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Diabetes Care Volume 41, Supplement 1, January 2018 S73

8. Pharmacologic Approaches to American Diabetes Association Glycemic Treatment: Standards of Medical Care in Diabetesd2018 Diabetes Care 2018;41(Suppl. 1):S73–S85 | https://doi.org/10.2337/dc18-S008 .PAMCLGCAPOCE OGYEI TREATMENT GLYCEMIC TO APPROACHES PHARMACOLOGIC 8.

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 and basal insulin or continuous subcutaneous insulin infusion. A c Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce risk. A c Consider educating individuals with type 1 diabetes on matching prandial insulin doses to 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 Suggested citation: American Diabetes Associ- 1.0 units/kg/day of total insulin with higher amounts required during puberty. ation. 8. Pharmacologic approaches to glyce- The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook notes mic treatment: Standards of Medical Care in 0.5 units/kg/day as a typical starting dose in patients with type 1 diabetes who Diabetesd2018. Diabetes Care 2018;41(Suppl. 1): are metabolically stable, with higher weight-based dosing required immediately S73–S85 following presentation with ketoacidosis (1), and provides detailed information © 2017 by the American Diabetes Association. on intensification of therapy to meet individualized needs. The American Diabetes Readers may use this article as long as the work “ is properly cited, the use is educational and not Association (ADA) position statement Type 1 Through for profit, and the work is not altered. More infor- theLifeSpan” additionally provides a thorough overview of type 1 diabetes mation is available at http://www.diabetesjournals treatment (2). .org/content/license. S74 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

