Standards of Medical Care in Diabetes - 2022: 9. Pharmacologic Approaches To Glycemic Treatment

Diabetes Care Volume 45, Supplement 1, January 2022 S125
9. Pharmacologic Approaches to American Diabetes Association

Professional Practice Committee*
Glycemic Treatment: Standards of
Medical Care in Diabetes—2022
Diabetes Care 2022;45(Suppl. 1):S125–S143 | https://doi.org/10.2337/dc22-S009
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9. PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT
The American Diabetes Association (ADA) “Standards of Medical Care in Dia-
betes” includes the 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 Pro-
fessional Practice Committee, a multidisciplinary expert committee (https://
doi.org/10.2337/dc22-SPPC), 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 sys-
tem for ADA’s clinical practice recommendations, please refer to the Standards
of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish
to comment on the Standards of Care are invited to do so at professional
.diabetes.org/SOC.
PHARMACOLOGIC THERAPY FOR ADULTS WITH TYPE 1 DIABETES
Recommendations
9.1 Most individuals with type 1 diabetes should be treated with multiple daily
injections of prandial and basal insulin, or continuous subcutaneous insulin
infusion. A
9.2 Most individuals with type 1 diabetes should use rapid-acting insulin analogs
to reduce hypoglycemia risk. A
9.3 Individuals with type 1 diabetes should receive education on how to match
mealtime insulin doses to carbohydrate intake, fat and protein content, and
anticipated physical activity. B
*A complete list of members of the American

Insulin Therapy Diabetes Association Professional Practice Com-
Because the hallmark of type 1 diabetes is absent or near-absent b-cell function, mittee can be found at https://doi.org/10.2337/
dc22-SPPC.
insulin treatment is essential for individuals with type 1 diabetes. In addition to
Suggested citation: American Diabetes Asso-
hyperglycemia, insulinopenia can contribute to other metabolic disturbances like ciation Professional Practice Committee. 9. Phar-
hypertriglyceridemia and ketoacidosis as well as tissue catabolism that can be life macologic approaches to glycemic treatment:
threatening. Severe metabolic decompensation can be, and was, mostly prevented Standards of Medical Care in Diabetes—2022.
with once or twice daily injections for the six or seven decades after the discovery Diabetes Care 2022;45(Suppl. 1):S125–S143
of insulin. However, over the past three decades, evidence has accumulated sup- © 2021 by the American Diabetes Association.
porting more intensive insulin replacement, using multiple daily injections of insulin Readers may use this article as long as the
work is properly cited, the use is educational
or continuous subcutaneous administration through an insulin pump, as providing
and not for profit, and the work is not altered.
the best combination of effectiveness and safety for people with type 1 diabetes. More information is available at https://
The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive diabetesjournals.org/journals/pages/license.
S126 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 45, Supplement 1, January 2022
therapy with multiple daily injections or treatment required for their use is pro- 14 years of age, the use of a closed-
continuous subcutaneous insulin infu- hibitive. There are multiple approaches loop system was associated with a
sion (CSII) reduced A1C and was associ- to insulin treatment, and the central greater percentage of time spent in the
ated with improved long-term out- precept in the management of type 1 target glycemic range, reduced mean
comes (1–3). The study was carried out diabetes is that some form of insulin be glucose and A1C levels, and a lower
with short-acting (regular) and interme- given in a planned regimen tailored to percentage of time spent in hypoglyce-
diate-acting (NPH) human insulins. In the individual to keep them safe and mia compared with use of a sensor-
this landmark trial, lower A1C with out of diabetic ketoacidosis and to avoid augmented pump (22).
intensive control (7%) led to 50% significant hypoglycemia, with every Intensive insulin management using a
reductions in microvascular complica- effort made to reach the individual’s version of CSII and continuous glucose
tions over 6 years of treatment. How- glycemic targets. monitoring should be considered in most
ever, intensive therapy was associated Most studies comparing multiple daily individuals with type 1 diabetes. AID sys-
with a higher rate of severe hypoglyce- injections with CSII have been relatively tems may be considered in individuals

mia than conventional treatment (62 small and of short duration. However, with type 1 diabetes who are capable of
compared with 19 episodes per 100 a recent systematic review and meta- using the device safely (either by them-
patient-years of therapy). Follow-up of analysis concluded that CSII via pump selves or with a caregiver) in order to
subjects from the DCCT more than 10 therapy has modest advantages for low- improve time in range and reduce A1C
years after the active treatment compo- ering A1C ( 0.30% [95% CI 0.58 to and hypoglycemia (22). See Section 7,
nent of the study demonstrated fewer 0.02]) and for reducing severe hypogly- “Diabetes Technology” (https://doi.org/
macrovascular as well as fewer micro- cemia rates in children and adults (15). 10.2337/dc22-S007), for a full discussion
vascular complications in the group that However, there is no consensus to guide of insulin delivery devices.
received intensive treatment (2,4). the choice of injection or pump therapy In general, individuals with type 1
Insulin replacement regimens typi- in a given individual, and research to diabetes require 50% of their daily
cally consist of basal insulin, mealtime guide this decision-making is needed insulin as basal and 50% as prandial,
insulin, and correction insulin (5). Basal (16). The arrival of continuous glucose but this is dependent on a number of
insulin includes NPH insulin, long-acting monitors (CGM) to clinical practice has factors, including whether the individ-
insulin analogs, and continuous delivery proven beneficial in people using insulin ual consumes lower or higher carbo-
of rapid-acting insulin via an insulin therapy. Its use is now considered stan- hydrate meals. Total daily insulin
pump. Basal insulin analogs have lon- dard of care for most people with type 1 requirements can be estimated based
ger duration of action with flatter, more diabetes (5) (see Section 7, “Diabetes on weight, with typical doses ranging
constant plasma concentrations and Technology,” https://doi.org10.2337/ from 0.4 to 1.0 units/kg/day. Higher
activity profiles than NPH insulin; rapid- dc22-S007). Reduction of nocturnal amounts are required during puberty,
acting analogs (RAA) have a quicker hypoglycemia in individuals with type 1 pregnancy, and medical illness. The
onset and peak and shorter duration of diabetes using insulin pumps with CGM American Diabetes Association/JDRF
action than regular human insulin. In is improved by automatic suspension of Type 1 Diabetes Sourcebook notes 0.5
people with type 1 diabetes, treatment insulin delivery at a preset glucose level units/kg/day as a typical starting dose
with analog insulins is associated with (16–18). When choosing among insulin in individuals with type 1 diabetes
less hypoglycemia and weight gain as delivery systems, patient preferences, who are metabolically stable, with
well as lower A1C compared with cost, insulin type and dosing regimen, half administered as prandial insulin
human insulins (6–8). More recently, and self-management capabilities should given to control blood glucose after
two new injectable insulin formulations be considered (see Section 7, “Diabetes meals and the other half as basal
with enhanced rapid action profiles Technology,” https://doi.org/10.2337/ insulin to control glycemia in the peri-
have been introduced. Inhaled human dc22-S007). ods between meal absorption (23);
insulin has a rapid peak and shortened The U.S. Food and Drug Administra- this guideline provides detailed infor-
duration of action compared with RAA tion (FDA) has now approved two mation on intensification of therapy
and may cause less hypoglycemia and hybrid closed-loop pump systems (also to meet individualized needs. In addi-
weight gain (9) (see also subsection called automated insulin delivery [AID] tion, the American Diabetes Associa-
“Inhaled Insulin” in PHARMACOLOGIC THERAPY systems). The safety and efficacy of tion (ADA) position statement “Type 1
FOR ADULTS WITH TYPE 2 DIABETES), and faster- hybrid closed-loop systems has been Diabetes Management Through the
acting insulin aspart and insulin lispro- supported in the literature in adoles- Life Span” provides a thorough over-
aabc may reduce prandial excursions cents and adults with type 1 diabetes view of type 1 diabetes treatment
better than RAA (10–12). In addition, (19,20), and recent evidence suggests (24).
new longer-acting basal analogs (U-300 that a closed-loop system is superior to Typical multidose regimens for indi-
glargine or degludec) may confer a sensor-augmented pump therapy for viduals with type 1 diabetes combine
lower hypoglycemia risk compared with glycemic control and reduction of hypo- premeal use of shorter-acting insulins
U-100 glargine in individuals with type 1 glycemia over 3 months of comparison with a longer-acting formulation. The
diabetes (13,14). Despite the advan- in children and adults with type 1 dia- long-acting basal dose is titrated to reg-
tages of insulin analogs in individuals betes (21). In the International Diabetes ulate overnight, fasting glucose. Post-
with type 1 diabetes, for some individu- Closed Loop (iDCL) trial, a 6-month trial prandial glucose excursions are best
als the expense and/or intensity of in people with type 1 diabetes at least controlled by a well-timed injection of
care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S127
prandial insulin. The optimal time to benefit (27) (see Section 5, “Faci- complications, and avoidance of intra-
administer prandial insulin varies, litating Behavior Change and Well- muscular (IM) insulin delivery.
based on the pharmacokinetics of the being to Improve Health Outcomes,” Exogenously delivered insulin should
formulation (regular, RAA, inhaled), https://doi.org/10.2337/dc22-S005). be injected into subcutaneous tissue, not
the premeal blood glucose level, and The 2021 ADA/European Association intramuscularly. Recommended sites for
carbohydrate consumption. Recom- for the Study of Diabetes (EASD) consen- insulin injection include the abdomen,
mendations for prandial insulin dose sus report on the management of type 1 thigh, buttock, and upper arm. Because
administration should therefore be diabetes in adults summarizes different insulin absorption from IM sites differs
individualized. Physiologic insulin insulin regimens and glucose monitoring according to the activity of the muscle,
secretion varies with glycemia, meal strategies in individuals with type 1 dia- inadvertent IM injection can lead to
size, meal composition, and tissue betes (Fig. 9.1 and Table 9.1) (5). unpredictable insulin absorption and var-
demands for glucose. To approach this iable effects on glucose, with IM injec-
tion being associated with frequent and

