Insulin Matters: A Practical Approach to Basal Insulin Management in Type 2 Diabetes

It is currently estimated that 11 million Canadians are living with diabetes or prediabetes. Although hyperglycemia is associated with serious complications, it is well established that improved glycemic control reduces the risk of microvascular complications and can also reduce cardiovascular (CV) complications over the long term. The UKPDS and ADVANCE landmark trials have resulted in diabetes guidelines recommending an A1C target of ≤ 7.0% for most patients or a target of ≤ 6.5% to further reduce the risk of nephropathy and retinopathy in those with type 2 diabetes (T2D), if it can be achieved safely. However, half of the people with T2D in Canada are not achieving these glycemic targets, despite advances in diabetes pharmacological management. There are many contributing factors to account for this poor outcome; however, one of the major factors is the delay in treatment advancement, particularly a resistance to insulin initiation and intensification. To simplify the process of initiating and titrating insulin in T2D patients, a group of Canadian experts reviewed the evidence and best clinical practices with the goal of providing guidance and practical recommendations to the diabetes healthcare community at large. This expert panel included general practitioners (GPs), nurses, nurse practitioners, endocrinologists, dieticians, pharmacists, and a psychologist. This article summarizes the panel recommendations.

initiating and titrating insulin in T2D patients, a group of Canadian experts reviewed the evidence and best clinical practices with the goal of providing guidance and practical recommendations to the diabetes healthcare community at large. This expert panel included general practitioners (GPs), nurses, nurse practitioners, endocrinologists, dieticians, pharmacists, and a psychologist. This article summarizes the panel recommendations.

Do We Still Need Insulin?
Type 2 diabetes (T2D) is a progressive disorder characterized by multiple pathophysiological defects. The core defects include insulin resistance in the muscle and liver and impaired insulin secretion due to b-cell failure [1,2]. The progressive nature of the disease is such that it requires therapy to be intensified over time to compensate for the ongoing b-cell deficiency [2][3][4]. At the time of T2D diagnosis, more than 50% of b-cells have already been lost, and continue to decline at an average rate of 5% per year [1,2,5]. Therefore, the use of insulin is an appropriate option at any point in the management of T2D to replace the insulin that the pancreas is unable to produce sufficiently [1,6].
In fact, when the maximum output of insulin has decreased to 15% or 20% of normal, noninsulin anti-hyperglycemic agents can no longer sustain glycemic control and insulin supplementation becomes a necessity [5]. The usual starting point for insulin therapy in T2D is with basal insulin owing to its simplicity and lower risk of hypoglycemia [7].

When and in Whom to Initiate Insulin in T2D
The panel recommendations as to when and in whom to initiate insulin are summarized in Table 1.

What are the Barriers to Insulin Initiation?
Clinical inertia, defined as the failure on the part of the provider to advance therapy when required, adversely affects timely management of T2D [9][10][11][12]. Insulin is often initiated late in the course of the disease, after failure with multiple antihyperglycemic agents, and at glycemic values well above the recommended targets [11][12][13][14][15]. In Canada, mean A1C levels are [8.5% and mean diabetes duration is C 9 years before initiation of basal insulin in T2D patients [13,15]. A UK retrospective study of pharmacologically treated T2D patients on one, two, or three oral antihyperglycemic agents reported that the median time to insulin initiation was [7 years with an A1C C 7.0% and the mean A1C levels at initiation was [9.0% [12].
There are many barriers that contribute to this delay in initiation and intensification of insulin in T2D. It is important to emphasize that many of these barriers reflect the attitudes and beliefs of both patient and provider. Identifying and addressing both provider and patient beliefs and attitudes are therefore essential to mitigate those barriers (Tables 2 and  3).

What is Your Role in Insulin Therapy?
Success in overcoming patient barriers relies greatly on listening to the patient and proactively addressing their fears and concerns [55,56]. Open dialogue with the patient throughout the continuum of diabetes management, with an emphasis on the positive benefits of insulin therapy, will significantly enhance the outcomes for patients with diabetes. See Table 4 for review of action points with your patient.

