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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.
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.
Resources
Rosenthal, L. D., & Burchum, J. R. (2021). Lehne’s pharmacotherapeutics for advanced practice nurses and physician assistants (2nd ed.) St. Louis, MO: Elsevier.
Chapter 48, “Drugs for Diabetes Mellitus” (pp. 397–415)
Chapter 49, “Drugs for Thyroid Disorders” (pp. 416–424)
American Diabetes Association. (2018). Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetesLinks to an external site.—2018. Diabetes Care, 41(Supplement 1), S73–S85. Retrieved from http://care.diabetesjournals.org/content/41/supple…
Document: Mid-Term Summary & Study Guide (PDF)
This article provides guidance on pharmacologic approaches to glycemic treatment as it pertains to treating patients with diabetes. Reflect on the content of this article as you continue to examine potential drug treatments for patients with diabetes.
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Diabetes Care Volume 41, Supplement 1, January 2018
8. Pharmacologic Approaches to
Glycemic Treatment: Standards of
Medical Care in Diabetesd2018
S73
American Diabetes Association
Diabetes Care 2018;41(Suppl. 1):S73–S85 | https://doi.org/10.2337/dc18-S008
8. PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT
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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 injections 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 on matching 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 Association. 8. Pharmacologic approaches to glycemic 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 information is available at http://www.diabetesjournals
.org/content/license.
S74
Diabetes Care Volume 41, Supplement 1, January 2018
Pharmacologic Approaches to Glycemic Treatment
compared with U-100 glargine in patients
with type 1 diabetes (19,20).
Rapid-acting inhaled insulin used before meals in patients with type 1 diabetes was shown to be noninferior when
compared with aspart insulin for A1C lowering, with less hypoglycemia observed
with inhaled insulin therapy (21). However, 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 cartridges 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 timing of prandial (bolus) insulin dose administration. The optimal time to administer
prandial insulin varies, based on the type
of insulin used (regular, rapid-acting analog, inhaled, etc.), measured blood glucose
level, timing of meals, and carbohydrate
consumption. Recommendations for prandial insulin dose administration should
therefore be individualized.
Pramlintide
Pramlintide, an amylin analog, is an agent
that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety. It is FDA-approved for use
in adults with type 1 diabetes. It has been
shown to induce weight loss and lower insulin doses. Concurrent reduction of prandial 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 glycemic control (absolute A1C reduction
0.11%, P 5 0.42) (22). A randomized clinical trial similarly found that, among overweight adolescents with type 1 diabetes,
the addition of metformin to insulin did
not improve glycemic control and increased risk for gastrointestinal adverse
events after 6 months compared with
placebo (23). The Reducing With Metformin
Vascular Adverse Lesions in Type 1 Diabetes
(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 significantly 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 improved (24). Metformin is not FDAapproved for use in patients with type 1
diabetes.
Incretin-Based Therapies
Due to their potential protection of b-cell
mass and suppression of 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 patients with type 1 diabetes.
Sodium–Glucose Cotransporter 2 Inhibitors
Sodium–glucose cotransporter 2 (SGLT2)
inhibitors provide insulin-independent
glucose lowering by blocking glucose reabsorption in the proximal 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 FDAapproved 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 hyperglycemia (euglycemic diabetic ketoacidosis)
in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors.
Symptoms of ketoacidosis include dyspnea, 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
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Education regarding matching prandial
insulin dosing to carbohydrate intake,
premeal glucose levels, and anticipated
activity should be considered, and selected individuals who have mastered
carbohydrate counting should be educated on fat and protein gram estimation
(3–5). Although most studies of multiple
daily injections versus continuous subcutaneous 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 severe hypoglycemia rates in children and
adults (6). A 3-month randomized trial in
patients with type 1 diabetes with nocturnal hypoglycemia reported that sensoraugmented insulin pump therapy with
the threshold suspend feature reduced
nocturnal hypoglycemia without increasing glycated hemoglobin levels (7). The
U.S. Food and Drug Administration (FDA)
has also approved the first hybrid closedloop system pump. The safety and efficacy of hybrid closed-loop systems has
been supported in the literature in adolescents 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 participation (10–12).
