Increasing Patient Acceptance and Adherence Toward Insulin

ABSTRACT

Because of the progressive nature of type 2 diabetes mellitus (T2DM), the majority of patients will need insulin to achieve and maintain glycemic control. By maintaining glycemic control, patients will avoid acute osmotic symptoms of hyperglycemia, instability in plasma glucose (PG) over time, and prevent or delay the development of diabetes complications without adversely affecting quality of life. Despite recommendations for initiating insulin therapy, both patient and health system barriers stand in the way. To develop confidence in individualizing patient therapy and maximize outcomes for patients with T2DM, healthcare practitioners (HCPs) were updated on recommendations and clinical evidence supporting when to initiate insulin therapy, strategies for overcoming provider and patient barriers for initiating insulin therapy, and the safety and efficacy of current and emerging insulin therapy and delivery technology for patients with T2DM.

KEYWORDS:

• Type 2 diabetes mellitus (T2DM)
• insulin therapy
• insulin barriers
• insulin delivery systems
• insulin adherence

CME/CE INFORMATION

Activity Title:

Increasing Patient Acceptance and Adherence Toward Insulin

Highlights from a CME Symposium held at the Cardiometabolic Health Congress (CMHC), Sheraton Boston Hotel, Boston, MA, October 23, 2015

Activity Format: CME/CE Spotlight

Estimated Time to Complete: 1 hour

Release Date: April 15, 2016

Expiration Date: April 15, 2017

Credit Type(s) Available: ACCME, CDR, ANCC, ACPE

Maximum Credits: 1 AMA PRA Category 1 Credit(s)^TM

Provided By: This activity is jointly provided by Medical Education Resources, Inc (MER) and Tarsus Cardio Inc. DBA Cardiometabolic Health Congress.

Commercial Supporter:

This activity is supported by an educational grant from Novo Nordisk.

Program Description:

Type 2 diabetes mellitus (T2DM) is a progressive disease and the majority of patients will need insulin to achieve and maintain glycemic control. Although guidelines recommend insulin, both patients and health care providers are hesitant to initiate and adhere to insulin therapy due to concerns regarding weight gain, hypoglycemia, and mainly feelings of personal failure. By maintaining glycemic control through insulin therapy, patients will avoid acute osmotic symptoms of hyperglycemia, instability in plasma glucose (PG) over time, and prevent or delay the development of diabetes complications. In addition to insulin monotherapy, combination therapy with non-insulin agents given in conjunction with insulin aim to improve glucose control in T2DM without increased risk of hypoglycemia or weight gain. This Spotlight Article will provide a concise account of presentations from a symposium held during the 2015 Cardiometabolic Health Congress (CMHC) meeting, October 22-24, at the Sheraton Boston Hotel, Boston, MA. The article will provide evidence-based analysis and insight into current research and clinical practice as presented by our expert faculty on the role of newer insulin analogs and other injectable therapies in the management of diabetes mellitus.

Purpose Statement:

To improve patient outcomes through communication and intervention strategies regarding insulin therapy for patients with type 2 diabetes and cardiovascular disease.

Intended Audience:

This activity is designed for advanced-level clinicians responsible for the prevention, diagnosis, and management of cardiometabolic risk.

Educational Objectives:

Upon completion of this activity, participants should be able to:

• Employ effective strategies to address patient concerns and/or barriers to acceptance or adherence regarding insulin therapy

• Compare and contrast safety, efficacy, and PK/PD data on available and emerging basal insulin analogs in patients with diabetes, especially regarding nocturnal hypoglycemia

• Analyze the clinical data on basal insulin and GLP-1 receptor agonist combination therapy in patients with diabetes

• Integrate novel strategies to optimize insulin therapy into clinical practice to improve glucose control, reduce risk of weight gain and hypoglycemia, and increase acceptance and adherence for patients with diabetes

FACULTY INFORMATION:

Corresponding Author:

Matthew Riddle, MD

Professor of Medicine

Division of Endocrinology, Diabetes & Clinical Nutrition

Oregon Health & Science University

Portland, Oregon

Disclosures:

