Diabetes and Drug Treatments

 

Each year, 1.5 million Americans are diagnosed with diabetes (American Diabetes Association, 2019). If left untreated, diabetic patients are at risk for several alterations, including heart disease, stroke, kidney failure, neuropathy, and blindness. There are various methods for treating diabetes, many of which include some form of drug therapy. The type of diabetes as well as the patient’s behavior factors will impact treatment recommendations.

For this Discussion, you compare types of diabetes, including drug treatments for type 1, type 2, gestational, and juvenile diabetes.

Reference: American Diabetes Association. (2019). Statistics about diabetes. Retrieved from http://diabetes.org/diabetes-basics/statistics/

 

                                                 To Prepare

Review the Resources for this module and reflect on differences between types of diabetes, including type 1, type 2, gestational, and juvenile diabetes.

Select one type of diabetes to focus on for this Discussion.

Consider one type of drug used to treat the type of diabetes you selected, including proper preparation and administration of this drug.

Then, reflect on dietary considerations related to treatment.

Think about the short-term and long-term impact of the diabetes you selected on patients, including effects of drug treatments.

Post a brief explanation of the differences between the types of diabetes, including type 1, type 2, gestational, and juvenile diabetes.

Describe one type of drug used to treat the type of diabetes you selected, including proper preparation and administration of this drug.

Be sure to include dietary considerations related to treatment.

Then, explain the short-term and long-term impact of this type of diabetes on patients. including effects of drug treatments.

Be specific and provide examples.

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Rubric Detail

 

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Name: NURS_6521_Week5_Discussion_Rubric

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  Excellent Good Fair Poor
Main Posting 45 (45%) – 50 (50%)

Answers all parts of the discussion question(s) expectations with reflective critical analysis and synthesis of knowledge gained from the course readings for the module and current credible sources. Supported by at least three current, credible sources. Written clearly and concisely with no grammatical or spelling errors and fully adheres to current APA manual writing rules and style.

40 (40%) – 44 (44%)

Responds to the discussion question(s) and is reflective with critical analysis and synthesis of knowledge gained from the course readings for the module. At least 75% of post has exceptional depth and breadth. Supported by at least three credible sources. Written clearly and concisely with one or no grammatical or spelling errors and fully adheres to current APA manual writing rules and style.

35 (35%) – 39 (39%)

Responds to some of the discussion question(s). One or two criteria are not addressed or are superficially addressed. Is somewhat lacking reflection and critical analysis and synthesis. Somewhat represents knowledge gained from the course readings for the module. Post is cited with two credible sources. Written somewhat concisely; may contain more than two spelling or grammatical errors. Contains some APA formatting errors.

0 (0%) – 34 (34%)

Does not respond to the discussion question(s) adequately. Lacks depth or superficially addresses criteria. Lacks reflection and critical analysis and synthesis. Does not represent knowledge gained from the course readings for the module. Contains only one or no credible sources. Not written clearly or concisely. Contains more than two spelling or grammatical errors. Does not adhere to current APA manual writing rules and style.

Main Post: Timeliness 10 (10%) – 10 (10%)

Posts main post by day 3

0 (0%) – 0 (0%) 0 (0%) – 0 (0%) 0 (0%) – 0 (0%)

Does not post by day 3

First Response 17 (17%) – 18 (18%)

Response exhibits synthesis, critical thinking, and application to practice settings. Responds fully to questions posed by faculty. Provides clear, concise opinions and ideas that are supported by at least two scholarly sources. Demonstrates synthesis and understanding of learning objectives. Communication is professional and respectful to colleagues. . Responses to faculty questions are fully answered, if posed. Response is effectively written in standard, edited English.

15 (15%) – 16 (16%)

Response exhibits synthesis, critical thinking, and application to practice settings. Responds fully to questions posed by faculty. Provides clear, concise opinions and ideas that are supported by at least two scholarly sources. Demonstrates synthesis and understanding of learning objectives. Communication is professional and respectful to colleagues. . Responses to faculty questions are fully answered, if posed. Response is effectively written in standard, edited English.

13 (13%) – 14 (14%)

Response is on topic and may have some depth. Responses posted in the discussion may lack effective professional communication. Responses to faculty questions are somewhat answered, if posed. Response may lack clear, concise opinions and ideas, and a few or no credible sources are cited.

0 (0%) – 12 (12%)

Response may not be on topic and lacks depth. Responses posted in the discussion lack effective professional communication. Responses to faculty questions are missing. No credible sources are cited.

Second Response 16 (16%) – 17 (17%)

Response exhibits synthesis, critical thinking, and application to practice settings. Responds fully to questions posed by faculty. Provides clear, concise opinions and ideas that are supported by at least two scholarly sources. Demonstrates synthesis and understanding of learning objectives. Communication is professional and respectful to colleagues. . Responses to faculty questions are fully answered, if posed. Response is effectively written in standard, edited English.

14 (14%) – 15 (15%)

Response exhibits critical thinking and application to practice settings. Communication is professional and respectful to colleagues. Responses to faculty questions are answered, if posed. Provides clear, concise opinions and ideas that are supported by two or more credible sources. Response is effectively written in standard, edited English.

12 (12%) – 13 (13%)

Response is on topic and may have some depth. Responses posted in the discussion may lack effective professional communication. Responses to faculty questions are somewhat answered, if posed. . Response may lack clear, concise opinions and ideas, and a few or no credible sources are cited.

0 (0%) – 11 (11%)

Response may not be on topic and lacks depth. Responses posted in the discussion lack effective professional communication. Responses to faculty questions are missing. No credible sources are cited.

Participation 5 (5%) – 5 (5%)

Meets requirements for participation by posting on three different days.

0 (0%) – 0 (0%) 0 (0%) – 0 (0%) 0 (0%) – 0 (0%)

Does not meet requirements for participation by posting on 3 different days

Total Points: 100

Name: NURS_6521_Week5_Discussion_Rubric

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8. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S73–S85 | https://doi.org/10.2337/dc18-S008

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES

Recommendations

c Most people with type 1 diabetes should be treated with multiple daily in- jections of prandial insulin and basal insulin or continuous subcutaneous insulin infusion. A

c Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk. A

c Consider educating individuals with type 1 diabetes onmatching prandial insulin doses to carbohydrate intake, premeal blood glucose levels, and anticipated physical activity. E

c Individuals with type 1 diabetes who have been successfully using continuous subcutaneous insulin infusion should have continued access to this therapy after they turn 65 years of age. E

Insulin Therapy Insulin is the mainstay of therapy for individuals with type 1 diabetes. Generally, the starting insulin dose is based on weight, with doses ranging from 0.4 to 1.0 units/kg/day of total insulin with higher amounts required during puberty. The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook notes 0.5 units/kg/day as a typical starting dose in patients with type 1 diabetes who are metabolically stable, with higher weight-based dosing required immediately following presentation with ketoacidosis (1), and provides detailed information on intensification of therapy to meet individualized needs. The American Diabetes Association (ADA) position statement “Type 1 Diabetes Management Through the Life Span” additionally provides a thorough overview of type 1 diabetes treatment (2).