Education regarding matching prandial compared with U-100 glargine in patients placebo (23). The Reducing With insulin dosing to carbohydrate intake, with type 1 diabetes (19,20). Vascular Adverse Lesions in Type 1 Diabetes premeal glucose levels, and anticipated Rapid-acting inhaled insulin used be- (REMOVAL) trial investigated the addition activity should be considered, and se- fore meals in patients with type 1 diabe- of metformin therapy to titrated insulin lected individuals who have mastered tes was shown to be noninferior when therapy in adults with type 1 diabetes at carbohydrate counting should be edu- compared with aspart insulin for A1C low- increased risk for cardiovascular disease cated on fat and protein gram estimation ering, with less hypoglycemia observed and found that metformin did not signifi- (3–5). Although most studies of multiple with inhaled insulin therapy (21). How- cantly improve glycemic control beyond daily injections versus continuous subcu- ever, the mean reduction in A1C was the first 3 months of treatment and that taneous insulin infusion (CSII) have been greater with aspart (–0.21% vs. –0.40%, progression of atherosclerosis (measured small and of short duration, a systematic satisfying the noninferiority margin of by carotid artery intima-media thickness) review and meta-analysis concluded that 0.4%), and more patients in the insulin was not significantly reduced, although there are minimal differences between aspart group achieved A1C goals of other cardiovascular risk factors such as the two forms of intensive insulin therapy #7.0% (53 mmol/mol) and #6.5% (48 body weight and LDL cholesterol im- in A1C (combined mean between-group mmol/mol). Because inhaled insulin car- proved (24). Metformin is not FDA- difference favoring therapy tridges are only available in 4-, 8-, and approved for use in patients with type 1 –0.30% [95% CI –0.58 to –0.02]) and se- 12-unit doses, limited dosing increments diabetes. vere hypoglycemia rates in children and to fine-tune prandial insulin doses in type 1 Incretin-Based Therapies adults (6). A 3-month randomized trial in diabetes are a potential limitation. Due to their potential protection of b-cell patients with type 1 diabetes with noctur- Postprandial glucose excursions may mass and suppression of glucagon release, nal hypoglycemia reported that sensor- be better controlled by adjusting the tim- glucagon-like peptide 1 (GLP-1) receptor augmented insulin pump therapy with ing of prandial (bolus) insulin dose admin- agonists (25) and dipeptidyl peptidase the threshold suspend feature reduced istration. The optimal time to administer 4 (DPP-4) inhibitors (26) are being studied nocturnal hypoglycemia without increas- prandial insulin varies, based on the type in patients with type 1 diabetes but are ing levels (7). The of insulin used (regular, rapid-acting ana- not currently FDA-approved for use in pa- U.S. Food and Drug Administration (FDA) log, inhaled, etc.), measured blood glucose tients with type 1 diabetes. has also approved the first hybrid closed- level, timing of meals, and carbohydrate loop system pump. The safety and effi- consumption. Recommendations for pran- Sodium–Glucose Cotransporter 2 Inhibitors cacy of hybrid closed-loop systems has dial insulin dose administration should Sodium–glucose cotransporter 2 (SGLT2) been supported in the literature in ado- therefore be individualized. inhibitors provide insulin-independent lescents and adults with type 1 diabetes glucose lowering by blocking glucose re- (8,9). absorption in the proximal renal tubule by Intensive management using CSII and Pramlintide, an analog, is an agent inhibiting SGLT2. These agents provide continuous glucose monitoring should be that delays gastric emptying, blunts pan- modest weight loss and blood pressure encouragedinselectedpatientswhen creatic secretion of glucagon, and en- reduction in . There are there is active patient/family participa- hances satiety. It is FDA-approved for use three FDA-approved agents for patients tion (10–12). in adults with type 1 diabetes. It has been with type 2 diabetes, but none are FDA- The Diabetes Control and Complica- shown to induce weight loss and lower in- approved for the treatment of patients tions Trial (DCCT) clearly showed that in- sulin doses. Concurrent reduction of pran- with type 1 diabetes (2). SGLT2 inhibitors tensive therapy with multiple daily dial insulin dosing is required to reduce the may have glycemic benefits in patients injections or CSII delivered by multidisci- risk of severe hypoglycemia. with type 1 or type 2 diabetes on insulin plinary teams of physicians, nurses, dieti- therapy (27). The FDA issued a warning tians, and behavioral scientists improved Investigational Agents about the risk of ketoacidosis occurring glycemia and resulted in better long-term Metformin in the absence of significant hyperglyce- outcomes (13–15). The study was carried Adding metformin to insulin therapy may mia (euglycemic ) out with short-acting and intermediate- reduce insulin requirements and improve in patients with type 1 or type 2 diabe- acting human . Despite better mi- metabolic control in patients with type 1 tes treated with SGLT2 inhibitors. crovascular, macrovascular, and all-cause diabetes. In one study, metformin was Symptoms of ketoacidosis include dysp- mortality outcomes, intensive therapy found to reduce insulin requirements nea, nausea, vomiting, and abdominal was associated with a high rate of severe (6.6 units/day, P , 0.001), and led to pain. Patients should be instructed to hypoglycemia (61 episodes per 100 patient- small reductions in weight and total and stop taking SGLT2 inhibitors and seek years of therapy). Since the DCCT, a number LDL cholesterol but not to improved gly- medical attention immediately if they of rapid-acting and long-acting insulin an- cemic control (absolute A1C reduction have symptoms or signs of ketoacidosis alogs have been developed. These analogs 0.11%, P 5 0.42) (22). A randomized clin- (28). are associated with less hypoglycemia, ical trial similarly found that, among over- less weight gain, and lower A1C than human weight adolescents with type 1 diabetes, SURGICAL TREATMENT FOR insulins in people with type 1 diabetes the addition of metformin to insulin did TYPE 1 DIABETES (16–18). Longer-acting basal analogs not improve glycemic control and in- Pancreas and Islet Transplantation (U-300 glargine or degludec) may addi- creased risk for gastrointestinal adverse Pancreas and islet transplantation have tionally convey a lower hypoglycemia risk events after 6 months compared with been shown to normalize glucose levels care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S75

