Safe and Appropriate Use of GLP-1 RAs in Treating Adult Patients With Type 2 Diabetes and Macrovascular Disease.

Over the past decade, the type 2 diabetes (T2D) treatment landscape has evolved, allowing for more therapeutic options and the opportunity to tailor treatments to achieve patient treatment goals. In this video roundtable series, James LaSalle, DO; Lucia M. Novak, CRNP; and Lawrence Blonde, MD, MACE, FACP, discuss the mechanisms of action and clinical trial data for use of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in the safe and effective primary care management of individuals with T2D and macrovascular disease.

Pharmacokinetic and pharmacodynamic differences of new generation, longer-acting basal insulins: potential implications for clinical practice in type 2 diabetes.

The treatment of type 2 diabetes (T2D) is often complicated by factors such as patient co-morbidities, complex drug-drug interactions, and management of adverse events. In addition, some of these factors are highly dependent on the nature of the treatment regimen and the molecular and physical properties of the drugs being used to treat patients with this disease. This calls for a better understanding of how the properties of individual drugs affect the overall outcome for patients with diabetes. Clinical pharmacology studies to assess the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of new diabetes drugs play an important role in advancing our understanding of the interactions between a drug and the human body. Specific PK and PD techniques such as the glucose clamp test can be applied to assess the properties of drugs used for the treatment of diabetes. Basal insulin analogs are a common treatment option for the maintenance of glycemic control in patients with T2D. These drugs work by mimicking endogenous insulin secretion within the body and provide stable and prolonged insulin action to achieve optimal glucose levels. Insulin glargine 300 U/mL (Gla-300) and insulin degludec (IDeg) 100 U/mL and 200 U/mL represent a new generation of longer-acting basal insulins. These drugs demonstrate improved PK and PD properties compared with previous basal insulins, allowing them to more closely mimic physiological basal insulin secretion. Here we review the methods used to evaluate the PK and PD profiles of Gla-300 and IDeg and describe studies that have investigated the PK/PD properties of these drugs in type 1 diabetes. The aim of this review is to inform primary care physicians of the value and limitations of data from clinical pharmacology studies when prescribing these agents for the management of T2D.

Low incidence of gastrointestinal adverse events over time with a fixed-ratio combination of insulin glargine and lixisenatide versus lixisenatide alone.

This post hoc analysis of gastrointestinal (GI) adverse events (AEs) from the phase 3 LixiLan-L (NCT02058160) and LixiLan-O (NCT02058147) trials aimed to determine the frequency and timing of nausea, vomiting, and diarrhoea for iGlarLixi, a titratable, fixed-ratio combination of insulin glargine 100 units/mL (iGlar) and lixisenatide, versus iGlar alone or iGlar and lixisenatide alone, in patients with type 2 diabetes uncontrolled with oral antidiabetes drugs (OADs) or basal insulin ± OADs. In iGlarLixi-treated patients, the rate of GI AEs during the initial weeks of treatment was lower versus patients treated with lixisenatide alone (9.6% and 11.7% of iGlarLixi-treated patients in LixiLan-L and LixiLan-O, respectively, vs. 27.5% of lixisenatide-treated patients in LixiLan-O). Beyond day 60, these rates were generally low and similar to those of lixisenatide. These lower rates are likely due to the gradual titration of lixisenatide in iGlarLixi. Median durations of intermittent GI AEs in the iGlarLixi arms were 6.0, 2.0 and 2.5 days (LixiLan-L), and 5.0, 1.0 and 3.5 days (LixiLan-O), respectively. iGlarLixi-associated GI AEs were transient, mostly mild or moderate in severity, and occurred mainly during initial titration.

Hot Topics in Primary Care: Titratable Fixed-Ratio Combinations in Type 2 Diabetes Mellitus: Focus on GLP-1R Agonists Combined With Basal Insulin.

The treatment of hyperglycemia in patients without glycemic control despite metformin monotherapy is the focus of this article, with particular focus on the use of fixed-dose (FDC) and fixed-ratio combination products.

Treatment urgency: The importance of getting people with type 2 diabetes to target promptly.

The burgeoning population of individuals with type 2 diabetes provides challenges for management in terms of risk of diabetes-related complications. Early, intensive glycemic control particularly in newly-diagnosed people with type 2 diabetes has been shown to be beneficial in terms of reducing diabetic complications, indeed various national and international guidelines now routinely recommend intensive blood glucose control as an essential element of type 2 diabetes management. However, despite this, current management of glycemia is suboptimal and not enough people achieve their glucose targets worldwide. The Global Partnership for Effective Diabetes Management believe that an improved understanding of these contributing factors should enable the development of practice and guidance that will promote a drive toward better quality clinical outcomes.

Individualized glycaemic targets and pharmacotherapy in type 2 diabetes.