Suggested citation: American Diabetes Associ- ation. 8. Pharmacologic approaches to glyce- mic treatment: Standards of Medical Care in Diabetesd2018. Diabetes Care 2018;41(Suppl. 1): S73–S85

© 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More infor- mation is available at http://www.diabetesjournals .org/content/license.

American Diabetes Association

Diabetes Care Volume 41, Supplement 1, January 2018 S73

8. P H A R M A C O LO

G IC

A P P R O A C H ES

TO G LY C EM

IC TR

EA TM

EN T

ADA
Comment on Text
This article contains updated information as of April 11, 2018. As of 2018, the ADA updates and revises the online version of the Standards of Care throughout the year, making necessary additions and annotations as new evidence and regulatory changes merit immediate incorporation. Read more about the living Standards of Care: https://doi.org/10.2337/dci17-0064 Read about the methodoloy: https://professional.diabetes.org/content-page/living-standards

Education regarding matching prandial insulin dosing to carbohydrate intake, premeal glucose levels, and anticipated activity should be considered, and se- lected individuals who have mastered carbohydrate counting should be edu- cated on fat and protein gram estimation (3–5). Although most studies of multiple daily injections versus continuous subcu- taneous insulin infusion (CSII) have been small and of short duration, a systematic review and meta-analysis concluded that there are minimal differences between the two forms of intensive insulin therapy in A1C (combined mean between-group difference favoring insulin pump therapy –0.30% [95% CI –0.58 to –0.02]) and se- vere hypoglycemia rates in children and adults (6). A 3-month randomized trial in patients with type 1 diabeteswith noctur- nal hypoglycemia reported that sensor- augmented insulin pump therapy with the threshold suspend feature reduced nocturnal hypoglycemia without increas- ing glycated hemoglobin levels (7). The U.S. Food and Drug Administration (FDA) has also approved the first hybrid closed- loop system pump. The safety and effi- cacy of hybrid closed-loop systems has been supported in the literature in ado- lescents and adults with type 1 diabetes (8,9). Intensive management using CSII and

continuous glucose monitoring should be encouraged in selected patients when there is active patient/family participa- tion (10–12). The Diabetes Control and Complica-

tions Trial (DCCT) clearly showed that in- tensive therapy with multiple daily injections or CSII delivered by multidisci- plinary teams of physicians, nurses, dieti- tians, and behavioral scientists improved glycemia and resulted in better long-term outcomes (13–15). The study was carried out with short-acting and intermediate- acting human insulins. Despite better mi- crovascular, macrovascular, and all-cause mortality outcomes, intensive therapy was associated with a high rate of severe hypoglycemia (61episodesper100patient- yearsof therapy). Since theDCCT, anumber of rapid-acting and long-acting insulin an- alogs have beendeveloped. These analogs are associated with less hypoglycemia, less weight gain, and lower A1C than human insulins in people with type 1 diabetes (16–18). Longer-acting basal analogs (U-300 glargine or degludec) may addi- tionally convey a lower hypoglycemia risk

compared with U-100 glargine in patients with type 1 diabetes (19,20).

Rapid-acting inhaled insulin used be- fore meals in patients with type 1 diabe- tes was shown to be noninferior when comparedwith aspart insulin for A1C low- ering, with less hypoglycemia observed with inhaled insulin therapy (21). How- ever, the mean reduction in A1C was greater with aspart (–0.21% vs. –0.40%, satisfying the noninferiority margin of 0.4%), and more patients in the insulin aspart group achieved A1C goals of #7.0% (53 mmol/mol) and #6.5% (48 mmol/mol). Because inhaled insulin car- tridges are only available in 4-, 8-, and 12-unit doses, limited dosing increments to fine-tune prandial insulin doses in type 1 diabetes are a potential limitation.

Postprandial glucose excursions may be better controlled by adjusting the tim- ing of prandial (bolus) insulin dose admin- istration. The optimal time to administer prandial insulin varies, based on the type of insulin used (regular, rapid-acting ana- log, inhaled, etc.), measured blood glucose level, timing of meals, and carbohydrate consumption. Recommendations for pran- dial insulin dose administration should therefore be individualized.

Pramlintide Pramlintide, an amylin analog, is an agent that delays gastric emptying, blunts pan- creatic secretion of glucagon, and en- hances satiety. It is FDA-approved for use in adults with type 1 diabetes. It has been shown to induce weight loss and lower in- sulin doses. Concurrent reduction of pran- dial insulin dosing is required to reduce the risk of severe hypoglycemia.

Investigational Agents

Metformin

Adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in patients with type 1 diabetes. In one study, metformin was found to reduce insulin requirements (6.6 units/day, P , 0.001), and led to small reductions in weight and total and LDL cholesterol but not to improved gly- cemic control (absolute A1C reduction 0.11%, P5 0.42) (22). A randomized clin- ical trial similarly found that, among over- weight adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control and in- creased risk for gastrointestinal adverse events after 6 months compared with

placebo (23). TheReducingWithMetformin Vascular Adverse Lesions in Type1Diabetes (REMOVAL) trial investigated the addition of metformin therapy to titrated insulin therapy in adults with type 1 diabetes at increased risk for cardiovascular disease and found that metformin did not signifi- cantly improve glycemic control beyond the first 3 months of treatment and that progression of atherosclerosis (measured by carotid artery intima-media thickness) was not significantly reduced, although other cardiovascular risk factors such as body weight and LDL cholesterol im- proved (24). Metformin is not FDA- approved for use in patients with type 1 diabetes.

Incretin-Based Therapies

Due to their potential protection of b-cell mass and suppressionof glucagon release, glucagon-like peptide 1 (GLP-1) receptor agonists (25) and dipeptidyl peptidase 4 (DPP-4) inhibitors (26) are being studied in patients with type 1 diabetes but are not currently FDA-approved for use in pa- tients with type 1 diabetes.