The Diabetes Control and Complications Trial (DCCT) clearly showed that intensive therapy with multiple daily
injections or CSII delivered by multidisciplinary teams of physicians, nurses, dietitians, and behavioral scientists improved
glycemia and resulted in better long-term
outcomes (13–15). The study was carried
out with short-acting and intermediateacting human insulins. Despite better microvascular, macrovascular, and all-cause
mortality outcomes, intensive therapy
was associated with a high rate of severe
hypoglycemia (61 episodes per 100 patientyears of therapy). Since the DCCT, a number
of rapid-acting and long-acting insulin analogs have been developed. 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 additionally convey a lower hypoglycemia risk
care.diabetesjournals.org
but require life-long immunosuppression
to prevent graft rejection and recurrence
of autoimmune islet destruction. Given
the potential adverse effects of immunosuppressive therapy, pancreas transplantation should be reserved for patients
with type 1 diabetes undergoing simultaneous renal transplantation, following renal transplantation, or for those with
recurrent ketoacidosis or severe hypoglycemia despite intensive glycemic management (29).
Recommendations
c
Metformin, if not contraindicated
and if tolerated, is the preferred initial 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 measurement of vitamin B12 levels should
be considered in metformin-treated
patients, especially in those with anemia or peripheral neuropathy. B
c Consider initiating insulin therapy
(with or without additional agents)
in patients with newly diagnosed
type 2 diabetes who are symptomatic and/or have A1C $10% (86
mmol/mol) and/or blood glucose
levels $300 mg/dL (16.7 mmol/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 monotherapy 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. Considerations include efficacy, hypoglycemia risk, history of atherosclerotic
cardiovascular disease, impact on
weight, potential side effects, renal effects, delivery method (oral
versus subcutaneous), cost, and
patient preferences. E
c In patients with type 2 diabetes and
established atherosclerotic cardiovascular disease, antihyperglycemic
therapy should begin with lifestyle
management and metformin and
subsequently incorporate an agent
proven to reduce major adverse cardiovascular events and cardiovascular 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 cardiovascular disease, after lifestyle management
and metformin, the antihyperglycemic
agent canagliflozin may be considered
to reduce major adverse cardiovascular
events, based on drug-specific and patient factors (Table 8.1). C*
c Continuous reevaluation of the medication regimen and adjustment as
needed to incorporate patient factors (Table 8.1) and regimen complexity is recommended. E
c For patients with type 2 diabetes
who are not achieving glycemic goals,
drug intensification, including consideration of insulin therapy, should not
be delayed. B
c Metformin should be continued
when used in combination with other
agents, including insulin, if not contraindicated and if tolerated. A
See Section 12 for recommendations
specific for children and adolescents
with type 2 diabetes. The use of metformin as first-line therapy was 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 “Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach”
(31) recommended a patient-centered approach, including assessment of efficacy,
hypoglycemia risk, impact on weight, side
effects, costs, and patient preferences. Renal effects may also be considered when
selecting glucose-lowering medications for
individual patients. Lifestyle modifications
that improve health (see Section 4 “Lifestyle
Management”) should be emphasized
along with any pharmacologic therapy.
Initial Therapy
Metformin monotherapy should be
started at diagnosis of type 2 diabetes unless there are contraindications. Metformin 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 filtration 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 advised to stop the medication in cases of
nausea, vomiting, or dehydration. Metformin 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 patients, especially in those with anemia
or peripheral neuropathy (35).
In patients with metformin contraindications or intolerance, consider an initial drug from another class depicted in
Fig. 8.1 under “Dual Therapy” and proceed accordingly. When A1C is $9% (75
mmol/mol), consider initiating dual combination therapy (Fig. 8.1) to more expeditiously achieve the target A1C level.
Insulin has the advantage of being effective where other agents may not be and
should be considered as part of any combination regimen when hyperglycemia is
severe, especially if catabolic features
(weight loss, ketosis) are present. Consider initiating combination insulin injectable 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 patient has symptoms of hyperglycemia
(i.e., polyuria or polydipsia). As the patient’s glucose toxicity resolves, the regimen may, potentially, be simplified.
Combination Therapy
Although there are numerous trials
comparing dual therapy with metformin
alone, few directly compare drugs as addon therapy. A comparative effectiveness
meta-analysis (36) suggests that each
new class of noninsulin agents added to
initial therapy generally lowers A1C approximately 0.7–1.0%. If the A1C target
is not achieved after approximately 3 months
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
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PHARMACOLOGIC THERAPY FOR
TYPE 2 DIABETES
Pharmacologic Approaches to Glycemic Treatment
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Pharmacologic Approaches to Glycemic Treatment
Diabetes Care Volume 41, Supplement 1, January 2018
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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
agonist, or basal insulin (Fig. 8.1); the choice
of which agent to add is based on drugspecific effects and patient factors (Table
8.1). For patients with ASCVD, add a
second agent with evidence of cardiovascular risk reduction after consideration of
drug-specific and patient factors (see p. S77
CARDIOVASCULAR OUTCOMES TRIALS). 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
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Pharmacologic Approaches to Glycemic Treatment
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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.