The Global Partnership for Effective Diabetes Management, established to provide practical guidance to improve patient outcomes in diabetes, has developed and modified recommendations to improve glycaemic control in type 2 diabetes. The Global Partnership advocates an individualized therapeutic approach and, as part of the process to customize therapy, has previously identified specific type 2 diabetes patient subgroups that require special consideration. This article builds on earlier publications, expanding the scope of practical guidance to include newly diagnosed individuals with complications and women with diabetes in pregnancy. Good glycaemic control remains the cornerstone of managing type 2 diabetes, and plays a vital role in preventing or delaying the onset and progression of diabetic complications. Individualizing therapeutic goals and treatments to meet glycaemic targets safely and without delay remains paramount, in addition to a wider programme of care to reduce cardiovascular risk factors and improve patient outcomes.

Insulin therapy in type 2 diabetes mellitus: a practical approach for primary care physicians and other health care professionals.

The responsibility of diabetes management and insulin therapy has definitively moved to primary care physicians. Within the primary care setting, there is a growing need for clear, evidence-based guidelines related to the management of insulin therapy. Straightforward algorithms regarding insulin initiation, titration, and follow-up management can help physicians effectively treat patients with type 2 diabetes mellitus. Once 2 oral diabetic drugs have failed in a patient whose disease duration is 7 to 10 years, use of insulin therapy with a basal insulin analog should be considered. For patients who receive maximal basal insulin doses without reaching fasting blood glucose and target glycated hemoglobin levels with basal insulin analogs, a mealtime-insulin intensification approach should be considered. The authors discuss how simplified insulin initiation and titration regimens allow primary care physicians and other health care professionals to care for patients with type 2 diabetes mellitus.

Empowering patients during insulin initiation: a real-world approach.

Glycemic control is suboptimal in many patients with type 2 diabetes mellitus (T2DM). Despite documented benefits of insulin therapy, initiation of insulin is delayed in many cases because of the reluctance of patients and physicians to use this important treatment. A review of the literature revealed that educating patients about the role of insulin in managing T2DM and the advantages of using insulin analogs and insulin delivery devices may help alleviate some patients' concerns regarding insulin therapy. Compared with standard clinic-directed approaches, patient-driven algorithms that empower patients to initiate and titrate basal insulin therapy have been shown to improve glycemic control. Additional research is needed to confirm the importance of patient empowerment programs in T2DM management.

Reaching HbA1c goals with saxagliptin in combination with other oral antidiabetic drugs.

A large percentage of individuals with type 2 diabetes in the United States are not reaching their glycemic goals. In response to data from large outcomes trials and newer classes of therapeutic agents, various organizations and opinion-forming bodies recently updated their clinical practice recommendations for type 2 diabetes. The recommendations, as set by the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD), the American Association of Clinical Endocrinologists/American College of Endocrinology, and the Canadian Diabetes Association, are similar in their emphasis on lifestyle modification and the importance of treating fasting and postprandial glucose, both of which are significant contributors to achieving glycated hemoglobin (HbA1c) targets. However, the recommendations differ in focus, depth, and specific treatment approaches. With the exception of the ADA/EASD consensus, dipeptidyl peptidase-4 (DPP-4) inhibitors have been included as alternative first- or second-line therapy due, in part, to their glucose-dependent mechanism of action that complements the actions of other oral antidiabetic drugs (OADs). The DPP-4 inhibitor, saxagliptin, demonstrates significant glycemia-lowering effects as monotherapy and in combination therapy, is weight neutral and well tolerated, and has a low risk of hypoglycemia. The added efficacy of saxagliptin in combination with other OADs in improving glycemic parameters has resulted in a significant proportion of patients achieving an HbA1c <7% versus monotherapy or active comparator. Combination therapy with saxagliptin can thus offer a potential advantage in achieving glycemic goals for the majority of patients with type 2 diabetes without additional tolerability concerns.

Oral combination therapy with thiazolidinediones in type 2 diabetes.

Insulin resistance occurs early in the type 2 diabetes disease process, leading to progressive beta cell failure and overt diabetes. By the time the diagnosis of diabetes is made, advanced macrovascular disease may already be present. Monotherapy with a sulfonylurea or metformin can slow, but does not prevent, the progression of disease. Successful management requires combination therapy that addresses both insulin resistance and beta cell dysfunction. Clinical trials support the use of combinations of agents with complementary mechanisms of action, such as a sulfonylurea or metformin plus a thiazolidinedione. Early aggressive treatment can improve patient outcomes while reducing overall healthcare costs.

Single-pill therapy in the treatment of concomitant hypertension and dyslipidemia (the amlodipine/atorvastatin gemini study).

