new and emerging injectable therapies for type 2 diabetes ... · diabetes, risk for hypoglycemia...

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independent educational grant from Novo Nordisk Inc.

New and Emerging Injectable Therapies for Type 2 Diabetes for

the Internal Medicine Physician: Experts Address Common Questions

Release date: March 1, 2017Expiration date: March 1, 2018Estimated time to complete: 1.25 hours

The American College of Physicians (ACP) and ACP Internist did not produce this material and are not responsible for its content.

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Table of Contents Target Audience ..................................................................................................................................................................... 3

Learning Objectives ................................................................................................................................................................ 3

Accreditation and Disclosures ................................................................................................................................................. 3

CME Material .......................................................................................................................................................................... 3

Abstract ................................................................................................................................................................................. 4

Introduction ........................................................................................................................................................................... 4

Question 1: What are current indications for initiating insulin therapy? ................................................................................. 5

Question 2: How should insulin therapy be initiated? ............................................................................................................ 6

Question 3: What are the new and emerging basal insulin analogs and their features? ......................................................... 7

Question 4: When do you stop titrating basal insulin? ............................................................................................................ 9

Question 5: What are some of the new options for intensifying therapy when basal insulin alone has not achieved target glycemia? ....................................................................................................................................... 10

Summary and Conclusion ..................................................................................................................................................... 11

References............................................................................................................................................................................ 12

Posttest Questions ................................................................................................................................................................................16

Posttest and Evaluation ........................................................................................................................................................................17

New and Emerging Injectable Therapies for Type 2 Diabetes for the Internal Medicine Physician: Experts Address Common Questions

Author NoteLawrence Blonde,1 Ayotunde Dokun,2 Frank Lavernia3

1 Director, Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology, Ochsner Medical Center, New Orleans, Louisiana 2 Associate Professor of Medicine and Endocrinology, Chief Endocrine Services, Regional One Health, University of Tennessee Health Sciences Center, Memphis, Tennessee3 Founder, North Broward Diabetes Center, Coconut Creek, FloridaCorresponding address: Dr. Blonde, 1514 Jefferson Hwy, New Orleans, LA 70121Funding: Supported by an independent educational grant from Novo Nordisk Inc.Based on a symposium held at the American College of Physicians Internal Medicine Meeting in Washington, DC, May 5, 2016. The medical writing assistance of Katherine V. Mann of E&S MedEd Group, Inc. is acknowledged.

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Target AudienceThis activity has been designed to meet the educational needs of general internal medicine physicians, internal medicine subspecialty physicians, and other healthcare professionals involved in the management of patients with type 2 diabetes mellitus (T2DM).

Learning Objectives1. Describe indications for starting basal insulin therapy in patients with type 2

diabetes mellitus.

2. Use appropriate basal insulin in a physiologic manner and titrate therapy to achieve fasting plasma glucose goals.

3. Acknowledge and address patient barriers to insulin therapy by explaining how new therapies have been designed to mitigate barriers.

4. Intensify therapy in a patient-specific manner using new and emerging options, whether by premixed insulin or other prandial insulin or injectable therapies.

Accreditation and Credit DesignationPhysiciansThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education through the joint providership of American Academy of CME, Inc., and E&S MedEd Group, Inc. American Academy of CME, Inc., is accredited by the ACCME to provide continuing medical education for physicians.

American Academy of CME, Inc., designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Disclosure StatementAccording to the disclosure policy of the Academy, all faculty, planning committee members, editors, managers and other individuals who are in a position to control content are required to disclose any relevant relationships with any commercial interests related to this activity. The existence of these interests or relationships is not viewed as implying bias or decreasing the value of the presen-tation. All educational materials are reviewed for fair balance, scientific objectivity and levels of evidence. Disclosures are as follows:

Lawrence Blonde, MD, FACP, MACEDr. Blonde states that he serves on the Advisory Board for scientific information for AstraZeneca, GlaxoSmithKline, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., and Sanofi. He has received Grant/Research Support to his institution from Lexicon Pharmaceuticals Inc., Novo Nordisk Inc., and Sanofi. He is on the Promotional Speaker’s Bureaus for AstraZeneca, Janssen Pharmaceuticals, Inc., and Novo Nordisk Inc.

Ayotunde O. Dokun, MD, PhDDr. Dokun states he has no relevant financial relationship to disclose.

Frank Lavernia, MDDr. Lavernia states he is on the Advisory Boards for marketing purposes and scientific information of Sanofi, Eli Lilly, and Janssen Pharmaceuticals. He is a Consultant for marketing purposes and is on the Promotional Speaker’s Bureau for Janssen Pharmaceuticals.

Planning CommitteeLaurie Ermentrout states that she has no relevant financial relationships to disclose.John JD Juchniewicz, MCIS, CHCP, states that he has no relevant financial relationships to disclose.Lisa Kehs states that she has no relevant financial relationships to disclose.Kate Mann, PharmD, states her spouse was a part-time employee (now retired) of Otsuka Pharmaceutical Development and Commercialization, Inc.

Off-Label or Investigational Information This activity may contain discussion of off-label or investigational information.

Method of ParticipationThere are no fees to participate in the activity. Participants must review the activity information including the learning objectives and disclosure statements, as well as the content of the activity. To receive CME credit for your participation, please complete the post-test (achieving a passing grade of 70% or greater), and program evaluation. You may:

1) Go online to www.academycme.org/actID=15ES3 (if asked, the activity code is 15ES3). Please register and complete the post-test and evaluation. Your certificate can be printed immediately.

2) Fax your post-test answers and evaluation to 609-921-6428. Your certificate will be sent to you within 4 weeks.

Disclaimer StatementThe opinions expressed in this educational activity are those of the faculty, and do not represent those of the Academy or E&S MedEd Group. This activity is intended as a supplement to existing knowledge, published information, and practice guidelines. Learners should appraise the information presented critically, and draw conclusions only after careful consideration of all available scientific information.

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Copyright© 2017. This CME-certified activity is held as copyrighted © by American Academy of CME and E&S MedEd Group, Inc. Through this notice, the Academy and E&S MedEd Group grant permission of its use for educational purposes only. These materials may not be used, in whole or in part, for any commercial purposes without prior permission in writing from the copyright owner(s).

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AbstractExogenous insulin has been in constant evolution since its development in the 1920s. New basal insulin agents have been developed to reduce some of the limitations of existing agents, such as hypoglycemia (particularly nocturnal hypoglycemia), and to provide once-daily dosing. More concentrated formulations of existing insulins have also been produced for patients who are very insulin resistant and require high doses/high volumes of insulin. Additionally, a new premixed insulin with less variability and less hypoglycemia has been approved. For prandial control or treatment intensification when basal insulin does not achieve treatment targets, the addition of some of the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has demonstrated good efficacy. Co-formulations of GLP-1 RAs with basal insulin agents have been developed. This review, which is based on a recent symposium designed specifically for internal medicine physicians, presents information on new and emerging injectable therapies in a question and case-based format. These new treatment options offer internal medicine physicians additional ways to improve glycemic control with the promise of greater tolerability.

Keywords:Type 2 diabetes mellitus, basal insulin, long-acting, degludec U100, degludec U200, premixed degludec/aspart, glargine U300, intensification, combination, GLP-1 receptor agonists, degludec/liraglutide, glargine/lixisenatide.

