How Effective Is the Fixed-Ratio Combination of Insulin Degludec and Liraglutide (IDegLira) in Different Patient Populations, and When Should It Be Used in Clinical Practice?

The efficacy and safety of the fixed-ratio combination of insulin degludec (degludec) and liraglutide (IDegLira) were confirmed in the DUAL clinical trial program, in which IDegLira demonstrated superior or noninferior glycemic control over comparators in addition to its low risks of hypoglycemia and weight gain. This article identifies the patient types for whom IDegLira is most appropriate by reviewing the DUAL results and subsequent post hoc analyses and presenting real-world cases in which IDegLira has been used effectively in U.S. clinical practice. In the clinic, IDegLira has been used effectively when patients wanted to avoid more complex injectable regimens, particularly those with renal insufficiency for whom treatment options are limited.

A comparative effectiveness study of degludec and insulin glargine 300 U/mL in insulin-naïve patients with type 2 diabetes.

AIMS: To compare the real-world effectiveness of insulin degludec (degludec) and glargine 300 units/mL (glargine U300) in insulin-naïve adult patients with type 2 diabetes in routine US clinical practice. MATERIALS AND METHODS: CONFIRM is a non-interventional comparative effectiveness study following US patients across the continuum of care, through electronic medical records from multiple health systems and integrated delivery networks. Propensity-score matching controlled for confounding. The primary endpoint, change in HbA1c from baseline to 180 days of follow-up, was estimated using a repeated-measure of covariance analysis with subject as random effect. Change in the rate of hypoglycaemic episodes (defined using International Classification of Diseases codes 9/10) and change in proportion of patients with hypoglycaemia were estimated using negative binomial and logistic regression, respectively. Time-to-discontinuation of the initial basal insulin/initiation with another prescribed basal insulin was analysed using a Cox Proportional Hazard model. RESULTS: Data concerning 4056 patients were analysed. After matching, baseline characteristics were comparable (n = 2028 in each group). After 180 days of follow-up, degludec was associated with a larger reduction in HbA1c (estimated treatment difference, -0.27%; P = 0.03), greater reductions in change in rate (rate ratio, 0.70; P < 0.05) and greater reductions in change in the likelihood of hypoglycaemia (odds ratio, 0.64; P < 0.01]) compared with glargine U300. In addition, patients treated with degludec were 27% less likely to discontinue treatment at follow-up compared with those treated with glargine U300 (hazard ratio, 0.73; P < 0.001). CONCLUSIONS: Significantly improved HbA1c, larger reductions in rates and likelihood of hypoglycaemia and lower risk of treatment discontinuation were demonstrated with degludec vs glargine U300.

Importance of postprandial glucose levels as a target for glycemic control in type 2 diabetes.

Increasing evidence supports the importance of postprandial glucose (PPG) in glycemic control with regard to the development of complications in patients with diabetes. PPG plays a critical role in determining overall glycemic control, particularly in patients who are close to their glycemic goals. Data also indicate that postprandial hyperglycemia may have a greater effect on the development of cardiovascular complications compared with elevated fasting plasma glucose. Several antidiabetic agents that specifically target PPG are currently available, including glinides, glucagon-like peptide-1 mimetics, dipeptidyl peptidase-4 inhibitors, and rapid-acting insulin analogs. A more intensive approach to managing PPG may improve the care of patients with diabetes and, ultimately, the outcome of these patients.

Actions of insulin beyond glycemic control: a perspective on insulin detemir.

The physiologic effects of insulin on carbohydrate metabolism in health in general and in diabetes are well known. Less understood, but far more intriguing, are the extrapancreatic effects of insulin that go beyond glycemic control to help sense, integrate, and maintain energy balance. Virtually every organ, including the brain, is a target for insulin action. When exogenous insulin is administered directly into the brains of experimental animals, the net effect is anorectic; however, patients with type 2 diabetes who transition to insulin therapy often gain weight--a tendency that opposes good glycemic control and overall therapeutic goals. After the brief review of extrapancreatic insulin--signaling pathways presented here, the physiologic impact of developing insulin resistance in relation to body weight is considered. Attention is then focused on insulin detemir, a longacting insulin analog that has consistently been associated with less weight gain than conventional formulations such as neutral protamine Hagedorn insulin. Mechanisms offered to explain this effect include the lower incidence of hypoglycemia and less within-patient variability associated with insulin detemir; however, recent observations and considerations of insulin-signaling pathways have shed light on other important properties of insulin detemir that may impart these weight-neutral effects. Namely, albumin binding, faster transport across the bloodbrain barrier, and preferential activity in brain and liver are characteristics of insulin detemir that potentially explain the observed weight benefit seen in clinical trials, as well as in the real-world practice setting.

