PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT: STANDARDSOF MEDICALCAREINDIABETESD2021
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Diabetes Care Volume 44, Supplement 1, January 2021 S111
9. Pharmacologic Approaches to American Diabetes Association
Glycemic Treatment: Standards of
Medical Care in Diabetesd2021
Diabetes Care 2021;44(Suppl. 1):S111–S124 | https://doi.org/10.2337/dc21-S009
9. PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT
The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”
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 Professional Practice
Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-
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 system for ADA’s clinical practice
recommendations, please refer to the Standards of Care Introduction (https://doi
.org/10.2337/dc21-SINT). 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
9.1 Most people 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 Patients with type 1 diabetes should receive education on how to match
prandial insulin doses to carbohydrate intake, premeal blood glucose, and
anticipated physical activity. C
Insulin Therapy
Because the hallmark of type 1 diabetes is absent or near-absent b-cell function,
insulin treatment is essential for individuals with type 1 diabetes. In addition to
hyperglycemia, insulinopenia can contribute to other metabolic disturbances like
hypertriglyceridemia and ketoacidosis as well as tissue catabolism that can be life
threatening. Severe metabolic decompensation can be, and was, mostly prevented Suggested citation: American Diabetes Association.
with once or twice daily injections for the six or seven decades after the discovery of 9. Pharmacologic approaches to glycemic treatment:
insulin. However, over the past three decades, evidence has accumulated supporting Standards of Medical Care in Diabetesd2021.
more intensive insulin replacement, using multiple daily injections of insulin or Diabetes Care 2021;44(Suppl. 1):S111–S124
continuous subcutaneous administration through an insulin pump, as providing the © 2020 by the American Diabetes Association.
best combination of effectiveness and safety for people with type 1 diabetes. The Readers may use this article as long as the work is
properly cited, the use is educational and not for
Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy profit, and the work is not altered. More infor-
with multiple daily injections or continuous subcutaneous insulin infusion (CSII) mation is available at https://www.diabetesjournals
reduced A1C and was associated with improved long-term outcomes (1–3). The study .org/content/license.S112 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 44, Supplement 1, January 2021
was carried out with short-acting (regu- effort made to reach the patient’s gly- See Section 7 “Diabetes Technology”
lar) and intermediate-acting (NPH) hu- cemic targets. (https://doi.org/10.2337/dc21-S007) for a
man insulins. In this landmark trial, Most studies comparing multiple daily full discussion of insulin delivery devices.
lower A1C with intensive control (7%) injections with CSII have been relatively In general, patients with type 1 di-
led to ;50% reductions in microvascular small and of short duration. However, a abetes require 50% of their daily insulin
complications over 6 years of treatment. recent systematic review and meta- as basal and 50% as prandial. Total daily
However, intensive therapy was asso- analysis concluded that pump therapy insulin requirements can be estimated
ciated with a higher rate of severe has modest advantages for lowering A1C based on weight, with typical doses
hypoglycemia than conventional treat- (20.30% [95% CI 20.58 to 20.02]) and ranging from 0.4 to 1.0 units/kg/day.
ment (62 compared with 19 episodes for reducing severe hypoglycemia rates Higher amounts are required during pu-
per 100 patient-years of therapy). Follow- in children and adults (12). However, berty, pregnancy, and medical illness.
up of subjects from the DCCT more than there is no consensus to guide the choice The American Diabetes Association/
10 years after the active treatment com- of injection or pump therapy in a given JDRF Type 1 Diabetes Sourcebook notes
ponent of the study demonstrated less patient, and research to guide this 0.5 units/kg/day as a typical starting dose
macrovascular as well as less microvas- decision-making is needed (13). The arrival in patients with type 1 diabetes who are
cular complications in the group that of continuous glucose monitors to clinical metabolically stable, with half adminis-
received intensive treatment (2,4). practice has proven beneficial in specific tered as prandial insulin given to control
Over the last 25 years, rapid-acting and circumstances. Reduction of nocturnal blood glucose after meals and the other
long-acting insulin analogs have been hypoglycemia in people with type 1 di- half as basal insulin to control glycemia
developed that have distinct pharma- abetes using insulin pumps with glucose in the periods between meal absorption
cokinetics compared with recombinant sensors is improved by automatic sus- (20); this guideline provides detailed
human insulins: basal insulin analogs have pension of insulin delivery at a preset information on intensification of ther-
longer duration of action with flatter, more glucose level (13–15). When choosing apy to meet individualized needs. In
constant plasma concentrations and activ- among insulin delivery systems, patient addition, the American Diabetes Asso-
ity profiles than NPH insulin; rapid-acting preferences, cost, insulin type and dosing ciation position statement “Type 1 Di-
analogs (RAA) have a quicker onset and regimen, and self-management capabil- abetes Management Through the Life
peak and shorter duration of action than ities should be considered (See Section Span” provides a thorough overview of
regular human insulin. In people with 7 “Diabetes Technology,” https://doi type 1 diabetes treatment (21).
