含量。结果盐酸二甲双胍的质量浓度在50.02~175.10 mg.L-1内,马来酸罗格列酮在0.530~1.855 mg.L-1内,与峰面积成良好的线性关系,相关系数分别为0.999 7和0.999 4。平均回收率分别为100.1%(RSD=0.80%)和99.56%(RSD=1.8%)。结论辅料不干扰主药测定,该方法可用于复方盐酸二甲双胍缓释片中药物含量测定。     

Adhering to the principles of clinical pharmacology - the correct fixed combinations of antihypertensive drugs

Introduction: Hypertension is one of the primary modifiable risk factor for cardiac and renal diseases with the prevalence around 30–45% of the general population, with a steep increase with ageing. The administration of blood pressure-lowering drugs is to reduce the risk of major clinical cardiovascular outcomes. Hypertension guidelines recommend combination therapy in patients with high cardiovascular risk and with subclinical organ damage as well as when monotherapy fails.

Areas covered: As the etiology of essential hypertension is multifactorial, combination therapy using different classes of antihypertensive agents have greater effect than each on its own (synergistic effect), may have better tolerability (two components minimizing each other’s side effects) and lead to improved patient compliance. Several studies assess the hypotensive efficacy on drug combination; there are also studies on triple drug combination.

Expert commentary: At present, dual and triple combination therapy is available to hypertensive patients with good clinical outcomes, compliance and low profile of side effects. It is critical as patients’ adherence to the pharmacological therapy significantly decreases the risk of long-term adverse events including mortality. It appears that combinations not only of hypotensive drugs but also with statins (as well as antidiabetics) will be widely used.     

不同剂量盐酸吡格列酮对胰岛素敏感性的影响

目的：研究2型糖尿病病人应用不同剂量盐酸吡格列酮对血糖控制、胰岛素敏感性和胰岛素分泌的影响。方法：30名单纯饮食、运动治疗无效或单用磺脲类药物治疗无效的2型糖尿病病人，随机、双盲给予15或30mg／d国产盐酸吡格列酮治疗12周，对治疗前后的各项疗效指标进行观察分析。结果：(1)15或30mg／d吡格列酮降低空腹血糖及糖化血红蛋白效果良好，两组间差异无统计学意义；(2)15mg／d吡格列酮治疗前后空腹胰岛素水平及稳态模型评估的胰岛素抵抗(HOMA—IR)指数无变化，30mg／d吡格列酮治疗前后空腹胰岛素水平及HOMA—IR均明显下降。结论：吡格列酮可有效地降低2型糖尿病病人的空腹血糖及糖化血红蛋白，耐受性好；吡格列酮对胰岛素敏感性的改善存在剂量依赖性。     

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.     

Overview of metformin: special focus on metformin extended release

Introduction: Diabetes is characterized by chronic hyperglycemia and vascular alterations, leading to micro-vascular and macro-vascular complications, which account for increased morbidity and mortality associated with the disease. Cardiovascular complications are the leading cause of death in patients with diabetes. Due to its cardio-protective effects, metformin is recommended as the initial agent of choice in the treatment of T2DM. Results of UKPDS, one of the largest and longest studies, showed reductions in cardiovascular mortality in patients using metformin.

Areas covered: This article reviews the history, structure, pharmacokinetics, clinical efficacy, and safety of extended-release metformin (XR). It also highlights fact that its use has been shown to have the same clinical and metabolic benefits as standard metformin, but also improved adherence and reduced side effects. The paper provides a side-by-side comparison of the main differences in the use of metformin XR versus metformin IR, i.e., their effect on lipids, and gastrointestinal (GI) side effects. Studies included in this review were selected from PUBMED and Embase databases.

Expert opinion: Given the chronic nature of diabetes, patient's adherence to therapy is very important in preventing complications of the disease. Compliance with the standard metformin formulation can be poor, due to multiple daily dosing and frequent GI side effects. Metformin XR can be given once daily and is associated with less GI side effects compared to immediate release metformin (IR); This leads to increased compliance, improved glycemic control and hence decreased risk of the associated micro- and macro-vascular complications.     