Biphasic insulin aspart 70/30 three times a day in older patients with type 2 diabetes not achieving optimal glycemic control on a twice-daily regimen: a retrospective case series analysis from clinical practice.

This retrospective study was conducted to determine whether the addition of a third injection of biphasic insulin aspart 70/30 (BIAsp 30) just before lunch in older patients with type 2 diabetes who did not achieve goals with a twice-daily (BID) regimen would optimize glycemic control in a clinical practice setting. A retrospective chart analysis was conducted. In 12 patients aged 52 to 80 y with type 2 diabetes that had been diagnosed between 5 and 24 y earlier and who remained on oral antidiabetes agents, a third injection of BIAsp 30 was added because optimal glycemic control (glycosylated hemoglobin [HbA1c]<7%) was not achieved on a BID regimen. Changes in HbA1c, body weight, total insulin dose, and frequency of hypoglycemia were analyzed after 6 mo of three times daily (TID) treatment. Mean HbA1c decreased from 8.4% to 7.2%. An HbA1c goal of <7% was attained by 58% of patients. Although the total insulin dose increased by 11% with the TID regimen, pre-breakfast and predinner doses decreased by 15%. No patient experienced major hypoglycemia on BID or TID dosing. With the TID regimen, no minor hypoglycemic events were reported by patients and mean body weight decreased by 2.25 lb. The addition of a third injection of BIAsp 30 substantially improved HbA1c and decreased body weight and the incidence of hypoglycemia in 12 patients with type 2 diabetes who did not achieve optimal glycemic control on a BID regimen.

Achieving glycemic goals with addition of incretin-based therapies to insulin in patients with type 2 diabetes mellitus.

As type 2 diabetes mellitus progresses, multiple antihyperglycemic agents are needed to maintain adequate glycemic control. Consensus guidelines recommend combining agents with complementary mechanisms of action. Given that hypoglycemic events increase the risk of cardiovascular disease and that weight gain affects mortality in obese individuals, it is important to control hyperglycemia without inducing hypoglycemia or weight gain. Peer-reviewed clinical trial data from patients requiring insulin-containing combination therapy suggest that insulin may be more effective at controlling hyperglycemia when given with appropriate combination therapy, but insulin is associated with weight gain and hypoglycemia. Some agents should not be combined with insulin because of associated weight gain and edema (ie, thiazolidinediones) or hypoglycemia (ie, sulfonylureas). Conversely, the lack of weight gain and hypoglycemia associated with metformin, glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors and suppression of glucagon secretion by both classes of incretin-based therapies suggest that these agents are well suited to combination therapy with insulin.

Incorporating incretin-based therapies into clinical practice for patients with type 2 diabetes.

BACKGROUND: Effective, evidence-based management of type 2 diabetes (T2D) requires the integration of the best available evidence with clinical experience and patient preferences. METHODS: Studies published from 2000 to 2012 evaluating glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were identified using PubMed. The author contextualized the study findings with his clinical experience. RESULTS: Incretin-based therapy targets multiple dysfunctional organs in T2D. Injectable GLP-1RAs provide substantial glycemic control and weight reduction; while oral DPP-4 inhibitors provide moderate glycemic control and weight neutrality. Both classes are effective, well tolerated, and associated with a low incidence of hypoglycemia when used alone or in combination with other antidiabetes agents. GLP-1RAs are associated with transient nausea and, like DPP-4 inhibitors, rare pancreatitis. CONCLUSION: Data indicate and clinical experience confirms that incretins are well tolerated in appropriate patients and provide sustained glycemic control and weight loss or weight neutrality throughout T2D progression.

Evolution of insulin: from human to analog.