type 1 diabetes, treatment with analog .org/10.2337/dc21-S007). Typical multidose regimens for pa-
insulins is associated with less hypogly- The U.S. Food and Drug Administration tients with type 1 diabetes combine
cemia and weight gain as well as lower (FDA) has now approved two hybrid premeal use of shorter-acting insulins
A1C compared with human insulins (5–7). closed-loop pump systems. The safety with a longer-acting formulation, usually
More recently, two new injectable insulin and efficacy of hybrid closed-loop sys- at night. The long-acting basal dose is
formulations with enhanced rapid action tems has been supported in the literature titrated to regulate overnight, fasting
profiles have been introduced. Inhaled in adolescents and adults with type 1 glucose. Postprandial glucose excursions
human insulin has a rapid peak and short- diabetes (16,17), and recent evidence are best controlled by a well-timed in-
ened duration of action compared with suggests that a closed-loop system is jection of prandial insulin. The optimal time
RAA and may cause less hypoglycemia and superior to sensor-augmented pump to administer prandial insulin varies,
weight gain (8), and faster-acting insulin therapy for glycemic control and reduc- based on the pharmacokinetics of the
aspart and insulin lispro-aabc may reduce tion of hypoglycemia over 3 months of formulation (regular, RAA, inhaled), the
prandial excursions better than RAA comparison in children and adults with premeal blood glucose level, and carbo-
(9,9a,9b); further investigation is needed type 1 diabetes (18). In the International hydrate consumption. Recommendations
to establish a clear place for these agents Diabetes Closed Loop (iDCL) trial, a for prandial insulin dose administration
in diabetes management. In addition, new 6-month trial in patients with type 1 should therefore be individualized. Phys-
longer-acting basal analogs (U-300 glargine diabetes at least 14 years of age, the iologic insulin secretion varies with glyce-
or degludec) may confer a lower hypogly- use of a closed-loop system was associ- mia, meal size, and tissue demands for
cemia risk compared with U-100 glargine ated with a greater percentage of time glucose. To approach this variability in
in patients with type 1 diabetes (10,11). spent in the target glycemic range, re- people using insulin treatment, strategies
Despite the advantages of insulin analogs duced mean glucose and A1C levels, and have evolved to adjust prandial doses
in patients with type 1 diabetes, for some lower percentage of time spent in hypo- based on predicted needs. Thus, edu-
patients the expense and/or intensity of glycemia compared with use of a sensor- cation of patients on how to adjust
treatment required for their use is pro- augmented pump (19). prandial insulin to account for carbohy-
hibitive. There are multiple approaches Intensive insulin management using a drate intake, premeal glucose levels,
to insulin treatment, and the central version of CSII and continuous glucose and anticipated activity can be effective
precept in the management of type 1 monitoring should be considered in most and should be offered to most patients
diabetes is that some form of insulin be patients. Automated insulin delivery sys- (22,23). For individuals in whom carbo-
given in a planned regimen tailored to the tems may be considered in adults with hydrate counting is effective, estimates
individual patient to keep them safe and type 1 diabetes who have the skills to use of the fat and protein content of meals
out of diabetic ketoacidosis and to avoid them in order to improve time in range can be incorporated into their prandial
significant hypoglycemia, with every and reduce A1C and hypoglycemia (19). dosing for added benefit (24).care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S113
Insulin Injection Technique of this therapy and, as such, holds the PHARMACOLOGIC THERAPY FOR
Ensuring that patients and/or caregivers potential for improved clinical outcomes. TYPE 2 DIABETES
understand correct insulin injection tech- Recommendations
nique is important to optimize glucose Noninsulin Treatments for Type 1
9.4 Metformin is the preferred ini-
control and insulin use safety. Thus, it is Diabetes
tial pharmacologic agent for the
important that insulin be delivered into Injectable and oral glucose-lowering
treatment of type 2 diabetes. A
the proper tissue in the correct way. drugs have been studied for their efficacy
9.5 Once initiated, metformin should
Recommendations have been pub- as adjuncts to insulin treatment of type 1
be continued as long as it is tol-