variability in people using insulin Insulin Injection Technique
treatment, strategies have evolved to Ensuring that patients and/or caregivers unexplained hypoglycemia in several
adjust prandial doses based on pre- understand correct insulin injection tech- reports. Risk for IM insulin delivery is
dicted needs. Thus, education of nique is important to optimize glucose increased in younger, leaner patients
patients on how to adjust prandial control and insulin use safety. Thus, it is when injecting into the limbs rather than
insulin to account for carbohydrate important that insulin be delivered into truncal sites (abdomen and buttocks)
intake, premeal glucose levels, and the proper tissue in the correct way. Rec- and when using longer needles. Recent
anticipated activity can be effective ommendations have been published evidence supports the use of short nee-
and should be offered to most elsewhere outlining best practices for dles (e.g., 4-mm pen needles) as effec-
patients (25,26). For individuals in insulin injection (28). Proper insulin injec- tive and well tolerated when compared
whom carbohydrate counting is effec- tion technique includes injecting into with longer needles, including a study
tive, estimates of the fat and protein appropriate body areas, injection site performed in adults with obesity (29).
content of meals can be incorporated rotation, appropriate care of injection Injection site rotation is additionally
necessary to avoid lipohypertrophy, an
into their prandial dosing for added sites to avoid infection or other
accumulation of subcutaneous fat in
response to the adipogenic actions of
insulin at a site of multiple injections.
Representative relative attributes of insulin delivery Lipohypertrophy appears as soft, smooth
approaches in people with type 1 diabetes1
raised areas several centimeters in
breadth and can contribute to erratic
Injected insulin regimens Flexibility
Lower risk of
Higher costs
insulin absorption, increased glycemic
hypoglycemia
variability, and unexplained hypoglycemic
MDI with LAA + RAA or URAA +++ +++ +++ episodes. Patients and/or caregivers
should receive education about proper
Less-preferred, alternative injected insulin regimens injection site rotation and how to recog-
nize and avoid areas of lipohypertrophy.
MDI with NPH + RAA or URAA ++ ++ ++ As noted in Table 4.1, examination of
insulin injection sites for the presence of
MDI with NPH + short-acting (regular) insulin ++ + + lipohypertrophy, as well as assess-
Two daily injections with NPH + short-acting (regular)
ment of injection device use and
insulin or premixed + + + injection technique, are key compo-
nents of a comprehensive diabetes
medical evaluation and treatment
Continuous insulin infusion regimens Flexibility
Lower risk of
Higher costs plan. Proper insulin injection tech-
hypoglycemia
nique may lead to more effective use
Hybrid closed-loop technology +++++ +++++ ++++++ of this therapy and, as such, holds
the potential for improved clinical
Insulin pump with threshold/
predictive low-glucose suspend ++++ ++++ +++++ outcomes.
Insulin pump therapy without automation +++ +++ ++++ Noninsulin Treatments for Type 1
Diabetes
Figure 9.1—Choices of insulin regimens in people with type 1 diabetes. Continuous glucose Injectable and oral glucose-lowering
monitoring improves outcomes with injected or infused insulin and is superior to blood glucose drugs have been studied for their effi-
monitoring. Inhaled insulin may be used in place of injectable prandial insulin in the U.S. 1The
number of plus signs (1) is an estimate of relative association of the regimen with increased
cacy as adjuncts to insulin treatment of
flexibility, lower risk of hypoglycemia, and higher costs between the considered regimens. LAA, type 1 diabetes. Pramlintide is based on
long-acting insulin analog; MDI, multiple daily injections; RAA, rapid-acting insulin analog; the naturally occurring b-cell peptide
URAA, ultra-rapid-acting insulin analog. Reprinted from Holt et al. (5). amylin and is approved for use in adults
S128
Table 9.1—Examples of subcutaneous insulin regimens

Regimen Timing and distribution Advantages Disadvantages Adjusting doses
Regimens that more closely mimic normal insulin secretion
Insulin pump therapy Basal delivery of URAA or Can adjust basal rates for Most expensive regimen. Mealtime insulin: if
(hybrid closed-loop, RAA; generally 40–60% varying insulin Must continuously wear carbohydrate counting
low-glucose suspend, of TDD. sensitivity by time of one or more devices. is accurate, change
CGM-augmented Mealtime and correction: day, for exercise and for Risk of rapid development ICR if glucose after
open-loop, BGM- URAA or RAA by bolus sick days. of ketosis or DKA with meal consistently out
augmented open- based on ICR and/or ISF Flexibility in meal timing interruption of insulin of target.
loop) and target glucose, with and content. delivery. Correction insulin: adjust
pre-meal insulin 15 Pump can deliver insulin Potential reactions to ISF and/or target
min before eating. in increments of adhesives and site glucose if correction
fractions of units. infections. does not consistently
Potential for integration Most technically complex bring glucose into
Pharmacologic Approaches to Glycemic Treatment
with CGM for low- approach (harder for range.

