Practical Guidance on Effective Basal Insulin Titration for Primary Care Providers.

IN BRIEF Basal insulin therapy is well established for glycemic control in patients with diabetes but often is not optimally implemented, leading to poor clinical outcomes and adherence. Primary care providers can and should work together with other members of the diabetes care team to allow for effective titration of basal insulin that involves patients and their caregivers. Adequate guidance and monitoring during the titration process can minimize some of the adverse effects caused by basal insulin administration, while improving glycemic control in a timely manner.

Differentiating Basal Insulin Preparations: Understanding How They Work Explains Why They Are Different.

Since the introduction of insulin as a life-saving agent for patients with type 1 diabetes, insulin preparations have evolved to approximate physiologic insulin delivery profiles to meet prandial and basal insulin needs. While prandial insulins are designed to have quick time-action profiles that minimize postprandial glucose excursions, basal insulins are designed to have a protracted time-action profile to facilitate basal glucose control over 24 h. Given that all insulins have the same mechanism of action at the target tissue level, the differences in time-action profiles are achieved through different mechanisms of protraction, resulting in different behaviors in the subcutaneous space and different rates of absorption into the circulation. Herein, we evaluate the differences in basal insulin preparations based on their differential mechanisms of protraction, and the resulting clinical action profiles. Multiple randomized control trials and real-world evidence studies have demonstrated that the newer second-generation basal insulin analogs, insulin glargine 300 units/mL and insulin degludec 100 or 200 units/mL, provide stable glycemic control with once-daily dosing and are associated with a reduced risk of hypoglycemia compared with previous-generation basal insulin analogs insulin glargine 100 units/mL and insulin detemir. These advantages can lead to decreased healthcare resource utilization and cost. With this collective knowledge, healthcare providers and payers can make educated and well-informed decisions when determining which treatment regimen best meets the needs of each individual patient.Funding: Sanofi US, Inc.

The Relevance of Clinical Pharmacology Studies of Basal Insulins to Primary Care.

Pharmacokinetic (PK) and pharmacodynamic (PD) properties of drugs form the basis for the development of drugs used in everyday clinical practice, such as commonly used insulin products. PK measures the concentration of a drug in the body, and reflects the rates and amounts absorbed and processed. PD is the biologic effect of a drug in the body, including the time-course of when the biologic effect starts, peaks, and ends. While the determination of PK/PD parameters is important and foundational for the development of different insulin products, studies are often complex and can be difficult to translate into real-world clinical practice. In this roundtable, the speakers discuss PK/PD concepts, focusing on the differentiation of basal insulin analogs and their use in individualized diabetes therapy. First, the speakers discuss the euglycemic glucose clamp methodology-the standard technique for evaluating PK/PD of insulin-including how it is performed, what parameters it measures (and how they can be interpreted), and its limitations. Next, the speakers discuss how PK/PD impacts drug development, with particular focus on PK/PD studies used in the development of the second-generation basal insulin analogs insulin glargine 300 U/mL (Gla-300) and insulin degludec. Finally, the speakers discuss how PK/PD data translate into clinical practice, including the relationship between PK/PD and drug efficacy and safety, and how it influences dosing strategies, hypoglycemia risk, and patient education. Further, the speakers discuss how the PK/PD profile of basal insulins can inform primary care providers when selecting appropriate individualized therapy for patients.

Higher concentration insulins: an overview of clinical considerations.

Three higher concentration insulin products (insulin lispro 200 units/mL, insulin degludec 200 units/mL, and insulin glargine 300 units/mL) received US Food and Drug Administration (FDA) approval in 2015. Although human regular insulin 500 units/mL (U-500) was approved in 1997, a pen and dedicated U-500 syringe became available in 2016. These products offer more treatment options for the increasing numbers of patients requiring insulin to achieve and maintain glycemic targets. Higher concentration insulins have some unique safety and efficacy considerations. Important considerations when transitioning patients from the 100 unit/mL concentration (U-100) to the higher concentration include bioequivalence, pen dose increments, and pen appearance. Bioequivalent insulins have similar pharmacokinetic properties and no dose adjustments are expected when transitioning from the U-100 to the higher concentration. In contrast, higher concentration insulins with different pharmacokinetic and pharmacodynamic properties compared with the U-100 formulation may require dose adjustments. In order to provide safe and effective therapy to patients with higher daily insulin dose requirements, it is important for healthcare professionals to become very familiar with the characteristics of and differences between each of the higher concentration insulins. This paper highlights differences between the U-100 and higher concentration insulins and focuses on practical aspects of use.

