Evidence-based clinical use of insulin premixtures

Diabetology & Metabolic Syndrome Evidence-based clinical use of insulin premixtures Marcos Antnio Tambascia 0 3 Mrcia Nery 2 Jorge Luiz Gross 1 Mariana Narbot Ermetice 4 5 Carolina Piras de Oliveira 5 0 Faculty of Medical Sciences, State University of Campinas , Brazil Rua Frei Manoel da Ressurreicao 965, Campinas, SP , Brazil 1 Department of Internal Medicine, Faculty of Medicine of Federal University of Rio Grande do Sul , Rio Grande do Sul , Brazil 2 Diabetes Unit - Endocrinology and Metabolism Service, Clinical Hospital of Faculty of Medicine, University of Sao Paulo , Sao Paulo , Brazil 3 Faculty of Medical Sciences, State University of Campinas , Brazil Rua Frei Manoel da Ressurreicao 965, Campinas, SP , Brazil 4 Currently at Novo Nordisk Brazil , Sao Paulo , Brazil 5 Diabetes Group, Eli Lilly do Brazil Sao Paulo , Sao Paulo , Brazil Brazil is expected to have 19.6 million patients with diabetes by the year 2030. A key concept in the treatment of type 2 diabetes mellitus (T2DM) is establishing individualized glycemic goals based on each patient's clinical characteristics, which impact the choice of antihyperglycemic therapy. Targets for glycemic control, including fasting blood glucose, postprandial blood glucose, and glycated hemoglobin (A1C), are often not reached solely with antihyperglycemic therapy, and insulin therapy is often required. Basal insulin is considered an initial strategy; however, premixed insulins are convenient and are equally or more effective, especially for patients who require both basal and prandial control but desire a more simplified strategy involving fewer daily injections than a basal-bolus regimen. Most physicians are reluctant to transition patients to insulin treatment due to inappropriate assumptions and insufficient information. We conducted a nonsystematic review in PubMed and identified the most relevant and recently published articles that compared the use of premixed insulin versus basal insulin analogues used alone or in combination with rapid-acting insulin analogues before meals in patients with T2DM. These studies suggest that premixed insulin analogues are equally or more effective in reducing A1C compared to basal insulin analogues alone in spite of the small increase in the risk of nonsevere hypoglycemic events and nonclinically significant weight gain. Premixed insulin analogues can be used in insulin-nave patients, in patients already on basal insulin therapy, and those using basal-bolus therapy who are noncompliant with blood glucose self-monitoring and titration of multiple insulin doses. We additionally provide practical aspects related to titration for the specific premixed insulin analogue formulations commercially available in Brazil. Type 2 diabetes mellitus; Insulin; Premixed; Lispro; Glycated hemoglobin; Treatment goals; Titration - Introduction In 2011, the prevalence of diabetes mellitus worldwide was approximately 366 million people [1]. In Central and South America, it has been estimated that 25.1 million people have diabetes [1]. Approximately 12.4 million adults (2079 years of age) in Brazil had diabetes in 2011; this is expected to increase to 19.6 million by 2030 [1]. In keeping with this epidemic, there have been a growing number of cases in younger individuals with longer life expectancies, many of whom will require treatment with exogenous insulin [1]. The United Kingdom Prospective Diabetes Study (UKPDS) comparing intensive treatment with conventional treatment in patients with type 2 diabetes mellitus (T2DM) showed that appropriate glycemic control significantly reduces the rate of microvascular complications, such as retinopathy, nephropathy, and neuropathy [2], which persisted in the long-term follow-up to this study [3]. Appropriate blood glucose (BG) control is also important for cardiovascular disease (CVD) [4], although the reduction of CVD requires a multifactorial approach: control of blood pressure, lipid profile, and body weight; smoking cessation; and regular aerobic exercise [5]. In order to control BG levels, medical associations, such as the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), the American Association of Clinical Endocrinologists (AACE), the American College of Endocrinology (ACE), and the Brazilian Diabetes Society, recommend that diet and lifestyle changes, increased physical activity, and treatment with metformin be implemented soon after diagnosis. Usually there is an improvement of glycemic control for a period of time, depending on the patients age, clinical condition, comorbidities, etc., but if it still remains inadequate or there is progressive deterioration, then the addition of other antihyperglycemic agents (AHAs) is usually necessary [6-11]. The combination of 2 or 3 noninsulin AHAs with different mechanisms of action is frequently used, since most patients are reluctant to start insulin. Moreover, patients with T2DM are sometimes able to maintain endogenous insulin secretion even in later stages of the disease [12]. If a patient has not reached the desirable glycemic control goals or presents signs that are related to low insulin action, such as catabolic features (e.g., weight loss and/or ketonuria) or persistent high levels of BG (>300-350 mg/dL), then insulin therapy is recommended [8]. Several strategies for insulin therapy in addition to oral AHAs can be used: neutral protamine Hagedorn (NPH) insulin, basal insulin analogues (detemir or glargine), or premixed insulins. Recent studies suggest that premixed insulin analogues are more effective in reducing glycated hemoglobin (A1C) than basal insulin analogues used alone [13-19]. However, premixed analogues tend to cause a small increase in the risk of nonsevere hypoglycemic events and a small, not clinically significant weight gain [13-19]. In general, premixed insulin analogues are options for providing basal and prandial insulin in a simple, less complicated way than the basal-bolus approach, and they can be used in insulin-nave patients. Advantages of this regimen include the need for fewer BG measurements during the day while ensuring that the patient receives both basal insulin and bolus insulin at meals with 2 or a maximum of 3 injections per day [13,20]. The aim of this nonsystematic overview is to discuss barriers to insulin initiation, individualized treatment goals, and recent studies that compared the use of premixed insulin versus basal insulin analogues used alone or in combination with rapid-acting insulin analogues before meals in patients with T2DM. It also aims to provide practical aspects of insulin treatment that can be used to encourage and motivate patients to comply with treatment and ultimately attain desirable glycemic control. A comprehensive literature search was conducted in PubMed (1995 to 2012) using the search terms: type 2 diabetes mellitus, insulin, premixed, lispro, glycated hemoglobin, biphasic insulin aspart, (...truncated)