Sodium–Glucose Cotransporter 2 Inhibitors

Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide insulin-independent glucose lowering by blocking glucose re- absorption in theproximal renal tubule by inhibiting SGLT2. These agents provide modest weight loss and blood pressure reduction in type 2 diabetes. There are three FDA-approved agents for patients with type 2 diabetes, but none are FDA- approved for the treatment of patients with type 1 diabetes (2). SGLT2 inhibitors may have glycemic benefits in patients with type 1 or type 2 diabetes on insulin therapy (27). The FDA issued a warning about the risk of ketoacidosis occurring in the absence of significant hyperglyce- mia (euglycemic diabetic ketoacidosis) in patients with type 1 or type 2 diabe- tes treated with SGLT2 inhibitors. Symptoms of ketoacidosis include dysp- nea, nausea, vomiting, and abdominal pain. Patients should be instructed to stop taking SGLT2 inhibitors and seek medical attention immediately if they have symptoms or signs of ketoacidosis (28).

SURGICAL TREATMENT FOR TYPE 1 DIABETES

Pancreas and Islet Transplantation Pancreas and islet transplantation have been shown to normalize glucose levels

S74 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

but require life-long immunosuppression to prevent graft rejection and recurrence of autoimmune islet destruction. Given the potential adverse effects of immuno- suppressive therapy, pancreas transplan- tation should be reserved for patients with type 1 diabetes undergoing simulta- neous renal transplantation, following re- nal transplantation, or for those with recurrent ketoacidosis or severe hypogly- cemia despite intensive glycemic man- agement (29).

PHARMACOLOGIC THERAPY FOR TYPE 2 DIABETES

Recommendations

c Metformin, if not contraindicated and if tolerated, is the preferred ini- tial pharmacologic agent for the treatment of type 2 diabetes. A

c Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic mea- surementofvitaminB12 levels should be considered in metformin-treated patients, especially in those with ane- mia or peripheral neuropathy. B

c Consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who are symptom- atic and/or have A1C $10% (86 mmol/mol) and/or blood glucose levels$300mg/dL (16.7mmol/L). E

c Consider initiating dual therapy in patients with newly diagnosed type 2 diabetes who have A1C $9% (75 mmol/mol). E

c In patients without atherosclerotic cardiovascular disease, if mono- therapy or dual therapy does not achieve or maintain the A1C goal over 3 months, add an additional antihyperglycemic agent based on drug-specific and patient factors (Table 8.1). A

c A patient-centered approach should be used to guide the choice of pharmacologic agents. Consider- ations include efficacy, hypoglyce- mia risk, history of atherosclerotic cardiovascular disease, impact on weight, potential side effects, re- nal effects, delivery method (oral versus subcutaneous), cost, and patient preferences. E

c In patients with type 2 diabetes and established atherosclerotic cardio- vascular disease, antihyperglycemic

therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse car- diovascular events and cardiovascu- lar mortality (currently empagliflozin and liraglutide), after considering drug-specific and patient factors (Table 8.1). A*

c In patients with type 2 diabetes and established atherosclerotic cardiovascu- lar disease, after lifestyle management and metformin, the antihyperglycemic agent canagliflozin may be considered to reduce major adverse cardiovascular events, based on drug-specific and pa- tient factors (Table 8.1). C*

c Continuous reevaluationof themed- ication regimen and adjustment as needed to incorporate patient fac- tors (Table 8.1) and regimen com- plexity is recommended. E

c For patients with type 2 diabetes whoarenot achieving glycemic goals, drug intensification, including consid- eration of insulin therapy, should not be delayed. B

c Metformin should be continued whenused in combinationwithother agents, including insulin, if not contra- indicated and if tolerated. A

See Section 12 for recommendations specific for children and adolescents with type 2 diabetes. The use of metfor- min as first-line therapywas supported by findings from a large meta-analysis, with selection of second-line therapies based on patient-specific considerations (30). An ADA/European Association for the Study of Diabetes position statement “Manage- ment of Hyperglycemia in Type 2 Diabe- tes, 2015: A Patient-Centered Approach” (31) recommended a patient-centered ap- proach, including assessment of efficacy, hypoglycemia risk, impact on weight, side effects, costs, and patient preferences. Re- nal effects may also be considered when selecting glucose-loweringmedications for individual patients. Lifestyle modifications that improvehealth (see Section4 “Lifestyle Management”) should be emphasized along with any pharmacologic therapy.

Initial Therapy Metformin monotherapy should be started at diagnosis of type 2 diabetes un- less there are contraindications. Metfor- min is effective and safe, is inexpensive,

and may reduce risk of cardiovascular events and death (32). Compared with sulfonylureas, metformin as first-line therapy has beneficial effects on A1C, weight, and cardiovascular mortality (33). Metformin may be safely used in patients with estimated glomerular filtra- tion rate (eGFR) as low as 30 mL/min/ 1.73 m2, and the FDA recently revised the label for metformin to reflect its safety in patients with eGFR $30 mL/ min/1.73 m2 (34). Patients should be ad- vised to stop the medication in cases of nausea, vomiting, or dehydration. Met- formin is associated with vitamin B12 deficiency, with a recent report from the Diabetes Prevention Program Outcomes Study (DPPOS) suggesting that periodic testing of vitamin B12 levels should be considered in metformin-treated pa- tients, especially in those with anemia or peripheral neuropathy (35).

In patients with metformin contrain- dications or intolerance, consider an ini- tial drug from another class depicted in Fig. 8.1 under “Dual Therapy” and pro- ceed accordingly. When A1C is $9% (75 mmol/mol), consider initiating dual com- bination therapy (Fig. 8.1) to more expe- ditiously achieve the target A1C level. Insulin has the advantage of being effec- tive where other agents may not be and should be considered as part of any com- bination regimen when hyperglycemia is severe, especially if catabolic features (weight loss, ketosis) are present. Con- sider initiating combination insulin in- jectable therapy (Fig. 8.2) when blood glucose is$300 mg/dL (16.7 mmol/L) or A1C is$10% (86 mmol/mol) or if the pa- tient has symptoms of hyperglycemia (i.e., polyuria or polydipsia). As the pa- tient’s glucose toxicity resolves, the regi- men may, potentially, be simplified.

Combination Therapy Although there are numerous trials comparing dual therapy with metformin alone, few directly compare drugs as add- on therapy. A comparative effectiveness meta-analysis (36) suggests that each new class of noninsulin agents added to initial therapy generally lowers A1C ap- proximately 0.7–1.0%. If the A1C target isnotachievedafterapproximately3months and patient does not have atherosclerotic cardiovascular disease (ASCVD), consider a combination of metformin and any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP-4

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S75

inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, orbasal insulin (Fig. 8.1); the choice of which agent to add is based on drug- specific effects and patient factors (Table 8.1). For patients with ASCVD, add a

second agent with evidence of cardiovas- cular risk reduction after consideration of drug-specific and patient factors (see p. S77 CARDIOVASCULAR OUTCOMESTRIALS). If A1C target is still not achieved after ;3 months of

dual therapy, proceed to a three-drug combination (Fig. 8.1). Again, if A1C target is not achieved after;3 months of triple therapy, proceed to combination injectable therapy (Fig. 8.2). Drug choice is based on

Figure 8.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations. *If patient does not tolerate or has contraindications tometformin, consider agents from another class in Table 8.1. #GLP-1 receptor agonists and DPP-4 inhibitors should not be prescribed in combination. If a patient with ASCVD is not yet on an agent with evidence of cardiovascular risk reduction, consider adding.