glucose suspend or people with lower Basal rates: adjust based
hybrid closed-loop. numeracy or literacy on overnight, fasting,
TIR % highest and TBR % skills). or daytime glucose
lowest with: hybrid outside of activity of
closed-loop > low- URAA/RAA bolus.
glucose suspend >
CGM-augmented open-
loop > BGM-
augmented open-loop.
MDI: LAA 1 flexible LAA once daily (insulin Can use pens for all At least four daily Mealtime insulin: if
doses of URAA or detemir or insulin components. injections. carbohydrate counting
RAA at meals glargine may require Flexibility in meal timing Most costly insulins. is accurate, change
twice-daily dosing); and content. Smallest increment of ICR if glucose after
generally 50% of TDD. Insulin analogs cause less insulin is 1 unit (0.5 meal consistently out
Mealtime and correction: hypoglycemia than unit with some pens). of target.
URAA or RAA based on human insulins. LAAs may not cover strong Correction insulin: adjust
ICR and/or ISF and dawn phenomenon ISF and/or target
target glucose. (rise in glucose in early glucose if correction
morning hours) as well does not consistently
as pump therapy. bring glucose into
range.
LAA: based on overnight
or fasting glucose or
daytime glucose
outside of activity
time course, or URAA
or RAA injections.
Continued on p. S129
Diabetes Care Volume 45, Supplement 1, January 2022

Table 9.1—Continued
Regimen Timing and distribution Advantages Disadvantages Adjusting doses
MDI regimens with less flexibility
Four injections daily Pre-breakfast: RAA 20% May be feasible if unable Shorter duration RAA may Pre-breakfast RAA:
with fixed doses of N of TDD. to carbohydrate count. lead to basal deficit based on BGM after
and RAA Pre-lunch: RAA 10% of All meals have RAA during day; may need breakfast or before
care.diabetesjournals.org
TDD. coverage. twice-daily N. lunch.

Pre-dinner: RAA 10% of N less expensive than Greater risk of nocturnal Pre-lunch RAA: based on
TDD. LAAs. hypoglycemia with N. BGM after lunch or
Bedtime: N 50% of TDD. Requires relatively before dinner.
consistent mealtimes Pre-dinner RAA: based
and carbohydrate on BGM after dinner
intake. or at bedtime.
Evening N: based on
fasting or overnight
BGM.
Four injections daily Pre-breakfast: R 20% of May be feasible if unable Greater risk of nocturnal Pre-breakfast R: based
with fixed doses of N TDD. to carbohydrate count. hypoglycemia with N. on BGM after
and R Pre-lunch: R 10% of R can be dosed based on Greater risk of delayed breakfast or before
TDD. ICR and correction. post-meal hypoglycemia lunch.
Pre-dinner: R 10% of All meals have R coverage. with R. Pre-lunch R: based on
TDD. Least expensive insulins. Requires relatively BGM after lunch or
Bedtime: N 50% of TDD. consistent mealtimes before dinner.
and carbohydrate Pre-dinner R: based on
intake. BGM after dinner or
R must be injected at at bedtime.
least 30 min before Evening N: based on
meal for better effect. fasting or overnight
BGM.
Regimens with fewer daily injections
Three injections daily: Pre-breakfast: 40% N 1 Morning insulins can be Greater risk of nocturnal Morning N: based on
N1R or N1RAA 15% R or RAA. mixed in one syringe. hypoglycemia with N pre-dinner BGM.
Pre-dinner: 15% R or May be appropriate for than LAAs. Morning R: based on
RAA. those who cannot take Greater risk of delayed pre-lunch BGM.
Bedtime: 30% N. injections in middle of post-meal hypoglycemia Morning RAA: based on
day. with R than RAAs. post-breakfast or pre-
Morning N covers lunch to Requires relatively lunch BGM.
some extent. consistent mealtimes Pre-dinner R: based on
Same advantages of RAAs and carbohydrate bedtime BGM.
over R. intake. Pre-dinner RAA: based
Least (N 1 R) or less Coverage of post-lunch on post-dinner or
expensive insulins than glucose often bedtime BGM.
MDI with analogs. suboptimal. Evening N: based on
R must be injected at fasting BGM.
least 30 min before
meal for better effect.

Continued on p. S130
S129

with type 1 diabetes. Clinical trials have
BGM, blood glucose monitoring; CGM, continuous glucose monitoring; ICR, insulin:carbohydrate ratio; ISF, insulin sensitivity factor; LAA, long-acting analog; MDI, multiple daily injections; N, NPH insulin;
post-breakfast or pre-
Morning RAA: based on
demonstrated a modest reduction in
Evening RAA: based on

Morning N: based on
Morning R: based on
Evening N: based on
Adjusting doses
Evening R: based on
A1C (0.3–0.4%) and modest weight loss
pre-dinner BGM.
pre-lunch BGM.
bedtime BGM.
bedtime BGM.
post-dinner or
(1 kg) with pramlintide (30–33). Simi-
fasting BGM.
lunch BGM.
larly, results have been reported for sev-
eral agents currently approved only for
the treatment of type 2 diabetes. The
addition of metformin in adults with
type 1 diabetes caused small reductions
in body weight and lipid levels but did
not improve A1C (34,35). The largest clin-
ical trials of glucagon-like peptide 1

receptor agonists (GLP-1 RAs) in type 1
Fixed mealtimes and meal
diabetes have been conducted with lira-

afternoon or middle of
without hypoglycemia.
Difficult to reach targets
Risk of hypoglycemia in
Coverage of post-lunch
glutide 1.8 mg daily, showing modest

Disadvantages
for blood glucose
A1C reductions (0.4%), decreases in

R, short-acting (regular) insulin; RAA, rapid-acting analog; TDD, total daily insulin dose; URAA, ultra-rapid-acting analog. Reprinted from Holt et al. (5).
night from N.
glucose often
weight (5 kg), and reductions in insulin

suboptimal.
doses (36,37). Similarly, sodium–glucose

content.
cotransporter 2 (SGLT2) inhibitors have

been studied in clinical trials in people
with type 1 diabetes, showing improve-
ments in A1C, reduced body weight, and
improved blood pressure (38–40); how-
ever, SGLT2 inhibitor use in type 1 diabe-
tes is associated with an increased rate
of diabetic ketoacidosis. The risks and
Least number of injections
Eliminates need for doses

for people with strong
benefits of adjunctive agents continue to

Insulins can be mixed in
(N1RAA) expensive
preference for this.
insulins vs analogs.
be evaluated, with consensus statements

Least (N1R) or less
Advantages
providing guidance on patient selection

during the day.
one syringe.
and precautions (41); only pramlintide is

approved for treatment of type 1
diabetes.
SURGICAL TREATMENT FOR

TYPE 1 DIABETES
Pancreas and Islet Transplantation
Successful pancreas and islet transplanta-
tion can normalize glucose levels and
mitigate microvascular complications of
Pre-breakfast: 40% N 1
Timing and distribution
type 1 diabetes. However, patients

Pre-dinner: 30% N 1
receiving these treatments require life-

15% R or RAA.
15% R or RAA.
long immunosuppression to prevent

graft rejection and/or 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
renal transplantation, or for those with
recurrent ketoacidosis or severe hypogly-
Twice-daily “split-mixed”:
cemia despite intensive glycemic man-

Table 9.1—Continued
agement (42).
N1R or N1RAA
The 2021 ADA/EASD consensus report

on the management of type 1 diabetes
in adults offers a simplified overview of
Regimen
indications for b-cell replacement ther-

apy in people with type 1 diabetes (Fig.
9.2) (5).
Simplified overview of indications for β-cell replacement therapy in people with type 1 diabetes
Severe metabolic complications

• Hypoglycemia
• Hypoglycemia unawareness
Severe diabetic chronic kidney disease
• Ketoacidosis
(GFR <30 mL min−1 [1.73 m]−2)
• Incapacitating problems with exogenous insulin therapy
• Failure of insulin-based management to prevent acute
complications

