going flat out for glycemic control: the role of new basal...

Supplement to Clinician Reviews | Vol 28, No 4 | November/December 2018 S1

FREE 1.5 CME/CE

CREDIT

Available at clinicianreviews.com

ACTIVITY OVERVIEW

Current type 2 diabetes mellitus (T2DM) guidelines emphasize individualizing care and prioritizing treatment regimens that mini-mize hypoglycemia and weight gain. Several new insulins have recently been approved, some of which are available in concentra-tions not previously available in the United States. Among these are next generation longer-acting (ultralong-acting) basal insulin analogues, which are associated with a lower risk of hypoglycemia than previous long- acting basal insulin analogues. With the availability of new basal insulins, there is a need to educate nurse practitioners (NPs) and physician assistants (PAs) about initiating, titrating, and individualizing insulin therapy.

This activity will review current evidence and best practices for individualizing and intensifying antihyperglycemic therapy us-ing current basal insulin options to achieve patient-centered goals in individuals with T2DM. Additionally, participants in this activ-ity will learn about the rationale for and role of different basal insulins for the treatment of patients with T2DM. To enhance the written information, embedded QR codes will feature video clips of patient cases and audio clips of faculty discussion, offering realistic insight regarding the personal and professional expe-riences of participants and expert opinions of program faculty in providing optimal diabetes care in patients with T2DM.

INTENDED AUDIENCEThis activity is intended for NPs, PAs, and other health care professionals (HCPs) with a particular interest in the clinical diagnosis and treatment of common metabolic and endo-crine diseases, especially those who provide care for or manage adult patients with T2DM.

LEARNING OBJECTIVES• Explain the role and appropriate use of next-

generation longer-acting (ultralong-acting) basal insulins for addressing the underlying pathophysiology of T2DM

• Compare next-generation longer-acting (ultralong-acting) and other basal insulins regarding therapeutic characteristics, in-cluding pharmacokinetic/pharmacodynamic profiles, efficacy, safety, and dosing

• Develop patient-centered treatment regimens that include next-generation longer-acting (ultralong-acting) insulins to minimize barriers to successful use of basal insulin therapy

CME AND CE ACCREDITATION AND CREDIT DESIGNATION STATEMENTSFor PhysiciansThe Institute for Medical and Nursing Educa-tion, Inc. (IMNE), is accredited by the Accredi-tation Council for Continuing Medical Educa-tion (ACCME) to provide continuing medical education for physicians.

IMNE designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credits™.

Physicians should claim only the credit com-mensurate with the extent of their participa-tion in the activity.

For Physician AssistantsThe American Academy of Physician As-sistants (AAPA) has determined that AMA PRA Category 1 Credit(s)™ is acceptable to meet AAPA CME requirements for PAs.

For Nurse Practitioners and NursesIMNE is accredited as a provider of continu-ing nursing education by the American Nurses Credentialing Center’s (ANCC’s) Commission on Accreditation.

This educational program provides 1.5 con-tact hours of continuing education credit.

IMNE has determined the 1.25 hours of this program will satisfy ANCC’s pharmacothera-peutics contact hour requirement for ANCC certified Clinical Nurse Specialists and Nurse Practitioners. The CEU certificate will reflect this credit.

For Certified Diabetes EducatorsANCC-accredited providers have been ap-proved by the National Certification Board for Diabetes Educators (NCBDE) as providers of continuing education (CE). Individuals seek-ing recertification from the NCBDE can use the CE contact hours received through their participation in this activity.

Going Flat Out for Glycemic Control: The Role of New Basal Insulins in Patient-Centered

T2DM Management

SUPPLEMENT TO

This activity has been peer reviewed by Clinician Reviews®.

Vanita Aroda, MDAssociate Director, Diabetes Clinical Research

Brigham and Women’s Hospital Boston, Massachusetts

This activity is provided by the Institute for Medical and Nursing Education, Inc. This activity is supported by an educational grant from Sanofi US.

NOVEMBER/DECEMBER 2018

PLEASE NOTE: There are pre-assessment questions associated with the content of this program that should be accessed at www.caringfordiabetes.com/CRinsulin prior to participating in this activity.

Davida Kruger, MSN, APN-BC, BC-ADMCertified Nurse Practitioner

Division of Endocrinology, Diabetes, and Bone and Mineral DisordersHenry Ford Health System

Detroit, Michigan

S2 November/December 2018 | Vol 28, No 4 | Supplement to Clinician Reviews

GOING FLAT OUT FOR GLYCEMIC CONTROL

CHALLENGING THE PATHOPHYSIOLOGY OF T2DM: THE ROLE OF BASAL INSULIN THERAPY An abundance of glucose-lowering agents are available for treating type 2 diabetes mellitus (T2DM). Because T2DM is a progressive disease, many individuals with T2DM eventually need insulin.1-6 As pancreatic β-cell function declines, insulin therapy becomes increas-ingly necessary.2,7,8 In the United Kingdom Prospective Diabetes Study, more than half of adults with newly diagnosed T2DM on monotherapy required addition-al therapy within 3 years, and 75% by 9 years.9 In the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial, 11.4% of adults in the standard-care arm of the trial (no insulin use at baseline) were treated with insulin within 7 years.10 Providing exogenous insu-lin can be thought of as hormone replacement therapy that addresses several core pathophysiological deficits associated with T2DM: it corrects the relative insulin deficiency seen in T2DM; lowers blood glucose, gluca-gon, and free fatty acid levels; and reverses glucotoxicity and lipotoxicity.1,4 Because many patients will eventu-ally need insulin therapy, every health care professional (HCP) who manages patients with T2DM should know

how to use this indispensable medication effectively and safely.

Current treatment algorithms from the American Diabetes Association (ADA) and the American Associa-tion of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) include basal insulin as a treatment option throughout the progression of T2DM.5,6 Indeed, insulin therapy is recommended in symptom-atic patients with newly diagnosed T2DM and/or those with elevated glycated hemoglobin (A1C; ie, A1C ≥10% per ADA or >9% per AACE/ACE).5,6 Patients who start insulin earlier in the disease process and at lower levels of A1C have a better glycemic response and likelihood of achieving glycemic goals.11 Given that many patients with T2DM may eventually need insulin therapy,9 it should be presented during the course of patient educa-tion as a reasonable therapeutic option, not as a threat or punishment.5,12

Current guidelines uniformly recommend a stepwise approach to initiating insulin therapy in T2DM, beginning with basal insulin.5,6 The ideal basal insulin matches physi-ological basal needs—and thus provides biological activity and coverage for a full 24 hours—and requires a minimal

METHOD OF PARTICIPATION To receive a maximum of 1.5 AMA PRA Cat-egory 1 Credits™ or ANCC continuing nursing education credit, participants should: • Complete the preassessment questions at

www.caringfordiabetes.com/CRinsulin• Read the entire activity • Complete the activity posttest and evaluation

at http://www.cvent.com/d/pbqrw7/7E• A CME/CE certificate will be emailed or

mailed to you upon achieving a score of 80%.