but require life-long immunosuppression and may reduce risk of cardiovascular therapy should begin with lifestyle to prevent graft rejection and recurrence events and death (32). Compared with management and metformin and of autoimmune islet destruction. Given , metformin as first-line subsequently incorporate an agent the potential adverse effects of immuno- therapy has beneficial effects on A1C, proven to reduce major adverse car- suppressive therapy, pancreas transplan- weight, and cardiovascular mortality diovascular events and cardiovascu- tation should be reserved for patients (33). Metformin may be safely used in larmortality(currentlyempagliflozin with type 1 diabetes undergoing simulta- patients with estimated glomerular filtra- and ), after considering neous renal transplantation, following re- tion rate (eGFR) as low as 30 mL/min/ drug-specific and patient factors nal transplantation, or for those with 1.73 m2, and the FDA recently revised (Table 8.1). A* recurrent ketoacidosis or severe hypogly- the label for metformin to reflect its c In patients with type 2 diabetes and cemia despite intensive glycemic man- safety in patients with eGFR $30 mL/ established atherosclerotic cardiovascu- agement (29). min/1.73 m2 (34). Patients should be ad- lar disease, after lifestyle management vised to stop the in cases of PHARMACOLOGIC THERAPY FOR and metformin, the antihyperglycemic nausea, vomiting, or dehydration. Met- TYPE 2 DIABETES agent canagliflozin may be considered formin is associated with vitamin B12 to reduce major adverse cardiovascular deficiency, with a recent report from the Recommendations events, based on drug-specific and pa- c Diabetes Prevention Program Outcomes Metformin, if not contraindicated tient factors (Table 8.1). C* and if tolerated, is the preferred ini- Study (DPPOS) suggesting that periodic c Continuous reevaluation of the med- testing of vitamin B12 levels should be tial pharmacologic agent for the ication regimen and adjustment as A considered in metformin-treated pa- treatment of type 2 diabetes. needed to incorporate patient fac- c tients, especially in those with anemia Long-term use of metformin may be tors (Table 8.1) and regimen com- or peripheral neuropathy (35). associated with biochemical vitamin plexity is recommended. E B12 deficiency, and periodic mea- In patients with metformin contrain- c For patients with type 2 diabetes dications or intolerance, consider an ini- surement of vitamin B12 levels should who are not achieving glycemic goals, tial drug from another class depicted in be considered in metformin-treated drug intensification, including consid- Fig. 8.1 under “Dual Therapy” and pro- patients, especially in those with ane- eration of insulin therapy, should not B ceed accordingly. When A1C is $9% (75 mia or peripheral neuropathy. be delayed. B c Consider initiating insulin therapy mmol/mol), consider initiating dual com- c Metformin should be continued bination therapy (Fig. 8.1)tomoreexpe- (with or without additional agents) when used in combination with other ditiously achieve the target A1C level. in patients with newly diagnosed agents, including insulin, if not contra- Insulin has the advantage of being effec- type 2 diabetes who are symptom- indicated and if tolerated. A atic and/or have A1C $10% (86 tive where other agents may not be and mmol/mol) and/or blood glucose should be considered as part of any com- levels $300 mg/dL (16.7 mmol/L). E See Section 12 for recommendations bination regimen when is c Consider initiating dual therapy in specific for children and adolescents severe, especially if catabolic features patients with newly diagnosed with type 2 diabetes. The use of metfor- (weight loss, ketosis) are present. Con- type 2 diabetes who have A1C min as first-line therapy was supported by sider initiating combination insulin in- $9% (75 mmol/mol). E findings from a large meta-analysis, with jectable therapy (Fig. 8.2)whenblood c In patients without atherosclerotic selection of second-line therapies based glucose is $300 mg/dL (16.7 mmol/L) or cardiovascular disease, if mono- on patient-specific considerations (30). A1C is $10% (86 mmol/mol) or if the pa- therapy or dual therapy does not An ADA/European Association for the Study tient has symptoms of hyperglycemia achieve or maintain the A1C goal of Diabetes position statement “Manage- (i.e., polyuria or polydipsia). As the pa- over 3 months, add an additional ment of Hyperglycemia in Type 2 Diabe- tient’s glucose toxicity resolves, the regi- antihyperglycemic agent based on tes, 2015: A Patient-Centered Approach” menmay,potentially,besimplified. drug-specific and patient factors (31) recommended a patient-centered ap- (Table 8.1). A proach, including assessment of efficacy, Combination Therapy c A patient-centered approach should hypoglycemia risk, impact on weight, side Although there are numerous trials be used to guide the choice of effects, costs, and patient preferences. Re- comparing dual therapy with metformin pharmacologic agents. Consider- nal effects may also be considered when alone, few directly compare drugs as add- ations include efficacy, hypoglyce- selecting glucose-lowering for on therapy. A comparative effectiveness mia risk, history of atherosclerotic individual patients. Lifestyle modifications meta-analysis (36) suggests that each cardiovascular disease, impact on that improve health (see Section 4 “Lifestyle new class of noninsulin agents added to weight, potential side effects, re- Management”) should be emphasized initial therapy generally lowers A1C ap- nal effects, delivery method (oral along with any pharmacologic therapy. proximately 0.7–1.0%. If the A1C target versus subcutaneous), cost, and is not achieved after approximately 3 months patient preferences. E Initial Therapy and patient does not have atherosclerotic c In patients with type 2 diabetes and Metformin monotherapy should be cardiovascular disease (ASCVD), consider established atherosclerotic cardio- started at diagnosis of type 2 diabetes un- a combination of metformin and any one vascular disease, antihyperglycemic less there are contraindications. Metfor- of the preferred six treatment options: min is effective and safe, is inexpensive, , , DPP-4 S76 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