IntroductionThe number of Americans diagnosed and living with type 2 diabetes mellitus (T2DM) has dramatically increased and represents a major health problem to the US healthcare system.1-3 Diabetes is a major cause of early mortality from atherosclerosis and cardiovascular disease (CVD);4-7 it is also the leading cause of adult blindness, non-traumatic leg amputations, and chronic kidney disease.2,8

Despite national efforts to improve quality in diabetes care, we have reached a plateau in stemming the diabetes crisis.9 Incremental improvements in achieving glycemic and blood pressure targets have been achieved, with a more robust change in reaching lipid goals.9 However 48% of Americans with diabetes still had not achieved A1C goals <7% (Table 1).9

One of the major challenges of T2DM is its progressive and multifactorial pathophysiology.10-12 The natural history of T2DM is characterized by progressive deterioration of pancreatic beta-cell function, leading to worsening glycemia over time. As current antihyperglycemic therapies have not yet been shown to profoundly alter this natural history, many patients eventually will require exogenous insulin therapy to attain or maintain adequate glycemic control. However, insulin can be useful at any point along the disease continuum.11

Table 1. A1C goals as recommended by the American Diabetes Association36

Blood Glucose Targets for Non-Pregnant Adults With DiabetesA1C <7.0% (53 mmol/L)

Preprandial capillary plasma glucose (PG) 80-130 mg/dL (4.4-7.2 mmol/L)

Peak postprandial capillary PG <180 mg/dL* (10.0 mmol/L)

More or less stringent targets may be appropriate for individual patients if achieved without significant hypoglycemia or adverse events. Targets may be individualized

based on patient characteristics.

More stringent (<6.5%)• Short diabetes duration• Long life expectancy• Type 2 diabetes treated with lifestyle

or metformin only• No significant CVD/vascular

complications

Less stringent (<8.0%)• Severe hypoglycemia history• Limited life expectancy• Advanced microvascular or

macrovascular complications• Extensive comorbidities• Long-term diabetes in which general

A1C targets are difficult to attain

Lowering A1C below or around 7.0% has been shown to reduce microvascular complications

The approach to glycemic management and glycemic targets must be individualized by considering the overall condition of each patient as well as the presence of complications and comorbid conditions, known duration of diabetes, risk for hypoglycemia and/or adverse consequences of hypoglycemia, and the presence of macro- and microvascular complications.13

Insulin is the oldest and most efficacious antihyperglycemic agent for patients with both type 1 diabetes mellitus (T1DM) and T2DM, yet there is still a need for clinician education in order to optimize its use.

Education for internal medicine physicians about how to best treat patients with diabetes has become increasingly important for several reasons: the sheer volume of patients with this chronic condition, the complexity of their treatment,14 and increase in available medication options. To this end, this supplement explores the use of new and emerging insulins and non-insulin injectable agents in treatment regimens for patients with T2DM, using a question and case-based format.

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Case Vignette #1

George is a 56-year-old white male with a 3-year history of T2DM. He is 5´11˝ tall and weighs 220 lb (BMI = 31 kg/m2). He is taking glimepiride 4 mg daily, metformin 1500 mg daily, and sitagliptin 100 mg once daily. He is unable to tolerate higher doses of metformin because of gastrointestinal side effects of nausea and diarrhea. George’s A1C level is 9.2%. His fasting plasma glucose (FPG) levels have ranged between 200 and 230 mg/dL for the past couple of weeks. George complains of frequent trips to the bathroom at night and of being tired. He has no history of CVD or hypoglycemia and no diabetes-related complications. He has hypertension and dyslipidemia, which are controlled with an angiotensin-converting enzyme inhibitor and a statin.

The Role of InsulinThe discovery of insulin was one of the greatest scientific accomplishments in the last century and changed the prognosis for those diagnosed with type 1 diabetes from a fatal illness to one that could be treated.15,16 Almost immediately there was a significant increase in survival rates.

To this day, insulin remains essential for patients with T1DM, and important for patients with T2DM, especially in later stages when endogenous insulin secretion can be markedly impaired. Dr. Cefalu and colleagues, in a recent editorial in Diabetes Care compared insulin to be considered the “essential black dress” of diabetes therapy – always there, always useful, and generally appropriate for use in most patient types and with most other treatment options.17 There have been major improvements in administration methods, purity, antigenicity, pharmacodynamics, pharmacokinetics, and other factors important to patients and healthcare professionals (HCPs) alike.18.19

Patients with diabetes who were treated with animal and human insulins were often unable to achieve glycemic targets because of a high incidence of both hyper- and hypoglycemia. This was partially because animal and human insulins were unable to provide a continuous, low level of basal insulin to mimic the normal basal secretory pattern of the beta cells.18,20 In the search for good glycemic control with less risk of hypoglycemia, the first basal insulin analogs with flatter and longer pharmacological profiles were developed.18 The evolution of insulin analogs has now progressed to even longer-acting basal insulin analogs with an even lower risk of hypoglycemia.21,22

Indications and Recommendations for the Use of Insulin in T2DMAcross the Treatment Spectrum of T2DMInsulin is a recommended option across the spectrum of diabetes progression for patients with T2DM.23 It is indicated as initial pharmacotherapy in patients with “severely” uncontrolled T2DM.24 Insulin also has the advantage of being effective where other agents may not be and should be considered a part of any combination regimen when hyperglycemia is severe, especially if the patient is symptomatic or if any catabolic signs are present—or, in those with glucose toxicity at diagnosis, where high glucose levels inhibit insulin secretion and insulin

activity. Objectively, this might be identified by one or some of the following: a random glucose >300 mg/dL, A1C >10%, ketonuria and weight loss, and where subjectively the patient may experience excessive urinating, excessive thirst, blurry vision, and fatigue.25

For the Management of Long-Standing T2DMIn cases of long-standing diabetes, pancreatic insulin secretory capacity is usually significantly reduced. For any patient who does not achieve a target A1C level despite intensive therapy with a combination of non-insulin pharmacotherapies basal insulin should be considered an essential part of the treatment strategy, according to the American Diabetes Association and the European Association for the Study of Diabetes (ADA/EASD) 2015 patient-centered position statement for the management of hyperglycemia in T2DM.13 Insulin is also useful for patients with advanced hepatic or renal disease.13

Treatment Intensification: When Non-insulin Therapy Fails to Achieve A1C GoalsIn the American Association of Clinical Endocrinologists (AACE) algorithm, the use of basal insulin should be considered when non-insulin antihyperglycemic therapy fails to achieve target A1C goals or when the patient, whether drug naïve or not, has symptomatic hyperglycemia.23 There are other special considerations for which insulin therapy is especially suited.23 These include the treatment of hyperglycemia in hospitalized patients,26 patients treated with high-dose steroids,27-29 and pregnant patients.23 Insulin is the traditional first-choice drug for blood glucose control during pregnancy because it doesn’t cross the placenta, and it is the most effective for fine-tuning blood glucose levels.30 All insulins are pregnancy category B except for glargine, glulisine, and degludec, which are labeled category C.31-33

Referring to the AACE 2016 algorithm for glycemic control (Figure 1),23 which breaks down recommendations based on a hierarchy of usage as well as the level of current A1C control, George is a candidate for insulin therapy. He is symptomatic while on triple therapy. He needs an agent that will lower his A1C level by at least 2 percentage points34 to bring it in line with the ADA goal of <7%.35 Insulin meets the criteria for being able to produce robust A1C-lowering of this magnitude.34

Many (if not most) patients with T2DM are likely to use insulin at some point in their lives (assuming reasonable longevity), whether for short-term use to treat acute hyperglycemia, or while hospitalized, or if they have diabetes long enough to result in marked impairment of beta-cell function.