Impaired kidney function
Living donor kidney Simultaneous transplantation
Balancing surgical risk, metabolic need, and the choice of the individual with diabetes
Simultaneous Pancreas Islet

Pancreas after Islet after Simultaneous
pancreas and transplantation transplantation
kidney kidney islet and kidney
kidney alone alone
Figure 9.2—Simplified overview of indications for b-cell replacement therapy in people with type 1 diabetes. The two main forms of b-cell
replacement therapy are whole-pancreas transplantation or islet cell transplantation. b-Cell replacement therapy can be combined with kidney
transplantation if the individual has end-stage renal disease, which may be performed simultaneously or after kidney transplantation. All deci-
sions about transplantation must balance the surgical risk, metabolic need, and the choice of the individual with diabetes. GFR, glomerular fil-
tration rate. Reprinted from Holt et al. (5).
PHARMACOLOGIC THERAPY FOR

ADULTS WITH TYPE 2 DIABETES
9.6 Early combination therapy can diovascular risk, established kid-
be considered in some patients at ney disease, or heart failure, a
Recommendations treatment initiation to extend the sodium–glucose cotransporter 2
9.4a First-line therapy depends on time to treatment failure. A inhibitor and/or glucagon-like
comorbidities, patient-centered 9.7 The early introduction of insulin peptide 1 receptor agonist
treatment factors, and manage- should be considered if there is with demonstrated cardio-
ment needs and generally inc- evidence of ongoing catabolism vascular disease benefit (Fig.
ludes metformin and compre- (weight loss), if symptoms of 9.3, Table 9.2, Table 10.3B,
hensive lifestyle modification. A hyperglycemia are present, or and Table 10.3C) is recom-
9.4b Other medications (glucagon- when A1C levels (>10% [86 mended as part of the glucose-
like peptide 1 receptor agonists, mmol/mol]) or blood glucose lev- lowering regimen and compre-
sodium–glucose cotransporter els ($300 mg/dL [16.7 mmol/L]) hensive cardiovascular risk reduc-
2 inhibitors), with or without are very high. E tion, indepenent of A1C and in
metformin based on glycemic 9.8 A patient-centered approach consideration of patient-specific
needs, are appropriate initial should guide the choice of factors (Fig. 9.3) (see Section 10,
therapy for individuals with pharmacologic agents. Consider “Cardiovascular Disease and Risk
type 2 diabetes with or at high the effects on cardiovascular and Management,” https://doi.org/
risk for atherosclerotic cardio- renal comorbidities, efficacy, 10.2337/dc22-S010, for details
vascular disease, heart failure, hypoglycemia risk, impact on on cardiovascular risk reduction
and/or chronic kidney disease weight, cost and access, risk for recommendations). A
(Fig. 9.3). A side effects, and patient preferen- 9.10 In patients with type 2 diabetes,
9.5 Metformin should be continued ces (Table 9.2 and Fig. 9.3). E a glucagon-like peptide 1 recep-
upon initiation of insulin therapy 9.9 Among individuals with type 2 tor agonist is preferred to insulin
(unless contraindicated or not tol- diabetes who have established when possible. A
erated) for ongoing glycemic and atherosclerotic cardiovascular dis- 9.11 If insulin is used, combination
metabolic benefits. A ease or indicators of high car- therapy with a glucagon-like
and Section 14, “Children and estimated glomerular filtration rates

peptide 1 receptor agonist is rec-
Adolescents” (https://doi.org/10.2337/ (eGFR); the FDA has revised the label
ommended for greater efficacy
dc22-S014), have recommendations spe- for metformin to reflect its safety in
and durability of treatment
cific for older adults and for children and patients with eGFR $30 mL/min/1.73
effect. A
adolescents with type 2 diabetes, respec- m2 (47). A randomized trial confirmed
9.12 Recommendation for treatment
tively. Section 10, “Cardiovascular Disease previous observations that metformin
intensification for patients not
and Risk Management” (https://doi.org/ use is associated with vitamin B12
meeting treatment goals should
10.2337/dc22-S010), and Section 11, deficiency and worsening of symp-
not be delayed. A
“Chronic Kidney Disease and Risk toms of neuropathy (48). This is com-
9.13 Medication regimen and medica-
Management” (https://doi.org/10.2337/ patible with a report from the
tion-taking behavior should be
dc22-S011), have recommendations for Diabetes Prevention Program Out-
reevaluated at regular intervals
the use of glucose-lowering drugs in the comes Study (DPPOS) suggesting peri-
(every 3–6 months) and adjusted

management of cardiovascular and renal odic testing of vitamin B12 (49).
as needed to incorporate specific
disease, respectively. In patients with contraindications or
factors that impact choice of
intolerance to metformin, initial ther-
treatment (Fig. 4.1 and Table
Initial Therapy apy should be based on patient fac-
9.2). E
First-line therapy depends on comorbid- tors; consider a drug from another
9.14 Clinicians should be aware of the
ities, patient-centered treatment factors, class depicted in Fig. 9.3. When A1C is
potential for overbasalization
and management needs but will generally $1.5% (12.5 mmol/mol) above the gly-
with insulin therapy. Clinical sig-
include metformin and comprehensive cemic target (see Section 6, “Glycemic
nals that may prompt evaluation
lifestyle modification. Pharmacotherapy Targets,” https://doi.org/10.2337/dc22-
of overbasalization include basal
should be started at the time type 2 dia- S006, for appropriate targets), many
dose more than 0.5 IU/kg/day,
betes is diagnosed unless there are con- patients will require dual combination
high bedtime-morning or post-
traindications; for many patients this will therapy to achieve their target A1C
preprandial glucose differential,
be metformin monotherapy in combina- level (50). Insulin has the advantage of
hypoglycemia (aware or unaware),
tion with lifestyle modifications. Addi- being effective where other agents are
and high glycemic variability. Indi-
tional and/or alternative agents may be not and should be considered as part
cation of overbasalization should
considered in special circumstances, such of any combination regimen when
prompt reevaluation to further
as in individuals with established or hyperglycemia is severe, especially if
individualize therapy. E
increased risk of cardiovascular or catabolic features (weight loss, hyper-
renal complications (see Section 10, triglyceridemia, ketosis) are present. It
The ADA/EASD consensus report “Mana- “Cardiovascular Disease and Risk is common practice to initiate insulin
gement of Hyperglycemia in Type 2 Dia- Management,” https://doi.org/10.2337/ therapy for patients who present with
betes, 2018” and the 2019 update dc22-S010, and Fig. 9.3). Metformin is blood glucose levels $300 mg/dL (16.7
(43,44) recommend a patient-centered effective and safe, is inexpensive, and mmol/L) or A1C >10% (86 mmol/mol)
approach to choosing appropriate phar- may reduce risk of cardiovascular events or if the patient has symptoms
macologic treatment of blood glucose. and death (45). Metformin is available in of hyperglycemia (i.e., polyuria or poly-
This includes consideration of efficacy an immediate-release form for twice-daily dipsia) or evidence of catabolism
and key patient factors: 1) important dosing or as an extended-release form (weight loss) (Fig. 9.4). As glucose tox-
comorbidities such as atherosclerotic car- that can be given once daily. Compared icity resolves, simplifying the regimen
diovascular disease (ASCVD) and indica- with sulfonylureas, metformin as first-line and/or changing to noninsulin agents is
tors of high ASCVD risk, chronic kidney therapy has beneficial effects on A1C, often possible. However, there is evi-
disease (CKD), and heart failure (HF) (see weight, and cardiovascular mortality (46); dence that patients with uncontrolled
Section 10, “Cardiovascular Disease and there is little systematic data available for hyperglycemia associated with type 2
Risk Management,” https://doi.org/ other oral agents as initial therapy of diabetes can also be effectively treated
10.2337/dc22-S010, and Section 11 type 2 diabetes. with a sulfonylurea (51).
“Chronic Kidney Disease and Risk The principal side effects of metfor-
Management,” https://doi.org/10.2337/ min are gastrointestinal intolerance due Combination Therapy
dc22-S011), 2) hypoglycemia risk, 3) to bloating, abdominal discomfort, and Because type 2 diabetes is a progressive
effects on body weight, 4) side effects, diarrhea; these can be mitigated by disease in many patients, maintenance
5) cost, and 6) patient preferences. Life- gradual dose titration. The drug is of glycemic targets with monotherapy is
style modifications that improve health cleared by renal filtration, and very high often possible for only a few years, after
(see Section 5, “Facilitating Behavior circulating levels (e.g., as a result of which combination therapy is necessary.
Change and Well-being to Improve overdose or acute renal failure) have Traditional recommendations have been
Health Outcomes,” https://doi.org/ been associated with lactic acidosis. to use stepwise addition of medica-
10.2337/dc22-S005) should be empha- However, the occurrence of this com- tions to metformin to maintain A1C at
sized along with any pharmacologic plication is now known to be very target. The advantage of this is to pro-
therapy. Section 13, “Older Adults” rare, and metformin may be safely vide a clear assessment of the positive
(https://doi.org/10.2337/dc22-S013), used in patients with reduced and negative effects of new drugs and
Table 9.2—Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes
care.diabetesjournals.org
ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP-4, dipeptidyl peptidase 4; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; eGFR, estimated glomerular
filtration rate; GI, gastrointestinal; GLP-1 RAs, glucagon-like peptide 1 receptor agonists; HF, heart failure; NASH, nonalcoholic steatohepatitis; SGLT2, sodium–glucose cotransporter 2; SQ, subcutaneous; T2D, type 2 diabe-
tes. *For agent-specific dosing recommendations, please refer to the manufacturers’ prescribing information. †FDA-approved for cardiovascular disease benefit. ‡FDA-approved for heart failure indication. §FDA-approved
for chronic kidney disease indication.
S133