Figure 8.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations. *If patient does not tolerate or has contraindications to metformin, 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.

inhibitor, SGLT2 inhibitor, GLP-1 receptor second agent with evidence of cardiovas- dual therapy, proceed to a three-drug agonist, or basal insulin (Fig. 8.1); the choice cular risk reduction after consideration of combination (Fig. 8.1). Again, if A1C target of which agent to add is based on drug- drug-specific and patient factors (see p. S77 is not achieved after ;3 months of triple specific effects and patient factors (Table CARDIOVASCULAR OUTCOMES TRIALS). If A1C target therapy, proceed to combination injectable 8.1). For patients with ASCVD, add a is still not achieved after ;3monthsof therapy (Fig. 8.2). Drug choice is based on Table 8.1—Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes

*See ref. 31 for description of efficacy. †FDA approved for CVD benefit. CVD, cardiovascular disease; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; NASH, nonalcoholic steatohepatitis; RAs, receptor agonists; SQ, subcutaneous; T2DM, type 2 diabetes. care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S77 S78 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

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

patient preferences (37), as well as various dual therapy, with continuous reevalu- Of note, prices listed are average whole- patient, disease, and drug characteristics, ation of patient factors to guide treat- sale prices (AWP) (39) and National Aver- with the goal of reducing blood glucose ment (Table 8.1). age Drug Acquisition Costs (NADAC) (40) levels while minimizing side effects, espe- Table 8.2 lists drugs commonly used in and do not account for discounts, re- cially hypoglycemia. If not already in- the U.S. Cost-effectiveness models of the bates, or other price adjustments often cluded in the treatment regimen, addition newer agents based on clinical utility and involved in prescription sales that affect of an agent with evidence of cardiovas- glycemic effect have been reported (38). the actual cost incurred by the patient. cular risk reduction should be consid- Table 8.3 provides cost information for Whiletherearealternativemeanstoesti- ered in patients with ASCVD beyond currently approved noninsulin therapies. mate medication prices, AWP and NADAC aedaeejunl.r hraooi prahst lcmcTetetS79 Treatment Glycemic to Approaches Pharmacologic care.diabetesjournals.org Table 8.2—Pharmacology of available glucose-lowering agents in the U.S. for the treatment of type 2 diabetes Class Compound(s) Cellular mechanism(s) Primary physiological action(s) Renal dosing recommendations (63–66)*

Biguanides c Metformin Activates AMP kinase (? other) ↓ Hepatic glucose production c No dose adjustment if eGFR .45; do not initiate OR assess risk/benefit if currently on metformin if eGFR 30–45; discontinue if eGFR ,30

Sulfonylureas (2nd c Glyburide Closes KATP channels on b-cell ↑ Insulin secretion c Avoid use in patients with renal impairment generation) c plasma membranes c Initiate conservatively at 2.5 mg daily to avoid hypoglycemia c c Initiate conservatively at 1 mg daily to avoid hypoglycemia