S76 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

T ab

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care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S77

patient preferences (37), as well as various patient, disease, and drug characteristics, with the goal of reducing blood glucose levelswhileminimizing side effects, espe- cially hypoglycemia. If not already in- cluded in the treatment regimen, addition of an agent with evidence of cardiovas- cular risk reduction should be consid- ered in patients with ASCVD beyond

dual therapy, with continuous reevalu- ation of patient factors to guide treat- ment (Table 8.1).

Table 8.2 lists drugs commonly used in the U.S. Cost-effectiveness models of the newer agents based on clinical utility and glycemic effect have been reported (38). Table 8.3 provides cost information for currently approved noninsulin therapies.

Of note, prices listed are average whole- sale prices (AWP) (39) and National Aver- age Drug Acquisition Costs (NADAC) (40) and do not account for discounts, re- bates, or other price adjustments often involved in prescription sales that affect the actual cost incurred by the patient. While there are alternative means to esti- mate medication prices, AWP and NADAC

Figure 8.2—Combination injectable therapy for type 2 diabetes. FBG, fasting blood glucose; hypo, hypoglycemia. Adapted with permission from Inzucchi et al. (31).

S78 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

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care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S79

ADA
Comment on Text
In December 2017, the U.S. Food and Drug Administration approved the SGLT2 inhibitor ertugliflozin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Reference: U.S. Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. Available from https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=209803. Accessed 1 January 2018 Rationale/Reason for Change: Approval of new treatments (medications or devices) has the potential to impact patient care. Annotation published April 11, 2018. Annotation approved by PPC: March 10, 2018. Suggested citation: American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2018 [web annotation]. Diabetes Care 2018;41(Suppl. 1):S73–S85. Retrieved from https://hyp.is/8Qjypj2VEei_E2-Ft0MSjQ/care.diabetesjournals.org/content/41/Supplement_1/S73.
EBerg
Sticky Note
Unmarked set by EBerg
ADA
Comment on Text
In December 2017, the U.S. FDA approved the GLP-1 receptor agonist semaglutide as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Reference: U.S. Food & Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=209637. Accessed January 1, 2018 Rationale/Reason for Change: Approval of new treatments (medications or devices) has the potential to impact patient care. Annotation published April 11, 2018. Annotation approved by PPC: March 10, 2018. Suggested citation: American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2018 [web annotation]. Diabetes Care 2018;41(Suppl. 1):S73–S85. Retrieved from https://hyp.is/D0tVED2WEeiK8ZvLIDyLZg/care.diabetesjournals.org/content/41/Supplement_1/S73.

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S80 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

were utilized to provide two separatemea- sures to allow for a comparison of drug prices with the primary goal of highlighting the importance of cost considerations when prescribing antihyperglycemic treat- ments. The ongoing Glycemia Reduction Approaches in Diabetes: A Comparative Ef- fectiveness Study (GRADE) will compare four drug classes (sulfonylurea, DPP-4 in- hibitor, GLP-1 receptor agonist, and basal insulin) when added tometformin therapy over 4 years on glycemic control and other medical, psychosocial, and health economic outcomes (41). Rapid-actingsecretagogues (meglitinides)

may be used instead of sulfonylureas in patients with sulfa allergies or irregular meal schedules or in those who develop

late postprandial hypoglycemia when taking a sulfonylurea. Other drugs not shown in Table 8.1 (e.g., inhaled insulin, a-glucosidase inhibitors, colesevelam,bro- mocriptine, and pramlintide) may be tried in specific situations but considerations includemodest efficacy in type 2 diabetes, frequency of administration, potential for drug interactions, cost, and/or side effects.

Cardiovascular Outcomes Trials

There are now three large randomized controlled trials reporting statistically sig- nificant reductions in cardiovascular events for two SGLT2 inhibitors (empagliflozin and canagliflozin) and one GLP-1 receptor agonist (liraglutide) where themajority, if not all patients, in the trial had ASCVD.

The empagliflozin and liraglutide trials demonstrated significant reductions in cardiovascular death. Exenatide once- weekly did not have statistically sig- nificant reductions in major adverse cardiovascular events or cardiovascu- lar mortality but did have a significant reduction in all-cause mortality. In con- trast, other GLP-1 receptor agonists have not shown similar reductions in cardiovascular events (Table 9.4). Whether the benefits of GLP-1 receptor agonists are a class effect remains to be definitively established. See ANTIHYPERGLYCEMIC THERAPIES AND CARDIOVASCULAR OUTCOMES in Section 9 “Cardiovascular Disease and Risk Management” and Table 9.4 for a de- tailed description of these cardiovascular

Table 8.3—Median monthly cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S.

Class Compound(s) Dosage strength/product

(if applicable) Median AWP (min, max)†

Median NADAC (min, max)†

Maximum approved daily dose*

Biguanides c Metformin 500 mg (IR) $84 ($4, $93) $2 2,000 mg 850 mg (IR) $108 ($6, $109) $3 2,550 mg 1,000 mg (IR) $87 ($4, $88) $2 2,000 mg 500 mg (ER) $89 ($82, $6,671) $5 ($5, $3,630) 2,000 mg 750 mg (ER) $72 ($65, $92) $5 1,500 mg 1,000 mg (ER) $1,028 ($1,028,

$7,214) $539 ($539, $5,189) 2,000 mg

Sulfonylureas (2nd generation)

c Glyburide 5 mg $93 ($63, $103) $17 20 mg 6 mg (micronized) $50 ($48, $71) $12 12 mg (micronized)

c Glipizide 10 mg (IR) $75 ($67, $97) $4 40 mg (IR) 10 mg (XL) $48 $16 20 mg (XL)

c Glimepiride 4 mg $71 ($71, $198) $7 8 mg

Meglitinides (glinides) c Repaglinide 2 mg $659 ($122, $673) $40 16 mg c Nateglinide 120 mg $155 $56 360 mg

Thiazolidinediones c Pioglitazone 45 mg $348 ($283, $349) $5 45 mg c Rosiglitazone 4 mg $387 $314 8 mg

a-Glucosidase inhibitors

c Acarbose 100 mg $104 ($104, $106) $25 300 mg c Miglitol 100 mg $241 N/A†† 300 mg

DPP-4 inhibitors c Sitagliptin 100 mg $477 $382 100 mg c Saxagliptin 5 mg $462 $370 5 mg c Linagliptin 5 mg $457 $367 5 mg c Alogliptin 25 mg $449 $357 25 mg