S134
Figure 9.3—Pharmacologic treatment of hyperglycemia in adults with type 2 diabetes. 2022 ADA Professional Practice Committee (PPC) adaptation of Davies et al. (43) and Buse et al. (44). For appropri-
ate context, see Fig. 4.1. The 2022 ADA PPC adaptation emphasizes incorporation of therapy rather than sequential add-on, which may require adjustment of current therapies. Therapeutic regimen
should be tailored to comorbidities, patient-centered treatment factors, and management needs. ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CVD, cardiovascular dis-
ease; CVOTs, cardiovascular outcomes trials; DPP-4i, dipeptidyl peptidase 4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure;
SGLT2i, sodium–glucose cotransporter 2 inhibitor; SU, sulfonylurea; T2D, type 2 diabetes; TZD, thiazolidinedione.
Diabetes Care Volume 45, Supplement 1, January 2022

reduce potential side effects and metformin generally lowers A1C glycemic goal. While most GLP-1 RAs
expense (52). However, there are data approximately 0.7–1.0% (57,58). (Fig. are injectable, an oral formulation of
to support initial combination therapy 9.3 and Table 9.2). semaglutide is now commercially avail-
for more rapid attainment of glycemic For patients with established ASCVD able (61). In trials comparing the addi-
goals (53,54) and later combination or indicators of high ASCVD risk (such as tion of an injectable GLP-1 RA or insulin
therapy for longer durability of glycemic patients $55 years of age with coronary, in patients needing further glucose low-
effect (55). The VERIFY (Vildagliptin Effi- carotid, or lower-extremity artery steno- ering, glycemic efficacy of injectable
cacy in combination with metfoRmIn sis >50% or left ventricular hypertrophy), GLP-1 RA was similar or greater than
For earlY treatment of type 2 diabetes) HF, or CKD, an SGLT2 inhibitor or GLP-1 that of basal insulin (62–68). GLP-1 RAs
trial demonstrated that initial combina- RA with demonstrated CVD benefit in these trials had a lower risk of hypo-
tion therapy is superior to sequential (Table 9.2, Table 10.3B, Table 10.3C, and glycemia and beneficial effects on body
addition of medications for extending Section 10, “Cardiovascular Disease and weight compared with insulin, albeit
primary and secondary failure (56). In Risk Management,” https://doi.org/

with greater gastrointestinal side
the VERIFY trial, participants receiving 10.2337/dc22-S010) is recommended as effects. Thus, trial results support GLP-1
the initial combination of metformin part of the glucose-lowering regimen RAs as the preferred option for patients
and the dipeptidyl peptidase 4 (DPP-4) independent of A1C, independent of requiring the potency of an injectable
inhibitor vildagliptin had a slower metformin use, and in consideration of therapy for glucose control (Fig. 9.4). In
decline of glycemic control compared patient-specific factors (Fig. 9.3). For patients who are intensified to insulin
with metformin alone and with vilda- patients without established ASCVD, indi- therapy, combination therapy with a
gliptin added sequentially to metformin. cators of high ASCVD risk, HF, or CKD, GLP-1 RA has been shown to have
These results have not been generalized the choice of a second agent to add to greater efficacy and durability of glyce-
to oral agents other than vildagliptin, metformin is not yet guided by empiric mic treatment effect than treatment
but they suggest that more intensive evidence comparing across multiple intensification with insulin alone. How-
early treatment has some benefits and classes. Rather, drug choice is based on ever, cost and tolerability issues are
should be considered through a shared efficacy, avoidance of side effects (partic-
important considerations in GLP-1 RA
decision-making process with patients, ularly hypoglycemia and weight gain),
use.
as appropriate. Initial combination ther- cost, and patient preferences (59). Similar
Costs for diabetes medications has
apy should be considered in patients considerations are applied in patients
increased dramatically over the past
presenting with A1C levels 1.5–2.0% who require a third agent to achieve gly-
two decades, and an increasing propor-
above target. Finally, incorporation of cemic goals. A recent systematic review
tion is now passed on to patients and
high glycemic efficacy therapies or ther- and network meta-analysis suggests
their families (69). Table 9.3 provides
apies for cardiovascular/renal risk greatest reductions in A1C level with
cost information for currently approved
reduction (e.g., GLP-1 RAs, SGLT2 inhibi- insulin regimens and specific GLP-1 RAs
noninsulin therapies. Of note, prices
tors) may allow for weaning of the cur- added to metformin-based background
listed are average wholesale prices
rent regimen, particularly of agents that therapy (60). In all cases, treatment regi-
mens need to be continuously reviewed (AWP) (70) and National Average Drug
may increase the risk of hypoglycemia.
Thus, treatment intensification may not for efficacy, side effects, and patient bur- Acquisition Costs (NADAC) (71), sepa-
necessarily follow a pure sequential den (Table 9.2). In some instances, rate measures to allow for a comparison
addition of therapy but instead reflect a patients will require medication reduction of drug prices, but do not account for
tailoring of the regimen in alignment or discontinuation. Common reasons for discounts, rebates, or other price adjust-
with patient-centered treatment goals this include ineffectiveness, intolerable ments often involved in prescription
(Fig. 9.3). side effects, expense, or a change in gly- sales that affect the actual cost incurred
Recommendations for treatment in- cemic goals (e.g., in response to develop- by the patient. Medication costs can be
tensification for patients not meeting ment of comorbidities or changes in a major source of stress for patients
treatment goals should not be delayed. treatment goals). Section 13, “Older with diabetes and contribute to worse
Shared decision-making is important in Adults” (https://doi.org/10.2337/dc22- adherence to medications (72); cost-
discussions regarding treatment inten- S013), has a full discussion of treat- reducing strategies may improve adher-
sification. The choice of medication ment considerations in older adults, in ence in some cases (73).
added to initial therapy is based on whom changes of glycemic goals and
the clinical characteristics of the de-escalation of therapy are common. Cardiovascular Outcomes Trials
patient and their preferences. Impor- The need for the greater potency of There are now multiple large randomized
tant clinical characteristics include the injectable medications is common, par- controlled trials reporting statistically sig-
presence of established ASCVD or indi- ticularly in people with a longer dura- nificant reductions in cardiovascular
cators of high ASCVD risk, HF, CKD, tion of diabetes. The addition of basal events in patients with type 2 diabetes
other comorbidities, and risk for spe- insulin, either human NPH or one of the treated with an SGLT2 inhibitor or GLP-1
cific adverse drug effects, as well as long-acting insulin analogs, to oral agent RA; see Section 10, “Cardiovascular Dis-
safety, tolerability, and cost. A compar- regimens is a well-established approach ease and Risk Management” (https://doi
ative effectiveness meta-analysis sug- that is effective for many patients. In .org/10.2337/dc22-S010) for details. Sub-
gests that each new class of noninsulin addition, recent evidence supports the jects enrolled in many of the cardiovascu-
agents added to initial therapy with utility of GLP-1 RAs in patients not at lar outcomes trials had A1C $6.5%, with
Figure 9.4—Intensifying to injectable therapies in type 2 diabetes. DSMES, diabetes self-management education and support; FPG, fasting plasma
glucose; GLP-1 RA, glucagon-like peptide 1 receptor agonist; max, maximum; PPG, postprandial glucose. Adapted from Davies et al. (43).
Table 9.3—Median monthly (30-day) AWP and NADAC of maximum approved daily dose of noninsulin glucose-lowering
agents in the U.S.
Dosage strength/ Median AWP Median NADAC Maximum approved
Class Compound(s) product (if applicable) (min, max)† (min, max)† daily dose*
Biguanides Metformin 850 mg (IR) $108 ($5, $109) $3 2,550 mg
1,000 mg (IR) $87 ($5, $88) $2 2,000 mg
1,000 mg (ER) $242 ($242, $7,214) $102 ($102, $430) 2,000 mg
Sulfonylureas (2nd Glimepiride 4 mg $74 ($71, $198) $3 8 mg
generation) Glipizide 10 mg (IR) $68 ($67, $70) $3 40 mg
10 mg (XL/ER) $48 $12 20 mg
Glyburide 6 mg (micronized) $52 ($48, $71) $11 12 mg
5 mg $82 ($63, $93) $12 20 mg