Meglitinides c Closes KATP channels on b-cell ↑ Insulin secretion c Initiate conservatively at 0.5 mg with meals if eGFR ,30 (glinides) c plasma membranes c Initiate conservatively at 60 mg with meals if eGFR ,30 c Activates the nuclear ↑ Insulin sensitivity c No dose adjustment required c § transcription factor PPAR-g c No dose adjustment required a-Glucosidase c Inhibits intestinal a-glucosidase Slows intestinal carbohydrate c Avoid if eGFR ,30 inhibitors c digestion/absorption c Avoid if eGFR ,25 DPP-4 inhibitors c Inhibits DPP-4 activity, ↑ Insulin secretion (glucose c 100 mg daily if eGFR .50; increasing postprandial incretin dependent); 50 mg daily if eGFR 30–50; (GLP-1, GIP) concentrations ↓ Glucagon secretion (glucose 25 mg daily if eGFR ,30 dependent) c c 5 mg daily if eGFR .50; 2.5 mg daily if eGFR #50 c c No dose adjustment required

c c 25 mg daily if eGFR .60; 12.5 mg daily if eGFR 30–60; 6.25 mg daily if eGFR ,30 Bile acid c Colesevelam Binds bile acids in intestinal ? ↓ Hepatic glucose production; c No specific dose adjustment recommended by manufacturer sequestrants tract, increasing hepatic bile ? ↑ Incretin levels acid production Dopamine-2 c (quick Activates dopaminergic receptors Modulates hypothalamic regulation c No specific dose adjustment recommended by manufacturer agonists release)§ of metabolism; ↑ Insulin sensitivity SGLT2 inhibitors c Canagliflozin Inhibits SGLT2 in the proximal Blocks glucose reabsorption by the c No dose adjustment required if eGFR $60; nephron kidney, increasing glucosuria 100 mg daily if eGFR 45–59; avoid use and discontinue in patients with eGFR persistently ,45 c Dapagliflozin c Avoid initiating if eGFR ,60; not recommended with eGFR 30–60; contraindicated with eGFR ,30 c Empagliflozin c Contraindicated with eGFR ,30 GLP-1 receptor c Activates GLP-1 ↑ Insulin secretion (glucose c Not recommended with eGFR ,30 agonists c Exenatide extended receptors dependent) c Not recommended with eGFR ,30 release Continued on p. S80 8 hraooi prahst lcmcTreatment Glycemic to Approaches Pharmacologic S80

Table 8.2—Continued Class Compound(s) Cellular mechanism(s) Primary physiological action(s) Renal dosing recommendations (63–66)* c Liraglutide ↓ Glucagon secretion (glucose c No specific dose adjustment recommended by the manufacturer; limited dependent); experience in patients with severe renal impairment c Slows gastric emptying; c No dose adjustment required for eGFR 15–89 per manufacturer; limited ↑ Satiety experience in patients with severe renal impairment c c No dose adjustment required for eGFR 60–89; no dose adjustment required for eGFR 30–59, but patients should be monitored for adverse effects and changes in kidney function; clinical experience is limited with eGFR 15–29; patients should be monitored for adverse effects and changes in kidney function; avoid if eGFR ,15 c c No specific dose adjustment recommended by the manufacturer; limited experience in patients with severe renal impairment Amylin mimetics c Pramlintide§ Activates amylin receptors ↓ Glucagon secretion; c No specific dose adjustment recommended by manufacturer Slows gastric emptying; ↑ Satiety Insulins c Rapid-acting analogs Activates insulin receptors ↑ Glucose disposal; c Lower insulin doses required with a decrease in eGFR; titrate per clinical Lispro ↓ Hepatic glucose production; response Aspart Suppresses ketogenesis Glulisine Inhaled insulin c Short-acting analogs

Human Regular Care Diabetes c Intermediate-acting analogs Human NPH c Basal insulin analogs Glargine