CME/CE CREDIT QUESTIONSFor questions about the content or obtaining CME/CE credit, please contact IMNE:Steve Weinman RN, CHCPEmail: [email protected] Phone: 1-609-936-7015Activity Release Date: December 1, 2018 Expiration Date: November 30, 2019

DISCLOSURESIt is the policy of IMNE to ensure fair balance, independence, objectivity, and scientific rigor in all programming. All individuals involved in planning (eg, faculty, CME/CE provider staff, and educational partner staff) are expected to disclose any significant financial relationships with commercial interests over the past 12 months. It is also required that faculty iden-tify and reference off-label product or inves-tigational uses of pharmaceutical agents and medical devices.

Resolutions of conflict of interest have been made in the form of external peer review.

The following disclosures have been made:

FacultyVanita Aroda, MD Consultant: Novo Nordisk; SanofiResearch Grants: AstraZeneca/Bristol-Myers Squibb; Calibra; Eisai; Janssen; Novo Nord-isk; Sanofi; Theracos

Davida Kruger, MSN, APN-BC, BC-ADMAdvisory Board: Abbott; Dexcom; Eli Lilly; Intarcia; Janssen; Novo Nordisk; SanofiSpeakers’ Bureau: Abbott; AstraZeneca; Boehringer Ingelheim; Dexcom; Eli Lilly; Insulet; Janssen; Novo Nordisk; ValeritasResearch Grants: AstraZeneca; Dexcom; Eli Lilly; The Leona M. and Harry B. Helmsley Charitable Trust; Lexicon; Novo NordiskStock: Dexcom

IMNE StaffAll staff of IMNE in a position to influence content have filed statements of disclosure with the continuing education provider. Any conflicts of interest were identified and re-solved prior to their involvement in planning this activity. These disclosures are available for review by contacting Steve Weinman at 1-609-936-7015 or [email protected].

Amy CarbonaraVice PresidentMs. Carbonara has nothing to disclose.

Margery Tamas, HBSE, MPHEditorial ManagerMs. Tamas has nothing to disclose.

Steve Weinman, RN, CHCPDirector of AccreditationMr. Weinman has nothing to disclose.

External CME/CE ReviewersMartin Quan, MDDr. Quan has nothing to disclose.

Darilyn Paul, APRNMs. Paul has nothing to disclose.

DISCLAIMERThis activity is designed for HCPs for edu-cational purposes. Information and opinions offered by the faculty/presenters represent their own viewpoints. Conclusions drawn by the participants should be derived from care-ful consideration of all available scientific information. While IMNE makes every effort to have accurate information presented, no warranty, expressed or implied, is offered. The participant should use his/her clinical judgment, knowledge, experience, and di-agnostic decision-making before applying any information, whether provided here or by others, for any professional use.

COMMERCIAL SUPPORT ACKNOWLEDGMENTThis activity is supported by an educational grant from Sanofi US.


FIGURE 1 Pharmacodynamic Response with Basal Insulin Analogues in Clamp Studies15,16

Abbreviations: GIR, glucose infusion rate; U, units.

number of injections (eg, once-daily).13,14 The ideal basal in-sulin would also work as consistently in the first 12 hours as in the last 12 hours, and work consistently from day to day and from patient to patient.13,14

Currently, there are several different basal insu-lins approved by the US Food and Drug Administration (Table 1).15 The most commonly used insulins contain 100 units of insulin per mL (U-100). Concentrated insu-lins are also available, at concentrations of 200 units/mL

(U-200), 300 units/mL (U-300), and 500 units/mL (U-500).15 HCPs should be aware of important differenc-es in the time-action profiles of basal insulins (Table 1, Figure 1).15 It is also important to note that switching from one basal insulin to another may require dose adjustment.15

The oldest basal insulin still available in the United States is neutral protamine Hagedorn (NPH) insulin, also called isophane insulin.15 NPH insulin is the least expen-sive of the basal insulins, but its biological activity is highly

TABLE 1 Currently Approved Basal Insulins15

Conc. Insulin Onset Time Time to Maximum Concentration Duration of ActionTime to Reach Steady State

U-100 NPHa 1 to 2 h Variable Variable, up to 24 h —

U-100 Detemirb — 6 to 8 h 7.6 to >24 h —

U-100 Glargineb,c — — 10.8 to >24 h —

U-100 Degludecb — 12 h >42 h 3 to 4 d

U-200 Degludecb — Comparable to U-100 degludec — —

U-300 Glargineb — 12 to 16 h 16 to >36 h <5 d

U-500 Regular humana

<15 min 0.5 to 8 h 13 to 24 h —

Abbreviations: Conc., concentration; NPH, neutral protamine Hagedorn; U, units.a Human insulins; b Analogue insulins; c Biosimilar insulins have equivalent characteristics.

These graphs show how a continuous

glucose infusion was

adjusted to keep blood

glucose levels as flat as

possible with older and newer

basal insulin analogues

U-100 detemir (0.4 U/kg)15

Time After Injection, hours

U-100 glargine (0.4 U/kg)16

U-300 glargine (0.4 U/kg)15,16

U-100 degludec (0.4 U/kg)15

3

2

1

0

3

2

1

0

3

2

1

0

3

2

1

00 6 12 18 24 30 36 42

GIR

, mg

/kg

/min



TABLE 2 How to Use Pattern Management to Adjust Basal Insulin25-28

Pattern Observed25-28 Action to Take25-28

All readings above targets Increase basal dose

PPG readings above targets Add GLP-1 RA, SGLT2i, or DPP-4iAdd/increase prandial insulin dose

Hypoglycemia Decrease basal dose

Frequent, unpredictable glycemic fluctuations Investigate lifestyle, activity, and alcohol habitsEvaluate meal/carbohydrate intakeLook for hypertrophiesMay be a pump candidate

Early morning glucose levels are not at target Increase/decrease bedtime dose accordingly

Abbreviations: DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; PPG, postprandial plasma glucose; SGLT2i, sodium-glucose cotransporter-2 inhibitor.