Grants/Research Support: Sanofi, Lilly, Novo Nordisk, AstraZeneca

Consulting Fees: Biodel, Elcelyx, AstraZeneca, Sanofi, Valeritas

Speakers’ Bureau: Sanofi

Co-authors:

Anne Peters, MD

Director, USC Clinical Diabetes Programs

Professor, Keck School of Medicine of USC

Los Angeles, CA

Disclosures:

Grants/Research Support: Janssen, Medtronic Foundation

Consulting Fees: Amgen, Abbott Diabetes Care, Becton Dickinson, Biodel, Bristol-Myers Squibb/AstraZeneca, Janssen, Lexicon, Lilly, Medtronic Minimed, Novo Nordisk, OptumRx, Sanofi, Takeda, Thermalin

Speakers’ Bureau: Bristol-Myers Squibb/AstraZeneca, Novo Nordisk, Janssen

Martha Funnell, MS, RN, CDE

Associate Research Scientist

Department of Learning Health Sciences

University of Michigan Medical School

Ann Arbor, MI

Disclosures:

Grants/Research Support: Bristol-Myers Squibb

Consulting Fees: Eli Lilly, Novo Nordisk, AstraZeneca, Johnson & Johnson

Speakers’ Bureau: Merck

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The following content managers reported no financial relationships with commercial interests whose products or services may be mentioned in this CME/CE activity:

MER: Julie Johnson, PharmD, Veronda Smith, FNP

CMHC: Erin Franceschini, MS, Karin McAdams, Mary Mihalovic, Melissa Wiles

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The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of MER, CMHC and/or the various industry supporters. The authors have disclosed if there is any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of MER, CMHC, and/or the various industry supporters. Before prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.

INSTRUCTIONS:

Participants are expected to read the full activity before attempting to complete the post-test and evaluation. Successful completion will lead to the issuance of a certificate for 1 AMA PRA Category 1 Credit(s)™.

To receive credit, the activity must be completed before April 15, 2017. There are no fees for participating in and receiving CME credit for this activity. In order to claim CME credit for this activity registration is required prior to completing the post-test and evaluation. During the period April 15, 2016 through April 15, 2017, participants must follow these steps in order to receive CME/CE credit:

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2. Read the full educational activity. Once completed, go to the following posttest and evaluation link: http://www.cardiometabolichealth.org/online/2016insulinspotlight and complete the post-test by recording the best answer to each question in the answer key. Successful completion of the post-test is required to earn CME/CE credit. Successful completion is defined as a cumulative score of at least 70%.

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Introduction

Goals of antihyperglycemic therapy are to avoid acute osmotic symptoms of hyperglycemia, instability in plasma glucose (PG) over time, and prevent or delay the development of diabetes complications without adversely affecting quality of life.[1,2] Research has shown that for every 1% lower hemoglobin A1c (HbA1c), the risk of diabetes complications is 20–40% lower.[3,4] Individuals with prolonged elevation of PG levels commonly suffer microvascular complications, which negatively affect the eyes (impaired vision), kidneys (renal insufficiency or failure), and nervous system (peripheral neuropathies), as well as macrovascular complications including heart disease, hypertension, and stroke.[1,2,5,6] When compared to those without diabetes, individuals with diabetes are two to four times more likely than those without the disease to die from cardiovascular (CV) events, which account for 65% of deaths in persons with diabetes.[5] All-cause mortality is also doubled for people with T2DM.[7]

Timely initiation of insulin therapy

The United Kingdom Prospective Diabetes Trial has demonstrated that because of the progressive nature of type 2 diabetes mellitus (T2DM), most patients eventually develop a need for insulin.[3] The study showed that by year 6, more than 50% of patients needed insulin to maintain a target fasting plasma glucose (FPG) of ≤6.0 mmol/L. Despite this evidence, insulin therapy is often delayed. On average, HbA1C levels remain elevated at 8% for approximately 5 years before insulin is initiated; patients typically wait more than 10 years with HbA1c readings above 7%,[8] and many patients develop complications during this time.