Bile acid sequestrants c Colesevelam 625 mg tabs $713 $570 3.75 g 1.875 g suspension $1,426 $572 3.75 g

Dopamine-2 agonists c Bromocriptine 0.8 mg $784 $629 4.8 mg

SGLT2 inhibitors c Canagliflozin 300 mg $512 $411 300 mg c Dapagliflozin 10 mg $517 $413 10 mg c Empagliflozin 25 mg $517 $415 25 mg

GLP-1 receptor agonists

c Exenatide 10 mg pen $802 $642 20 mg c Lixisenatide 20 mg pen $669 N/A†† 20 mg c Liraglutide 18 mg/3 mL pen $968 $775 1.8 mg c Exenatide (extended release)

2 mg powder for suspension or pen

$747 $600 2 mg**

c Albiglutide 50 mg pen $626 $500 50 mg** c Dulaglutide 1.5/0.5 mL pen $811 $648 1.5 mg**

Amylin mimetics c Pramlintide 120 mg pen $2,336 N/A†† 120 mg/injection†††

ER and XL, extended release; IR, immediate release. †Calculated for 30-day supply (AWP or NADAC unit price3 number of doses required to provide maximum approved daily dose3 30 days); median AWP or NADAC listed alone when only one product and/or price. *Utilized to calculate median AWP and NADAC (min, max); generic prices used, if available commercially. ††Not applicable; data not available. **Administered once weekly. †††AWP and NADAC calculated based on 120 mg three times daily.

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S81

outcomes trials. Additional large random- ized trials of other agents in these classes are ongoing. Of note, these studies examined the

drugs in combination with metformin (Table 9.4) in the great majority of pa- tients for whom metformin was not con- traindicated or not tolerated. For patients with type 2 diabetes who have ASCVD, on lifestyle and metformin therapy, it is rec- ommended to incorporate an agent with strong evidence for cardiovascular risk re- duction especially those with proven ben- efit on both major adverse cardiovascular events and cardiovascular death after con- sideration of drug-specific patient factors (Table 8.1). See Fig. 8.1 for additional rec- ommendations on antihyperglycemic treatment in adults with type 2 diabetes.

Insulin Therapy Many patients with type 2 diabetes even- tually require and benefit from insulin therapy. The progressive nature of type 2 diabetes shouldbe regularly andobjectively explained to patients. Providers should

avoid using insulin as a threat or de- scribing it as a sign of personal failure or punishment.

Equipping patientswith an algorithm for self-titration of insulin doses based on self- monitoring of blood glucose improves glycemic control in patients with type 2 di- abetes initiating insulin (42). Comprehen- sive education regarding self-monitoring of blood glucose, diet, and the avoidance of and appropriate treatment of hypogly- cemia are critically important in any pa- tient using insulin.

Basal Insulin

Basal insulin alone is themost convenient initial insulin regimen, beginning at 10units per day or 0.1–0.2 units/kg/day, depend- ing on the degree of hyperglycemia. Basal insulin is usually prescribed in conjunc- tion with metformin and sometimes one additional noninsulin agent. When basal insulin is added to antihyperglycemic agents in patients with type 2 diabetes, long-acting basal analogs (U-100 glargine or detemir) can be used instead of NPH

to reduce the risk of symptomatic and noc- turnal hypoglycemia (43–48). Longer- acting basal analogs (U-300 glargine or degludec) may additionally convey a lower hypoglycemia risk compared with U-100 glargine when used in combination with oral antihyperglycemic agents (49– 55). While there is evidence for reduced hypoglycemia with newer, longer-acting basal insulin analogs, people without a history of hypoglycemia are at decreased risk and could potentially be switched to human insulin safely. Thus, due to high costs of analog insulins, use of human in- sulin may be a practical option for some patients, and clinicians should be familiar with its use (56). Table 8.4 provides AWP (39) and NADAC (40) information (cost per 1,000 units) for currently available in- sulin and insulin combination products in the U.S. There have been substantial increases in the price of insulin over the past decade and the cost-effectiveness of different antihyperglycemic agents is an important consideration in a patient- centered approach to care, along with

Table 8.4—Median cost of insulin products in the U.S. calculated as AWP (39) and NADAC (40) per 1,000 units of specified dosage form/product

Insulins Compounds Dosage form/product Median AWP (min, max)*

Median NADAC (min, max)*

Rapid-acting analogs

c Lispro U-100 vial; $330 $264 U-100 3 mL cartridges; $408 $326 U-100 prefilled pen; U-200 prefilled pen $424 $339

c Aspart U-100 vial; $331 $265 U-100 3 mL cartridges; $410 $330 U-100 prefilled pen $426 $341

c Glulisine U-100 vial; $306 $245 U-100 prefilled pen $394 $315

c Inhaled insulin Inhalation cartridges $725 ($544, $911) N/A†

Short-acting analogs c Human Regular U-100 vial $165 ($165, $178) $135 ($135, $145)

Intermediate-acting analogs c Human NPH U-100 vial; $165 ($165, $178) $135 ($135, $145) U-100 prefilled pen $377 $305

Concentrated Human Regular insulin

c U-500 Human Regular insulin

U-500 vial; $178 $143 U-500 prefilled pen $230 $184

Basal analogs c Glargine U-100 vial; U-100 prefilled pen; U-300 prefilled pen

$298 $239 ($239, $241)

c Glargine biosimilar U-100 prefilled pen $253 $203 c Detemir U-100 vial; U-100 prefilled pen $323 $259 c Degludec U-100 prefilled pen; U-200 prefilled pen $355 $285

Premixed insulin products c NPH/Regular 70/30 U-100 vial; $165 ($165, $178) $134 ($134, $146) U-100 prefilled pen $377 $305

c Lispro 50/50 U-100 vial; $342 $278 U-100 prefilled pen $424 $339

c Lispro 75/25 U-100 vial; $342 $273 U-100 prefilled pen $424 $340

c Aspart 70/30 U-100 vial; $343 $275 U-100 prefilled pen $426 $341

Premixed insulin/GLP-1 receptor agonist products

c Degludec/Liraglutide 100/3.6 prefilled pen $763 N/A† c Glargine/Lixisenatide 100/33 prefilled pen $508 $404

*AWP or NADAC calculated as in Table 8.3; median listed alone when only one product and/or price. †Not applicable; data not available.

S82 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

efficacy, hypoglycemia risk, weight, and other patient and drug-specific factors (Table 8.1) (57).