variable, and it has a pronounced peak.5,15,17 The peak can vary from day to day and from person to person.17 The stat-ed duration of action of NPH insulin is “variable, and up to 24 hours,” and twice-daily dosing is typical, although some patients may be able to use once-daily dosing.8,15,18 In a large database study, an average of 1.6 doses/d of NPH in-sulin was used by patients with T2DM who were managed exclusively on insulin therapy.19 Importantly, NPH insulin requires thorough resuspension prior to injection; failure to do so can result in glucodynamic effects that are twice or half as large as intended.20

The time-action profiles of basal insulin ana-logues more closely resemble that of the ideal insulin (Figure 1). U-100 detemir and U-100 glargine have more consistent action from day to day than NPH insulin.17,18 However, for patients with T2DM man-aged exclusively with insulin therapy, the average number of basal doses per day still exceeds 1 (1.4 for U-100 detemir vs 1.1 for U-100 glargine, respectively), consistent with a duration of action of <24 hours.19

U-100 degludec, U-200 degludec, and U-300 glargine are nearly peakless and have durations of action >36 hours (Table 1, Figure 1).15,16,21-23 Pen injection devices are associated with significantly better out-comes in A1C reduction, hypoglycemia, adherence, and persistence, and are generally preferred by pa-tients over vial-and-syringe insulin delivery.24

Clearly, HCPs have many decisions to make in se-lecting a basal insulin for their patients with T2DM. Choices such as once- or twice-daily dosing, the need for resuspension, variability in peak effect, and selec-tion of delivery device have important practical impli-cations and need to be discussed with patients. The following sections of this activity demonstrate how to individualize therapy for patients with T2DM using currently available insulins.

GOOD VS BETTER CHOICES IN BASAL INSULIN THERAPY: REDUCING HYPOGLYCEMIA WITH BASAL INSULIN ANALOGUESInsulin is the oldest treatment for diabetes. It is consid-ered to be the most efficacious agent for reducing blood glucose, and, for many patients with T2DM, it is the most appropriate treatment option. Current guidelines recom-mend initiating basal insulin at a weight-based dose of 0.1 to 0.2 U/kg/d.5,6 Alternatively, the ADA recommends initi-ating basal insulin at 10 U/d,5 and the AACE recommends initiating it at 0.2 to 0.3 U/kg/d if A1C is greater than 8%.6 Uptitrating from the initial dose until the fasting blood glu-cose (FBG) target is reached is the key to successful glyce-mic control with insulin therapy.5 Blood glucose patterns, from patient self-monitoring or continuous blood glucose monitoring records, provide a wealth of information that can be used to adjust insulin therapy (Table 2). Current guidelines recommend that patient blood glucose records be reviewed at every office visit.29

Several algorithms for self-adjusted dosing have been evaluated in clinical trials; such dosing appears to be as safe and effective as dose adjustment by HCPs, with no single “best” self-titration algorithm observed (Table 3).30 The algorithms specified in the ADA and AACE/ACE guidelines were developed for use with U-100 NPH, detemir, and glargine.5,6,30 Of note, since U-100 or U-200 degludec and U-300 glargine have a duration of ac-tion that exceeds 24 hours, dose adjustments should be made less frequently in patients using these insulins.15,31,32

• Insulin can be used at any time in the progression of T2DM

• U-100 or U-200 degludec and U-300 glargine are nearly peakless, longer-acting basal insulin ana-logues


The preferred algorithm for insulin dose adjust-ment may vary between HCPs and patients.30 For exam-ple, in a small study (N = 186) comparing self-titration algorithms for U-100 glargine initiation, HCPs preferred the algorithm used in current guidelines, which re-quires calculation of a 3-day average FBG (Table 3, al-gorithm 2), while patients preferred the Implementing New Strategies With Insulin Glargine for Hyperglycemia Treatment (INSIGHT) clinical trial algorithm, in which insulin is adjusted by 1 U per day (Table 3, algorithm 1), a method patients described as simple, convenient, and safe.30 Similar reductions in FBG were reported regard-less of the algorithm used, and only 1 episode of hypo-glycemia was reported in this trial, demonstrating that patients can self-titrate with appropriate instruction.30

Hypoglycemia is the most common adverse effect associated with insulin therapy.15,33 To avoid inappropri-ate changes in insulin dose, HCPs may need additional data to determine why unexpected high or low glucose readings are occurring. Underlying factors leading to hy-poglycemia include mistimed insulin doses in relation to meals, math errors when calculating doses, miscalcula-tion of carbohydrate content, physical activity, missed meals, use of insulin in conjunction with other medica-tions that potentiate insulin’s effects, and even intention-al overdose.15,33,34

Insulin-induced hypoglycemia is the most frequent cause of emergency department visits and hospitaliza-tions among patients who use any medication to reduce blood glucose.33,35 In 2015, the costs of a hypoglycemia episode for which medical consultation was sought were estimated at $332 for outpatient management,

$1163 for emergency department management, and $16,794 for emergency and inpatient management.36

Severe hypoglycemia, by definition, requires assis-tance from others to treat and is potentially fatal.29,37 Fur-thermore, the risk of major adverse cardiovascular events (MACE) or death is generally increased within 1 year of an episode of severe hypoglycemia.38 But insulin therapy per se did not appear to increase the risk of MACE in cardio-vascular outcomes trials of insulin therapies: the ORIGIN trial demonstrated that U-100 glargine has a neutral risk of MACE relative to standard care, and there was no dif-ference in the risk of MACE between U-100 glargine and U-100 degludec in a Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Pa-tients With Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE).10,39

Even if it is not severe, hypoglycemia of any degree is always clinically significant.29,37 For example, nocturnal hypoglycemia may interfere with sleep—and because the patient is sleeping, the low glucose level may not be detected early enough to self-treat.40 Nonsevere noctur-nal hypoglycemia may require hours of recovery time, impairing productivity, affecting attendance at work, and reducing quality of life.40-42 However, patients may not consult an HCP for nonsevere episodes. For this rea-son, HCPs need to inquire about hypoglycemia at every office visit because patients may not recall or volunteer this information.29 Not surprisingly, hypoglycemia is a common reason for insulin discontinuation.43,44

Meta-analyses of clinical trials demonstrate that all available basal insulins are equally effective at re-ducing A1C (Table 4).45,46 However, basal insulins

TABLE 3 Characteristics of Five Frequently Cited Insulin Titration Algorithms for Older Basal Insulin Analogues30

Algorithm 1 2 3 4 5

Source of algorithm INSIGHTAT.LANTUS option 1, ADA,

AACE/ACE option 1PREDICTIVE

303AACE/ACE

option 2Treat-to-Target Trial,

AT.LANTUS option 2, etc

Frequency of adjustment Daily Every 3 days based on 3-day mean FBGa Weekly based on 3-day mean FBG