Weight change in patients with type 2 diabetes starting basal insulin therapy: correlates and impact on outcomes.

BACKGROUND: An increase in body weight is a commonly perceived effect of insulin therapy for type 2 diabetes mellitus, and this may serve as a barrier to insulin initiation and usage. OBJECTIVE: To investigate the baseline clinical and demographic factors associated with weight gain during insulin glargine therapy, and the implications of weight change on clinical outcomes. METHODS: This was a retrospective analysis of patient-level data from phase 3 or 4 randomized controlled, treat-to-target (fasting plasma glucose [FPG] ≤ 100 mg/dL) trials evaluating basal insulin glargine for ≥ 24 weeks. The Pearson correlation coefficient and Cochran-Armitage trend statistic were used to calculate the existence of a trend between absolute and relative weight change, and relative glycated hemoglobin (HbA1c) change from baseline; likelihood of achieving target HbA1c < 7.0%; change from baseline FPG; insulin dose requirements; incidence of hypoglycemia; and adverse events. RESULTS: Eleven studies were included, encompassing a total of 2140 patients. Patients starting insulin glargine treatment gained a mean ± standard deviation 1.8 ± 3.7 kg (4.0 ± 8.2 lb). Most patients had limited weight change (± 2.5 kg or 5.5 lb). Younger age, higher baseline HbA1c, and higher baseline FPG were predictive of greater weight gain (P < 0.0001). Those who gained more weight experienced the largest decrease from baseline in HbA1c and FPG. More weight gain was associated with higher insulin dose requirements, an increased risk of experiencing either symptomatic or glucose-confirmed (< 70 mg/dL) hypoglycemia, and more adverse events. Older patients (> 65 years) were less likely to gain weight or to experience glucose-confirmed hypoglycemia, but more likely to experience severe hypoglycemia. CONCLUSIONS: In this retrospective analysis of patient-level data, most patients had a stable weight (defined as ± 2.5 kg) after 24 weeks of insulin glargine, and weight gain varied with patient demographics. Therefore, insulin glargine can be used in these patient groups with type 2 diabetes without expectation of significant weight gain.

Canagliflozin, a sodium glucose co-transporter 2 inhibitor, for the management of type 2 diabetes.

The kidney plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes mellitus (T2DM). Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of antihyperglycemic agents for the treatment of T2DM with a novel insulin-independent mechanism of action that targets the kidney. The SGLT2 inhibitors decrease renal glucose reabsorption, thereby increasing urinary glucose excretion and lowering plasma glucose levels in patients with hyperglycemia. SGLT2 inhibitor canagliflozin has demonstrated efficacy in improving glycemic control and reducing body weight and blood pressure as monotherapy or as add-on to other antihyperglycemic agents across a broad range of patients with T2DM. Canagliflozin is generally well tolerated, with increased incidences of specific adverse events that are related to the mechanism of SGLT2 inhibition. Findings suggest that canagliflozin is a useful treatment option for patients with T2DM.

A short-acting GLP-1 analog or prandial insulin to supplement basal insulin?--Moving toward personalized management of type 2 diabetes mellitus.

New models of health care delivery that emphasize patient-centered care affirm the need for alternatives to add-on prandial insulin therapy when optimized basal insulin fails to maintain glycemic control in patients with type 2 diabetes mellitus. Regimens that are easy to teach, convenient, and flexible generally improve the outlook for long-term success. Our review reconsiders traditional barriers to insulin intensification in primary care and provides an illustration of how the benefits and drawbacks of > 1 choice of action--specifically, adding rapid-acting insulin or a short-acting glucagon-like peptide-1 analog--can be weighed by the patient and provider together to determine the best next treatment step that balances efficacy, safety, and adherence to therapy. Technological, organizational, and interpersonal strategies for applying personalized management at this often challenging crossroads of diabetes management are also described.

Integrating advances in insulin into clinical practice: Effective utilization of insulin in patient management.

The management of a patient with type 2 diabetes mellitus (T2DM) is typically a long-term process characterized by evolving strategies to meet and maintain the patient's glycemic, cardiovascular, lifestyle, and other goals.

A practice-based research network focused on comparative effectiveness research in type 2 diabetes management.