Detemir 2018 January 1, Supplement 41, Volume Degludec c Premixed insulin products NPH/Regular 70/30 70/30 aspart mix 75/25 lispro mix 50/50 lispro mix *eGFR is given in mL/min/1.73 m2. §Not licensed in Europe for type 2 diabetes. GIP, glucose-dependent insulinotropic peptide; PPAR-g, peroxisome proliferator–activated receptor g. care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S81

Table 8.3—Median monthly cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S. Dosage strength/product Median AWP Median NADAC Maximum approved Class Compound(s) (if applicable) (min, max)† (min, max)† daily dose* 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, $539 ($539, $5,189) 2,000 mg $7,214) Sulfonylureas c Glyburide 5 mg $93 ($63, $103) $17 20 mg (2nd generation) 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 (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 c Acarbose 100 mg $104 ($104, $106) $25 300 mg inhibitors 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 c Exenatide 10 mg pen $802 $642 20 mg agonists 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 2 mg powder for $747 $600 2 mg** release) suspension or pen 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 price 3 number of doses required to provide maximum approved daily dose 3 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. wereutilizedtoprovidetwoseparatemea- late postprandial hypoglycemia when The empagliflozin and liraglutide trials sures to allow for a comparison of drug taking a sulfonylurea. Other drugs not demonstrated significant reductions in prices with the primary goal of highlighting shown in Table 8.1 (e.g., inhaled insulin, cardiovascular death. Exenatide once- the importance of cost considerations a-glucosidase inhibitors, colesevelam, bro- weekly did not have statistically sig- when prescribing antihyperglycemic treat- mocriptine, and pramlintide) may be tried nificant reductions in major adverse ments. The ongoing Glycemia Reduction in specific situations but considerations cardiovascular events or cardiovascu- Approaches in Diabetes: A Comparative Ef- include modest efficacy in type 2 diabetes, lar mortality but did have a significant fectiveness Study (GRADE) will compare frequency of administration, potential for reduction in all-cause mortality. In con- four drug classes (sulfonylurea, DPP-4 in- drug interactions, cost, and/or side effects. trast, other GLP-1 receptor agonists hibitor, GLP-1 receptor agonist, and basal have not shown similar reductions in insulin) when added to metformin therapy Cardiovascular Outcomes Trials cardiovascular events (Table 9.4). over 4 years on glycemic control and other There are now three large randomized Whether the benefits of GLP-1 receptor medical, psychosocial, and health economic controlled trials reporting statistically sig- agonists are a class effect remains to be outcomes (41). nificant reductions in cardiovascular events definitively established. See ANTIHYPERGLYCEMIC Rapid-acting secretagogues (meglitinides) for two SGLT2 inhibitors (empagliflozin THERAPIES AND CARDIOVASCULAR OUTCOMES in may be used instead of sulfonylureas in and canagliflozin) and one GLP-1 receptor Section 9 “Cardiovascular Disease and patients with sulfa allergies or irregular agonist (liraglutide) where the majority, if Risk Management” and Table 9.4 for a de- meal schedules or in those who develop not all patients, in the trial had ASCVD. tailed description of these cardiovascular S82 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

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 Median AWP Median NADAC Insulins Compounds Dosage form/product (min, max)* (min, max)* Rapid-acting c Lispro U-100 vial; $330 $264 analogs 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 c U-500 Human U-500 vial; $178 $143 Regular insulin U-500 prefilled pen $230 $184 Basal analogs c Glargine U-100 vial; U-100 prefilled pen; $298 $239 ($239, $241) U-300 prefilled pen 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 c Degludec/Liraglutide 100/3.6 prefilled pen $763 N/A† receptor agonist products 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.