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Pharmacologic Approaches to Glycemic Treatment
Diabetes Care Volume 41, Supplement 1, January 2018
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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
patient, disease, and drug characteristics,
with the goal of reducing blood glucose
levels while minimizing side effects, especially hypoglycemia. If not already included in the treatment regimen, addition
of an agent with evidence of cardiovascular risk reduction should be considered in patients with ASCVD beyond
dual therapy, with continuous reevaluation of patient factors to guide treatment (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 wholesale prices (AWP) (39) and National Average Drug Acquisition Costs (NADAC) (40)
and do not account for discounts, rebates, or other price adjustments often
involved in prescription sales that affect
the actual cost incurred by the patient.
While there are alternative means to estimate medication prices, AWP and NADAC
c Pioglitazone
Thiazolidinediones
GLP-1 receptor
agonists
release
↑ Insulin secretion (glucose
dependent)
c Not recommended with eGFR ,30
c Not recommended with eGFR ,30
Activates GLP-1
receptors
c Exenatide
c Exenatide extended
c Empagliflozin
Continued on p. S80
100 mg daily if eGFR 45–59;
avoid use and discontinue in patients with eGFR persistently ,45
c No dose adjustment required if eGFR $60;
not recommended with eGFR 30–60;
contraindicated with eGFR ,30
c Contraindicated with eGFR ,30
Blocks glucose reabsorption by the
kidney, increasing glucosuria
c Avoid initiating if eGFR ,60;
Inhibits SGLT2 in the proximal
nephron
c No specific dose adjustment recommended by manufacturer
c No specific dose adjustment recommended by manufacturer
c Dapagliflozin
c Canagliflozin
Modulates hypothalamic regulation
of metabolism;
↑ Insulin sensitivity
? ↓ Hepatic glucose production;
? ↑ Incretin levels
12.5 mg daily if eGFR 30–60;
6.25 mg daily if eGFR ,30
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SGLT2 inhibitors
Activates dopaminergic receptors
c Bromocriptine (quick
Dopamine-2
agonists
release)§
Binds bile acids in intestinal
tract, increasing hepatic bile
acid production
c Colesevelam
Bile acid
sequestrants
c 25 mg daily if eGFR .60;
c Alogliptin
2.5 mg daily if eGFR #50
c No dose adjustment required
50 mg daily if eGFR 30–50;
25 mg daily if eGFR ,30
c 100 mg daily if eGFR .50;
c Linagliptin
↑ Insulin secretion (glucose
dependent);
↓ Glucagon secretion (glucose
dependent)
c Avoid if eGFR ,25
c Avoid if eGFR ,30
c No dose adjustment required
c No dose adjustment required
c Initiate conservatively at 60 mg with meals if eGFR ,30
c 5 mg daily if eGFR .50;
c Sitagliptin
DPP-4 inhibitors
Slows intestinal carbohydrate
digestion/absorption
↑ Insulin sensitivity
c Initiate conservatively at 0.5 mg with meals if eGFR ,30
c Initiate conservatively at 1 mg daily to avoid hypoglycemia
c Initiate conservatively at 2.5 mg daily to avoid hypoglycemia
c Avoid use in patients with renal impairment
do not initiate OR assess risk/benefit if currently on metformin if eGFR 30–45;
discontinue if eGFR ,30
c No dose adjustment if eGFR .45;
Renal dosing recommendations (63–66)*
c Saxagliptin
c Miglitol
c Acarbose
a-Glucosidase
inhibitors
Inhibits DPP-4 activity,
increasing postprandial incretin
(GLP-1, GIP) concentrations
Activates the nuclear
transcription factor PPAR-g
Inhibits intestinal a-glucosidase
c Nateglinide
c Rosiglitazone§
Closes KATP channels on b-cell
plasma membranes
c Repaglinide
Meglitinides
(glinides)
c Glimepiride
↑ Insulin secretion
↑ Insulin secretion
Closes KATP channels on b-cell
plasma membranes
c Glipizide
c Glyburide
Sulfonylureas (2nd
generation)
Primary physiological action(s)
↓ Hepatic glucose production
Cellular mechanism(s)
Activates AMP kinase (? other)
c Metformin
Biguanides
Compound(s)
Table 8.2—Pharmacology of available glucose-lowering agents in the U.S. for the treatment of type 2 diabetes
Class
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Pharmacologic Approaches to Glycemic Treatment
S79
Compound(s)
Activates insulin receptors
c Rapid-acting analogs
Insulins
Primary physiological action(s)
↑ Glucose disposal;
↓ Hepatic glucose production;
Suppresses ketogenesis
↓ Glucagon secretion;
Slows gastric emptying;
↑ Satiety
↓ Glucagon secretion (glucose
dependent);
Slows gastric emptying;
↑ Satiety
Renal dosing recommendations (63–66)*
response
c Lower insulin doses required with a decrease in eGFR; titrate per clinical
c No specific dose adjustment recommended by manufacturer
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 No specific dose adjustment recommended by the manufacturer; limited
experience in patients with severe renal impairment
c No dose adjustment required for eGFR 60–89;
experience in patients with severe renal impairment
c No dose adjustment required for eGFR 15–89 per manufacturer; limited
experience in patients with severe renal impairment
c No specific dose adjustment recommended by the manufacturer; limited
Pharmacologic Approaches to Glycemic Treatment
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*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.