PURPOSE: To establish a real-world research platform focused on comparative effectiveness research and health care decision making in diabetes care in order to obtain a detailed understanding of individualized patient management in primary care. METHODS: Diabetes FORWARD (Foundation of Real-World Assessment and Research in Diabetes) is a North American research platform being organized to conduct longitudinal, noninterventional investigations of an anticipated 10,000 patients with type 2 diabetes mellitus (T2DM). Recruitment will be stratified to reflect typical (primarily primary care) clinical T2DM populations. Streamlined data collection relying on electronic medical records (retrospective) and periodic surveys (prospective) will reduce the burden of study participation and, therefore, enhance enrollment by busy primary care and endocrinology practices. Physician data will include baseline demographic and practice information. Patient data will include demographics, T2DM characteristics and treatment, resource utilization information, and patient-reported outcomes. Responses can be tracked within the observation window in near-real time, allowing immediate, noninterventional reaction at the point of nonresponse. EXPECTED OUTCOMES: Diabetes FORWARD is expected to provide important real-world data describing how actual clinical T2DM management differs across sites, settings, and clinicians, and its impact on glycemic control, treatment adherence and persistence, and clinical outcomes. These data will also help to identify the effect of diabetes management on the onset and progression of retinopathy, neuropathy, nephropathy, and cardiovascular disease at 6-month intervals. CONCLUSION: To our knowledge, Diabetes FORWARD is the first diabetes-focused, practice-based research network in the United States and Canada. The current study will provide robust data that should reflect typical management of T2DM in clinical practice in North America.

Distinguishing among incretin-based therapies. Glucose-lowering effects of incretin-based therapies.

Extensive experience from randomized clinical trials demonstrates the efficacy of GLP-1 agonists and DPP-4 inhibitors as monotherapy and in combination with metformin and other agents, although reductions in FPG and PPG, and consequently A1C, are greater with GLP-1 agonists than with DPP-4 inhibitors. This difference may result from the pharmacologic levels of GLP-1 activity that are achieved with the GLP-1 agonists and their direct action on the GLP-1 receptor. The GLP-1 agonists have attributes that would make either of them an appropriate choice in the management of all 3 patients in our case studies, while either DPP-4 inhibitor would be an appropriate choice for Case 1. Differences in dosing, administration, safety, and tolerability should be considered.

Distinguishing among incretin-based therapies. Patient education and self-management.

Working closely with patients and providing ongoing education, ideally in conjunction with a diabetes care team, can help ensure that the best treatment options are selected for an individual patient and that the patient is capable of effective self-management.

Distinguishing among incretin-based therapies. Safety, tolerability, and nonglycemic effects of incretin-based therapies.

The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.

Distinguishing among incretin-based therapies. Pathophysiology of type 2 diabetes mellitus: potential role of incretin-based therapies.

The multifactorial nature of the pathogenesis of T2DM provides an opportunity to combine treatments that act upon different mechanisms. In addition to improving insulin resistance and pancreatic ß-cell dysfunction, the GLP-1 agonists and DPP-4 inhibitors improve the impaired incretin response, as well as increase insulin secretion and reduce glucagon secretion, both in a glucose-dependent manner. As a result of these multiple actions, the GLP-1 agonists and DPP-4 inhibitors lower both fasting and postprandial glucose levels. The effects of GLP-1 agonists tend to be greater, probably because they produce pharmacologic levels of GLP-1 compared to physiologic levels with the DPP-4 inhibitors. Another difference is that unlike the DPP-4 inhibitors, the GLP-1 agonists also slow gastric emptying and promote satiety.

Distinguishing among incretin-based therapies. Introduction.

The "treat to target" approach is to quickly achieve the target glycosylated hemoglobin (AIC) goal of <7% in most people, and then intensify or change therapy as needed to maintain glycemic control. Results of an online survey demonstrate uncertainty regarding the clinical differences between glucagon-like peptide (GLP-1) agonists and dipeptidyl peptidase (DPP)-4 inhibitors. The increasingly important roles of the GLP-1 agonists and DPP-4 inhibitors stem from their overall good efficacy and safety profiles compared with other treatment options.

The importance and treatment of postprandial hyperglycemia.

PPG is an important target to address in the overall management of T2DM. Lifestyle interventions play an important role in PPG control, as well as global diabetes management goals. Oral antihyperglycemic agents lower PPG to varying degrees. Our most powerful treatment option to address PPG is prandial insulin. Collaboration between patient, primary care clinician, diabetes educator, and dietitian is critical to successful initiation of insulin therapy.