FBG, mg/dL Dose adjustments, U (unless otherwise specified)

<70 −2 −2 −3 −20% of TDD −2

70-125 0 0 0 0 0

126-143 +1 +2 +3 +1 +2

144-161 +1 +2 +3 +10% of TDD +4

162-179 +1 +2 +3 +10% of TDD +6

≥180 +1 +2 +3 +20% of TDD +8

Abbreviations: AACE, American Association of Clinical Endocrinologists; ACE, American College of Endocrinology; ADA, American Diabetes Association; FBG, fasting blood glucose; TDD, total daily dose; U, units. aFBG as measured before first meal of the day.



vary in terms of hypoglycemia risk, and the clearest differences are observed for nocturnal hypoglycemia (Table 4).46-48,51 NPH insulin was more likely to cause nocturnal hypoglycemia than U-100 glargine, but U-100 glargine and U-100 detemir were equally likely to cause nocturnal hypoglycemia.48 Of all the available basal insulins, U-300 glargine and U-100 degludec are the least likely to cause nocturnal hypoglycemia.46,47,51 A head-to-head study found that U-300 glargine and U-100 degludec have equivalent risks of nocturnal hy-poglycemia.52 Comparing rates of severe hypoglycemia among basal insulins is difficult, since it is infrequent in short-term clinical trials.45 However, in DEVOTE—a double-blind, 2-year trial comparing U-100 glargine and U-100 degludec in patients at high risk of cardio-vascular events—there was a 40% lower risk of severe hypoglycemia with U-100 degludec.39 Importantly, there was no difference in the rate of MACE between U-100 glargine and U-100 degludec.39

According to ADA guidelines, the choice of insulin for a patient with T2DM depends on their history of hy-poglycemia irrespective of their level of glycemic con-trol.5 The ADA recommends NPH insulin for patients with T2DM only if they do not have a history of hypogly-cemia.5 Additionally, U-100 NPH insulin regimens are best suited for patients with a predictable lunchtime.8 The ADA guidelines note that U-100 glargine and U-100 detemir are less likely to cause hypoglycemia than U-100 NPH insulin and that U-100 or U-200 degludec or U-300 glargine may further reduce this risk and are preferred for patients with frequent hypoglycemia.5

This case study will consider 4 potential treatment regimen modifications for an adult with insulin-treat-ed T2DM who has experienced frequent episodes of severe hypoglycemia (Table 5).

Please review Katonya’s case now. Use your smart phone or mobile device to scan here for a video recording of a simulated clinician-patient scenario.

What if you warned Katonya about the consequences of not adhering to insulin therapy?

T2DM is largely self-managed, with occasional guidance and support from HCPs.53 Approximately 15% of adults with T2DM in the United States use both insulin and an oral medication in addition to diet and exercise,54 like Katonya, and these patients need sup-port in using insulin safely and effectively.53 Katonya at-tributes 2 of her 3 episodes of severe hypoglycemia to common mistakes that patients make with insulin ther-apy: administering the insulin but skipping a meal or accidentally drawing up a dose larger than intended.33 However, the assumption that Katonya can reduce the risk of severe hypoglycemic events by simply improv-ing her adherence to instructions for insulin use is not necessarily productive for identifying other underlying reasons for her recent hypoglycemic events.

She states that she switched from her initial insu-lin, U-100 glargine once-daily at bedtime, to U-100 NPH to reduce her out-of-pocket costs when her employer instituted a high-deductible health insurance plan. Katonya varies her insulin dose according to her FBG level; although the algorithm she’s using to self-titrate

TABLE 4 Therapeutic Characteristics of Currently Available Basal Insulins vs Those of U-100 Glargine in Patients With T2DM39,47-51

U-100 NPH48 U-100 Detemir48 U-100 Glargine Equivalent49 U-300 Glargine47 U-100 Degludec39,50,51

Insulin dose = 12% 4%

A1C = = = = =

Weight = 0.77 kg = 0.28 kg =

Overall hypoglycemia = = = 14% 26%a

Nocturnal hypoglycemia

37% = = 31% 29%

Severe hypoglycemia = = = = 35% - 40%

Abbreviations: A1C, glycated hemoglobin; NPH, neutral protamine Hagedorn; T2DM, type 2 diabetes mellitus; U, units.Arrows indicate statistically significant difference at P<.05 or better.aAll confirmed hypoglycemia during maintenance period, in meta-analysis.


her doses is not specified, episodes of severe hypogly-cemia have occurred only since she switched to NPH insulin. It appears that when Katonya switched to NPH insulin, she continued taking the entire dose of her previous insulin at bedtime. Typically, the total dose of NPH insulin would be split over 2 injections: at break-fast and dinner or at breakfast and bedtime. Since U-100 NPH is shorter acting than U-100 glargine, its unpre-dictable peak action will occur while she is sleeping; the peak will be even more unpredictable if she isn’t resuspending the dose.20

Beyond any potential concerns about adher-ence, there are other reasons why U-100 NPH is not a suitable choice for Katonya. The scheduling de-mands of Katonya’s work are mostly out of her con-trol and result in an unpredictable lunchtime. Her emergency department visits and the evidence of hypoglycemia in her blood glucose monitoring record provide ample justification for switching her to a more predictable basal insulin.

What if you increased her basal insulin dose?

The ADA recommends A1C less than 7% as a reason-able general target, with FBG between 80 and 130 mg/dL.5 A more-stringent target of A1C less than 6.5% may be reasonable in patients with a long life expectancy and no significant cardiovascular disease and treated only with lifestyle changes and/or metformin, if this goal can

be achieved without hypoglycemia or polypharmacy.5 The AACE/ACE generally recommends A1C 6.5% or less, but for insulin-treated patients with T2DM, the general target is A1C less than 7%; the AACE/ACE guidelines of-fer a similar rationale to that of the ADA for individualiz-ing glycemic targets.6 Conversely, a less-stringent target of A1C less than 8% is recommended for patients with advanced microvascular complications or extensive comorbidities, long-standing diabetes, limited life expectancy, or a history of severe hypoglycemia.5,6

Katonya is young and has no major comorbidities, but her A1C is 8.2%. Yet her recent episode of severe hypoglycemia and the evidence of nocturnal hypogly-cemia—based on her description of symptoms that are consistent with this condition (nightmares, feeling tired even after a full night’s sleep) and revealed in her blood glucose monitoring records—indicates that Katonya’s glucose levels have wide variations (her blood glucose must be spiking frequently to offset the effect of her hypoglycemic episodes enough for her to have A1C = 8.2%). Wide glycemic variation is a well-known risk factor for severe hypoglycemia, and accumulating evidence suggests that it is also a risk factor for MACE.55-58

Taking her full daily dose of insulin as a single injection of NPH would account for this pattern, and these varia-tions would be exacerbated if she overtreats her episodes of low blood glucose with high carbohydrate intake.