Bolus Insulin

Many individuals with type 2 diabetes may require mealtime bolus insulin dos- ing in addition to basal insulin. Rapid- acting analogs are preferred due to their prompt onset of action after dosing. In September 2017, the FDA approved a new faster-acting formulation of insulin aspart. The recommended starting dose of meal- time insulin is 4 units, 0.1 units/kg, or 10% of the basal dose. If A1C is,8% (64 mmol/ mol) when starting mealtime bolus in- sulin, consideration should be given to decreasing the basal insulin dose.

Premixed Insulin

Premixed insulin products contain both a basal and prandial component, allowing coverage of both basal and prandial needs with a single injection. NPH/Regular 70/30 insulin, for example, is composed of 70% NPH insulin and30% regular insulin. Theuse of premixed insulin products has its advan- tages and disadvantages, as discussed be- low in COMBINATION INJECTABLE THERAPY.

Concentrated Insulin Products

Several concentrated insulin preparations are currently available. U-500 regular insu- lin, by definition, is five times as concen- trated as U-100 regular insulin and has a delayed onset and longer duration of ac- tion than U-100 regular, possessing both prandial and basal properties. U-300 glar- gine and U-200 degludec are three and two times as concentrated as their U-100 formulationsandallowhigherdosesofbasal insulin administration per volume used. U-300 glargine has a longer duration of ac- tion than U-100 glargine. The FDA has also approved a concentrated formulation of rapid-acting insulin lispro, U-200 (200 units/mL). These concentrated preparations may be more comfortable for the patient and may improve adherence for patients with insulin resistance who require large doses of insulin.While U-500 regular insulin is available in both prefilled pens and vials (a dedicated syringe was FDA approved in July 2016), other concentrated insulins are avail- able only in prefilled pens to minimize the risk of dosing errors.

Inhaled Insulin

Inhaled insulin is available for prandial use withamore limiteddosing range. It is contra- indicated in patients with chronic lung dis- ease such as asthma and chronic obstructive

pulmonarydisease and is not recommended inpatientswho smokeorwho recently stop- ped smoking. It requires spirometry (FEV1) testing to identifypotential lungdisease inall patients prior to and after starting therapy.

Combination Injectable Therapy If basal insulin has been titrated to an ac- ceptable fasting blood glucose level (or if thedose is.0.5 units/kg/day) andA1C re- mains above target, consider advancing to combination injectable therapy (Fig. 8.2). When initiating combination inject- able therapy, metformin therapy should be maintained while other oral agents may be discontinued on an individual ba- sis to avoid unnecessarily complex or costly regimens (i.e., adding a fourth anti- hyperglycemic agent). In general, GLP-1 receptor agonists should not be discon- tinued with the initiation of basal insulin. Sulfonylureas, DPP-4 inhibitors, and GLP- 1 receptor agonists are typically stopped once more complex insulin regimens be- yond basal are used. In patients with sub- optimal blood glucose control, especially those requiring large insulin doses, adjunc- tive use of a thiazolidinedione or SGLT2 inhibitor may help to improve control and reduce the amount of insulin needed, though potential side effects should be considered. Once an insulin regimen is ini- tiated, dose titration is important with ad- justments made in both mealtime and basal insulins based on the blood glucose levels and an understanding of the phar- macodynamic profile of each formulation (pattern control).

Studies have demonstrated the non- inferiority of basal insulin plus a single injectionof rapid-acting insulin at the larg- est meal relative to basal insulin plus a GLP-1 receptor agonist relative to two daily injections of premixed insulins (Fig. 8.2). Basal insulin plus GLP-1 recep- tor agonists are associated with less hy- poglycemia and with weight loss instead of weight gain but may be less tolerable and have a greater cost (58,59). In No- vember 2016, the FDA approved two dif- ferent once-daily fixed-dual combination products containing basal insulin plus a GLP-1 receptor agonist: insulin glargine plus lixisenatide and insulin degludec plus liraglutide. Other options for treat- ment intensification include adding a sin- gle injection of rapid-acting insulin analog (lispro, aspart, or glulisine) before the largest meal or stopping the basal insulin and initiating a premixed (or biphasic)

insulin (NPH/Regular 70/30, 70/30 aspart mix, 75/25 or 50/50 lispro mix) twice daily, usually before breakfast and before dinner. Each approach has its advan- tages and disadvantages. For example, providers may wish to consider regimen flexibility when devising a plan for the ini- tiation and adjustment of insulin therapy in people with type 2 diabetes, with rapid- acting insulin offering greater flexibility in terms of meal planning than premixed in- sulin. If one regimen is not effective (i.e., basal insulin plus GLP-1 receptor agonist), consider switching to another regimen to achieve A1C targets (i.e., basal insulin plus single injectionof rapid-acting insulinorpre- mixed insulin twice daily) (60,61). Regular human insulin and human NPH/Regular premixed formulations (70/30) are less costly alternatives to rapid-acting insulin analogs and premixed insulin analogs, respectively, but their pharmacody- namicprofilesmaymake them lessoptimal.

Fig. 8.2 outlines these options, as well as recommendations for further intensifi- cation, if needed, to achieve glycemic goals. If a patient is still above the A1C target on premixed insulin twice daily, consider switching to premixed analog in- sulin three times daily (70/30 aspart mix, 75/25 or 50/50 lispro mix). In general, three times daily premixed analog insu- lins have been found to be noninferior to basal-bolus regimens with similar rates of hypoglycemia (62). If a patient is still above the A1C target on basal insulin plus single injection of rapid-acting insulin before the largest meal, advance to a basal-bolus regimen with $2 injections of rapid-acting insulin before meals. Con- sider switching patients from one regimen to another (i.e., premixed analog insulin three times daily to basal-bolus regimen or vice-versa) if A1C targets are not being met and/or depending on other patient considerations (60,61).Metformin should be continued in patients on combination injectable insulin therapy, if not contra- indicated and if tolerated, for further gly- cemic benefits.