盐酸罗格列酮与马来酸罗格列酮治疗2型糖尿病的疗效和药费比较

目的比较2种罗格列酮治疗2型糖尿病的临床疗效与费用。方法80例2型糖尿病病人随机分为2组,每组40例,在原治疗基础上,A组予盐酸罗格列酮片,B组予马来酸罗格列酮片,均为4 mg,po,qd。观察16 wk,比较2组疗效与费用。结果16 wk后,2组空腹和餐后2 h血糖和胰岛素、糖化血红蛋白均明显下降(P<0.01),但2组间比较无显著差异(P>0.05)。A组罗格列酮总费用合计为336元,B组为1 243.2元。2组均无严重不良反应发生。结论盐酸罗格列酮治疗2型糖尿病,疗效与马来酸罗格列酮相近,但费用明显降低。     

Combination therapy for type 2 diabetes: dapagliflozin plus metformin

Introduction: Type 2 diabetes (T2D) is a chronic and multifactorial metabolic disease, which brings great threats to public health. The morbidity of T2D keeps growing, and it is estimated that the population with T2D will rise to 552 million throughout the world by 2030. Effective glycemic control in patients is crucial for the treatment of T2D. However, with progressive deterioration of disease, most patients are usually unable to achieve glycemic targets receiving antidiabetic agent monotherapy. In such cases, combination therapy with different mechanisms of antidiabetic agents is highly desired. In addition, combination therapy can provide advantages beyond better glycemic improvement such as reduced incidence of hypoglycemia and cardiovascular events.

Areas covered: We reviewed all the published data regarding the fixed-dose combination therapy of dapagliflozin combined with metformin, including complementary mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy and safety.

Expert opinion: The fixed-dose combination of dapagliflozin and metformin exerts synergistic effects based on two antidiabetic agents with complementary mechanisms of action. Rational co-administration of dapagliflozin and metformin provides better glycemic control with potential weight loss and the reduced incidence of hypoglycaemia.     

The power of two: an update on fixed-dose combinations for type 2 diabetes

Introduction: Patients with type 2 diabetes mellitus (T2DM) are unlikely to maintain glycemic control with monotherapy, and will eventually require therapy with multiple antihyperglycemic agents (AHAs). Combination therapy regimens with multiple AHAs may be complex and negatively impact patient adherence. Fixed-dose combinations (FDCs) are used successfully for management of numerous chronic diseases.

Areas covered: This article includes a brief overview of the add-on approach of current treatment guidelines for T2DM and reviews the evidence supporting the utility of oral FDCs in the treatment of T2DM, including recently developed oral FDCs (2010–2016). Benefits regarding safety and tolerability, adherence and cost are also discussed. Finally, the barriers limiting the use of FDCs and how these barriers may be overcome are addressed.

Expert commentary: Therapeutic strategies including FDCs need to be implemented on a larger scale. FDCs have the potential to simplify treatment regimens, improve adherence and provide long-term glycemic control.     

Chart review of patients on valsartan-based single-pill combinations vs. ARB-based free combinations for BP goal achievement

Abstract

Objective:

To compare blood pressure (BP) goal achievement associated with the use of valsartan-based single pill combinations (SPCs) vs. angiotensin II receptor blocker (ARB)-based free combinations (FCs) among adult hypertension patients.     

Insulin glargine in the management of diabetes mellitus: an evidence-based assessment of its clinical efficacy and economic value

INTRODUCTION: Diabetes is a chronic disease associated with high morbidity and mortality, which represents a major public health concern. Interventions that can enhance patient care and reduce clinic visits will not only relieve some of this burden, they will also improve patient QOL and wellbeing. AIMS: This review assesses the evidence for the use of insulin glargine in type 1 and type 2 diabetes mellitus. EVIDENCE REVIEW: Once-daily insulin glargine has a prolonged, peakless activity profile, making it a candidate as a long-acting (basal) insulin. In combination with bolus insulin to cover prandial glucose surges, it facilitates a more physiologic approach to patient management. Evidence from large, randomized, controlled clinical trials in patients with type 1 diabetes has confirmed its effectiveness and tolerability relative to neutral protamine hagedorn (NPH) insulin, with a tendency toward causing less hypoglycemia. In patients with type 2 diabetes requiring insulin therapy, once-daily insulin glargine has proven to be clinically superior to NPH insulin in terms of providing at least as effective glycemic control, but with significantly fewer episodes of nocturnal hypoglycemia. A variety of economic analyses have confirmed the cost effectiveness of insulin glargine in type 1 and type 2 diabetes and in particular it was shown to be significantly superior to NPH insulin. CLINICAL VALUE: Insulin glargine has established itself as a first-line choice in patients with type 1 diabetes, including children (>6 years) and adolescents, and is a recommended treatment option. In patients with type 2 diabetes it is clearly associated with less hypoglycemia than NPH insulin, and this may help overcome one of the major barriers to starting insulin therapy in this class of patient. Thus, insulin glargine is a valuable addition to the therapeutic armamentarium available to physicians and it has the potential to significantly improve the quality of life of patients with diabetes.     