Since the glucose-lowering effect of insulin is largely dose-dependent, it is tempting to think that increasing Katonya’s insulin dose will reduce her A1C level. How-ever, her total daily insulin dose is approximately 0.5 to 0.6 U/kg. Insulin doses above 0.5 U/kg may have little additional effect on FBG levels,59 and increasing her

TABLE 5 Highlights from Katonya’s Medical Records

Personal/Social History Medical History Physical Examination/Laboratory Results Current Medications

Age = 41 years

Married for 22 years

Co mmercial laundry supervisor

Works full time

Hi gh-deductible health insurance plan through employer

T2 DM diagnosed 12 years ago

A1C = 8.2%

FBG = 70-170 mg/dL

Evidence of hypoglycemia in BG diary

Height = 5 ft, 10 in (178 cm)

Weight = 276 lb (125 kg)

BMI = 39.6 kg/m2

BP = 130/80 mm Hg

eGFR >90 mL/min/1.732

TC = 180 mg/dL

HDL-C = 60 mg/dL

LDL-C = 90 mg/dL

TG = 150 mg/dL

M e tformin ER 1500 mg/d (maximum tolerated dose)

U- 100 NPH insulin, 50 to 60 U/d

Li sinopril/HCTZ 20 mg/ 25 mg, once-daily

Rosuvastatin 20 mg/d

All medications taken at bedtime

Abbreviations: A1C, glycated hemoglobin; BG, blood glucose; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; ER, extended release; FBG, fasting blood glucose; HCTZ, hydrochlorothiazide; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NPH, neutral protamine Hagedorn; T2DM, type 2 diabetes mellitus; TC, total cholesterol; TG, triglyceride; U, units.



insulin dose is likely to cause even more hypoglyce-mia.60 In the video, Katonya recognizes this risk and is frustrated by the HCP’s recommendation to increase her basal insulin dose; doing so is almost certain to cause another frightening, expensive, and dangerous episode of severe hypoglycemia, and she fears that it could jeopardize her continued employment. Cor-recting the NPH insulin dosing is necessary before considering additional interventions to improve her postprandial control (to reduce her A1C without further reducing her FBG). For all of these reasons, increasing her insulin dose is not the correct answer.

What if you decreased Katonya’s basal insulin dose?

Katonya has been able to rule out meal skipping, dose miscalculation, and increased physical activity as reasons for her most recent episode of severe hypogly-cemia. She administers her current insulin from a vial using a syringe. Current guidelines recommend at least temporary insulin dose reduction if the cause of hypo-glycemia cannot be attributed to simple errors such as missing a meal or miscalculating a dose.5,6,29 Reducing Katonya’s basal insulin dose should reduce the risk of hypoglycemia, but her A1C level is higher than would generally be recommended for someone who is her age with her health history.

In the video, Katonya was relieved to report that she has not experienced further episodes of severe hypogly-cemia but was concerned when she learned how high her A1C had risen; she recognized that this could result in worse outcomes in the long term. Reducing her in-sulin dose will drive her A1C higher, so dose reduction alone is not the best answer because it will also increase her risk of high glucose levels. It’s a short-term fix but not a long-term solution, as the risk of both microvas-cular and macrovascular complications increases with increasing A1C in patients with T2DM.61,62

What if you switched her to a different basal insulin?

A more predictable, longer-lasting basal insu-lin could be a good choice for Katonya. We know that Katonya previously used U-100 glargine, with-out hypoglycemia. Switching her back to U-100

glargine (or to the recently approved U-100 glargine equivalent) is a reasonable option.5,15 Katonya has had 3 episodes of severe hypoglycemia in the past year as well as other episodes of hypoglycemia. Therefore, switching her to U-100 or U-200 degludec or U-300 glargine would also be a reasonable option.5

In a double-blind crossover study of patients with T2DM with 1 or more risk factors for hypoglycemia, insulin degludec was associated with a significantly lower risk of overall and nocturnal hypoglycemia over 32 weeks than U-100 glargine.63 Recently, the head-to-head Efficacy and Safety of Toujeo Versus Tresiba in Insulin-Naive Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Oral Antihypergly-cemic Drug(s) ± GLP-1 Receptor Agonist (BRIGHT) study found that U-300 glargine and U-100 degludec offer equivalent glycemic control in insulin-naive pa-tients.52 In addition, in 2 real-world studies relevant to Katonya’s case, patients with T2DM and approximate-ly A1C 9% at baseline who switched from one basal insulin analogue to another experienced A1C reduc-tions of approximately 0.5% at 6 months regardless of the type of insulin they switched to.64,65 In patients who switched from U-100 glargine or U-100 detemir to U-300 glargine or U-100 or U-200 degludec, hypogly-cemia (blood glucose <70 mg/dL) was reduced by the switch, and the difference was statistically significant in patients who switched to U-300 glargine.65

ACTION PLAN FOR KATONYAKatonya is a young patient with T2DM who works a full-time job with a demanding schedule. To stay healthy in the long term, Katonya needs better glycemic control, but her hypoglycemic episodes must be alleviated in order to keep her healthy in the short term.

Severe hypoglycemia is itself a risk factor for further episodes of hypoglycemia.29 Patients at high risk of hy-poglycemia include:

• Those with a long duration of diabetes63,66

• Those with a high risk of MACE56,63,67

• Those with hypoglycemia unawareness29,63 • Those with unexplained, clinically relevant blood

glucose fluctuations14,55-57

• Older adults68,69

• Adults with multiple comorbidities66

NPH insulin has a notoriously variable duration of action, but it may be a suitable choice for patients with T2DM who do not have a history of hypoglyce-mia, have a regular lunchtime, and balance their car-bohydrate intake across meals.5,8 For these reasons, NPH insulin is not likely to be the best option for Katonya; since she has a history of hypoglycemia and an irregular lunch schedule, a once-daily injection


of a longer-acting insulin would be a better choice. Of the available basal insulins, U-100 glargine, U-100 glargine equivalent, U-100 or U-200 degludec, or U-300 glargine would be suitable.