To Manage Acute HyperglycemiaInsulin therapy also has been used on a short-term basis to manage acute hyperglycemia in patients newly diagnosed with T2DM.36 The temporary use of short-term intensive insulin therapy (for example, 3 weeks to 6 months of basal-bolus insulin therapy)37,38 early in the course of T2DM has been effective and may offer favorable long-term effects on beta-cell function. After receiving this treatment, some patients will often experience sustained euglycemia without requiring antihyperglycemic therapy for up to a year or more. This apparent “remission” of diabetes is likely secondary to improved beta-cell function. Hyperglycemia eventually returns, and patients often go on to receive oral agents.39

Question 1: What are current indications for initiating insulin therapy?

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Entry A1C ≥ 7.5%

LIFESTYLE THERAPY(Including Medically Assisted Weight Lost)

GLYCEMIC CONTROL ALGORITHM

NO YES

Entry A1C < 7.5% Entry A1C > 9.0%

INSULIN ±

OtherAgents

DUALTherapy

OR

TRIPLETherapy

ADD OR INTENSIFY INSULIN

* Order of medications represents a suggested hierarchy of usage; Length of line reflects strength of recommendation

LEGEND

Few adverse events and/or possible benefits

Use with caution

P R O G R E S S I O N O F D I S E A S E

MONOTHERAPY*Metformin

GLP-1 RA

SGLT-2i

DPP-4i

AGi

TZD

SU/GLN

If not at goal in 3 monthsproceed to Dual Therapy

DUAL THERAPY*GLP-1 RA

SGLT-2i

DPP-4i

AGi

Colesevelam

Bromocriptine QR

TZD

Basal Insulin

SU/GLN

If not at goal in 3 monthsproceed to Triple Therapy

MET

+or other 1st-line agent

TRIPLE THERAPY*GLP-1 RA

SGLT-2i

DPP-4i

AGi

Colesevelam

Bromocriptine QR

TZD

Basal Insulin

SU/GLN

If not at goal in 3 months proceed to or intensifyinsulin therapy

MET

+

or other 1st-line agent +2nd-lineagent

SYMPTOMS

Refer to Insulin Algorithm

Figure 1. American Association for Clinical Endocrinologists Algorithm for Glycemic Control Based on A1C Level.50 Order of medications are based on a suggested hierarchy of usage

Reprinted with permission from American Association of Clinical Endocrinologists © 2016 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 2016. Endocr Pract. 2016;22:84-113.

Start the Discussion About Insulin Early in the Course of DiabetesIf possible, physicians should begin discussion with their patients about insulin therapy well before its projected time of initiation. Many physicians like to introduce the concept of using insulin as a safe, effective, and relatively painless treatment “option” early in their discussion of treatment choices rather than using it as a “threat” if other treatments or lifestyle modifications are not effective. Patients are more likely to accept insulin if they understand its benefits, the relative lack of pain of injections using newer, narrower-gauge needles, and have received education and had their questions answered.40 They need to know goals of therapy and be taught insulin self-titration. Self-management education should be provided by Certified Diabetes Educators (CDEs), ideally working in ADA-recognized diabetes education programs that are widely available throughout the United States.

Consider Patient-Specific Factors and BarriersBeyond any patient misconceptions about insulin treatment, the patient’s general approach to medication can influence whether prescribing insulin will be successful.41 Questions that HCPs working with patients starting on insulin may want to ask about the patient are:

• What traditionally has been their level of adherence to medications? Perceived physician inattention and lack of engagement has a direct relationship with insulin adherence and glycemic control.42

• What is the health literacy of the patient? Health literacy is the ability to obtain, read, understand and use healthcare information to make appropriate health decisions and follow instructions for treatment. Limited health literacy has been shown to be associated with poor glycemic control in insulin-taking T2DM patients, suggesting that additional, patient-specific measures are needed if therapy is to be successful.43

• What support is available for patients (perhaps the patient is someone who lives alone) making it more dangerous if they were to suffer severe hypoglycemia?

• To what extent do their comorbidities put them at greater risk for hypoglycemia or its effects?44 Older adults with diabetes have a higher risk for hypoglycemia due to altered adaptive physiologic responses to low glucose levels.45

• What about cost? Does this patient have insurance to pay for the therapy you are prescribing? What will their co-pay be? Are they going to pay out of pocket for their medications? Are they going to get into the Medicare “donut hole” quickly?

These general factors are important to consider and to discuss with any patient prior to starting insulin.

Part of the more specific and essential conversation about insulin includes talking about normal beta-cell physiology and how endogenous insulin is secreted in response to a meal or in response to a glucose load, how insulin works, and why insulin is taken the way it’s taken. Does the patient understand the need for the kind of insulin prescribed (eg, basal insulin versus basal-bolus insulin?)

The availability of pen devices has definitely eased the burden of introducing the use of insulin to patients. Patients find this delivery method much more acceptable and less painful, and are more adherent to therapy than with older vial and syringe delivery methods.46 Pens also allow more accurate insulin dosing by patients.46 Although the percentage of patients using insulin pen delivery devices in the United States is increasing, it is still low compared with other countries47 and is a factor that should be considered when trying to address barriers to the introduction of insulin to a patient.

Other common barriers to the use of subcutaneous insulin include fear of hypoglycemia, number of injections, weight gain, and concerns regarding regimen flexibility.48 Currently available insulins do not address the barriers typically associated with insulin, nor the desired physiologic rapid-on, rapid-off control of prandial hyperglycemia coupled with reduced rates of hypoglycemia.49 With current prandial insulin options, data show 5.7 days per month of prandial

Question 2: How should insulin therapy be initiated?

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insulin omission/non-adherence.48 Studies of patient adherence reveal a need for insulin regimens that are less restrictive and burdensome, and with lower risk of hypoglycemia.48

Although basal insulin analogs and neutral protamine Hagedorn (NPH) insulin have been shown to be equally effective in reducing A1C levels in clinical trials, basal insulin analogs are associated with significantly less hypoglycemia.50 AACE recommendations suggest starting with a basal insulin analog, if possible.50 Newer longer acting basal insulin analogs provide some additional benefits compared to the basal insulin analogs that have been available (ie, detemir U100, glargine U100); compares some of the properties of the newest basal insulin preparations with those of the older basal insulin analogs and NPH.

Case Vignette #1, continued

The merits of insulin for replacing a hormone deficiency and reducing glucose “toxicity” with a single daily injection is explained to George. Based on the AACE algorithm,23 he is prescribed a starting dose of 0.2-0.3 U/kg of a basal insulin analog because his A1C is >8% (Figure 2).23 The nurse in the office teaches him how to do the subcutaneous injections and has him inject the first dose in the office so that he can (1) demonstrate proper injection technique and (2) confirm that the injection is associated with minimal if any discomfort. George is asked to perform fasting SMBG daily and based on these values titrate his insulin dose every 3 days aiming for an FPG value of < 110 mg/dL. (See the AACE algorithm for self-titration against FBG and goals, Figure 2).23 Metformin is continued. Glimepiride is reduced to 2 mg daily to lower the risk of hypoglycemia with the concomitant use of insulin. Alternatively it could be discontinued. The nurse provides counseling about hypoglycemia, nutrition, and the possibility of insulin-related weight gain. He has a follow-up appointment in 3 months. In the interim, he will be seen by a CDE.