The safety of empagliflozin plus metformin for the treatment of type 2 diabetes

Introduction: Metformin is the first-line glucose-lowering medication in type 2 diabetes mellitus (T2DM), but it generally requires soon or later the addition of a second-line therapy, among which a sodium-glucose cotransporter type 2 (SGLT-2) inhibitor, to reach and maintain adequate glucose control.

Areas covered: This narrative review provides an analysis of both efficacy and safety of a dual therapy combining metformin and empagliflozin, a SGLT-2 inhibitor that has proven its’ potential to reduce major cardiovascular (CV) events, mortality, and renal outcomes in patients with T2DM and established CV disease. Pharmacokinetic studies showed the absence of drug–drug interactions and demonstrate bioequivalence between fixed-dose combination (FDC) and individual tablets of empagliflozin and metformin. Focus will be put on the use of this dual therapy in special populations.

Expert opinion: The addition of empagliflozin to metformin therapy improves glucose control, with a minimal risk of hypoglycemia, while reducing body weight and arterial blood pressure. EMPA-REG OUTCOME showed that this combined therapy may be used in patients with established CV disease or heart failure. However, caution may be required in fragile elderly patients and in patients with severe impaired renal function. Further post-marketing surveillance is recommended to demonstrate long-term safety. FDC may improve adherence.     

The contentious nature of gestational diabetes: diet,insulin, glyburide and metformin

Gestational diabetes (GD) develops because pregnancy increases requirements for insulin secretion while increasing insulin resistance. Women with GD often have impaired pancreatic β-cell compensation for insulin resistance. The nature of GD is currently contentious, with debate about its existence, diagnosis and ramifications for both mother and offspring from pregnancy into later life. Also contentious are the outcomes of intervention with diet, insulin, glyburide (Glynase?, Pharmacia Upjohn) and metformin (Glucophage?, Bristol-Myers Squibb). There is consensus that women with unequivocal GD have a significant risk of adverse perinatal outcomes and increased risk of later type 2 diabetes mellitus. Foetuses from pregnancies with GD have a higher risk of macrosomia (associated with higher rate of birth injuries), asphyxia, and neonatal hypoglycaemia and hyperinsulinaemia. Uncontrolled GD predisposes foetuses to accelerated, excessive fat accumulation, insulin resistance, pancreatic exhaustion secondary to prenatal hyperglycaemia and possible higher risk of child and adult obesity and type 2 diabetes mellitus later in adult life. However, there is no consensus as to whether glucose intolerance of a severity below unequivocal GD is related to adverse maternal, fetal or perinatal outcomes, and whether this relationship is a continuous one. If dietary intervention is not sufficient in the treatment of GD, then, historically, insulin has been added. Recent studies suggest that glyburide may be efficaciously substituted for insulin. Preliminary studies suggest that metformin may have the unique potential to prevent the development of GD.     

Pioglitazone and metformin fixed-dose combination in type 2 diabetes mellitus: an evidence-based review of its place in therapy

Introduction:

Type 2 diabetes mellitus, a metabolic disease with increasing incidence, is one of the most important cardiovascular risk factors. Insulin resistance represents the common mechanism that leads to type 2 diabetes in obese subjects. Metformin and the thiazolidinediones, pioglitazone and rosiglitazone, are insulin-sensitizing agents available for treatment of type 2 diabetes. Large clinical trials have demonstrated the effectiveness of both metformin and pioglitazone in reducing cardiovascular morbidity and mortality. The fixed-dose combination of metformin and pioglitazone appears to be a good option for treating diabetes in insulin-resistant patients.