Lispro
Aspart
Glulisine
Inhaled insulin
c Short-acting analogs
Human Regular
c Intermediate-acting analogs
Human NPH
c Basal insulin analogs
Glargine
Detemir
Degludec
c Premixed insulin products
NPH/Regular 70/30
70/30 aspart mix
75/25 lispro mix
50/50 lispro mix
Activates amylin receptors
Cellular mechanism(s)
c Pramlintide§
c Dulaglutide
c Lixisenatide
c Albiglutide
c Liraglutide
Amylin mimetics
Class
Table 8.2—Continued
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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.
Class
Compound(s)
Dosage strength/product
(if applicable)
Median NADAC
(min, max)†
Maximum approved
daily dose*
$2
$3
$2
$5 ($5, $3,630)
$5
$539 ($539, $5,189)
2,000 mg
2,550 mg
2,000 mg
2,000 mg
1,500 mg
2,000 mg
$17
$12
$4
$16
$7
20 mg
12 mg (micronized)
40 mg (IR)
20 mg (XL)
8 mg
Biguanides
c Metformin
500 mg (IR)
850 mg (IR)
1,000 mg (IR)
500 mg (ER)
750 mg (ER)
1,000 mg (ER)
Sulfonylureas
(2nd generation)
c Glyburide
5 mg
6 mg (micronized)
10 mg (IR)
10 mg (XL)
4 mg
$84 ($4, $93)
$108 ($6, $109)
$87 ($4, $88)
$89 ($82, $6,671)
$72 ($65, $92)
$1,028 ($1,028,
$7,214)
$93 ($63, $103)
$50 ($48, $71)
$75 ($67, $97)
$48
$71 ($71, $198)
2 mg
120 mg
$659 ($122, $673) $40
$155
$56
16 mg
360 mg
45 mg
4 mg
100 mg
100 mg
$348 ($283, $349)
$387
$104 ($104, $106)
$241
$5
$314
$25
N/A††
45 mg
8 mg
300 mg
300 mg
100 mg
5 mg
5 mg
25 mg
$477
$462
$457
$449
$382
$370
$367
$357
100 mg
5 mg
5 mg
25 mg
c Glipizide
c Glimepiride
Meglitinides (glinides)
c Repaglinide
c Nateglinide
Thiazolidinediones
c Pioglitazone
c Rosiglitazone
a-Glucosidase
inhibitors
c Acarbose
DPP-4 inhibitors
c Sitagliptin
c Miglitol
c Saxagliptin
c Linagliptin
c Alogliptin
Bile acid sequestrants
c Colesevelam
625 mg tabs
1.875 g suspension
$713
$1,426
$570
$572
3.75 g
3.75 g
Dopamine-2 agonists
c Bromocriptine
0.8 mg
$784
$629
4.8 mg
SGLT2 inhibitors
c Canagliflozin
300 mg
10 mg
25 mg
$512
$517
$517
$411
$413
$415
300 mg
10 mg
25 mg
$802
$669
$968
$747
$642
N/A††
$775
$600
20 mg
20 mg
1.8 mg
2 mg**
c Dulaglutide
10 mg pen
20 mg pen
18 mg/3 mL pen
2 mg powder for
suspension or pen
50 mg pen
1.5/0.5 mL pen
$626
$811
$500
$648
50 mg**
1.5 mg**
c Pramlintide
120 mg pen
$2,336
N/A††
120 mg/injection†††
c Dapagliflozin
c Empagliflozin
GLP-1 receptor
agonists
c Exenatide
c Lixisenatide
c Liraglutide
c Exenatide (extended
release)
c Albiglutide
Amylin mimetics
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.