Figure 2. American Association for Clinical Endocrinologists Algorithm for Glycemic Control. Algorithm for Adding Insulin50

A1C > 8%

START BASAL (Long-Acting Insulin)

A1C < 8%

TDD 0.1–0.2 U/kg TDD 0.2–0.3 U/kg

Insulin titration every 2–3 daysto reach glycemic goal

• Fixed regimen: Increase TDD by 2 U• Adjustable regimen: • FBG > 180 mg/dL: add 20% of TDD • FBG 140–180 mg/dL: add 10% of TDD • FBG 110–139 mg/dL: add 1 unit• If hypoglycemia, reduce TDD by: • BG < 70 mg/dL: 10% – 20% • BG < 40 mg/dL: 20% – 40%

Consider discontinuing or reducing sulfonylurea after starting basal insulin (basal analogs preferred to NPH)

*Glycemic Goal:

• <7% for most patients with T2D; fasting and premeal BE < 110 mg/dL; absence of hypoglycemia• A1C and FBG targets may be adjusted based on patient’s age, duration of diabetes, presence of comorbidities, diabetic complications, and hypoglycemia risk


Case Vignette #2

Caroline is a 62-year-old female who has had T2DM for 8 years. She is currently

taking metformin 1000 mg BID, sitagliptin 100 mg QD, and NPH insulin 50 U at

bedtime. Her A1C level has been trending up from 6.8% to a current level of 7.3%.

She has also noted some hypoglycemic episodes that have awakened her during the

night (she has documented these in her blood glucose log; levels ranged from 50 to

65 mg/dL) as well as some pre-breakfast hyperglycemia [fasting] (200-210 mg/dL).

She sometimes takes less than the prescribed dose of the NPH insulin because of

concern about hypoglycemia.

Caroline is experiencing some nocturnal hypoglycemia. Nocturnal hypoglycemia, even if non-severe, can adversely affect patient’s quality of life, feeling and function,51 and result in work loss and reduced productivity.52 Adverse effects may be noted both at the time the hypoglycemia occurs and during recovery, which may take an extended period of time.41

A change to this patient’s therapeutic regimen is clearly indicated. She is taking NPH insulin, which has several less-than-desirable properties for an “ideal” insulin.53 NPH had been the predominant basal insulin in clinical use, until the advent of basal insulin analogs. NPH requires resuspension before injection. The time-action profile (peak activity 4-9 hours after subcutaneous administration) increases the risk for between-meal and especially nocturnal hypoglycemia.53,54 Therefore, it acts more as an intermediate-acting insulin, without the flat pharmacodynamic profile that is desired to provide a steady level of insulin action over a 24-hour period.55 NPH has a duration of action of usually less than 24 hours and may need to be administered twice daily. It often has significant intra- and inter-individual variability.53,56,57

The basal insulin analogs (such as insulin glargine U100 and insulin detemir U100) have a longer duration of action, a flatter time-action profile with less of a peak, less variability, and less hypoglycemia than NPH insulin.58-60 Meta-analyses have provided evidence that existing basal insulin analogs are associated with less nocturnal hypoglycemia than NPH insulin.61-63 These would be options for Caroline, as would some newer basal insulin analogs. For example, ultra-long-

Question 3: What are the new and emerging basal insulin analogs and their features?

8


acting insulin formulations are being introduced with the potential for more durable antihyperglycemic efficacy of 24 hours or longer, less glycemic variability, and less hypoglycemia than traditional basal insulin analogs and human NPH insulins.21,64

It is important for physicians to understand the newer insulin options and their pharmacokinetics to be able to appropriately select the best insulin for a particular patient. Table 2 compares some of the properties of the newest basal insulin preparations with those of the older basal insulin analogs and NPH; 55,65-68 however, some of the data reported are from patients with T1DM rather than T2DM.

Table 2. Select PK/PD parameters of recently approved insulin component agents and their existing comparator counterparts (long-acing)55,65-68

Pk/PD Parameter

Degludec U100, U200

Glargine U300

Glargine U100

Determir U100

NPH

Onset of action

30-90 minutes

Develops over 6 hours

2-4 hours 0.8-2 hours

2-4 hours

Duration of action

42 hours >30 hours Up to 24 hours

Up to 24 hours

10-16 hours

Half-life 25 hours 18-19 hours

~12 hours 5-7 hours 6.6 hours

Time to steady state

3-4 days 3-4 days 2-3 days 24 hours Not available

Insulin DetemirFor information on insulin detemir, readers are referred to a meta-analysis versus NPH, which showed that insulin detemir treatment provided similar or better glycemic control, lower within-subject variability, similar or lower frequency of hypoglycemia and less weight gain when compared with NPH insulin.69 Insulin detemir is also a viable option for the management of diabetes during pregnancy (Pregnancy Category B).70

Currently, no head-to-head trials of insulin detemir versus glargine U300 or insulin degludec have been reported in the medical literature.

Insulin Glargine U300 vs Insulin Glargine U100The new concentrated insulin glargine U300 delivers insulin glargine at a higher concentration (300 units/mL). Once injected, glargine U300 forms a compact subcutaneous depot with a smaller surface area to produce a more gradual and prolonged release than glargine U100.67 Compared with glargine U100, blood glucose control (≤105 mg/dL) was maintained for approximately 5 hours longer (median of 30 hours) with glargine U300.67 There was low fluctuation and high reproducibility in insulin exposure with the more concentrated formulation.71

The glucose-lowering effect of glargine U300 has generally been comparable to that of glargine U100, with less hypoglycemia at any time of day in a broad range of patients.72 Weight gain (<1 kg) was low with glargine U300 in the patient- level meta-analysis of the EDITION 1, 2, and 3 studies and was statistically lower than observed with glargine U100 (p<0.05).72

Importantly, glargine U300 also was associated with comparable or reduced nocturnal hypoglycemia compared with glargine U100. Annualized rates of confirmed (≤70 mg/dL) or severe hypoglycemia (that requiring 3rd party assistance) were lower with glargine U300 than with glargine U100 during the night (31% difference in rate ratio over 6 months) and at any time (14% difference).72,73 In the EDITION 3 study, which was conducted in insulin-naïve patients, the risk of severe hypoglycemia was statistically lower with the more concentrated formulation (relative risk 0.89) compared with glargine U100.74

Unit for unit, patients started on, or changed to, glargine U300 tend to require a higher dose than patients whose diabetes is controlled with glargine U100. When changing from another basal insulin to glargine U300, patients may experience higher average FPG levels during the first few weeks of therapy until their doses are titrated to their individualized FPG targets.75 Insulin-naïve patients tend to do well when started on 10 units or 0.1 to 0.2 U/kg and then titrated upward until target FPG levels are attained. Frequent monitoring of blood glucose levels is suggested during the early weeks of treatment. Patients should be informed that the insulin pen device for glargine U300 shows the number of units to be injected and that no dose conversion is required.