References 1. Peters AL, Laffel L, Eds. American Diabetes Association/JDRF Type 1 Diabetes Sourcebook. Alexandria, VA, American Diabetes Association, 2013 2. Chiang JL, Kirkman MS, Laffel LMB, Peters AL; Type 1 Diabetes Sourcebook Authors. Type 1 di- abetes through the life span: a position statement of the American Diabetes Association. Diabetes Care 2014;37:2034–2054

care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S83

3. Wolpert HA, Atakov-Castillo A, Smith SA, Steil GM. Dietary fat acutely increases glucose con- centrations and insulin requirements in pa- tients with type 1 diabetes: implications for carbohydrate-based bolus dose calculation and intensive diabetes management. Diabetes Care 2013;36:810–816 4. Bell KJ, Toschi E, Steil GM, Wolpert HA. Opti- mized mealtime insulin dosing for fat and protein in type 1 diabetes: application of a model-based approach to derive insulin doses for open-loop diabetes management. Diabetes Care 2016;39: 1631–1634 5. Bell KJ, Smart CE, Steil GM, Brand-Miller JC, King B, Wolpert HA. Impact of fat, protein, and glycemic index on postprandial glucose control in type 1 diabetes: implications for intensive diabetes management in the continuous glucosemonitoring era. Diabetes Care 2015;38:1008–1015 6. Yeh H-C, Brown TT,Maruthur N, et al. Compar- ative effectiveness and safety of methods of in- sulin delivery and glucosemonitoring for diabetes mellitus: a systematic review and meta-analysis. Ann Intern Med 2012;157:336–347 7. Bergenstal RM, Klonoff DC, Garg SK, et al.; ASPIRE In-Home Study Group. Threshold-based insulin-pump interruption for reduction of hypo- glycemia. N Engl J Med 2013;369:224–232 8. Bergenstal RM, Garg S, Weinzimer SA, et al. Safety of a hybrid closed-loop insulin delivery sys- tem in patients with type 1 diabetes. JAMA 2016; 316:1407–1408 9. Garg SK, Weinzimer SA, TamborlaneWV, et al. Glucose outcomes with the in-home use of a hy- brid closed-loop insulin delivery system in adoles- cents and adults with type 1 diabetes. Diabetes Technol Ther 2017;19:155–163 10. Wood JR, Miller KM, Maahs DM, et al.; T1D Exchange Clinic Network. Most youth with type 1 diabetes in the T1D Exchange Clinic Registry do not meet American Diabetes Association or International Society for Pediatric and Adolescent Diabetes clinical guidelines. Diabetes Care 2013;36:2035–2037 11. Kmietowicz Z. Insulin pumps improve control and reduce complications in children with type 1 diabetes. BMJ 2013;347:f5154 12. Phillip M, Battelino T, Atlas E, et al. Nocturnal glucose control with an artificial pancreas at a di- abetes camp. N Engl J Med 2013;368:824–833 13. Nathan DM, Genuth S, Lachin J, et al.; Diabe- tes Control and Complications Trial Research Group. The effect of intensive treatment of dia- betes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977– 986 14. Nathan DM, Cleary PA, Backlund J-YC, et al.; Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Com- plications (DCCT/EDIC) Study Research Group. In- tensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–2653 15. Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Mortality in type 1 diabetes in the DCCT/EDIC versus the general population. Diabetes Care 2016;39:1378–1383 16. Tricco AC, Ashoor HM, Antony J, et al. Safety, effectiveness, and cost effectiveness of long act- ing versus intermediate acting insulin for patients

with type 1 diabetes: systematic review and net- work meta-analysis. BMJ 2014;349:g5459 17. Bartley PC, BogoevM, Larsen J, Philotheou A. Long-term efficacy and safety of insulin detemir compared to Neutral Protamine Hagedorn insulin in patients with type 1 diabetes using a treat-to- target basal-bolus regimen with insulin aspart at meals: a 2-year, randomized, controlled trial. Dia- bet Med 2008;25:442–449 18. DeWitt DE, Hirsch IB. Outpatient insulin ther- apy in type 1 and type 2 diabetes mellitus: scien- tific review. JAMA 2003;289:2254–2264 19. LaneW, Bailey TS, Gerety G, et al.; SWITCH 1. Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes: the SWITCH 1 Randomized Clinical Trial. JAMA 2017;318:33–44 20. Home PD, Bergenstal RM, Bolli GB, et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 1 diabetes: a randomized, phase 3a, open-label clinical trial (EDITION 4). Diabetes Care 2015;38:2217–2225

21. Bode BW, McGill JB, Lorber DL, Gross JL, Chang PC, Bregman DB; Affinity 1 Study Group. Inhaled technosphere insulin compared with in- jected prandial insulin in type 1 diabetes: a ran- domized 24-week trial. Diabetes Care 2015;38: 2266–2273 22. Vella S, Buetow L, Royle P, Livingstone S, Colhoun HM, Petrie JR. The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 2010;53:809–820 23. Libman IM,Miller KM,DiMeglio LA, et al.; T1D Exchange Clinic Network Metformin RCT Study Group. Effect of metformin added to insulin on glycemic control among overweight/obese ado- lescents with type 1 diabetes: a randomized clin- ical trial. JAMA 2015;314:2241–2250 24. Petrie JR, Chaturvedi N, Ford I, et al.; REMOVAL Study Group. Cardiovascular and met- abolic effects ofmetformin in patientswith type 1 diabetes (REMOVAL): a double-blind, rando- mised, placebo-controlled trial. Lancet Diabetes Endocrinol 2017;5:597–609 25. Dejgaard TF, Frandsen CS, Hansen TS, et al. Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): a randomised, double- blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2016;4:221–232 26. Guo H, Fang C, Huang Y, Pei Y, Chen L, Hu J. The efficacy and safety of DPP4 inhibitors in pa- tients with type 1 diabetes: a systematic review and meta-analysis. Diabetes Res Clin Pract 2016; 121:184–191 27. Yang Y, Chen S, Pan H, et al. Safety and effi- ciency of SGLT2 inhibitor combiningwith insulin in subjects with diabetes: systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2017;96:e6944 28. U.S. Food and Drug Administration. SGLT2 inhibitors: drug safety communication – labels to include warnings about too much acid in the blood and serious urinary tract infections [Internet], 2015. Available from http://www.fda.gov/safety/ medwatch/safetyinformation/safetyalertsforhuma nmedicalproducts/ucm475553.htm. Accessed 3 October 2016 29. Robertson RP, Davis C, Larsen J, Stratta R, Sutherland DER; American Diabetes Association. Pancreas and islet transplantation in type 1 dia- betes. Diabetes Care 2006;29:935