outcomes trials. Additional large random- avoid using insulin as a threat or de- to reduce the risk of symptomatic and noc- ized trials of other agents in these classes scribing it as a sign of personal failure turnal hypoglycemia (43–48). Longer- are ongoing. or punishment. acting basal analogs (U-300 glargine or Of note, these studies examined the Equipping patients with an algorithm for degludec) may additionally convey a drugs in combination with metformin self-titration of insulin doses based on self- lower hypoglycemia risk compared with (Table 9.4) in the great majority of pa- monitoring of blood glucose improves U-100 glargine when used in combination tients for whom metformin was not con- glycemic control in patients with type 2 di- with oral antihyperglycemic agents (49– traindicated or not tolerated. For patients abetes initiating insulin (42). Comprehen- 55). While there is evidence for reduced with type 2 diabetes who have ASCVD, on sive education regarding self-monitoring hypoglycemia with newer, longer-acting lifestyle and metformin therapy, it is rec- of blood glucose, diet, and the avoidance basal insulin analogs, people without a ommended to incorporate an agent with of and appropriate treatment of hypogly- history of hypoglycemia are at decreased strong evidence for cardiovascular risk re- cemia are critically important in any pa- risk and could potentially be switched to duction especially those with proven ben- tient using insulin. human insulin safely. Thus, due to high efit on both major adverse cardiovascular costs of analog insulins, use of human in- events and cardiovascular death after con- Basal Insulin sulin may be a practical option for some sideration of drug-specific patient factors Basal insulin alone is the most convenient patients, and clinicians should be familiar (Table 8.1). See Fig. 8.1 for additional rec- initial insulin regimen, beginning at 10 units with its use (56). Table 8.4 provides AWP ommendations on antihyperglycemic per day or 0.1–0.2 units/kg/day, depend- (39) and NADAC (40) information (cost treatment in adults with type 2 diabetes. ing on the degree of hyperglycemia. Basal per 1,000 units) for currently available in- insulin is usually prescribed in conjunc- sulin and insulin combination products Insulin Therapy tion with metformin and sometimes one in the U.S. There have been substantial Many patients with type 2 diabetes even- additional noninsulin agent. When basal increases in the price of insulin over the tually require and benefitfrominsulin insulin is added to antihyperglycemic past decade and the cost-effectiveness therapy. The progressive nature of type 2 agents in patients with type 2 diabetes, of different antihyperglycemic agents is diabetes should be regularly and objectively long-acting basal analogs (U-100 glargine an important consideration in a patient- explained to patients. Providers should or detemir) can be used instead of NPH centered approach to care, along with care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S83