Insulin Degludec U200 and U100 vs Insulin Glargine U100Insulin degludec is another of the new ultra-long-acting basal insulin analogs. It comes in 2 dose formulations: U200 (pen device: maximum dose of 160 units per injection [in 2-unit increments]) and U100 (pen device: maximum dose of 80 units per injection [in 1-unit increments]). It is also approved as part of a new premixed product with insulin aspart (described below) and combination product with a GLP-1 RA (liraglutide). Insulin degludec forms soluble and stable dihexamer with the help of phenol and zinc.76 Immediately following subcutaneous injection of insulin degludec, phenol from the vehicle diffuses rapidly. Insulin degludec hexamers then link via single side-chain contacts, assembling long, multihexamer chains. Zinc diffuses slowly, causing individual hexamers to disassemble and release monomers, which are absorbed from the depot into circulation. The result is protracted activity, caused primarily by the slow release from these long hexamer chains.77 This helps degludec to achieve a steady-state concentrations with a half-life of more than 25 hours and duration of action of up to 42 hours.77 As shown in patients with T1DM, insulin degludec has one-fourth the pharmacodynamic variability of glargine U100.78

The BEGIN clinical trial program for degludec is reportedly the largest insulin development clinical trial program on record.79 It was designed to evaluate this new once-daily basal insulin across a broad spectrum of patients and dosing regimens. The patient populations included insulin-naïve T2DM, insulin-treated T2DM and T1DM, patients, and treatments included basal-bolus therapy, basal plus oral therapy, basal versus oral therapy, and a study assessing use of degludec in an alternating-time dosing regimen.76

A pre-planned meta-analysis of all of the phase 3 T2DM trials confirmed that similar improvements in A1C levels are achievable with insulin degludec when compared with insulin glargine U100.80 Among insulin-naïve T2DM subjects, significantly lower rates of overall confirmed and nocturnal confirmed hypoglycemia were reported with insulin degludec relative to insulin glargine U100 (estimated rate ratio [RR]:0.8 and RR:0.64). In the overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes were reported with insulin degludec relative to insulin glargine U100 (RR:0.83 and

9

RR:0.68).80 The lower rate of nocturnal confirmed hypoglycemia observed with insulin degludec relative to insulin glargine U100 is accompanied by a reduction in mean FPG.81

In the SWITCH 2 trial,82 which was reported at the American Diabetes Association’s 76th Scientific Sessions, June, 2016, patients with T2DM taking degludec compared with insulin glargine U100 experienced a rate reduction of 30% in overall confirmed symptomatic hypoglycemic episodes and a rate reduction of 42% in nocturnal confirmed symptomatic hypoglycemic episodes. In the full treatment period, a significant 51% rate reduction in severe hypoglycemia was observed in patients receiving degludec relative to insulin glargine U100.82

Insulin degludec can be administered once daily at any time of day, but patients should be advised to ensure that at least 8 hours have elapsed between consecutive degludec injections. If patients miss a dose of degludec, they should be instructed to inject their daily dose during waking hours upon discovering the missed dose. The recommended time between dose increases is 3 to 4 days. As with insulin glargine U300, no dose conversion is needed—the dose window for both the degludec U100 and U200 pens shows the number of units to be delivered. The recommended starting dose of insulin degludec in insulin-naïve patients with T2DM is 10 units once daily. For patients already taking insulin, the dose is unit for unit of the total daily dose of basal insulin or intermediate insulin

being used. Currently, no head-to-head trials of glargine U300 versus degludec or versus insulin detemir have been reported in the medical literature.


Knowing that studies of the newer ultra long-acting basal insulin analogs demonstrate a longer duration of action and a lower rate of nocturnal and/or overall hypoglycemia than NPH or basal insulin analogs such as insulin glargine, the decision is made to change Caroline's insulin to one of these preparations.

You switch Caroline unit-for-unit to insulin degludec U200 to be taken once daily at the same time each day and instruct her how to titrate it based on her FPG levels, as well as how to treat and manage any episodes of hypoglycemia (with instructions to test blood glucose levels, to document the actual glucose levels). She could have also been switched unit for unit to glargine U300 to be taken once daily at the same time each day from her NPH once daily dose. If she happened to have been a patient who required twice daily NPH, her recommended initial dose would be 80% of the total daily NPH dose that is being discontinued; this dose reduction will lower the likelihood of hypoglycemia.

Case Vignette #3

Gena is 47-year-old female with a 9-year history of T2DM. She is a busy accountant, especially during tax season. Initially her A1C levels were under control (<6.5%) on metformin 1500 mg daily, glimepiride 4 mg QD, and U100 insulin glargine, 55 U once daily at bedtime, with an average FPG of 120 mg/dL. However, at her last two 3-month checkups, her A1C level had increased to 7.3%. She had initially attributed the increase to some transient poor adherence to lifestyle – medical nutrition therapy and physical activity had suffered during the busy times at the office. However, tax season is now over, and there have been no improvements in her glycemic control. Her current weight is 212 lb and her height is 5´10˝, resulting in a calculated BMI of 30.4 kg/m2.

Given Gena’s findings, would you increase her dose of insulin glargine? At what unit per kg body weight of basal insulin should you stop up-titrating basal insulin and instead consider adding an agent to address prandial control? (Her current dose of insulin glargine is approximately 0.57 U/kg.)

Both fasting hyperglycemia and increments of glucose after meals contribute to overall glycemic exposure. In general, once FPG levels are well controlled, the contribution of postprandial glucose (PPG) excursions needs to be addressed in patients with A1C levels close to, but not at, goal.83 Postprandial hyperglycemia accounts for the majority of overall glycemic exposure above normal levels in patients in the lowest range of A1C (<7.3%) in the landmark trial by Monnier.83

These results were confirmed in a study by Riddle and colleagues in T2DM patients treated with basal insulin.84

Continuing to increase basal insulin doses increases the likelihood of hypoglycemia with little chance of successfully lowering total A1C.85 Gena’s FPG levels are close to target, so increasing the basal insulin dose, which targets fasting hyperglycemia, would be unlikely to achieve target A1C levels without causing hypoglycemia. Data from 15 randomized, treat-to-target trials in patients on insulin glargine, with or without oral antidiabetic drugs (OADs) for 24 or more weeks have shown that continued upward titration of basal insulin glargine to doses greater than 0.5, 0.7, and even >1.0 U/kg did not result in further improvements in glycemic control.85 The data showed that one can obtain about a 0.5% decrease in A1C level for each 0.1-U/kg/day increment in insulin dose, up to a threshold of 0.5 U/kg. Beyond this dose, improvement in A1C level is often minimal, and there is increased risk for weight gain 86 and hypoglycemia85 continues. ADA/EASD13,87 and AACE/ACE23 treatment recommendations suggest adding agents that target PPHG when basal insulin doses reach or exceed 0.5 U/kg. Other considerations for stopping titration of basal insulin are when A1C levels are not at goal despite achieving the target FPG with basal insulin; FPG is at target with basal insulin but PPG levels are persistently above goal; when further increases in basal insulin result in hypoglycemia; and when large glucose drops occur overnight or between meals.88-90


Based on these data, you would not continue to increase the dose of insulin glargine. After checking postmeal glucose levels, which were elevated at 180-200 mg/dL, consideration was given to reducing her basal insulin dose and adding an agent that could address postprandial glucose levels.

Question 4: When do you stop titrating basal insulin?

