Diabetes And Drug Treatments

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

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

le 8 .1 — D ru

g -sp

ecifi c a n d p a tien

t facto

rs to

co n sid

e r w h e n sele

ctin g an

tih y p e rg ly ce

m ic

tre atm

en t in

a d u lts

w ith

ty p e 2 d iab

etes

*See ref.31

for descriptio

n o f efficacy.

†FD A app

roved for

C V D bene

fit.C V D ,cardio

vascu lar

disease;D KA

,d iabetic

ketoacidosis;D KD

,d iabetic

kidn ey

disease;N A SH

,n onalcoh

olic steatohepatitis;

R A s,receptor

agonists;SQ ,sub

cutan eous;T2D

M ,type

2 diabetes.

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

T ab

le 8 .2 — P h ar m ac

o lo g y o f av

ai la b le

g lu co

se -l o w er in g ag

en ts

in th e U .S . fo r th e tr ea

tm en

t o f ty p e 2 d ia b et es

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ar y p h ys io lo gi ca la ct io n (s )

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al d o si n g re co m m en

d at io n s (6 3– 66 )*

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in A ct iv at es

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care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S79

T ab

le 8 .2 — C o n ti n u ed

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s ga st ri c em

pt yi ng ;

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se ad ju st m en t re co m m en de d by

th e m an uf ac tu re r; lim

it ed

ex pe ri en ce

in pa ti en ts w it h se ve re

re na li m pa ir m en t

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ir ed

fo r eG

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it ed

ex pe ri en ce

in pa ti en ts w it h se ve re

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t pa ti en ts sh ou

ld be

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it ed

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ld be

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it ed

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Sl ow

s ga st ri c em

pt yi ng ;

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se ad ju st m en t re co m m en de d by

m an uf ac tu re r

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in su lin

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in su lin ot ro pi c pe pt id e; PP A R -g ,p er ox is om

e pr ol ife ra to r– ac ti va te d re ce pt or

g .

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.

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