BASAL INSULIN DOSE AND TITRATION RECOMMENDATIONS
In light of the persistent barriers contributing to delays in diabetes management with insulin, there is an urgent need for a simplified and practical approach to the initiation and intensification of insulin. Complex regimens and unrealistic targets can worsen the patient's engagement in the process and ultimately the patient's well-being [3,4,57]. Simplification allows for empowerment by engaging the patient in doable tasks, which provides the context for behavior shaping (next step goals) and self-efficacy (confidence in the face of barriers) [58].

What Do We Want in a Basal Insulin Recommendation?
• A starting dose that can be safely applied and individualized. • A titration schedule that is simple and can be safely patient-driven, with a fasting blood glucose (FBG) target that can be individualized. Patient-driven titration schedules are as effective as provider-driven titration schedules [19, [59][60][61][62][63][64] and engage the patient, which in turn can lower barriers to insulin therapy [4,65,66]. • Clear instructions to the patient on how the dose will be titrated, to manage expectations which will empower the patient and improve adherence to therapy [3,4,16,66]. • Recognition that insulin initiation and titration are two separate behaviors for the patient, each of which needs to be addressed in relation to patient readiness to change.
How to Select a Basal Insulin?
Three generations of basal insulins are available in Canada. The first generation of basal insulin is NPH, a human insulin that has been available for many decades, since 1946. The basal analogues (insulins detemir and glargine (Gla-100)) emerged in the 2000s and provided longer duration of action, improved day-to-day variability, reduced hypoglycemia, especially nocturnal, and did not require resuspension (as does NPH) [67]. A next generation of long-acting basal insulins-insulins glargine 300 U/mL (Gla-300) and degludec-have emerged with an extended action profile, improved safety, and the advantage of being administered in smaller volumes [29]. Table 5 summarizes the main characteristics of the currently available basal insulins. The panel recognizes that the choice of basal insulin may depend on access, cost, and clinical judgment with respect to the patient's individual needs and lifestyle [29].

How to Dose?
There are several important concepts to remember when dosing basal insulin: (a) the starting dose will be wrong; (b) there is no maximal insulin dose; (c) titration of insulin dose is the key [8]. Each of these concepts needs to be explicitly discussed and understood by the patient in order for titration to be successful. Despite 92% of physicians agreeing that

Fear of needles or apprehension toward injections
Feeling that insulin is too complicated [3,11,16,33,44] Demonstrate injection technique: show the insulin pen and small needle tips. Apply the principles of systematic desensitization (self-controlled exposure) Highlight that the injection is into subcutaneous tissue, not a vein Invite patient to try these without insulin, in your office (i.e., dry injection); give first injection together with patient to observe, support and ensure correct administration of insulin Educating on injections: see http://www.fit4diabetes.com/canada-english/fit-recommendations/ Feeling that this is a personal failure [3,11,16,33,45] Pro-action. Do not wait to talk about insulin once the patient needs insulin. Explain from the time of diagnosis that insulin is a likely treatment option in the course of T2D [46] Discuss with the patient, using decisional balance analysis (pros and cons), that need to advance therapy is due to the progressive nature of diabetes, not because the patient has done something wrong Belief that insulin causes diabetes complications [3,11,16,33] Insulin is a natural hormone and a replacement therapy [42] Explain why insulin becomes necessary for most patients with diabetes eventually; it is not a punishment [46] Explain that use of insulin will help achieve glycemic target and minimize the risk of complications [47,48] Concerns over hypoglycemia (BG\4.0 mmol/L) [3,11,16,33,[49][50][51][52] Reassure the patient that most hypoglycemic episodes are mild. Severe hypoglycemia (defined as requiring assistance by another person) is relatively rare a [52]  Educate the patient on how to recognize and respond to symptoms [52] http://guidelines. diabetes.ca/browse/chapter14 Make sure the patient and partner/family (if applicable) know how to recognize, treat, and avoid hypoglycemia, and how to self-adjust insulin [34] Choose insulins and regimens with lower rates of hypoglycemia [14,29] Use systematic desensitization to allow the patient to work from a psychologically safe zone to a medically safe zone Concerns over weight gain [3, 11,  ''insulin intensification is an essential element of diabetes management,'' 30% of primary care physicians ''never or rarely'' personally intensified insulin (vs 4% of specialists) in the multinational survey MODIFY [14,81]. Interestingly, in a recent multinational survey, HCPs generally preferred a gradual and safe approach to titration to avoid hypoglycemia whereas patients are frustrated by time to reach goal [66]. It is therefore important to manage the patient's expectations.
The starting dose for basal insulin recommended by this panel is 10 U/day. The dose should be incrementally increased on a regular basis using target FBG as the determinant for dose adjustments. At initiation, educating patients that many people will need at least 40-50 units of basal insulin to achieve target FBG is useful for goal setting and behavior shaping. This may help mitigate patient fear/ reluctance to up-titrate [8]. Table 3 continued