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Case Vignette #4

Javier is an uncircumcised 64-year-old male with a 9-year history of T2DM. He is 5´10˝ tall and weighs 190 lb, with a BMI of 28 kg/m2. His current diabetes medications include metformin 2000 mg daily, sitagliptin 100 mg/daily, and insulin glargine U100, 55 U at bedtime. His A1C level initially declined but now has increased to 7.5%; FPG averages about 120 mg/dL; PPG levels are elevated, especially after his evening meal (220 mg/dL). His past medical history is significant for recurrent urinary tract infections (balantis [swelling of the foreskin]). Otherwise, he is a relatively healthy, overweight individual, exercising 4-5 times a week, and following a a diet recommended by his CDE who is a registered dietitian. What therapeutic strategies will you discuss with Javier?

His A1C remains elevated despite having achieved a near target FPG with insulin glargine treatment. He therefore needs treatment addressing elevated PPG levels to achieve his A1C goal. Several treatments and strategies are available for internal medicine physicians when intensifying therapy for patients on optimized basal insulin therapy. AACE treatment recommendations suggest that if patients are not at goal on basal insulin, clinicians should consider adding a GLP-1 RA, a dipeptidyl peptidase-4 (DPP-4) inhibitor, or a sodium glucose cotransporter-2 (SGLT-2) inhibitor before prandial insulin in most patients (Figure 3).23 All of these agents improve glycemic control when combined with basal insulin. They also have a lower risk for weight gain and/or hypoglycemia and so may be preferred to sulfonylureas or thiazolidinediones for combination with insulin.11


Javier is already on a DPP-4 inhibitor. He is probably not a good candidate for a SGLT-2 inhibitor, given his history of urinary tract infections; and genital mycotic infections are an adverse effect reported more commonly in those who have had them before and in uncircumcised men on SGLT-2 inhibitors.91

Figure 3. AACE Algorithm: options for intensifying insulin when glycemic control not at goal 2

The 2017 ADA/EASD treatment algorithm recommends adding 1 rapid-acting insulin injection before largest meal (basal plus), slowly moving the patient to a basal-bolus regimen,92 or switching the patient to an alternative insulin regimen.13 These types of regimens are frequently used, but there is still widespread reluctance to intensify insulin treatment due to fear of weight gain and hypoglycemia.93 Intensive insulin treatment can be limited by factors such as the number of injections, mealtime restrictions, complex titration algorithms, and patient adherence.94

Degludec 70 units/Insulin and Aspart 30 units per mL (100 units/mL for the Combination)There is a new premixed insulin approved for use in the United States and currently available in Europe.95 Insulin degludec with insulin aspart offers physicians and patients with T2DM a simpler regimen than other basal-bolus or premix-based insulin regimens. This combination offers stable daytime basal coverage, a lower rate of hypoglycemia, and some flexibility in injection timing96 compared with other premixed insulins. The onset of action for the insulin aspart component is 14 minutes; the peak plasma time for aspart is 72 minutes, and that of insulin degludec is 9 hours. Steady state for insulin degludec occurs in 3 to 4 days. The half-life of insulin degludec is approximately 25 hours.97

The initial dose of premixed insulin degludec/aspart is 10 units subcutaneously once a day. When switching from other once- or twice-daily premixed insulin, clinicians should start with the same unit dose and injection schedule as the current original premixed preparation. Short- or rapid-acting insulin may be used for meals not covered by this insulin mix. If the patient is switching or intensifying from once- or twice-daily basal insulin, they should be started at the same unit dose as the basal insulin once a day with the main meal of the day. It is important to monitor blood glucose levels after starting therapy, especially for patients switching from once-daily basal insulin to this insulin mix, due to the rapid-acting insulin component.97 Weight gain can occur with insulin therapy, including the degludec/aspart premixed combination.

Use of GLP-1 RAs in Combination with Basal Insulin and Coformulations Containing Basal Insulin and a GLP-1 RA in the Same PreparationGLP-1 RAs provide supraphysiologic GLP-1 receptor activation compared with DPP-4 inhibition.98 This results in enhancement of glucose-dependent insulin secretion, a glucose-dependent decrease in excessive glucagon secretion, slowing of gastric emptying, and enhanced satiety, which can be associated with weight reduction.99 GLP-1 RAs by themselves have a low risk for hypoglycemia or weight gain. The main adverse effect associated with their use is are gastrointestinal in nature (nausea, vomiting, and diarrhea).100,101

Several GLP-1 RAs have been used successfully in combination with basal insulin.102 In particular, the shorter-acting GLP-1 RAs that have effects on postprandial hyperglycemia are well suited for this purpose. Many studies reported weight loss and a reduction in insulin use when a GLP-1 RA was added to existing insulin therapy. The most common finding across all types of studies

Add Prandial Insulin• Basal plus one

(adding to largest meal),Basal plus two, Basal plus 3

OR

Add GLP-1 RA

Add SGLT-2 inhibitor

OR

ORBasal bolus

Question 5: What are some of the new options for intensifying therapy when basal insulin alone has not achieved target glycemia?


11

was that combination therapy improved glycemic control without weight gain or an increased risk of hypoglycemia.102 Other GLP-1 RAs that have approval for use with basal insulin include once-weekly albiglutide.

The rationale for the use of the 2 classes of injectable agents together was defined suc-cinctly by Balena and colleagues in 2013.103-108 Their line of reasoning was as follows:

• T2DM is a progressive, multifactorial disease.

• However, the more intensively T2DM is treated, the greater is the risk of hypoglycemia and weight gain.

• Achieving treatment intensification while moderating these risks poses a challenge to patient management.

• Basal insulin analogs provide control of FPG; however, their utility in the control of PPHG is limited.

• GLP-1 RAs stimulate glucose-dependent insulin secretion, suppress glucagon secretion, delay gastric emptying, and decrease appetite.

• Use of GLP-1 RAs in combination with basal insulin offers an alternative approach to insulin therapy intensification.

• Prospective interventional trials demonstrate that GLP-1 RAs added to basal insulin decrease PPHG, lower A1C levels, decrease weight, and lower basal insulin requirements without increasing the risk of major hypoglycemic events.

Today, this combination therapy requires more than 1 injection, as each drug class has to be given separately. However, 2 products are in development as

fixed-dose combinations that include both a basal insulin and one of the relatively shorter-acting GLP-1 RAs. A number of clinical trials have been published for the fixed-dose combination of insulin degludec/liraglutide,103-105,107-112 and for the fixed-dose combination of insulin glargine/lixisenatide.113-115 As these fixed-dose combinations become available, more barriers to insulin therapy will be reduced and more opportunities to successfully lower A1C levels with low risks of weight gain and hypoglycemia will be available. In addition, positive cardiovascular outcomes data for liraglutide were reported at last year’s ADA meeting, supporting a macrovascular benefit of this particular GLP-1 RA.116

Summary and ConclusionThe majority of patients with T2DM are likely to eventually require insulin to obtain or preserve satisfactory glucose control and to achieve an A1C level <7%. Insulin should be considered for T2DM when non-insulin antihyperglycemic therapy fails to achieve target glycemic control or when a patient, whether drug naïve or not, has very elevated blood glucose levels and is symptomatic. Attention should be paid to both fasting hyperglycemia and PPHG in order to achieve optimal glycemic control. Using medications that are associated with fewer adverse events may improve adherence. New and emerging insulins and insulin combination products are available that can be employed by internal medicine specialists to improve glycemic control.