Thiazolidinediones Pioglitazone 45 mg $348 ($7, $349) $5 45 mg
Rosiglitazone 4 mg N/A $324 8 mg
a-Glucosidase Acarbose 100 mg $106 ($104, $106) $26 300 mg
inhibitors Miglitol 100 mg $284 ($241, $346) N/A 300 mg
Meglitinides Nateglinide 120 mg $155 $28 360 mg
(glinides) Repaglinide 2 mg $878 ($58, $897) $34 16 mg
DPP-4 inhibitors Alogliptin 25 mg $234 $166 25 mg
Saxagliptin 5 mg $549 $438 5 mg
Linagliptin 5 mg $583 $466 5 mg
Sitagliptin 100 mg $596 $477 100 mg
SGLT2 inhibitors Ertugliflozin 15 mg $372 $297 15 mg
Dapagliflozin 10 mg $639 $511 10 mg
Canagliflozin 300 mg $652 $521 300 mg
Empagliflozin 25 mg $658 $526 25 mg
GLP-1 RAs Exenatide 2 mg powder for $909 $727 2 mg**
(extended release) suspension or pen
Exenatide 10 mg pen $933 $746 20 mg
Dulaglutide 4.5 mg mL pen $1,013 $811 4.5 mg**
Semaglutide 1 mg pen $1,022 $822 1 mg**
14 mg (tablet) $1,022 $819 14 mg
Liraglutide 1.8 mg pen $1,220 $975 1.8 mg
Lixisenatide 20 mg pen $814 N/A 20 mg
Bile acid Colesevelam 625 mg tabs $710 ($674, $712) $75 3.75 g
sequestrant 3.75 g suspension $674 $222 3.75 g
Dopamine-2 agonist Bromocriptine 0.8 mg $1,036 $833 4.8 mg
Amylin mimetic Pramlintide 120 mg pen $2,702 N/A 120 mg/injection††
AWP, average wholesale price; DPP-4, dipeptidyl peptidase 4; ER and XL, extended release; GLP-1 RA, glucagon-like peptide 1 receptor ago-
nist; IR, immediate release; max, maximum; min, minimum; N/A, data not available; NADAC, National Average Drug Acquisition Cost; SGLT2,
sodium–glucose cotransporter 2. †Calculated for 30-day supply (AWP [70] or NADAC [71] unit price × number of doses required to provide
maximum approved daily dose × 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. **Administered once weekly. ††AWP and NADAC calcu-
lated based on 120 mg three times daily.
more than 70% taking metformin at mended (Table 9.2, Fig. 9.3, and Section ciated with these classes of medication
baseline. Thus, a practical extension of 10, “Cardiovascular Disease and Risk (74). In cardiovascular outcomes trials,
these results to clinical practice is to use Management,” https://doi.org/10.2337/ empagliflozin, canagliflozin, dapagliflozin,
these drugs preferentially in patients dc22-S010). Emerging data suggest that liraglutide, semaglutide, and dulaglutide
with type 2 diabetes and established use of both classes of drugs will provide all had beneficial effects on indices of
ASCVD or indicators of high ASCVD risk. additional cardiovascular and kidney out- CKD, while dedicated renal outcomes
For these patients, incorporating one of comes benefit; thus, combination ther- studies have demonstrated benefit of
the SGLT2 inhibitors and/or GLP-1 RAs apy with an SGLT2 inhibitor and a GLP-1 specific SGLT2 inhibitors. See Section 11,
that have been demonstrated to have RA may be considered to provide the “Chronic Kidney Disease and Risk
cardiovascular disease benefit is recom- complementary outcomes benefits asso- Management” (https://doi.org/10.2337/
Table 9.4—Median cost of insulin products in the U.S. calculated as AWP (70) and NADAC (71) per 1,000 units of specified
dosage form/product
Median AWP Median
Insulins Compounds Dosage form/product (min, max)* NADAC*
Rapid-acting Lispro follow-on product U-100 vial $157 $125
U-100 prefilled pen $202 $161
Lispro U-100 vial $165† $132†
U-100 cartridge $408 $325
U-100 prefilled pen $212† $170†
Lispro-aabc U-100 vial $330 N/A
U-100 prefilled pen $424 N/A
U-200 prefilled pen $424 N/A