Aims:

The purpose of this article is to review the place in therapy of a fixed-dose combination of pioglitazone and metformin in the management of patients with type 2 diabetes.

Evidence review:

The current evidence suggests that combined therapy may help to achieve the recommended goals in the management of diabetes. A fixed-dose formulation of pioglitazone and metformin may provide advantages in terms of glycemic control and other cardiovascular risk factors frequently associated with diabetes.

Place in therapy:

The current evidence shows that a fixed-dose formulation of pioglitazone and metformin offers an effective option for the management of patients with type 2 diabetes when monotherapy fails in the achievement of the recommended standards of care.     

2型糖尿病不同降糖药物联合治疗方案疗效比较

目的比较2型糖尿病不同降糖药物联合治疗方案的疗效。方法2型糖尿病病人60例,均为经磺脲类口服药治疗血糖未达标者,随机分为3组,胰岛素替代治疗组(A组)20例:停用磺脲类口服降糖药,改用预混胰岛素早晚餐前皮下注射;胰岛素补充治疗组(B组)20例:在原有磺脲类降糖药剂量不变的基础上,加用中效胰岛素睡前皮下注射;对照组20例:单纯调整磺脲类药物的剂量或加用其他口服降糖药,不加用胰岛素,随访时间共12 wk。观察3组病人治疗前后血糖、体重的变化,胰岛素的用量以及低血糖发生率等。结果12 wk后,3组空腹血糖(FBS)、餐后2 h血糖(PBS)和糖化血红蛋白(HbA_(lc))与治疗前相比,均有明显下降(P<0.01),A组和B组下降幅度大于对照组(P<0.01)。A组治疗后的病人体重较治疗前有所升高(P<0.01),其余2组病人体重无明显改变。A组胰岛素用量(37±s 5)U·d~(-1),高于B组(10.4±2.1)U·d~(-1),有非常显著差异(P<0.01)。A组低血糖发生率25%(5/ 20),B组为10%(2/20)。结论磺脲类口服降糖药加用中效胰岛素睡前皮下注射可作为2型糖尿病血糖控制未达标门诊调整血糖满意而又安全的治疗措施。     

Combination therapy for patients with uncontrolled type 2 diabetes mellitus: adding empagliflozin to pioglitazone or pioglitazone plus metformin

Introduction: For patients with type 2 diabetes mellitus (T2DM), there is a growing interest in sodium glucose co-transporter 2 (SGLT2) inhibitors, a class of glucose-lowering agents that act independently of insulin secretion and insulin action and also have a weight-lowering effect. Empagliflozin is an SGLT2 inhibitor that has been demonstrated to significantly reduce blood glucose levels and is well tolerated in patients with T2DM.

Areas covered: Kovacs et al. have reported a randomized, placebo-controlled study of empagliflozin as add-on to pioglitazone or pioglitazone plus metformin in patients with T2DM. The study results are evaluated, and potential impact on clinical practice is considered.

Expert opinion: The addition of empagliflozin to pioglitazone or pioglitazone plus metformin treatment may offer some advantages. Together, their complementary mechanisms of action result in significant reductions in glycated hemoglobin levels, weight, and blood pressure, with a low risk of hypoglycemia, but were associated with an increased risk of events consistent with genital mycotic infections.     

Glimepiride versus pioglitazone combination therapy in subjects with type 2 diabetes inadequately controlled on metformin monotherapy: results of a randomized clinical trial

ABSTRACT

Objective: To compare the effect of add-on glimepiride or pioglitazone in subjects with type 2 diabetes inadequately controlled on metformin monotherapy.

Research design and methods: Multicenter, randomized, parallel-group, open-label, forced-titration study involving 203 adults with poorly controlled type 2 diabetes (A1C 7.5–10%) on metformin monotherapy. Subjects were randomized to receive glimepiride or pioglitazone, titrated to the maximum dose for 26 weeks. Subjects were evaluated for A1C changes, fasting plasma glucose (FPG), insulin, C‐peptide, and lipid levels. Safety outcomes and diabetes-related healthcare resource utilization were also evaluated.