The decision about which insulin to choose will likely depend on the out-of-pocket cost. Katonya ex-presses concern about prescription copayments, so this will be an important point for shared decision making. Insurance formularies and prescription copayments vary widely by insurer, location, and plan type.70,71 Out-of-pocket medication costs are a significant concern for many patients with T2DM, and individuals with high-deductible insurance plans like Katonya’s may be at in-creased risk for emergency department utilization.72,73 A study of privately insured patients conducted during 2011 found that adherence to diabetes medications declined when patients’ out-of-pocket cost exceeded $50/month or when total out-of-pocket costs for all medications exceeded $90/month.72

To ensure that Katonya has no further episodes of severe hypoglycemia, the most appropriate course of action is to switch to a basal insulin analogue—ideally one of the newer, long-acting analogues (U-100 or U-200 degludec or U-300 glargine) since they have the lowest hypoglycemia risk—or U-100 glargine or U-100 glargine equivalent if the newer insulins are not available (Table 4). It would be prudent to initiate the new insulin at a lower dose since Katonya is experiencing hypoglycemia (Table 3), then use blood glucose monitoring and pattern management to adjust the dose as needed.

BETTER VS BEST CHOICES IN BASAL INSULIN THERAPY: IMPROVING INJECTION COMFORT WITH CONCENTRATED BASAL INSULIN ANALOGUESOne of the great strengths of insulin therapy is that the doses are individualized. Patients with T2DM who are treated with basal insulin can require widely varying total daily doses to reach their glycemic goals. For example, in the large-scale ORIGIN trial, insulin glargine was titrat-ed to achieve a fasting plasma glucose goal of less than 95 mg/dL, and, after 1 year, the median dose was 0.31 U/kg, with an interquartile range of 0.19 to 0.46 U/kg (approxi-mately 16-38 U/d, based on a mean weight of 83 kg).10 Patients who are insulin resistant may require very large

doses of insulin to maintain glycemic control.74 Among patients with T2DM, some of the more common eti-ologies of insulin resistance include obesity and nonal-coholic fatty liver disease.75 Concomitant medications for comorbid diseases can also increase insulin resis-tance.76 Corticosteroids—used to manage inflammatory conditions including asthma, rheumatoid arthritis, and inflammatory bowel disease—are commonly rec-ognized as agents that increase insulin resistance and raise blood glucose levels.76

Large insulin doses required by some patients with T2DM may exceed the amount of insulin that can be delivered in a single injection using a pen injector device. U-100 insulin pens contain 3 mL of insulin, or 300 U/pen, but the devices can administer only 60 to 80 U in a single injection.15 Patients who require larger doses of basal insulin face the inconvenience of split-ting the dose between 2 (or more) injections. However, another option is to use a concentrated basal insulin (Table 1). An important advantage of concentrated in-sulins is that they permit the dose of insulin to be ad-ministered with a smaller volume of injectate than the same dose of a U-100 basal insulin. This is especially advantageous for patients who require large doses of insulin, as large injectate volumes may be uncomfort-able to inject.77 For many years, the only concentrated insulin available in the United States was U-500 regu-lar human insulin.15 This highly concentrated insulin is recommended for patients who need greater than 200 U/d.15,74 U-500 regular human insulin has both prandial and basal characteristics: it has the rapid onset time of short-acting regular human insulin (<15 min) but a much longer duration of action (13-24 hours) than short-acting regular human insulin (Table 1).15 The total daily dose of U-500 regular human insulin is split between 2 or 3 daily injections and administered at intervals throughout the day.15 New additions to the concentrated insulin armamentarium are the basal in-sulin analogues U-200 degludec and U-300 glargine, which are administered only once-daily.15 The dura-tion of action of each of these insulins is longer than for U-500 regular human insulin (Table 1).15

All concentrated insulins sold in the United States are available in pens.15 With pens, the dose (in units) is simply dialed up regardless of the concentration of the insulin inside. This has the potential to avoid serious dosing errors, such as those that have been documented when U-500 regular human insulin was administered from vials using syringes intended for U-100 insulin.78,79

In this case study, we will discuss 4 potential treat-ment regimen modifications for an adult with T2DM who is using a high dose of insulin and is reluctant to further intensify his glycemic control (Table 6).

• Review blood glucose monitoring records at every office visit

• Basal insulins differ in their risk of hypoglycemia but not in their efficacy

• With appropriate education, most patients can self-titrate basal insulin safely



Please review Frank’s case now.

What if you tell Frank to split his basal insulin dose?

It is necessary to determine whether Frank is adher-ent to his insulin therapy and to assess his insulin ad-ministration technique—but it needs to be made clear that the intention is to help him achieve his goals rather than punish him for not doing as he was told.53,80,81 Scold-ing patients is likely to be counterproductive.82 Instead, HCPs should ask patients about any successes, con-cerns, struggles, and questions and whether decisions the patient has made have helped them reach treatment goals.53 This information can help HCPs and patients work together to create realistic action plans.53

Frank mentions missing a few injections when he’s busy, and more daily injections may increase the number of skipped doses. About one-third of patients with T2DM report missing a scheduled dose of basal insulin at least 1 day each month; on average, patients state that doses are missed 3.3 days/month.83 It is possible that patients are skipping more doses than this, but obtaining accurate information from patients about the dosing and tim-ing of insulin injections may be very challenging.84 The most common reasons that patients cite for skipping in-sulin doses are being too busy, traveling, and skipping a

meal.83 Skipping insulin doses may have contributed to Frank’s elevated A1C level.

Although adherence to basal insulin therapy is gen-erally associated with lower overall health care costs than nonadherence, the difficulties that patients encounter in adhering to therapy should not be underestimated.53,85 In particular, HCPs should keep in mind that efforts to main-tain day-to-day behaviors for diabetes care may be chal-lenged by many factors, including mood fluctuations, relationships, external obstacles, and environments, and that maintaining consistency may be difficult for patients who are facing change.86 An empathetic approach to the demands of self-management is advised.53,86

What if you increased his basal insulin dose?