Concern Panel recommendations
Belief that insulin can never be stopped and will restrict lifestyle [3,4,16,33,42] Offer a 3-month trial period with subsequent reassessment. http://guidelines.diabetes.ca/ fullguidelines Recall that engaging the patient in the decision empowers them and leads to better outcomes [3,4] Prescribe once-daily basal insulin that minimizes inconvenience and is easy to use. http:// guidelines.diabetes.ca/bloodglucoselowering/insulinprescriptiontool NIAHA non-insulin anti-hyperglycemic agent, BG blood glucose a In UKPDS, the annual incidence of severe hypoglycemia in insulin-treated patients was \3%. With the newer longacting basal insulins this is even lower (2.3%) [47]  Listen and ask Actively listen to fears and concerns. Normalize these concerns before discussing alternatives Invite discussion, show conviction of belief and supportive body language

Educate
Ask permission to educate about the importance of insulin, the progressive nature of the disease, how to selfmanage their disease Box 1A details the recommendations by the panel for basal insulin dose and titration.
Box 1B provides a summary of key recommendations, including a starting dose and titration schedule. Dose adjustments Select a simple titration algorithm that matches patient lifestyle [57] The following dose adjustment algorithms have been shown to be safe and effective. Select the one that is easiest for the patient to follow: One easy titration algorithm is For other considerations, see Table 6 Measure glucose level at least every morning before breakfast c [57] http://guidelines.diabetes.ca/browse/appendices/ appendix3 Remind patient to adjust the basal insulin based on morning glucose not bedtime glucose c [57] Assess for possible hypoglycemia (\ 4.0 mmol/L) and decrease titration [52] http://guidelines.diabetes.ca/ fullguidelines/chapter14 Recognize that patient fear of hypoglycemia is easily elicited (hypoglycemia is a traumatic stress) and that providers underestimate the psychological impact of nonsevere hypoglycemia [51] Mitigating hypoglycemia: Is there an identifiable cause? [52]   Communicate how long it will take them to reach target (e.g., if the expected dose is 60 units at 1 U/day increase, then it will take on average 6 weeks) Indication that basal insulin is not enough includes: Up-titrations without a corresponding drop on BG (verify patient adherence and check injection sites). http://www.fit4diabetes.com/canada-english/fitrecommendations/ Patient has surpassed 1 U/kg/day of basal insulin without sufficient FBG control [87] FBG in target, but A1C above target BG blood glucose, FBG fasting blood glucose, SMBG self-monitored blood glucose a For more information on how to handle any oral agents and other FAQs, see Tables 6 and 7 b Algorithm proven safe and effective with insulin glargine 100 units/mL (Lantus Ò ) and 300 units/mL (Toujeo TM ) c Adjust accordingly if shift worker d Pseudo-hypoglycemia: an event in which the patient experiences symptoms of hypoglycemia with a BG [ 3.9 mmol/L but approaching that level [54]  Additional comments: Suggest using supportive tools or an insulin pen that has a memory feature that will indicate if the dose was given and when

Additional comments
Recall that new long-acting basal insulins provide greater flexibility [24,86] Does insulin stacking (build-up of insulin in the circulation) occur with the long-acting basal insulins? [90] No, there will be a steady state reached. The steady state will take longer to reach the longer the half-life of the insulin, minimizing the fluctuations in insulin levels [90] When to consider seeking support from other HCPs? [87] Patient has surpassed 1 U/kg/day of basal insulin without sufficient FBG control Patient has recurrent episodes of hypoglycemia Patient lacks engagement in the titration process. It is important to explore reasons for lack of engagement by screening for diabetes distress When to refer to a specialist? [87] Patient has frequent episodes of unexplained hypoglycemia Patient experiences complications (allergic reactions, lack of treatment response, edema, etc.) A1C level remains above individual target after 3-6 months despite appropriate treatment initiation and optimization have occurred At any point when comfort level is exceeded with available resources. It should be openly acknowledged that if either the patient or provider thinks they are ' 'in over their head,' ' accessing additional resources is appropriate SGLT2 sodium-glucose co-transporter 2, ACE angiotensin-converting enzyme, ARB angiotensin receptor blockers, NSAIDs non-steroidal anti-inflammatory drugs