Current recommendations from the American Diabetes Association (ADA) for treating diabetes suggest initiating therapy with metformin, together with lifestyle efforts and progressing to dual therapy by adding either another oral agent, insulin, or an injectable GLP-1 receptor agonist (GLP-1RA). If targeted HbA1C levels are not achieved after 3 months of dual therapy, then a third agent may be needed. When HbA1C goals are not achieved after 3 months of triple oral therapy, adding an injectable agent is recommended. Either basal insulin or a GLP-1RA may be used as the first injectable agent, and they may later be used together.

The latest recommendations also suggest on how to initiate and titrate basal insulin.[1,2,5] Either a fixed initial dose (e.g. 10 units) or a weight-based dose (e.g. 0.1–0.2 units per kg body weight) may be used to initiate basal insulin. Further titration of basal insulin dosage is usually needed, but sometimes this is not done, due to fear of weight gain and hypoglycemia. Titration can be done in various ways, but should be done systematically. One recommended way is to advance the dose by 2–4 units once or twice weekly until fasting glucose targets are reached, typically between 80 mg/dL and 130 mg/dL. The usual HbA1C target of 7.0% or less can be reached by approximately 50% of patients, and those who start insulin before HbA1C has risen to markedly elevated levels are most often successful. An observational study conducted at Kaiser Permanente Northwest, which evaluated over 1,000 patients who were newly started on insulin, supports this approach.[9,10] After 3–9 months, investigators found that 41% of patients reached HbA1C levels of <7% after initiation of insulin. However, those with a baseline HbA1C of 8.2% were more likely to reach target than those with a baseline HbA1c of 9.2%, reinforcing the value of timely insulin therapy. When basal insulin together with oral agents does not maintain HbA1C at the desired target, further improvement of control can be sought by adding a GLP-1RA or by adding a dose of rapid-acting insulin with the patient’s main meal.

Further, there are promising findings in studies of using insulin as the first form of drug therapy for T2DM.[11] Chen et al. studied people with new-onset diabetes who were cared for in a hospital setting and received intensive insulin therapy as the initial intervention.[12] In some cases, PG values will remain well controlled with oral therapy alone for some time after insulin has restored good control. Once target HbA1C levels were reached in this study, patients were kept on either insulin or an oral agent. Those on oral therapy developed higher PG levels over time when compared to those who continued on insulin. Weng et al. obtained similar results in a multicenter study.[10]

The question remains: is it more beneficial to initiate injectable antihyperglycemic therapy with a GLP-1 RA or basal insulin? Studies have found that on average the same HbA1C reduction occurs when either basal insulin or a GLP-1 RA is added to oral therapy.[13,14] In a study by Buse et al. starting once-weekly exenatide as a GLP-1RA was as effective at controlling PG as basal insulin.[15] Even study participants with an HbA1C level of approximately 10% experienced results comparable to well-titrated insulin for the duration of the study. However, the side effects of these two options differ: hypoglycemia and weight gain with basal insulin, versus nausea and other gastrointestinal side effects with a GLP-1RA. A patient’s preferences are naturally important in deciding which to use. Basal insulin can always be added after a GLP-1RA when that approach is not tolerated or not fully effective.

In summary, because of the progressive nature of T2DM, insulin will eventually be necessary to achieve and maintain a patient’s glycemic target. The sooner insulin is initiated, the more quickly and reliably that target will be achieved. Clinical practice guidelines recommend initiating insulin, usually as basal insulin, if glycemic targets are not achieved after 3 months of lifestyle modification together with one or more antihyperglycemic medications. After engaging the patient in the decision to begin insulin, the provider’s next challenge is to involve the patient and/or the caregiver(s) in education regarding the logistics of insulin therapy and ways to make it a success.

Identifying barriers to insulin therapy: a proactive approach

Behavioral studies have shed light on why some patients resist taking insulin. Polansky et al. surveyed 1,400 people who had never taken insulin and found 48.1% would be willing to do so; 34.7% were ambivalent, and 17% refused.[16] Compared to those who were willing, unwilling, and ambivalent patients had more negative and fewer positive beliefs about insulin therapy.