Frank’s current A1C is 8.1%; given his age, lack of hypoglycemia, and lack of comorbidities, A1C less than 7% would be considered a reasonable goal.5,6 Frank is currently using up to 150 U of U-100 glargine daily, split into 2 doses that are administered at different times of the day. However, the prescribing information for U-100 glargine and U-100 glargine equivalent state that they are indicated for once-daily administration.15 His maximum total daily dose is 1.23 U/kg (150 U divided by 122 kg). Although technically there is no maximum dose of insulin,87 basal insulin doses above 0.5 U/kg/d may have little incremental effect on A1C for most pa-tients with T2DM.59 However, for patients with insulin resistance, further reductions in blood glucose levels may indeed be achievable with higher insulin doses.74

TABLE 6 Highlights from Frank’s Medical Records

Personal/Social History Medical History Physical Examination/Laboratory Results Current Medications

Age = 62 years

Married for 31 years

C ustomer service representative

W orks part time; start time varies by 3 to 4 hours throughout the week

S ilver-level health insurance plan from state health exchange

T2 DM diagnosed 15 years ago

A1C = 8.1%FBG = 154 mg/dLNo evidence of hypoglycemia in BG diaryHeight = 5 ft, 8 in (173 cm)Weight = 240 lb (109 kg)BMI = 36.5 kg/m2 BP = 126/72 mm Hg eGFR = 75 mL/min/1.732

TC = 166 mg/dLHDL-C = 38 mg/dL LDL-C = 100 mg/dL TG = 140 mg/dL

M etformin ER 2000 mg/d (maximum dose)

U -100 glargine equivalent, 140 to 150 U/d, split between 2 doses

A mlodipine/valsartan 10 mg/ 320 mg, once-daily

Atorvastatin 10 mg/d

Aspirin 81 mg/d

A ll medications taken at bedtime except aspirin and 1 dose of insulin taken in the morning

Abbreviations: A1C, glycated hemoglobin; BG, blood glucose; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; ER, extended release; FBG, fasting blood glucose; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; T2DM, type 2 diabetes mellitus; TC, total cholesterol; TG, triglyceride; U, units.


Only limited data are available to guide treatment deci-sions in patients with T2DM who are unable to attain glycemic goals using high doses of insulin.88

In the previous case (Katonya), we learned that in-creasing the insulin dose in a patient who is experiencing hypoglycemia on their current insulin dose is never the correct choice. However, Frank does not have a history of hypoglycemia. Increasing his insulin dose may indeed be an appropriate approach, but in and of itself is only partly correct. In the video, Frank makes it clear that he is unhappy with the HCP’s recommendation to further increase the dose of his current insulin. Frank is already frustrated by the discomfort of his insulin injections; in-creasing his insulin dose without changing the insulin concentration will make the injections even more un-comfortable or increase the number of injections. HCPs are encouraged to fit insulin regimens to patients8; ask-ing patients to rearrange their lives to suit the needs of a treatment regimen is inconsistent with the principles of patient-centered care and is likely to reduce adherence.

What if you advised Frank to reduce his daily caloric intake?

Limiting caloric intake, especially calories from carbohydrates, may be somewhat helpful in reducing the size of Frank’s insulin doses, but it is unclear wheth-er this tactic will lower his insulin requirement dramati-cally. Glucose is derived from the carbohydrate content of food, and, for this reason, reducing carbohydrate in-take also reduces blood glucose levels. Expert opinion suggests that a healthy eating plan should derive 45% to 65% of an individual’s daily calories from carbohy-drates.89 If Frank eats 2400 kcal/d, his total carbohy-drate intake would be 1080 to 1560 kcal, or 270 to 390 g. A small study conducted in hospital inpatients with se-vere insulin resistance found that restricting carbohy-drate intake by an average of 16.5% (400 kcal/d [100 g]) reduced insulin doses by an average of 44% (from 4.8 to 2.2 U/kg/d), far more than would be predicted with calorie restriction alone.88 But the amount of in-sulin dose reduction varied markedly among study participants, ranging from 90% to unchanged, and it is unknown whether the carbohydrate restriction and dose reductions were maintained after the patients were discharged. The fat content of meals has also been shown to affect blood glucose levels and insulin doses in patients with type 1 diabetes mellitus.90

In the video, Frank also expresses frustration with weight gain that he attributes to insulin use. Basal in-

sulins may vary in their propensity to cause weight gain (Table 4). One meta-analysis found that all basal insu-lins caused approximately the same amount of weight gain.45 Another meta-analysis found that U-100 detemir and U-300 glargine may cause less weight gain than other basal insulins.46 In DEVOTE, a large cardiovascu-lar outcomes trial, weight increased in both treatment arms over 2 years: 4.2 ± 1.9 kg with U-100 glargine and 4.9 ± 2.2 kg with U-100 degludec.39 In BRIGHT, a head-to-head trial of newer basal insulin analogues, weight increased in both treatment arms over 24 weeks: 2 ± 3.8 kg with U-300 glargine and 2.3 ± 3.6 kg with U-100 degludec.52 Perceived weight gain is a commonly cited reason for discontinuing insulin therapy, but im-proved glycemic control, physical well-being, and HCP encouragement are the most common motivators for continuing insulin therapy.43

What if you switched him to a different type of basal insulin?

Switching Frank to a different type of basal insulin may reduce the discomfort associated with the volume of the injectate in his current regimen. All of the currently available concentrated insulins would enable Frank to administer his full daily dose in a single injection.15 Rel-ative to a U-100 insulin at any given dose, the injectate is half the volume for a U-200 insulin, one-third the vol-ume for a U-300 insulin, and one-fifth the volume for a U-500 insulin. Frank is currently using up to 150 U/d. U-200 degludec and U-300 glargine (900-U pen) per-mit administration of up to 160 U in a single injection.15 U-300 glargine (450-U pen) permits administration of up to 80 U in a single injection.15 The U-500 regular human insulin pen permits administration of up to 300 U in a single injection; however, because of its shorter duration of action, Frank would have to perform injections 2 to 3 times daily, so this insulin would be less suitable for him than the newer, longer-acting basal insulin analogues.

For insulin-naive patients, the initial dose of U-300 glargine is 0.2 U/kg/d and the initial dose of U-200 degludec is 10 U.15 The prescribing information recommends dose titration once every 3 to 4 days at most.15 Even less-frequent dose adjustments (ie, once- weekly) are recommended for insulin degludec based on clinical experience.32 The smallest dose increment for U-300 glargine and U-200 degludec is 2 U.15 In the BRIGHT trial, the same titration algorithm was used for U-300 glargine as for U-100 degludec (Table 7).52 Al-though U-100 glargine and U-300 glargine have markedly



different time-action profiles, U-200 degludec has the same time-action profile as U-100 degludec,15 suggest-ing that the same algorithm could be used for it. Alter-natively, a similar algorithm for insulin degludec based on clinical experience that limited dose increases to 2 U could be used (Table 7).32