Results: Both treatment groups achieved similar and significant mean decreases from baseline to endpoint (week 26) in A1C (?p = 0.0001) and FPG (?p < 0.05). Glimepiride therapy, however, resulted in a more rapid decline in A1C levels at weeks 6, 12, and 20 vs. pioglitazone (?p < 0.05). A mean A1C ≤ 7% was reached faster in the glimepiride group (median, 80–90 days vs. 140–150 days [p = 0.024]). Total and LDL cholesterol were significantly higher with pioglitazone treatment than with glimepiride at endpoint (?p < 0.05). Glimepiride treatment was associated with an increased risk of hypoglycemia and pioglitazone with higher rate of peripheral edema. Healthcare resource utilization was similar between groups, but total healthcare costs were significantly lower for glimepiride versus pioglitazone over the course of the study, driven largely by drug costs. The use of fasting C‐peptide concentration ≥ 0.27?nmol/L in the inclusion criteria was a potential limitation as it may have included those patients with an improved probability for glimepiride or pioglitazone response. In addition, a larger patient population would have provided a greater degree of data applicability.

Conclusions: In patients with type 2 diabetes inadequately controlled on metformin monotherapy, add-on glimepiride or pioglitazone results in similar overall improvements in glycemic control. Compared with pioglitazone, glimepiride is associated with faster glycemic control, lower total and LDL cholesterol levels and reduced short-term healthcare costs.     

Recent advances of starch-based excipients used in extended-release tablets: a review

In recent years, polysaccharides, including starch and its derivatives, have been widely used in the pharmaceutical industry, including as diluents, fillers, binders, disintegrants and glidants. The use of native starch as excipient in extended-release tablets is limited due to its low compactibility and enzymatic degradability, leading to the formation of weakly structured tablets. To overcome these limitations and expand the application of starch as an excipient, researchers have modified starch by physical and chemical methods, as well as by enzymatic hydrolysis. Some starch derivatives, including retrograded starch, pregelatinized starch, carboxymethyl starch, starch acetate, cross-linked starch and grafted starch have recently been introduced as excipients in oral tablets to control drug release. In this review, applications of starch and its derivatives as extended release excipients are reviewed and future frontiers are described.     

Randomized study of repaglinide alone and in combination with metformin in Chinese subjects with type 2 diabetes naive to oral antidiabetes therapy

Objective: The aim of this research is to determine efficacy and safety of repaglinide alone and in combination with metformin in Chinese subjects with type 2 diabetes naive to oral antidiabetes therapy.

Methods: A 16-week, open-label, randomized, active-controlled, parallel-group trial was carried out. Subjects were randomized (1:1) to repaglinide 1 mg t.i.d. (maximum dose, 4 mg t.i.d.) or repaglinide plus metformin 1 mg/500 mg t.i.d. (maximum dose, 4 mg/500 mg t.i.d.). Eligible subjects (18 – 75 years old) had type 2 diabetes, A1C > 8.5%, BMI ≤ 35 kg/m², and were naive to oral antidiabetes agents.

Results: The primary outcome was A1C reduction. Secondary end points included fasting plasma glucose (FPG), 2-h postprandial glucose (PPG), and 7-point plasma glucose. Baseline characteristics (repaglinide/metformin, n = 218; repaglinide-only, n = 214) were similar between groups. Mean A1C reduction (± SD) was 4.51 ± 1.64% (combination) and 4.05 ± 1.59% (monotherapy). Estimated mean treatment difference for repaglinide/metformin versus repaglinide-only was -0.30% (95% CI -0.49 to -0.11; p < 0.01). Combination treatment demonstrated significant improvements versus monotherapy in FPG, 7-point plasma glucose, and lunchtime and dinnertime 2-h PPG (all p < 0.05). Hypoglycemia rates were 2.04 (combination) versus 1.35 (monotherapy) events/subject-year (p = 0.058). Adverse events were comparable between groups.

Conclusions: Repaglinide plus metformin and repaglinide alone provided significant improvements in glycemic control and were well tolerated in Chinese patients naive to treatment with oral antidiabetes agents. Combination therapy with repaglinide plus metformin showed superiority to repaglinide monotherapy in this population. Limitations of this study are that subjects were newly diagnosed and had high mean baseline A1C, which may affect generalizability of results.