According to Martha Funnell, MS, RN, CDE, ‘Research shows that contrary to popular belief, the number one reason patients avoid insulin therapy is not fear of needles; but rather, they perceive the need to take insulin as a personal failure. This is because they are frequently told that if they take care of themselves they could avoid insulin.’[17] Additionally, many patients believe initiating insulin means their diabetes is worse. Other concerns include fears about hypoglycemia, loss of independence, weight gain, and the safety of insulin.[17]

Another study evaluated patients who agreed to start insulin, but never filled the prescription.[18] Of those patients, 25% planned to work harder on their lifestyle and 13% did not initiate treatment due to fear of needles. Researchers also uncovered beliefs that suggested actual reasons why patients did not initiate insulin: 47% believed that others who take insulin have not taken care of themselves in the past, and 35% believed that taking insulin increased the risk of long-term complications.[18]

Many concerns surrounding insulin can be addressed through patient education. The ADA, American Association of Diabetes Educators (AADE), and the Nutrition Foundation Academy for Nutrition Science have published a position statement that discusses when a diabetes education referral for adults with type 2 diabetes is appropriate.[19] Insulin initiation is a time when patients should be referred for diabetes education, and is generally covered by insurers.[19]

Patients should also be assessed to determine what they believe and what they have heard, asking questions such as follows:

• What do you think is going to happen if your HbA1c level remains high or you do not achieve your glycemic target(s)?

• What have you heard about insulin?

• What have been the experiences of others you know (e.g. family, friends) with insulin?

• How do you think insulin is going to help you?

• What are you most worried about?

• What do you need to know to even think about insulin?

Clinicians also need to help patients understand that insulin therapy is not a failure. The body simply needs more help. One strategy to help patients recognize this is by discussing insulin at diagnosis. When a patient is initially diagnosed and a treatment plan is discussed, insulin should be laid out as one step, albeit the last step, in the treatment plan of the patient. It should be clear to the patient that insulin is part of how diabetes is treated as a whole. Another strategy for patients struggling with the decision to start insulin is to ask: ‘Would you be willing to try it for a week, just to see what it’s like?’ Most patients will come back and say that insulin therapy was not as negative of an experience as they thought it was. Furthermore, in order to help patients recognize that insulin therapy is not a failure on their part, clinicians need to stress to patients that over time the body makes less insulin and that at this time, this is just what the body needs.

Those who do agree to insulin therapy will need instructions on administration. The American Association of Diabetes Educators published a review on how to safely administer insulin injections [20]:

• All adults can use micro-needles (4–6 mm; no reason for >8 mm)

• There is no need to ‘pinch an inch’ with these short needles

• Insert the needle at a 90-degree angle

• Patients can use sites other than the abdomen

• There is no evidence that cleaning the top of the vial or skin with alcohol is needed

• To minimize discomfort, new syringe/needle should be used each time—or at least every 24 hours

Among the most critical mistakes patients make when injecting insulin include not rolling or tilting the vial or pen to re-suspend neutral protamine Hagedorn (NPH) insulins, forgetting to give an air shot when using an insulin pen, and keeping short needles in place for less than 10 seconds. All patients on insulin need to be taught the signs, symptoms, and treatment for hypoglycemia, and sick day management.

Patients also need assistance with self-monitoring blood glucose (SMBG). Patients need to learn how to use the information from SMBG, for example, by using fasting or preprandial PG levels (or in some cases 12 hour postprandial levels) to determine the effectiveness of the preceding insulin doses.

Recognizing the importance of health literacy and providing clear instructions can improve insulin self-management. A statement like ‘Take your insulin twice a day’ can be interpreted in many different ways by patients. Does it mean once in the morning and once in the afternoon, or upon waking and at bedtime, or before breakfast and before supper, or 6 am and 6 pm? If a patient is taking insulin at bedtime, but goes to bed at 9:00 pm 3 days out of the week, and 1:00 am 4 days out of the week, that is going to affect how the insulin works. Similarly, telling patients ‘If you are sick, increase your insulin’ can be interpreted multiple ways. Does it mean increase basal insulin, meal insulin, correction insulin, or all doses? Once specific instructions are given, clinicians should ask patients to repeat back exactly how they are going to take their insulin so that there are no misunderstandings.