The Gemini Study was a 14-week, open-label, non-comparative, office-based, multicenter trial to evaluate single-pill therapy in the treatment of concomitant hypertension and dyslipidemia. In addition to recommending lifestyle modifications, eight dosage strengths of amlodipine/atorvastatin single pill (5/10, 5/20, 5/40, 5/80, 10/10, 10/20, 10/40, and 10/80 mg) were electively titrated to improve blood pressure and lipid control. A total of 1220 patients with uncontrolled hypertension at baseline received study medication. At baseline, mean blood pressure was 146.6/87.9 mm Hg and mean low-density lipoprotein cholesterol concentration was 152.9 mg/dL. At study end, 57.7% of patients had achieved both their blood pressure and low-density lipoprotein cholesterol goals (51.9% of patients with uncontrolled low-density lipoprotein cholesterol at baseline). The mean dose of study medication at end point was amlodipine component 7.1 mg and atorvastatin component 26.2 mg. Fifty-eight patients (4.8%) discontinued therapy due to adverse events. Single-pill therapy is effective in reducing both blood pressure and lipid levels and in helping patients achieve goals for both hypertension and dyslipidemia.

Comparison of treatment with fluvastatin extended-release 80-mg tablets and immediate-release 40-mg capsules in patients with primary hypercholesterolemia.

BACKGROUND: According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines, hypercholesterolemic patients with greater risk for cardiovascular heart disease require more aggressive lowering of low-density lipoprotein cholesterol (LDL-C) levels. Numerous studies have demonstrated that despite these guidelines, patients often do not reach their target levels, and that physicians frequently do not titrate the drug beyond the starting dose. For these patients, it may be more suitable to initiate treatment with a higher starting dose of statin. With the immediate-release (IR) formulation of fluvastatin, the maximal dose of 80 mg is recommended to be administered in divided doses (40 mg BID). An extended-release (ER) formulation of fluvastatin at a higher dose (fluvastatin ER 80 mg) was designed to provide greater LDL-C lowering with QD dosing. Use of this formulation should bring more patients into compliance with target LDL-C levels. OBJECTIVE: This analysis compared the efficacy and tolerability of fluvastatin ER 80 mg QD and fluvastatin IR 40 mg QD in lowering total cholesterol, LDL-C, triglyceride, and apolipoprotein (apo) B levels and raising high-density lipoprotein cholesterol (HDL-C) and apo A-I levels in patients with hypercholesterolemia over a 12-week treatment period. METHODS: This was a prospective, multicenter, double-blind, double-dummy, randomized, parallel-group, active-controlled study Patients with primary hypercholesterolemia who qualified for lipid-lowering drug therapy based on NCEP ATP II guidelines were randomized to fluvastatin ER 80 mg QD or fluvastatin IR 40 mg QD, and treated for 12 weeks. RESULTS: A total of 173 patients were randomized to treatment: 86 to the fluvastatin ER 80-mg group and 87 to the fluvastatin IR 40-mg group. Compared with fluvastatin IR 40 mg, fluvastatin ER 80 mg produced greater mean reductions in LDL-C (32% vs 22%, respectively; P < 0.001). For each of the 3 coronary heart disease (CHD) risk groups (defined by the NCEP), as well as for the total population studied, more patients from the fluvastatin ER 80-mg group than the IR 40 group achieved NCEP ATP II target LDL-C levels (79% vs 47%, respectively [P = NS], for patients with < 2 risk factors; 58% vs 15%, respectively [P < 0.001], for patients with > or = 2 risk factors; and 40% vs 14%, respectively [P = 0.012], for patients with CHD). The 80-mg ER dose of fluvastatin provided 9.1% greater LDL-C lowering than the 40-mg IR dose. The incidence of elevations in transaminase levels was low and similar for both doses, with 1 patient in each of the treatment groups being discontinued due to repeated elevation of transaminases > 3 x the upper limit of normal (ULN). Clinically relevant elevations in creatine kinase (ie, > or = 10x ULN) were not observed with either dose. Nine patients (5 in the fluvastatin ER group and 4 in the fluvastatin IR group) discontinued because of adverse events. CONCLUSIONS: Treatment with fluvastatin ER 80 mg resulted in greater reductions in LDL-C, total cholesterol, and apo B levels compared with fluvastatin IR 40 mg, with clinically equivalent reduction in triglyceride levels and elevation of HDL-C levels. Furthermore, there were few tolerability concerns of clinical relevance with either formulation and no clinically meaningful difference in the tolerability parameters between the 2 formulations. For patients with higher baseline LDL-C levels, and for patients who require greater LDL-C lowering, it may be appropriate to initiate therapy with fluvastatin ER 80 mg. Use of the higher starting dose likely would bring a greater proportion of high-risk patients into compliance with NCEP ATP II target LDL-C levels and would provide LDL-C lowering that is in the same range that has been proved in clinical trials to be associated with reductions in CHD event rates.