Frequent Questions and What to Do with Previous Drugs When Initiating Basal Insulin
Tables 6 and 7 outline some of the frequently encountered questions and concerns facing HCPs when initiating and titrating basal insulin.

PATIENT SUPPORT AND MEDICAL FOLLOW-UP
How to Ensure Success of Basal Insulin Management?
The success of basal insulin initiation and titration relies not only on identifying and addressing the patient and practitioner barriers but also on contact frequency with the patient. Post-initiation follow-up may occur by many means including via phone, text, email (depending on jurisdiction), cloud, or virtual consult. Regular contact presents an opportunity to provide or revisit diabetes education, to provide support to patients on how to effectively selfmanage their disease and to identify any causes of concern [3,34]. Furthermore, titration should be revisited when the patient is not achieving goal, hypoglycemia occurs, or there is a change in the insulin type or brand (e.g., biosimilar) [87].
The panel provides guidelines for medical follow-up with patients in Box 2.

CONCLUSION
Several factors underlie the importance of the initiative put forth by this expert panel: there is a rising prevalence of diabetes [98]; half of the T2D population is not at target, among which 61% were receiving insulin therapy [99], suggesting delayed insulin initiation and intensification; there are multiple titration algorithms to choose from which adds to the confusion and complexity for patients and providers; and the arrival of new long-acting basal insulins and other pharmacological and technological advances that require consideration. This document was developed by a multidisciplinary panel to address frequently asked questions on insulin initiation and titration, and it establishes simple and practical guidelines for diabetes HCPs for effective initiation and titration of basal insulin, with the intent that it may translate to effective glycemic outcomes in clinical practice.

Compliance with Ethical Guidelines
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

ACKNOWLEDGEMENTS
Funding. This publication was supported by Sanofi-Aventis Canada (Laval, Quebec), who funded editorial and managerial support in the preparation of this publication, provided by a third party, HIT Global Consulting Services Inc. The article processing charges were also funded by Sanofi-aventis Canada (Laval, Quebec).
Medical Writing and Editorial Assistance. The manuscript was designed, drafted, and edited by the panel with the help of medical writer, Maria Ferraiuolo of HIT Global Consulting Services Inc. The authors, individually and collectively, were responsible for content and editorial decisions.
Authorship. The manuscript was conceived by the panel of experts recognized here as the co-authors. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. All authors had full access to all of the data used for this article and take complete responsibility for the integrity and accuracy of the data analysis.
Disclosures. Lori Berard has received consultancy/advisory board honorarium from Sanofi, Novo Nordisk, Eli Lilly, BD, and MontMed. Noreen Antonishyn has received consultancy/advisory board honorarium from Sanofi. Kathryn Arcudi has received consultancy/advisory board honorarium from Janssen, Abbott Nutrition, Astra Zeneca, Eli Lilly, and Sanofi. Sarah Blunden has received consultancy/advisory board honorarium from Ascencia, Abbott Diabetes, Eli Lilly, Medtronic, Roche Diagnostics, and Sanofi. Alice Cheng has received consultancy/advisory board honorarium, speaker honorarium, or research support from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, Servier, and Takeda. Ronald Goldenberg has received consultancy/advisory board honorarium, speaker honorarium, or research support from Eli Lilly, Novo Nordisk, and Sanofi. Stewart Harris has received consultancy/advisory board honorarium or research support from Sanofi, Novo Nordisk, AstraZeneca, Bi/ Lilly, Merck, and Janssen. Shelley Jones has received consultancy/advisory board honorarium from Abbott, AZ, Janssen, Eli Lilly, Merck, Novo Nordisk, and Sanofi. Upender Mehan has received consultancy/advisory board honorarium or unrestricted funding from Sanofi, AstraZeneca, Amgen, Janssen, Novo Nordisk,