It is also important to recognize that insulin is perceived differently among different cultures. Ask all patients about cultural health beliefs and practices, with questions including ‘Do you have any cultural/religious practices that influence how you care for your diabetes? Do you practice fasting at certain times? If so, how can we best help you to manage your diabetes?’ The assessment should also consider the role of family members and friends in making health-care decisions and look for a way to include family members in discussions.

The National Diabetes Education Program (NDEP) has developed a valuable resource to help patients address behavioral and psychosocial issues called Diabetes HealthSense. It is a compendium of approximately 160 resources for patients and professionals, designed to help patients make lifestyle and other behavioral changes, and to improve initiation and continuation of medication. It is available on the NDEP website and is located at http://www.yourdiabetesinfo.org/healthsense.

In summary, skillful self-management is critical to achieve and maintain glycemic targets and minimize complications of diabetes. Many patients are reluctant to start insulin for a variety of reasons, and also may be reluctant to make daily decisions on dosing and matching insulin to meals and daily activities. Identifying and proactively addressing patients’ concerns and barriers through assessment, education, and ongoing support is essential to engaging them in self-care to improve metabolic and quality of life outcomes.

‘The number one reason that patients avoid insulin therapy is not fear of needles, but they perceive the need to take insulin as a personal failure.’ [17]

Newer therapies and novel combinations: improving patient satisfaction and addressing cardiometabolic risk

Health-care practitioners continue to need to develop strategies to improve patient satisfaction and increase a patient’s quality of life. There are several issues to consider: the benefits versus risks, namely hypoglycemia and weight gain, of insulin therapy, patient preference, quality of life, and adherence.[14,17] The following review of current and emerging insulin therapy addresses these issues.

Basal insulin

Current and emerging options for basal insulin therapy in the United States are included in Figure 1.[21,22] Limitations of NPH insulin include less than 24 hours of action, peaks and troughs of glucose lowering, and clinically meaningful rates of nocturnal hypoglycemia. Despite these limitations, NPH can achieve glycemic targets for some patients. Insulin detemir and insulin glargine U-100 produce more nearly normal patterns of insulin replacement than NPH, but their duration of action can be less than 24 hours and nocturnal hypoglycemia can still be problematic. Newer, longer-acting insulins may further improve the results of treatment for some patients.

Figure 1. Current and emerging basal insulins in the United States. Adapted from Refs. [21,22].

^aApproved by the US FDA since February 2015.^bApproved by the US FDA since September 2015.^cApproved by the US FDA since 18 December 2015.*Peglispro is no longer in development.

Studies of insulin glargine U-300, a more concentrated formulation of glargine, have demonstrated a more prolonged and flatter profile of action than U-100 glargine, together with less hypoglycemia, especially at night.[23] Insulin glargine U-300 may have less tendency to cause weight gain, but this finding was not present in all studies and a mechanism for this difference is not known.

Insulin degludec also has a flatter profile and an even longer-lasting duration of action, and it too results in less nocturnal hypoglycemia compared to U-100 glargine. Insulin peglispro, another longer-acting insulin analog, has desirable pharmacokinetic and glucose-lowering properties, but because of concerns about lipid patterns and liver fat accumulation, its development has been discontinued.

Prandial insulin

Current and emerging prandial insulins fall into three broad categories: short-acting human insulins, rapid-acting analogs, and ultra-rapid acting analogs, as shown in Figure 2.[22] The difficulty with existing prandial therapy is more complicated than that observed with basal therapy. The pharmacokinetics of existing prandial insulins does not always closely match mealtime needs of most patients. The onset of action can be delayed and the duration may not be long enough after some meals, depending on the size and composition of the meal.[23,24] For breakfast, where the carbohydrate content may be higher relative to protein and fats, an insulin with a rapid onset is needed, but with a rather short duration of action. However, at dinner, the meal may be larger and eaten over a longer period of time. Additionally, dinner may often contain more fat and protein relative to carbohydrates and food is absorbed more slowly. As a result, rapid onset may be less important and a more prolonged effect may be desired for the evening meal.