12


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79. Wangnoo SK, Chowdhury S, Rao PV. Treating to target in type 2 diabetes: the BEGIN trial programme. J Assoc Physicians India. Jan 2014;62(1 Suppl):21-26.

80. Ratner RE, Gough SC, Mathieu C, et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta- analysis of phase 3 trials. Diabetes Obes Metab. Feb 2013;15(2):175-184.

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81. Russell-Jones D, Gall MA, Niemeyer M, Diamant M, Del Prato S. Insulin degludec results in lower rates of nocturnal hypoglycaemia and fasting plasma glucose vs. insulin glargine: A meta-analysis of seven clinical trials. Nutr Metab Cardiovasc Dis. Oct 2015;25(10):898-905.

82. Wysham C, Bhargava A, Chaykin L, et al. SWITCH 2: Reduced Hypoglycaemia With Insulin Degludec (IDeg) vs Insulin Glargine (IGlar), both U100, in Patients With T2D at High Risk of Hypoglycaemia: A Randomised, Double-Blind Crossover Trial. Paper presented at: 76th Annual Scientific Sessions of the American Diabetes Association (ADA) June 2016. , 2016; New Orleans, USA.

83. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care. Mar 2003;26(3):881-885.

84. Riddle M, Umpierrez G, DiGenio A, Zhou R, Rosenstock J. Contributions of basal and postprandial hyperglycemia over a wide range of A1C levels before and after treatment intensification in type 2 diabetes. Diabetes Care. Dec 2011;34(12):2508-2514.

85. Reid T, Gao L, Gill J, et al. How much is too much? Outcomes in patients using high-dose insulin glargine. Int J Clin Pract. Jan 2016;70(1):56-65.

86. Monnier L, Colette C. Addition of rapid-acting insulin to basal insulin therapy in type 2 diabetes: indications and modalities. Diabetes Metab. Feb 2006;32(1):7-13.

87. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. Mar 2015;58(3):429-442.

88. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. Jun 2012;35(6):1364-1379.

89. ADA. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed.

90. Zisman A, Morales F, Stewart J, Stuhr A, Vlajnic A, Zhou R. BeAM value: an indicator of the need to initiate and intensify prandial therapy in patients with type 2 diabetes mellitus receiving basal insulin. BMJ Open Diabetes Res Care. 2016;4(1):e000171.

91. Raskin P. Sodium-glucose cotransporter inhibition: therapeutic potential for the treat-ment of type 2 diabetes mellitus. Diabetes Metab Res Rev. Jul 2013;29(5):347-356.

92. American Diabetes Association. Pharmacologic approaches to glycemic treatment. Sec. 8 Standards of Medical Care in Diabetes—2017. Diabetes Care 2017;40(Suppl.1):S64-S74.

93. Vora J, Cohen N, Evans M, Hockey A, Speight J, Whately-Smith C. Intensifying insulin regimen after basal insulin optimization in adults with type 2 diabetes: a 24-week, ran-domized, open-label trial comparing insulin glargine plus insulin glulisine with biphasic insulin aspart (LanScape). Diabetes Obes Metab. Dec 2015;17(12):1133-1141.

94. Shaefer CF, Anderson J. The importance of postprandial glycemic control: optimizing add-on therapy to basal insulin. Postgrad Med. Jan 2016;128(1):137-144.

95. Niskanen L, Leiter LA, Franek E, et al. Comparison of a soluble co-formulation of insulin degludec/insulin aspart vs biphasic insulin aspart 30 in type 2 diabetes: a randomised trial. European journal of endocrinology / European Federation of Endocrine Societies. Aug 2012;167(2):287-294.

96. Kumar S, Jang HC, Demirağ NG, Skjøth TV, Endahl L, Bode B. Efficacy and safety of once-daily insulin degludec/insulin aspart compared with once-daily insulin glargine in participants with Type 2 diabetes: a randomized, treat-to-target study. Diabet Med. 2016 Mar 30. doi: 10.1111/dme.13125. [Epub ahead of print].

97. Gould JC, Kasichayanula S, Shepperly DC, Boulton DW. Use of low-dose clinical pharmacodynamic and pharmacokinetic data to establish an occupational exposure

limit for dapagliflozin, a potent inhibitor of the renal sodium glucose co-transporter 2. Regulatory toxicology and pharmacology: RTP. Oct 2013;67(1):89-97.

98. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. Nov 11 2006;368(9548):1696-1705.

99. Drucker DJ. The biology of incretin hormones. Cell Metab. Mar 2006;3(3): 153-165.

100. Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care. Feb 2010;33(2):428-433.

101. Wang Y, Li L, Yang M, Liu H, Boden G, Yang G. Glucagon-like peptide-1 receptor agonists versus insulin in inadequately controlled patients with type 2 diabetes mellitus: a meta-analysis of clinical trials. Diabetes Obes Metab. Nov 2011;13(11):972-981.

102. Balena R, Hensley IE, Miller S, Barnett AH. Combination therapy with GLP-1 receptor agonists and basal insulin: a systematic review of the literature. Diabetes Obes Metab. Jun 2013;15(6):485-502.

103. Gough SC, Jain R, Woo VC. Insulin degludec/liraglutide (IDegLira) for the treatment of type 2 diabetes. Expert Rev Endocrinol Metab. Jan 2 2016;11(1):7-19.

104. Minze MG, Chastain LM. Combination therapies in the management of type 2 diabetes: the use of insulin degludec/liraglutide. Ther Clin Risk Manag. 2016;12:471-478.

105. Rendell M. First fixed-ratio combination of insulin degludec and liraglutide for the treatment of type 2 diabetes. Drugs Today (Barc). Mar 2015;51(3):185-196.

106. Rodbard HW, Buse JB, Woo V, et al. Benefits of combination of insulin degludec and liraglutide are independent of baseline glycated haemoglobin level and duration of type 2 diabetes. Diabetes Obes Metab. Jan 2016;18(1):40-48.

107. Simpson R, King A. Can a fixed-ratio combination of insulin degludec and liraglutide help Type 2 diabetes patients to optimize glycemic control across the day? Expert Rev Clin Pharmacol. Mar 2015;8(2):179-188.

108. Vilsboll T, Vora J, Jarlov H, Kvist K, Blonde L. Type 2 Diabetes Patients Reach Target Glycemic Control Faster Using IDegLira than Either InsulinDegludec or Liraglutide Given Alone. Clin Drug Investig. Apr 2016;36(4): 293-303.

109. Buse JB, Vilsboll T, Thurman J, et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care. Nov 2014;37(11):2926-2933.

110. Gough SC, Bode B, Woo V, et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol. Nov 2014;2(11):885-893.

111. Gough SC, Bode BW, Woo VC, et al. One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial. Diabetes Obes Metab. Oct 2015;17(10):965-973.

112. Lingvay I, Manghi FP, Garcia-Hernandez P, et al. Effect of Insulin Glargine Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients With Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial. JAMA. Mar 1 2016;315(9):898-907.

113. Rosenstock J, Diamant M, Aroda VR, et al. Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Lixisenatide and Insulin Glargine, Versus Insulin Glargine in Type 2 Diabetes Inadequately Controlled on Metformin Monotherapy: The LixiLan Proof-of-Concept Randomized Trial. Diabetes Care. 2016;39(9):1579-1586.