For patients who are switching from older to new-er basal insulins, dose adjustment may be needed (Figure 2).15 Frank is currently using U-100 glargine equivalent and is injecting twice daily. If he switches to U-200 degludec, no dose adjustment is recommended.15 If he switches to U-300 glargine, reducing his basal dose by 20% would be recommended as a precaution against hypoglycemia based on his twice-daily injection regi-men.15 Switching from U-100 glargine to U-200 degludec has been shown to improve patient-reported outcomes among patients with T2DM who require high basal in-sulin doses.92 Among insulin-naive patients, initiating therapy with U-300 glargine is associated with better real-world persistence with insulin therapy than initiat-ing U-100 NPH, U-100 detemir, or U-100 glargine.93

New, longer-acting basal insulins tend to be more forgiving of variations in the time at which the daily injection is administered.15,94-96 Basal insulin an-alogues are typically injected at 24-hour intervals.15 U-100 degludec and U-300 glargine have been evalu-ated at injection intervals varying from 8 to 40 hours and 21 to 27 hours, respectively.94,95 No significant dif-ferences in insulin dose, change in A1C, or hypogly-cemia were observed with flexible dosing compared with fixed 24-hour dosing.94,95 The prescribing infor-mation for insulin degludec states that doses should be administered no less than 8 hours apart.15 Some flexibility in dosing intervals may be especially help-ful for people like Frank who work irregular sched-ules or rotating shifts.

In the video, Frank expresses satisfaction with the new insulin. He’s pleased that the injections are no longer uncomfortable and that he needs to inject insulin only once-daily.

ACTION PLAN FOR FRANKFrank is a 62-year-old patient with T2DM who works a part-time job with irregular hours. His treatment regi-men includes high-dose basal insulin. He is frustrated by the discomfort associated with these U-100 glargine equivalent injections and by the need for multiple daily injections.

But even with the high dose of insulin that Frank is using (1.23 U/kg/d), he is not attaining his glycemic goal of A1C less than 7%. As a general rule of thumb, increasing insulin doses beyond 0.5 U/kg/d may be ineffective,59 but patients like Frank who are insulin re-sistant may achieve further improvements in glycemic control with increasing doses.74 However, increasing Frank’s insulin dose without reducing the volume of the injections will cause further discomfort and may exac-erbate lack of adherence to insulin therapy.

Three different concentrated basal insulins are currently available in the United States: U-200 de-gludec, U-300 glargine, and U-500 regular human insulin.15 U-500 regular human insulin must be ad-ministered 2 to 3 times daily15; Frank is already hav-ing difficulty adhering to his current twice-daily injection regimen, so U-500 regular human insulin would not be the best choice for him at the current time. U-200 degludec and U-300 glargine need to be administered only once daily, and, with currently available pens, doses of up to 160 U can be given in a single injection.15 The final decision about which insulin to choose will likely depend on Frank’s insur-ance formulary and the out-of-pocket cost.

TABLE 7 Titration Algorithm for U-100 or U-200 Degludec or U-300 Glargine52,91

Median Fasting SMPG,a mg/dL

Dose Adjustment, U

BRIGHT52 U-100 or U-200 Degludec US HCP Information91

>140 +6

+2 if above goal>120 to ≤140 +4

>100 to ≤120 +2

≥80 to ≤100 0 0 if at goal

<80 or 1 symptomatic confirmed hypoglycemic episode in the preceding week

−2 or at investigator’s discretion

−2 if below goal

Abbreviations: HCP, health care professional; SMPG, self-monitored plasma glucose; U, units; US, United States.aCalculated from the last 3 measurements.


CONCLUSIONInsulin therapy addresses the core pathophysiol-ogy of T2DM by surmounting the insulin deficit that results from the loss of β-cell function, reversing glucotoxicity, and reducing blood glucose levels.1,2 Insulin therapy also suppresses hepatic glucose pro-duction and reduces plasma-free fatty acids, overcom-ing the effects of insulin resistance.1,4 Insulin is also a versatile therapy, since it can be used at any stage of disease progression and in any patient—regardless of their comorbidities.5

Basal insulin is recommended as the first step in insulin therapy for patients with T2DM.5,6 Basal insu-lins are available with intermediate, long, and very long durations of action (Table 1, Figure 1).15 The insulins U-100 degludec, U-200 degludec, and U-300 glargine all have durations of action that may exceed 36 hours.15 And, unlike some older insulins,19 these newer, longer-acting insulins need to be injected only once-daily. Furthermore, these longer-acting insulins are less likely to cause hypoglycemia than shorter-acting insulins (Table 4).46

Some patients with T2DM require high doses of in-sulin to attain glycemic control, which also increase the injection volume.5,74,77 Doses may exceed the amount that can be injected with U-100 insulin pens.15 Moreover, such injections become increasingly uncomfortable as the volume of injectate increases.77 Concentrated insu-lins reduce the volume of injectate, improving injection comfort and potentially reducing the number of injec-tions that must be administered.77,92 U-200 degludec and U-300 glargine are newer concentrated insulins as-sociated with higher patient preference and/or persis-tence with insulin therapy compared with older basal insulins.92,93

Patients encounter many barriers to the use of basal insulin therapy, including irregular schedules, variabil-ity in the peak and/or duration of action of their insulin, and out-of-pocket medication costs.17,53,72,73,83,97 HCPs are urged to share decision making with patients and adjust treatment plans so that patients can reach their clinical, psychosocial, and behavioral goals, individual-ized to their schedules and insurance plans.53 Current basal insulin analogues offer considerable flexibility for individualizing treatment regimens.

REFERENCES 1. Hanefeld M, Monnier L, Schnell O, Owens D. Early treatment

with basal insulin glargine in people with type 2 diabetes: les-sons from ORIGIN and other cardiovascular trials. Diabetes Ther. 2016;7(2):187-201.

2. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabe-tologia. 2003;46(1):3-19.

• Use shared decision making to adjust treatment plans as needed in collaboration with the patient

• Titrate newer basal insulins weekly or no more fre-quently than every 3 to 4 days

• Overly aggressive basal insulin dosing increases the risk of severe hypoglycemia without reducing A1C—don’t overbasalize to address postprandial plasma glucose excursions!

FIGURE 2 Dose Adjustments When Switching from Older to Newer Basal Insulin Analogues15

Abbreviation: U, units.aReduce dose by 20% in pediatric patients.

How many basal injections are they using

with their current insulin?

1 daily

injection

Which insulin are they

switching to?

U-100 orU-200

degludec

U-300glargine

Keep total basaldose the samea

Keep total basaldose the same

2 daily

injections

Which insulin are they

switching to?

U-100 orU-200

degludec

U-300glargine

Keep total basaldose the samea

Reduce total basal dose by 20%

If previous insulin was U-100 glargine, expect to uptitrate

beyond the former basal dose to maintain same degree of

glycemic control



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