Figure 2. Current and emerging prandial insulins in the United States. Adapted from Ref. [22].

^aApproved by the US FDA since June 2014.^bNot currently approved by the US FDA.^cApproved by the US FDA in May 2015.

Several research groups have worked to develop more rapidly acting insulins. Injectable ultra-rapid insulins are not yet in use clinically, but Technosphere inhaled (TI) insulin is currently available. With TI, the onset is quicker and duration of action is less than for regular human insulin.[25] Excellent postprandial PG suppression has been observed in a double-blind, placebo-controlled trial of TI in insulin-naive patients with T2DM using oral antidiabetic medications.[26] However, there are safety concerns with inhaled insulins, including contraindications for certain lung diseases, complexity of dosing decisions, and hypoglycemia.[27]

More concentrated insulin formulations, such as U-200 lispro and U-500 human regular insulin, have a potential advantage over the U-100 concentrations in that smaller volumes and less frequent injections can be administered to those with high prandial insulin requirements, aiding in adherence.[28,29] The pharmacokinetics are similar to the U-100 concentration, but compared to regular human insulin, insulin lispro has a faster onset and a shorter duration of action.[30]

Available premixed insulins include NPH/regular, protamine lispro/lispro, protamine aspart/aspart, and degludec/aspart.[24,31] These mixtures provide both basal and prandial effects, but at a fixed ratio. They offer a convenient alternative to basal-plus or basal-bolus insulin for some patients, but have the disadvantage of causing more hypoglycemia and weight gain than similarly complex regimens using basal and prandial insulins separately.[24,31]

Combination therapy

Another area of interest for clinicians is combination therapy, in which non-insulin agents are given in conjunction with insulin with the aim of improving glucose control in T2DM without increased risk of hypoglycemia or weight gain. Exenatide, a short-acting GLP-1RA with strong prandial and relatively weak overnight effects when taken twice daily, can be combined with basal insulin as an alternative to prandial insulin and basal insulin. This regimen has been shown to attain similar glucose control without weight gain and limited hypoglycemia compared with basal bolus therapy.[32] Other studies have shown that adding a GLP-1 RA to basal insulin was equally or more effective compared with increasing the basal insulin dose, using the GLP-1 RA alone, or adding prandial insulin.[33]

Recently introduced SGLT2 blockers are generating a great deal of interest for treating patients with CV disorders. When SGLT2 inhibitors are combined with basal insulin, there is a low risk of hypoglycemia and weight gain,[34] and also desirable effects on hypertension and fluid retention. A recently reported long-term trial of the SGLT-2 blocker empagliflozin versus placebo demonstrated clear reductions of CV events and mortality in people with T2DM and known CV disease, many of whom were using insulin.[35] Another class of agents, DPP-4 inhibitors, when combined with basal insulin displays similar effects of low risk of severe hypoglycemia and weight gain.[36]

Insulin delivery systems

In addition to new developments in insulin products and combination therapies, there have also been advances in the methods for insulin delivery. Hollow and ultrafine/ultra-beveled needles have been developed to help reduce anxiety and pain at the injection site which minimizes the fear of needles.[37,38] From 2005 to 2011, the use of insulin pens has steadily increased in patients with T2DM while the use of vials and syringes has declined.[39] Insulin analogs are most often administered with a pen while recombinant human insulins are administered with a vial and syringe. Insulin pens may be associated with lower risks of dosing errors [40] and hypoglycemia.[41] Use of insulin pens also offers greater convenience and has demonstrated increases in patient adherence compared to vials and syringes.[42,43] Despite the potential advantages of delivering insulin by pens, there have been barriers to their adoption in the US, notably greater cost and lack of education in their use.[44,45]

Insulin infusion pumps offer advantages over multiple daily injections for many patients with type 1 diabetes and some with T2DM, which also provides greater adherence.[29] Newer versions of these devices have high levels of user satisfaction. They may be considered for patients with recurrent diabetic ketoacidosis, frequent severe hypoglycemia, or hypoglycemia unawareness, and for competitive athletes.[46] In addition to the sophisticated pumps developed for type 1 diabetes, simpler disposable devices have recently come into use for selected patients with T2DM.