Glulisine U-100 vial $341 $272
Aspart U-100 vial $174† $139†
U-100 cartridge $215 $172
U-100 prefilled pen $223† $179†
Aspart (“faster acting product”) U-100 vial $347 $278
U-100 cartridge $430 N/A
Inhaled insulin Inhalation cartridges $1,325 $606
Short-acting human regular U-100 vial $165†† $132††
Intermediate-acting human NPH U-100 vial $165†† $132††
Concentrated human U-500 human regular insulin U-500 vial $178 $143
regular insulin U-500 prefilled pen $230 $184
Long-acting Glargine follow-on products U-100 prefilled pen $118 $96
U-100 vial $190 (118, 261) $95
Glargine U-100 vial; U-100 prefilled pen $340 $277
Detemir U-100 vial; U-100 prefilled pen $370 $296
Degludec U-100 vial; U-100 prefilled pen; U-200 $407 $325
prefilled pen
Premixed insulin NPH/regular 70/30 U-100 vial $165†† $133††
products U-100 prefilled pen $208 $167
Lispro 50/50 U-100 vial $342 $274
Lispro 75/25 U-100 vial $152 $273
Aspart 70/30 U-100 vial $180 $144
Premixed insulin/GLP-1 Glargine/Lixisenatide 100/33 mg prefilled pen $619 $495
RA products Degludec/Liraglutide 100/3.6 mg prefilled pen $917 $732
AWP, average wholesale price; GLP-1 RA, glucagon-like peptide 1 receptor agonist; N/A, not available; NADAC, National Average Drug Acquisition Cost.
*AWP or NADAC calculated as in Table 9.3. †Generic prices used when available. ††AWP and NADAC data presented do not include vials of
regular human insulin and NPH available at Walmart for approximately $25/vial; median listed alone when only one product and/or price.
dc22-S011) for discussion of how CKD guidance on how to administer insulin effect of other agents should be empha-
may impact treatment choices. Additional safely and effectively. The progressive sized. Educating and involving patients in
large randomized trials of other agents in nature of type 2 diabetes should be reg- insulin management is beneficial. For
these classes are ongoing. ularly and objectively explained to example, instruction of patients in self-
patients, and clinicians should avoid using titration of insulin doses based on glucose
Insulin Therapy insulin as a threat or describing it as a monitoring improves glycemic control in
Many patients with type 2 diabetes sign of personal failure or punishment. patients with type 2 diabetes initiating
eventually require and benefit from Rather, the utility and importance of insu- insulin (75). Comprehensive education
insulin therapy (Fig. 9.4). See the sec- lin to maintain glycemic control once pro- regarding self-monitoring of blood glu-
tion INSULIN INJECTION TECHNIQUE, above, for gression of the disease overcomes the cose, diet, and the avoidance and
appropriate treatment of hypoglycemia be familiar with its use (94). Human regu- insulin lispro, U-200 (200 units/mL) and
are critically important in any patient lar insulin, NPH, and 70/30 NPH/regular insulin lispro-aabc (U-200). These con-
using insulin. products can be purchased for consider- centrated preparations may be more
ably less than the AWP and NADAC prices convenient and comfortable for individ-
Basal Insulin listed in Table 9.4 at select pharmacies. uals to inject and may improve adher-
Basal insulin alone is the most conve- Additionally, approval of follow-on biolog- ence in those with insulin resistance
nient initial insulin regimen and can be ics for insulin glargine, the first inter- who require large doses of insulin.
added to metformin and other oral changeable insulin glargine product, and While U-500 regular insulin is available
agents. Starting doses can be estimated generic versions of analog insulins may in both prefilled pens and vials, other
based on body weight (0.1–0.2 units/kg/ expand cost-effective options. concentrated insulins are available only
day) and the degree of hyperglycemia, in prefilled pens to minimize the risk of
with individualized titration over days to Prandial Insulin dosing errors.
weeks as needed. The principal action of Many individuals with type 2 diabetes

basal insulin is to restrain hepatic glucose require doses of insulin before meals, in Inhaled Insulin
production and limit hyperglycemia over- addition to basal insulin, to reach glyce- Inhaled insulin is available as a rapid-act-
night and between meals (76,77). Con- mic targets. A dose of 4 units or 10% of ing insulin; studies in individuals with
trol of fasting glucose can be achieved the amount of basal insulin at the larg- type 1 diabetes suggest rapid pharmaco-
with human NPH insulin or a long-acting est meal or the meal with the greatest kinetics (8). A pilot study found evidence
insulin analog. In clinical trials, long- postprandial excursion is a safe estimate that compared with injectable rapid-act-
acting basal analogs (U-100 glargine or for initiating therapy. The prandial insu- ing insulin, supplemental doses of
detemir) have been demonstrated to lin regimen can then be intensified inhaled insulin taken based on postpran-
reduce the risk of symptomatic and noc- based on individual needs (see Fig. 9.4). dial glucose levels may improve blood
turnal hypoglycemia compared with NPH Individuals with type 2 diabetes are glucose management without additional
insulin (78–83), although these advan- generally more insulin resistant than hypoglycemia or weight gain (101),
tages are modest and may not persist those with type 1 diabetes, require although results from a larger study are
(84). Longer-acting basal analogs (U-300 higher daily doses (1 unit/kg), and needed for confirmation. Use of inhaled
glargine or degludec) may convey a have lower rates of hypoglycemia (95).
insulin may result in a decline in lung
lower hypoglycemia risk compared with Titration can be based on home glucose
function (reduced forced expiratory vol-
U-100 glargine when used in combina- monitoring or A1C. With significant
ume in 1 s [FEV1]). Inhaled insulin is con-
tion with oral agents (85–91). Clinicians additions to the prandial insulin dose,
traindicated in individuals with chronic
should be aware of the potential for particularly with the evening meal, con-
lung disease, such as asthma and chronic
overbasalization with insulin therapy. sideration should be given to decreasing
obstructive pulmonary disease, and is
Clinical signals that may prompt evalua- basal insulin. Meta-analyses of trials
not recommended in individuals who
tion of overbasalization include basal comparing rapid-acting insulin analogs
smoke or who recently stopped smoking.
dose greater than 0.5 units/kg, high with human regular insulin in with type
All individuals require spirometry (FEV1)
bedtime-morning or post-preprandial 2 diabetes have not reported important
glucose differential (e.g., bedtime-morn- differences in A1C or hypoglycemia testing to identify potential lung disease
ing glucose differential $50 mg/dL), (96,97). prior to and after starting inhaled insulin
hypoglycemia (aware or unaware), and therapy.
high variability. Indication of overbasali- Concentrated Insulins
zation should prompt reevaluation to Several concentrated insulin prepara- Combination Injectable Therapy
further individualize therapy (92). tions are currently available. U-500 reg- If basal insulin has been titrated to an
The cost of insulin has been rising ular insulin is, by definition, five times acceptable fasting blood glucose level
steadily over the past two decades, at a more concentrated than U-100 regular (or if the dose is >0.5 units/kg/day with
pace several fold that of other medical insulin. U-500 regular insulin has distinct indications of need for other therapy)
expenditures (93). This expense contrib- pharmacokinetics with delayed onset and A1C remains above target, consider
utes significant burden to patients as and longer duration of action, has char- advancing to combination injectable
insulin has become a growing “out-of- acteristics more like an intermediate- therapy (Fig. 9.4). This approach can
pocket” cost for people with diabetes, acting (NPH) insulin, and can be used as use a GLP-1 RA added to basal insulin
and direct patient costs contribute to two or three daily injections (98). U-300 or multiple doses of insulin. The combi-
treatment nonadherence (93). Therefore, glargine and U-200 degludec are three nation of basal insulin and GLP-1 RA has
consideration of cost is an important and two times as concentrated as their potent glucose-lowering actions and
component of effective management. For U-100 formulations, respectively, and less weight gain and hypoglycemia com-
many individuals with type 2 diabetes allow higher doses of basal insulin pared with intensified insulin regimens
(e.g., individuals with relaxed A1C goals, administration per volume used. U-300 (102–106). The DUAL VIII randomized
low rates of hypoglycemia, and promi- glargine has a longer duration of action controlled trial demonstrated greater
nent insulin resistance, as well as those than U-100 glargine but modestly lower durability of glycemic treatment effect
with cost concerns), human insulin (NPH efficacy per unit administered (99,100). with the combination GLP-1 RA–insulin
and regular) may be the appropriate The FDA has also approved a concen- therapy compared with addition of
choice of therapy, and clinicians should trated formulation of rapid-acting basal insulin alone (55). In select
individuals, complex insulin regimens 2022 ADA Professional Practice 4. 1HF. This pathway highlights the
can also be simplified with combination Committee Updates to Fig. 9.3 emerging evidence of improvement
GLP-1 RA–insulin therapy in type 2 dia- The 2022 ADA Professional Practice in cardiovascular outcomes with
betes (107). Two different once-daily, Committee focused on several key areas SGLT2 inhibitors in individuals with
fixed dual-combination products con- in Fig. 9.3 to reconcile emerging evi- type 2 diabetes and existing HF.
taining basal insulin plus a GLP-1 RA are dence and support harmonization of 5. 1CKD. This pathway has been
available: insulin glargine plus lixisena- guidelines. Areas of discussion and updated based on populations
tide (iGlarLixi) and insulin degludec plus updated changes are outlined below. studied in renal and cardiovascular
liraglutide (IDegLira). outcomes studies and to specify
Intensification of insulin treatment can 1. Title and Purpose of Algorithm. Given recommendations when further
be done by adding doses of prandial the significant impact the cardiovas- intensification is required (e.g., for
insulin to basal insulin. Starting with a cular outcomes trials have had on patients on an SGLT2 inhibitor, con-
understanding the management of