efficacy, hypoglycemia risk, weight, and pulmonary disease and is not recommended insulin (NPH/Regular 70/30, 70/30 aspart other patient and drug-specific factors in patients who smoke or who recently stop- mix, 75/25 or 50/50 lispro mix) twice (Table 8.1)(57). ped smoking. It requires spirometry (FEV1) daily, usually before breakfast and before testing to identify potential lung disease in all dinner. Each approach has its advan- Bolus Insulin Many individuals with type 2 diabetes patients prior to and after starting therapy. tages and disadvantages. For example, may require mealtime bolus insulin dos- providers may wish to consider regimen fl ing in addition to basal insulin. Rapid- Combination Injectable Therapy exibility when devising a plan for the ini- acting analogs are preferred due to their If basal insulin has been titrated to an ac- tiation and adjustment of insulin therapy prompt onset of action after dosing. In ceptable fasting blood glucose level (or if in people with type 2 diabetes, with rapid- . fl September 2017, the FDA approved a new the dose is 0.5 units/kg/day) and A1C re- acting insulin offering greater exibility in faster-acting formulation of . mains above target, consider advancing terms of meal planning than premixed in- Fig. The recommended starting dose of meal- to combination injectable therapy ( sulin. If one regimen is not effective (i.e., 8.2 time insulin is 4 units, 0.1 units/kg, or 10% ). When initiating combination inject- basal insulin plus GLP-1 receptor agonist), of the basal dose. If A1C is ,8% (64 mmol/ able therapy, metformin therapy should consider switching to another regimen to mol) when starting mealtime bolus in- be maintained while other oral agents achieve A1C targets (i.e., basal insulin plus sulin, consideration should be given to may be discontinued on an individual ba- single injection of rapid-acting insulin or pre- decreasing the basal insulin dose. sis to avoid unnecessarily complex or mixed insulin twice daily) (60,61). Regular costly regimens (i.e., adding a fourth anti- human insulin and human NPH/Regular Premixed Insulin hyperglycemic agent). In general, GLP-1 premixed formulations (70/30) are less Premixed insulin products contain both a receptor agonists should not be discon- costly alternatives to rapid-acting insulin basal and prandial component, allowing tinued with the initiation of basal insulin. analogs and premixed insulin analogs, coverage of both basal and prandial needs Sulfonylureas, DPP-4 inhibitors, and GLP- respectively, but their pharmacody- with a single injection. NPH/Regular 70/30 1 receptor agonists are typically stopped namic profiles may make them less optimal. insulin, for example, is composed of 70% once more complex insulin regimens be- Fig. 8.2 outlines these options, as well NPH insulin and 30% regular insulin. The use yond basal are used. In patients with sub- as recommendations for further intensifi- of premixed insulin products has its advan- optimal blood glucose control, especially cation, if needed, to achieve glycemic tages and disadvantages, as discussed be- those requiring large insulin doses, adjunc- goals. If a patient is still above the A1C low in COMBINATION INJECTABLE THERAPY. tive use of a thiazolidinedione or SGLT2 target on premixed insulin twice daily, Concentrated Insulin Products inhibitor may help to improve control consider switching to premixed analog in- Several concentrated insulin preparations and reduce the amount of insulin needed, sulin three times daily (70/30 aspart mix, are currently available. U-500 regular insu- though potential side effects should be 75/25 or 50/50 lispro mix). In general, lin, by definition, is fivetimesasconcen- considered. Once an insulin regimen is ini- three times daily premixed analog insu- trated as U-100 regular insulin and has a tiated, dose titration is important with ad- lins have been found to be noninferior delayed onset and longer duration of ac- justments made in both mealtime and to basal-bolus regimens with similar rates tion than U-100 regular, possessing both basal insulins based on the blood glucose of hypoglycemia (62). If a patient is still prandial and basal properties. U-300 glar- levels and an understanding of the phar- above the A1C target on basal insulin gine and U-200 degludec are three and macodynamic profile of each formulation plus single injection of rapid-acting insulin two times as concentrated as their U-100 (pattern control). before the largest meal, advance to a formulations and allow higher doses of basal Studies have demonstrated the non- basal-bolus regimen with $2 injections insulin administration per volume used. inferiority of basal insulin plus a single of rapid-acting insulin before meals. Con- U-300 glargine has a longer duration of ac- injection of rapid-acting insulin at the larg- sider switching patients from one regimen tion than U-100 glargine. The FDA has also est meal relative to basal insulin plus a to another (i.e., premixed analog insulin approved a concentrated formulation of GLP-1 receptor agonist relative to two three times daily to basal-bolus regimen rapid-acting , U-200 (200 daily injections of premixed insulins or vice-versa) if A1C targets are not being units/mL). These concentrated preparations (Fig. 8.2). Basal insulin plus GLP-1 recep- met and/or depending on other patient may be more comfortable for the patient tor agonists are associated with less hy- considerations (60,61). Metformin should and may improve adherence for patients poglycemia and with weight loss instead be continued in patients on combination with insulin resistance who require large of weight gain but may be less tolerable injectable insulin therapy, if not contra- doses of insulin. While U-500 regular insulin and have a greater cost (58,59). In No- indicated and if tolerated, for further gly- is available in both prefilledpensandvials(a vember 2016, the FDA approved two dif- cemic benefits. dedicated syringe was FDA approved in July ferent once-daily fixed-dual combination 2016), other concentrated insulins are avail- products containing basal insulin plus a References fi GLP-1 receptor agonist: able only in pre lled pens to minimize the 1. Peters AL, Laffel L, Eds. American Diabetes risk of dosing errors. plus lixisenatide and Association/JDRF Type 1 Diabetes Sourcebook. plus liraglutide. Other options for treat- Alexandria, VA, American Diabetes Association, Inhaled Insulin ment intensification include adding a sin- 2013 Inhaled insulin is available for prandial use gle injection of rapid-acting 2. Chiang JL, Kirkman MS, Laffel LMB, Peters AL; Type 1 Diabetes Sourcebook Authors. Type 1 di- with a more limited dosing range. 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