Omni-Pod is a basal bolus device with automated cannula insertion and a personal digital assistant (PDA)-like controller that can accommodate up to 200 units/day of U-100. The V-Go system is also a basal bolus device, which delivers an automated basal dose of 20, 30, or 40 units/day and a manual 2-unit bolus dose delivery of up to 36 units/day. The device requires no batteries because its design is completely mechanical in nature. The Finesse device has received FDA approval for bolus delivery only and is anticipated to launch in 2016.

Finally, the future holds promise for the concept of ‘smart insulin’ delivery. One option involves a micro-needle patch that penetrates the outer surface of the skin.[47,48] With this device, insulin is delivered through prongs on the patch and is released in proportion to glucose levels. This single disposable device consists of a 6 mm² patch with 121 microneedles embedded in it. Glucose oxidase converts glucose to gluconic acid, consuming oxygen. The resulting hypoxia disassembles the polymer coating on the patch’s microneedles, releasing insulin. To date, it has been tested only in a mouse model of type 1 diabetes mellitus.

In summary, a wide array of formulations and delivery devices are now available. Selecting the best options for an individual patient is an important step toward achieving treatment goals and minimizing adverse events. New longer-acting basal insulins have a flatter glycemic profile and for some patients may cause less hypoglycemia than their predecessors. Higher concentration insulins are as effective as the U-100 concentrations, and may allow fewer injections due to lower volumes needed to deliver appropriate doses. Faster-acting insulins may reduce postprandial glucose concentrations more effectively, and may cause less hypoglycemia, than human regular insulin and currently available rapid-acting analogs. Inhaled insulin can have a very rapid onset and offset compared with subcutaneous rapid-acting insulin. Premixed insulin may be an alternative to basal-plus or basal-bolus insulin for some patients. Insulin pens are convenient to use and may improve adherence to prandial regimens and insulin infusion devices can improve the consistency and accuracy of insulin delivery for some patients with T2DM.

Paving the way to patient acceptance and satisfaction: case studies and panel discussionCase one

The patient is a 48-year-old female Caucasian office supervisor with a relatively sedentary life. She has had diabetes for 3 years, but no family history. She was asymptomatic at diagnosis, and now complains only of paresthesias in her toes. BMI is 27 kg/m², HbA1c is 8.2%. She is currently taking metformin 850 mg BID and glimepiride 4 mg once daily.

She agrees to add insulin detemir 10 units at bedtime with titration to aim for fasting glucose <120 mg/dL. Three months later she returns with symptoms of hypoglycemia between 2 and 4 am; her paresthesias have worsened. At this second visit, HbA1c is 7.6%, FPG varies between 80 and 180 mg/dL, and her weight increased by 1.5 kg. After titration, her dose of insulin detemir is 24 units at bedtime.

What would be the next steps for this patient to improve glucose control?

Among the viable options to consider are the following:

• Refer her for diabetes self-management education and medical nutritional therapy

• Prescribe continuous glucose monitoring

• Add a GLP-1 RA

• Measure glutamic acid decarboxylase antibodies

• Split the detemir dose to 12 U in morning and 12 U at bedtime

Expert recommendations include the following:

Martha Funnell—‘Emphasize the need to work with this patient to discuss titration of her insulin dose, and meal planning. She would also benefit from a more comprehensive diabetes self-management education (DSME) program for ongoing support and continued success.’