30. Palmer SC,MavridisD,Nicolucci A, et al. Com- parison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA 2016; 316:313–324 31. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabe- tes, 2015: a patient-centered approach: update to a position statement of the American Diabe- tes Association and the European Association for the Study of Diabetes. Diabetes Care 2015; 38:140–149 32. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glu- cose control in type2diabetes.N Engl JMed2008; 359:1577–1589 33. Maruthur NM, Tseng E, Hutfless S, et al. Di- abetesmedications asmonotherapy ormetformin- based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2016;164:740–751 34. U.S. Food and Drug Administration. Metformin- containing drugs: drug safety communication – revised warnings for certain patients with reduced kidney function [Internet], 2016. Available from http://www.fda.gov/Safety/MedWatch/ SafetyInformation/SafetyAlertsforHumanMedical Products/ucm494829.htm?source5govdelivery& utm_medium5email&utm_source5govdelivery. Accessed 3 October 2016 35. Aroda VR, Edelstein SL, Goldberg RB, et al.; Diabetes Prevention Program Research Group. Long-term metformin use and vitamin B12 defi- ciency in the Diabetes Prevention Program Out- comes Study. J Clin Endocrinol Metab 2016;101: 1754–1761 36. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medica- tions for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 2011;154:602–613 37. Vijan S, Sussman JB, Yudkin JS, Hayward RA. Effect of patients’ risks and preferences on health gains with plasma glucose level lowering in type 2 diabetes mellitus. JAMA Intern Med 2014;174: 1227–1234 38. Institute for Clinical and Economic Review. Controversies in the management of patients with type 2 diabetes [Internet], 2014. Available from https://icer-review.org/wp-content/uploads/ 2015/03/CEPAC-T2D-Final-Report-December-22 .pdf. Accessed 2 November 2017 39. Truven Health Analytics. Red Book: A Com- prehensive, Consistent Drug Pricing Resource [Internet], 2016. Available from: http://www .micromedexsolutions.com/micromedex2/librarian. Accessed 18 July 2017 40. Centers for Medicare & Medicaid Services. Pharmacy pricing: national average drug acquisi- tion cost [Internet], 2017. Available from https:// www.medicaid.gov/medicaid/prescription-drugs/ pharmacy-pricing/index.html. Accessed 19 July 2017 41. Nathan DM, Buse JB, Kahn SE, et al.; GRADE Study Research Group. Rationale and design of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Di- abetes Care 2013;36:2254–2261 42. Blonde L, Merilainen M, Karwe V, Raskin P; TITRATE Study Group. Patient-directed titra- tion for achieving glycaemic goals using a once- daily basal insulin analogue: an assessment of

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two different fasting plasma glucose targets – the TITRATE study. Diabetes Obes Metab 2009;11: 623–631 43. Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H. Efficacy and safety of insulin analogues for the managementof diabetesmellitus: ameta-analysis. CMAJ 2009;180:385–397 44. Horvath K, Jeitler K, Berghold A, et al. Long- acting insulin analogues versus NPH insulin (hu- man isophane insulin) for type2diabetesmellitus. Cochrane Database Syst Rev 2007;2:CD005613 45. MonamiM,Marchionni N,Mannucci E. Long- acting insulin analogues versus NPH human insu- lin in type 2 diabetes: a meta-analysis. Diabetes Res Clin Pract 2008;81:184–189 46. Owens DR, Traylor L, Mullins P, Landgraf W. Patient-level meta-analysis of efficacy and hypo- glycaemia in peoplewith type 2 diabetes initiating insulin glargine 100U/mL or neutral protamine Hagedorn insulin analysed according to concomi- tant oral antidiabetes therapy. Diabetes Res Clin Pract 2017;124(Suppl. C):57–65 47. RiddleMC,Rosenstock J,Gerich J; InsulinGlar- gine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26:3080–3086 48. Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial compar- ing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin- naive people with type 2 diabetes. Diabetes Care 2006;29:1269–1274 49. Bolli GB, Riddle MC, Bergenstal RM, et al.; EDITION 3 Study Investigators. New insulin glar- gine 300 U/ml compared with glargine 100 U/ml in insulin-näıve people with type 2 diabetes on oral glucose-lowering drugs: a randomized con- trolled trial (EDITION 3). Diabetes Obes Metab 2015;17:386–394 50. Terauchi Y, Koyama M, Cheng X, et al. New insulin glargine 300U/ml versus glargine 100U/ml

in Japanese people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs: glucose control and hypoglycaemia in a random- ized controlled trial (EDITION JP 2). Diabetes Obes Metab 2016;18:366–374 51. Yki-Järvinen H, Bergenstal RM, Bolli GB, et al. Glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus insulin glargine 100 U/ml in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs: the EDITION2 randomized 12-month trial including 6-month extension. Diabetes Obes Metab 2015; 17:1142–1149 52. Marso SP, McGuire DK, Zinman B, et al. Effi- cacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med 2017;377:723–732 53. RodbardHW,CariouB, ZinmanB, et al.; BEGIN Once Long trial investigators. Comparison of insu- lin degludec with insulin glargine in insulin-naive subjects with Type 2 diabetes: a 2-year random- ized, treat-to-target trial. Diabet Med 2013;30: 1298–1304 54. WyshamC,BhargavaA, Chaykin L, et al. Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes: the SWITCH 2 Randomized Clinical Trial. JAMA 2017;318:45–56 55. Zinman B, Philis-Tsimikas A, Cariou B, et al.; NN1250-3579 (BEGIN Once Long) Trial Investiga- tors. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long). Diabetes Care 2012;35:2464–2471 56. Lipska KJ, Hirsch IB, RiddleMC.Human insulin for type 2 diabetes: an effective, less-expensive option. JAMA 2017;318:23–24 57. Hua X, Carvalho N, TewM, Huang ES, Herman WH, Clarke P. Expenditures and prices of antihy- perglycemic medications in the United States: 2002-2013. JAMA 2016;315:1400–1402 58. DiamantM, NauckMA, Shaginian R, et al.; 4B StudyGroup. Glucagon-like peptide 1 receptor ag- onist or bolus insulin with optimized basal insulin

in type 2 diabetes. Diabetes Care 2014;37:2763– 2773 59. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet 2014;384: 2228–2234 60. Dieuzeide G, Chuang L-M, Almaghamsi A, Zilov A, Chen J-W, Lavalle-González FJ. Safety and effectiveness of biphasic insulin aspart 30 in people with type 2 diabetes switching from basal- bolus insulin regimens in the A1chieve study. Prim Care Diabetes 2014;8:111–117 61. Mathieu C, Storms F, Tits J, VenemanTF, Colin IM. Switching from premixed insulin to basal- bolus insulin glargine plus rapid-acting insulin: the ATLANTIC study. Acta Clin Belg 2013;68:28– 33 62. Giugliano D, Chiodini P, Maiorino MI, Bellastella G, Esposito K. Intensification of insulin therapy with basal-bolus or premixed insulin reg- imens in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. En- docrine 2016;51:417–428 63. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care 2014;37:2864–2883 64. Neumiller JJ, Alicic RZ, Tuttle KR. Therapeutic considerations for antihyperglycemic agents in di- abetic kidney disease. J Am Soc Nephrol 2017;28: 2263–2274 65. U.S. Food and Drug Administration. Cycloset [bromocriptine] prescribing information [In- ternet], 2017. [Available from https://www .accessdata.fda.gov/drugsatfda_docs/label/2017/ 020866s006s007lbl.pdf. Accessed 22 September 2017 66. U.S. Food and Drug Administration. Welchol [Colesevelam] prescribing information [Internet], 2014. Available from https://www.accessdata.fda .gov/drugsatfda_docs/label/2011/022362s007lbl .pdf. Accessed 22 September 2017

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