single prandial dose with the largest sider incorporating GLP-1 RA and
meal of the day is simple and effective, type 2 diabetes and the different vice versa).
and it can be advanced to a regimen guidelines and algorithms being pro- 6. Principle of Incorporation. Prior algo-
with multiple prandial doses if necessary posed by different societies, it was rithms have conveyed sequential
(108). Alternatively, in an individual on important to identify the purpose addition of therapy. Recognizing the
basal insulin in whom additional prandial of Fig. 9.3, recognizing that no single importance of tailoring the therapeu-
coverage is desired, the regimen can be algorithm covers all circumstances tic regimen to the individual’s needs
converted to two doses of a premixed or goals. The purpose of this guidance and comorbidities, the principle of
insulin. Each approach has advantages is to support achievement of glyce- incorporation is emphasized through-
and disadvantages. For example, basal/ mic goals to reduce long-term com- out Fig. 9.3. Not all treatment intensi-
prandial regimens offer greater flexibility plications, highlighting aspects of fication results in sequential add-on
for individuals who eat on irregular therapy that support patient- therapy, but in some cases it may
schedules. On the other hand, two doses centered goals. Thus, the scope of involve switching therapy or weaning
of premixed insulin is a simple, conve- this algorithm is defined as the current therapy to accommodate
nient means of spreading insulin across “Pharmacologic Treatment of Hyper- therapeutic changes. For example,
the day. Moreover, human insulins, sepa- glycemia in Adults with Type 2 Dia- discontinuation of the DPP-4 inhibitor
rately, self-mixed, or as premixed NPH/ betes.” Toward this goal, glycemic is recommended when intensifying
regular (70/30) formulations, are less status should be assessed, with treat- from a DPP-4 inhibitor to a GLP-1 RA,
costly alternatives to insulin analogs. Fig- ment modified regularly (e.g., at least given overlapping mechanisms. In
ure 9.4 outlines these options as well as twice yearly if stable and more often addition, when cardioprotective
recommendations for further intensifica- if not to goal) to achieve patient-cen- agents (e.g., SGLT2 inhibitors, GLP-1
tion, if needed, to achieve glycemic goals. tered treatment goals and to avoid RAs) are introduced in the regimen,
When initiating combination injectable therapeutic inertia. this may require weaning current
therapy, metformin therapy should be 2. Initial Therapy. First-line therapy for therapy to minimize hypoglycemia,
maintained, while sulfonylureas and DPP- the treatment of hyperglycemia has dependent on baseline A1C status.
4 inhibitors are typically weaned or dis- traditionally been metformin and 7. Treatment Intensification. For the
continued. In individuals with suboptimal comprehensive lifestyle. Recognizing individual with high risk or estab-
blood glucose control, especially those the multiple treatment goals and lished ASCVD, CKD, or HF whose A1C
requiring large insulin doses, adjunctive comorbidities for individuals with remains above target, further treat-
use of a thiazolidinedione or an SGLT2 type 2 diabetes, alternative initial ment intensification should be based
inhibitor may help to improve control treatment approaches to metformin on comorbidities, patient-centered
and reduce the amount of insulin are acceptable, depending on comor- treatment factors, and management
needed, though potential side effects bidities, patient-centered treatment needs as highlighted on the right side
should be considered. Once a basal/bolus factors, and glycemic and comorbid- of Fig. 9.3.
insulin regimen is initiated, dose titration ity management needs. 8. Efficacy. Agents should be considered
is important, with adjustments made in 3. 1ASCVD/Indicators of High Cardio- that provide adequate efficacy to
both mealtime and basal insulins based vascular Risk. Please see Section 10, achieve and maintain glycemic goals
on the blood glucose levels and an “Cardiovascular Disease and Risk (Table 9.2) (60) while considering
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profile of each formulation (also known .2337/dc22-S010), for comprehen- (e.g., focus on minimizing hypoglyce-
as pattern control or pattern manage- sive review of evidence. This pathway mia, focus on minimizing weight gain
ment). As people with type 2 diabetes has been streamlined to highlight and promoting weight loss, and
get older, it may become necessary to therapies that have evidence to sup- access/cost considerations).
simplify complex insulin regimens port cardiovascular risk reduction 9. Minimize Hypoglycemia. Agents with
because of a decline in self-management and glycemic management, prioritiz- no/low inherent risk of hypoglycemia
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Diabetes Care Volume 45, Supplement 1, January 2022 S125

9. Pharmacologic Approaches to American Diabetes Association

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PHARMACOLOGIC THERAPY FOR ADULTS WITH TYPE 1 DIABETES

*A complete list of members of the American

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Table 9.1—Examples of subcutaneous insulin regimens

with CGM for low- approach (harder for range.

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TDD. coverage. twice-daily N. lunch.

meal for better effect.

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with type 1 diabetes. Clinical trials have

Evening RAA: based on

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diabetes have been conducted with lira-

glutide 1.8 mg daily, showing modest

for blood glucose

A1C reductions (0.4%), decreases in

weight (5 kg), and reductions in insulin

doses (36,37). Similarly, sodium–glucose

cotransporter 2 (SGLT2) inhibitors have

Eliminates need for doses

beneﬁts of adjunctive agents continue to

be evaluated, with consensus statements

providing guidance on patient selection

and precautions (41); only pramlintide is

SURGICAL TREATMENT FOR

type 1 diabetes. However, patients

receiving these treatments require life-

long immunosuppression to prevent

cemia despite intensive glycemic man-

The 2021 ADA/EASD consensus report

indications for b-cell replacement ther-

Severe metabolic complications

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Living donor kidney Simultaneous transplantation

Simultaneous Pancreas Islet

PHARMACOLOGIC THERAPY FOR

and Section 14, “Children and estimated glomerular ﬁltration rates

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Amylin mimetic  Pramlintide 120 mg pen $2,702 N/A 120 mg/injection††

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A1C reductions (0.4%), decreases in

weight (5 kg), and reductions in insulin

Amylin mimetic Pramlintide 120 mg pen $2,702 N/A 120 mg/injection††