The development of insulin analogs has made improved treatment of type 2 diabetes possible. In this article, structural alterations, pharmacokinetics and pharmacodynamics, clinical end points, and safety issues are reviewed for the currently available basal insulins, rapid-acting insulins, and premixes. The flatter activity profiles of insulin glargine and insulin detemir translate into good clinical efficacy with a lower risk of hypoglycemia relative to neutral protamine Hagedorn insulin. Weight gain is consistently lower with insulin detemir than with neutral protamine Hagedorn insulin. Insulin degludec, licensed in Europe and Japan but not yet in the United States, has a mean half-life of 25.4 hours, a duration of action of >42 hours, and low variability. In trials in type 2 diabetes, rates of nocturnal hypoglycemia were lower with insulin degludec than with insulin glargine, and more flexible; once-daily dose timing was shown to be possible. Insulin lispro, insulin aspart, and insulin glulisine are rapidly absorbed after injection and thus provide better coverage of the post-prandial glucose surge compared with human insulin. Trials and meta-analyses show that reductions in glycated hemoglobin are similar and control of postprandial glucose is better with the rapid-acting analogs versus human insulin. Convenience is greater for patients because the analogs can be injected just before a meal. In premix or biphasic insulins, a proportion of the rapid-acting analog is protaminated, providing both rapid-acting and intermediate-acting components in one formulation, thus reducing the number of injections required. Alterations to human insulin have resulted in improvements in safety, efficacy, tolerability, and convenience for patients.

The future of insulin therapy for patients with type 2 diabetes mellitus.

Insulin therapy has been the mainstay of therapy for patients with type 2 diabetes mellitus for the past 90 years. This trend is likely to continue as new formulations are developed to more closely mimic physiologic insulin secretion and to provide patients who have diabetes with more convenient options for integrating this therapy into their lifestyle. The present article reviews how the role of insulin continues to evolve, from its earlier use in the treatment paradigm (even at first diagnosis) to its role in combination therapy with incretin-based therapies, as well as new formulations that provide more-convenient forms of insulin replacement therapy.

Evolution of insulin development: focus on key parameters.

INTRODUCTION: Although insulin products and treatment strategies have improved significantly, clinical challenges still exist. Meeting glycemic goals while minimizing glucose variability and hypoglycemia is of utmost importance when considering existing insulin therapies and designing investigational insulin treatments. METHODS: A PubMed search identified relevant, peer-reviewed articles related to the evolution of insulin development for this nonsystematic review. Search terms included "animal insulin," "synthetic insulin," "regular human insulin," "insulin lispro," "insulin aspart," "insulin glulisine," "insulin glargine," "insulin detemir," "insulin degludec," "biphasic human insulin," "insulin premixes," "ultra-long acting," "oral insulin," and "inhaled insulin." RESULTS: While the discovery of animal insulin significantly decreased mortality rates from diabetes, issues with availability and large variability between batches led to difficulty in determining proper doses and, subsequently, challenges in achieving glycemic control and avoiding hypoglycemia. The development of synthetic insulin created a more readily available supply, but hypoglycemia still persisted. Recombinant DNA technology solved insulin production problems and allowed for the development of better retarding agents, but pharmacokinetic/pharmacodynamic profiles still did not mimic natural insulin. Insulin premixes offered improved glycemic control, decreased intrapatient variability versus self-mixing, and required fewer injections per day; however, patient adherence remained a problem due to the need to inject 30-60 minutes before a meal for optimal control. This prompted the development of rapid-acting insulin analogs that could be injected right before a meal and long-acting insulin analogs with flatter time-action profiles. CONCLUSION: Despite advances in insulin development, a need to provide more physiologic basal insulin coverage and reduce hypoglycemic risk in patients with diabetes remains. Newer insulin analogs and more convenient routes of insulin delivery have shown promising safety and efficacy results. Many patients with diabetes have not reached glycemic goals on currently available insulins. Additional studies are necessary to tailor optimal insulin delivery strategies to specific subsets of diabetes patients.

Intensifying insulin therapy in type 2 diabetes mellitus: dosing options for insulin analogue premixes.