were utilized to provide two separate measures to allow for a comparison of drug
prices with the primary goal of highlighting
the importance of cost considerations
when prescribing antihyperglycemic treatments. The ongoing Glycemia Reduction
Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) will compare
four drug classes (sulfonylurea, DPP-4 inhibitor, GLP-1 receptor agonist, and basal
insulin) when added to metformin therapy
over 4 years on glycemic control and other
medical, psychosocial, and health economic
outcomes (41).
Rapid-acting secretagogues (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, bromocriptine, and pramlintide) may be tried
in specific situations but considerations
include modest 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 significant reductions in cardiovascular events
for two SGLT2 inhibitors (empagliflozin
and canagliflozin) and one GLP-1 receptor
agonist (liraglutide) where the majority, if
not all patients, in the trial had ASCVD.
The empagliflozin and liraglutide trials
demonstrated significant reductions in
cardiovascular death. Exenatide onceweekly did not have statistically significant reductions in major adverse
cardiovascular events or cardiovascular mortality but did have a significant
reduction in all-cause mortality. In contrast, 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 detailed description of these cardiovascular
Downloaded from http://diabetesjournals.org/care/article-pdf/41/Supplement_1/S73/550204/dc18s008.pdf by guest on 26 December 2023
Median AWP
(min, max)†
S82
Diabetes Care Volume 41, Supplement 1, January 2018
Pharmacologic Approaches to Glycemic Treatment
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)*
c Lispro
Short-acting analogs
c Human Regular
U-100 vial
$165 ($165, $178)
$135 ($135, $145)
Intermediate-acting analogs
c Human NPH
U-100 vial;
U-100 prefilled pen
$165 ($165, $178)
$377
$135 ($135, $145)
$305
Concentrated Human
Regular insulin
c U-500 Human
U-500 vial;
U-500 prefilled pen
$178
$230
$143
$184
Basal analogs
c Glargine
U-100 vial; U-100 prefilled pen;
U-300 prefilled pen
U-100 prefilled pen
U-100 vial; U-100 prefilled pen
U-100 prefilled pen; U-200 prefilled pen
$298
$239 ($239, $241)
$253
$323
$355
$203
$259
$285
U-100 vial;
U-100 prefilled pen
U-100 vial;
U-100 prefilled pen
U-100 vial;
U-100 prefilled pen
U-100 vial;
U-100 prefilled pen
$165 ($165, $178)
$377
$342
$424
$342
$424
$343
$426
$134 ($134, $146)
$305
$278
$339
$273
$340
$275
$341
100/3.6 prefilled pen
100/33 prefilled pen
$763
$508
N/A†
$404
c Aspart
c Glulisine
Regular insulin
c Glargine biosimilar
c Detemir
c Degludec
Premixed insulin products
c NPH/Regular 70/30
c Lispro 50/50
c Lispro 75/25
c Aspart 70/30
Premixed insulin/GLP-1
receptor agonist products
c Degludec/Liraglutide
c Glargine/Lixisenatide
$330
$408
$424
$331
$410
$426
$306
$394
$725 ($544, $911)
$264
$326
$339
$265
$330
$341
$245
$315
N/A†
*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 randomized 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 patients for whom metformin was not contraindicated or not tolerated. For patients
with type 2 diabetes who have ASCVD, on
lifestyle and metformin therapy, it is recommended to incorporate an agent with
strong evidence for cardiovascular risk reduction especially those with proven benefit on both major adverse cardiovascular
events and cardiovascular death after consideration of drug-specific patient factors
(Table 8.1). See Fig. 8.1 for additional recommendations on antihyperglycemic
treatment in adults with type 2 diabetes.
Insulin Therapy
Many patients with type 2 diabetes eventually require and benefit from insulin
therapy. The progressive nature of type 2
diabetes should be regularly and objectively
explained to patients. Providers should
avoid using insulin as a threat or describing it as a sign of personal failure
or punishment.
Equipping patients with an algorithm for
self-titration of insulin doses based on selfmonitoring of blood glucose improves
glycemic control in patients with type 2 diabetes initiating insulin (42). Comprehensive education regar