Anne Peters—‘There is value in utilizing continuous glucose monitoring to help guide therapy. There is also importance in measuring fasting C-peptide level. If the patient’s level is really low, there may be a need to put a patient like this on a more complete basal-bolus insulin regimen. The measurement of glutamic acid decarboxylase (GAD) antibodies can be of value for this patient. About 10% of the type 2 population is anti-GAD-positive or has other evidence of autoimmune injury to the beta cell. In addition these patients have a different natural history from patients with standard T2DM. They more rapidly progress to complete dependency on insulin, or have a greater tendency to do so. They respond less well to oral therapies, and they have an inheritable disease that is passed on in families. One of the unanswered questions in patients like this is that we urgently need more data to determine what can be done, if anything, to preserve their remaining beta cell function. In broad-based population studies, the best evidence for preservation of beta cell function results from the use of insulin.’

‘In broad-based population studies, the best evidence for preservation of beta cell function results from the use of insulin.’Anne Peters, MD

Case two

A 62-year-old Latino man who is a security guard was diagnosed with T2DM 8 years ago. Because of his disease, he often worries about money and his health. He has a strong family history of both diabetes and heart disease. His BMI is 34 kg/m²; HbA1c is 10.2%. Medication history reveals the patient is taking sitagliptin 100 mg daily and Lispro premix (75/25): 30 units BID. He is willing to try basal bolus therapy with insulin glargine 40 units at bedtime, and 10 units of insulin aspart before each meal.

The patient misses his first follow-up appointment and comes to the emergency room with chest pain, but there is no evidence of myocardial infarction. At his next office visit, he is tired and discouraged; HbA1c is 9.6% and he has gained 6 pounds.

Some of the possible reasons for this patient’s poor response to basal bolus insulin are as follows:

• Severe insulin resistance

• Binge eating and alcohol excess

• Omission of insulin doses due to cost

• Poor adherence to regimen due to depression

In a subsequent conversation with this patient, he reveals that he cannot afford the copay for several of his medications. Among the options that may help this patient: prescribe inexpensive oral therapies to the extent possible, stop all oral agents and increase the patient’s insulin, prescribe a human insulin, which is less expensive.

Dr. Peters commented: ‘I recommend putting this patient on a combination of insulin and oral medication, such as metformin, because it is so inexpensive. Sulfonylureas are also an inexpensive option. But it is also important to have a straightforward conversation with the patient to determine if he is taking his medication, and if not, why not.’

Conclusions

Insulin will eventually be needed by most patients with T2DM because of the progressive nature of the disease over time. Patients should be actively engaged in making the decision to initiate insulin therapy. This requires identifying and addressing patient barriers and concerns surrounding the treatment, and providing DSME and ongoing support. Also, selecting the correct insulin regimen for each individual patient is essential for success in self-management and minimizing adverse events. Furthermore, utilizing the most appropriate delivery device (syringe and needle, pen, or pump), the individual’s needs can be cost-effective and improve patient satisfaction. Discussions during this symposium provided clinicians with objective information about the safety and efficacy of each type of insulin, so as to feel confident when individualizing patient therapy to minimize complications and improve outcomes.

Financial & competing interests disclosure

This manuscript was funded by Novo Nordisk, through support provided to the 2015 Cardiometabolic Health Congress. Editorial support was provided by Paul Cerrato and Robert E. Lamb, sponsored by Novo Nordisk. M Riddle has received grants/research support from Sanofi, Lilly, Novo Nordisk and AstraZeneca, consulting fees from Biodel, Elcelyx, AstraZeneca, Sanofi and Valeritas, and he has been on the Speakers‘ Bureau for Sanofi. A Peters has received grants/research support from Janssen and Medtronic Foundation, as well as consulting fees from Amgen, Abbott Diabetes Care, Becton Dickinson, Biodel, Bristol-Myers Squibb/AstraZeneca, Janssen, Lexicon, Lilly Medtronic Minimed, Novo Nordisk, OptumRx, Sanofi, Takeda and Thermalin. She has also been on the Speakers’ Bureau for Bristol-Myers Squibb/AstraZeneca, Novo Nordisk and Janssen. M Funnell has received grants/research support from Bristol-Myers Squibb and consulting fees from Eli Lilly, Novo Nordisk, AstraZeneca and Johnson & Johnson. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.