BACKGROUND: As the diabetes epidemic expands, health care providers need more options to achieve glycemic control. Insulin analogue premixes provide basal and prandial insulin with 1 injection. OBJECTIVES: The aim of this review was to provide an overview of the efficacy and tolerability of insulin analogue premixes in patients with type 2 diabetes mellitus (T2DM). METHODS: Sources of information for the present review included guidelines from the American Association of Clinical Endocrinologists, the American Diabetes Association (ADA), and the European Association for the Study of Diabetes. A PubMed search of clinical trials that have assessed the efficacy and tolerability of insulin lispro, biphasic insulin aspart, biphasic human insulin, insulin analogue premix, insulin glargine, insulin detemir, and neutral protamine Hagedorn, as well as the Oxford Centre for Evidence-Based Medicine grades of recommendation and ADA levels of evidence, were employed. RESULTS: Of the 240 articles identified, 19 presented relevant clinical trial data. Biphasic insulin analogues have been associated with changes in hemoglobin A(1c), including aspart 70/30 (BIAsp 30) (changes, -1.23% to -2.89%), lispro mix 75/25 (-1.8%), and lispro mix 50/50 (-1.87%). Hypoglycemic events were reported in 18%, 23% to 42%, and 32% to 40% of patients who received BIAsp 30, lispro 75/25, and lispro 50/50, respectively. In some studies, algorithms were used for ensuring correct doses of BIAsp 30 and lispro mix 75/25. These algorithms were reported to be useful for guiding patients and physicians when more intense therapy with biphasic insulin analogues was required for effective glycemic control. CONCLUSIONS: Based on the findings from the present review, health care providers may improve patient care by using the most appropriate insulin type and individualizing dosing regimens. The initiation of treatment with biphasic insulin analogue premixes should be considered when basal insulin therapy alone is not sufficient to obtain optimal glycemic control.

Initiating and intensifying insulin therapy in type 2 diabetes mellitus.

Although insulin therapy for type 2 diabetes mellitus is perceived to be challenging to initiate and intensify, it forms a vital part of treatment as the disease progresses. This review discusses the challenges, real and perceived, faced by patients and their carers, and presents some practical suggestions concerning patient education and management of insulin therapy. A positive attitude toward insulin therapy can be achieved through patient education that focuses on disease pathophysiology and active involvement in treatment that enables them to manage concerns such as possible hypoglycemia, weight gain, and injection anxiety. Insulin analogues have more physiologic time-action profiles and are more convenient compared with older human insulins. Clinical trials show that insulin analogue regimens enable glycemic targets to be achieved with potentially less risk for hypoglycemia and more convenient dosing. Furthermore, finer needles and more convenient insulin-delivery systems are now available. With titration algorithms, intensification of an insulin regimen to improve glycemic control is relatively straightforward. Furthermore, patients with type 2 diabetes are less susceptible to hypoglycemia than are those with type 1 diabetes. With modern treatment options, insulin therapy need no longer be feared by patients with type 2 diabetes or their carers. Many common concerns in this respect are unfounded, and today's insulin regimens are generally simple, effective, and well tolerated.

Intensifying treatment in poorly controlled type 2 diabetes mellitus: case reports.

There is no single correct treatment option for all patients with type 2 diabetes mellitus. Duration of diabetes and stage of the disease, level of control, lifestyle habits, and attitude toward disease management all affect the choice of treatment for any given individual. Indeed, the above factors should be especially considered when considering initiating insulin therapy in these patients. Basal insulin and premixed insulin remain the most common formulations used when initiating insulin in patients with type 2 diabetes and, as demonstrated in this article, both of these insulin strategies can be effective in controlling hyperglycemia when therapy is individualized to the patient.

Preserving insulin secretion in Type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by insulin resistance and a progressive decline in ß-cell function and mass. Current evidence suggests that ß-cell dysfunction is present early in the course of the disease and that this dysfunction, rather than insulin resistance, is primarily responsible for the progression of T2DM. ß-cell dysfunction can be accelerated by glucose toxicity, lipotoxicity, oxidative stress, chronic increases in inflammatory mediators and, potentially, the use of sulfonylureas. This review suggests that future efforts to limit the impact of T2DM must focus on strategies to preserve ß-cell function. Several interventions have shown promise in this regard, including lifestyle modifications, thiazolidinediones, potassium channel openers, incretin mimetics, cytokine antagonists, bariatric surgery and dipeptidyl peptidase IV inhibitors, although therapeutic insulin remains the most robust and physiological approach.