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114. Rosenstock J, Aronson R, Grunberger G, et al. Benefits of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide, Versus Insulin Glargine and Lixisenati-de Monocomponents in Type 2 Diabetes Inadequately Controlled With Oral Agents: The LixiLan-O Randomized Trial. Diabetes Care. 2016;39(11):2026-2035.

115. Forst T. Lixisenatide as add-on to insulin glargine for the treatment of type 2 diabetes mellitus. Expert Opin Pharmacother. Aug 2016;17(12): 1703-1708.

116. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. Jul 28 2016; 375(4):311-322.

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1. Anna is a 65-year-old female with a 5-year history of T2DM treated with dual oral therapy and who had an A1C level of 6.8% until 12 months ago. After retiring from her job as a tour guide, she has settled into a more sedentary lifestyle and has taken several cruises as a benefit of her former job. Anna has been enjoying the large buffets and gained weight during the trips. Recently she has also contracted an upper respiratory tract infection. She presents with complaints of polyuria, nocturia, and polyphagia. A random blood glucose level is 320 mg/dL. Which of the following is a reasonable indication to start insulin therapy in this patient?

A. Acute hyperglycemia B. Long-duration T2DM C. When non-insulin therapy is no longer achieving

goals D. Weight gain

2. According to the ADA, based on the limited history you have on Anna, what are the fasting plasma glucose (FPG) and postprandial glucose (PPG) goals would you discuss with her, knowing her relatively short history of T2DM and assuming a relatively healthy status?

A. FPG: 70-120 mg/dL, peak PPG: <150 mg/dL

B. FPG: 80-130 mg/dL, peak PPG: <180 mg/dL

C. FPG: 100-120 mg/dL, peak PPG: <200 mg/dL

D. FPG: 140 mg/dL, peak PPG: <220 mg/dL

3. According to the ADA, above which dose should you consider stopping increases in basal insulin doses and consider adding an agent to address PPHG?

A. >0.3 U/kg/day B. >0.5 U/kg/day C. >0.7 U/kg/day D. >1.0 U/kg/day

4. Which of the following is NOT a reason to stop increasing basal insulin doses past the maximum “optimal” U/kg/day of basal insulin identified in Q3?

A. No greater efficacy in A1C lowering past recommended maximum basal insulin U/kg/day

B. Increased risk of hypoglycemia past the recommended maximum basal insulin U/kg/day

C. Increased risk of injection site reactions past the recommended maximum basal insulin U/kg/day

D. Increased weight gain past the recommended maximum basal insulin U/kg/day

5. Which of the following is NOT an advantage of newer longer-acting basal insulins that is supported by clinical trial evidence?

A. Insulin degludec can be administered at any time of day, once daily (as long as 8 hours have elapsed between doses).

B. Insulin glargine U300 can be administered at a lower dose in the same patient who has used insulin glargine U100 previously.

C. Both insulin degludec and insulin glargine U300 have lower risks of nocturnal hypoglycemia than insulin glargine U100.

D. The more concentrated insulins require lower volumes of insulin to be injected and come in prefilled pens that do not require patients or physicians to calculate dose conversions.

6. Which of the following is NOT part of the 2016 AACE/ACE recommendations for adding prandial control once basal insulin has been intensified as much as possible?

A. Add a dose of prandial insulin before largest meal

B. Add an oral SGLT-2 inhibitor

C. Add a GLP-1 RA

D. Discontinue basal insulin and start a premixed insulin twice daily

7. Which of the following is NOT a common barrier to the use of intensified insulin therapy that may be addressed by emerging fixed-dose combination products (e.g., a basal insulin with a GLP-1 receptor agonist)?

A. Fear of hypoglycemia B. Lack of injections C. Number of injections D. Weight gain

8. When a GLP-1 RA is used in combination with insulin therapy, the most common findings in clinical trials are (compared to increasing insulin doses alone)

A. Equivalent glycemic control without weight gain or an increased risk of hypoglycemia

B. Improved glycemic control without an increased risk of hypoglycemia, but with an increased risk of pancreatitis

C. Improved glycemic control without weight gain but with an increase in daytime hypoglycemia

D. Improved glycemic control without weight gain or an increased risk of hypoglycemia

9. Which of the following is NOT a common barrier to the use of intensified insulin therapy that can be addressed by the first approved premixed insulin product in more than a decade?

A. Concerns regarding regimen flexibility B. Fear of hypoglycemia C. Number of injections D. Weight gain

10. Which of the following is NOT a correct statement about insulin therapy in the modern approach to T2DM treatment?

A. Insulin continues to be a mainstay of therapy, and most patients will require its use at some point in their lives.

B. Patient barriers to the use of insulin can be addressed through education, communication, and the selection of new and emerging insulin analogs.

C. There is a rationale for the use of 2 injectable classes of antidiabetic agents in the treatment of T2DM.

D. The role of prandial insulin continues to remain important because no other non-insulin therapies can adequately address postprandial hyperglycemia.

Posttest Questions


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New and Emerging Injectable Therapies for Type 2 Diabetes for the Internal Medicine Physician: Experts Address Common QuestionsInstructions for Posttest and Evaluation

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EVALUATION FORM (* = required question)

Profession*£ Physician £ Advanced Practice Nurse £ Nurse £ Physician Assistant £ Pharmacist £ Other please specify _____________________________

Specialty*£ Internal Medicine £ Endocrinology £ Family Medicine £ Other please specify __________________________________________________

Approximately how many patients do you see per week who may be impacted by this education?*£ 0 / I do not see patients £ 1-10 £ 11-20 £ 31-40 £ 41-50 £ >50

Number of years in practice*£ <5 £ 6-10 £ 11-15 £ 16-20 £ 21-25 £ >25

This activity improved my: (check all that apply)*£ Knowledge £ Competence/Skills £ Performance £ Patient Outcomes £ None of the above

Please list one new concept you learned in this activity. ____________________________________________________________________________________

Please indicate your agreement with the following statements about this activityStrongly

Agree Agree Neutral DisagreeStrongly Disagree

The content covered was useful and relevant to my practice.* 5 4 3 2 1The activity was fair, balanced, and free of commercial bias.* 5 4 3 2 1The information learned during this activity will help improve my skills or judgment within the next six months.* 5 4 3 2 1

I am better able to: Describe indications for starting basal insulin therapy in patients with type 2 diabetes mellitus* 5 4 3 2 1

I am better able to: Use appropriate basal insulin in a physiologic manner and titrate therapy to achieve fasting plasma glucose goals* 5 4 3 2 1

I am better able to: Acknowledge and address patient barriers to insulin therapy by explaining how new therapies have been designed to mitigate barriers* 5 4 3 2 1

I am better able to: Intensify therapy in a patient-specific manner using new and emerging options, whether by premixed insulin or other prandial insulin or injectable therapies* 5 4 3 2 1

I would recommend this activity to others.* 5 4 3 2 1

Comments about the content/learning materials. ________________________________________________________________________________________

Based on what you learned in this activity, what will you do differently in the care of your patients? (check all that apply)*£ Implement new information or skill in my practice £ Create/revise protocols, policies, and/or procedures£ Seek additional information £ Activity validated current practice £ Do nothing differently—The content was not convincing £ Do nothing differently—System barriers prevent me from changing my practice£ Not applicable. I have no patient contact.

Please list one change you anticipate making in your practice (if none, please write “N/A”)*. _______________________________________________________________

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£ Other please specify ___________________________________ £ No barriers

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