lished elsewhere outlining best practi- diabetes. Pramlintide is based on the
erated and not contraindicated;
ces for insulin injection (25). Proper naturally occurring b-cell peptide amylin
other agents, including insulin,
insulin injection technique includes in- and is approved for use in adults with
should be added to metformin. A
jecting into appropriate body areas, in- type 1 diabetes. Results from random-
9.6 Early combination therapy can
jection site rotation, appropriate care of ized controlled studies show variable
be considered in some patients
injection sites to avoid infection or other reductions of A1C (0–0.3%) and body
at treatment initiation to extend
complications, and avoidance of intra- weight (1–2 kg) with addition of pramlin-
the time to treatment failure. A
muscular (IM) insulin delivery. tide to insulin (27,28). Similarly, results
9.7 The early introduction of insulin
Exogenously delivered insulin should have been reported for several agents
should be considered if there is
be injected into subcutaneous tissue, not currently approved only for the treat-
evidence of ongoing catabolism
intramuscularly. Recommended sites for ment of type 2 diabetes. The addition of
(weight loss), if symptoms of
insulin injection include the abdomen, metformin in adults with type 1 diabetes
hyperglycemia are present, or
thigh, buttock, and upper arm. Because caused small reductions in body weight
when A1C levels (.10% [86
insulin absorption from IM sites differs and lipid levels but did not improve A1C
mmol/mol]) or blood glucose
according to the activity of the muscle, (29,30). The addition of the glucagon-like
levels ($300 mg/dL [16.7 mmol/L])
inadvertent IM injection can lead to un- peptide 1 (GLP-1) receptor agonist (RA)
are very high. E
predictable insulin absorption and vari- liraglutide or exenatide to insulin therapy
9.8 A patient-centered approach
able effects on glucose, with IM injection caused small (0.2%) reductions in A1C
should be used to guide the
being associated with frequent and un- compared with insulin alone in people
choice of pharmacologic agents.
explained hypoglycemia in several re- with type 1 diabetes and also reduced
Considerations include effect
ports. Risk for IM insulin delivery is body weight by ;3 kg (31). Similarly, the
on cardiovascular and renal co-
increased in younger, leaner patients addition of a sodium–glucose cotrans-
morbidities, efficacy, hypogly-
when injecting into the limbs rather than porter 2 (SGLT2) inhibitor to insulin therapy
cemia risk, impact on weight,
truncal sites (abdomen and buttocks) and has been associated with improvements
cost, risk for side effects, and
when using longer needles. Recent ev- in A1C and body weight when compared
patient preferences (Table 9.1
idence supports the use of short needles with insulin alone (32,33); however, SGLT2
and Fig. 9.1). E
(e.g., 4-mm pen needles) as effective and inhibitor use in type 1 diabetes is asso-
9.9 Among patients with type 2 di-
well tolerated when compared with lon- ciated with a two- to fourfold increase in
abetes who have established
ger needles, including a study performed ketoacidosis. The risks and benefits of
atherosclerotic cardiovascular
in adults with obesity (26). adjunctive agents continue to be evalu-
disease or indicators of high risk,
Injection site rotation is additionally ated, but only pramlintide is approved for
established kidney disease, or
necessary to avoid lipohypertrophy, an treatment of type 1 diabetes.
heart failure, a sodium–glucose
accumulation of subcutaneous fat in re- cotransporter 2 inhibitor or
sponse to the adipogenic actions of in- SURGICAL TREATMENT FOR TYPE
glucagon-like peptide 1 receptor
sulin at a site of multiple injections. 1 DIABETES
agonist with demonstrated car-
Lipohypertrophy appears as soft, smooth Pancreas and Islet Transplantation diovascular disease benefit
raised areas several centimeters in breadth Successful pancreas and islet transplan- (Table 9.1, Table 10.3B, Table
and can contribute to erratic insulin tation can normalize glucose levels and 10.3C) is recommended as part
absorption, increased glycemic variabil- mitigate microvascular complications of of the glucose-lowering regi-
ity, and unexplained hypoglycemic epi- type 1 diabetes. However, patients re- men independent of A1C and
sodes. Patients and/or caregivers should ceiving these treatments require lifelong in consideration of patient-spe-
receive education about proper injection immunosuppression to prevent graft re- cific factors (Fig. 9.1 and Section
site rotation and to recognize and avoid jection and/or recurrence of autoimmune 10). A
areas of lipohypertrophy. As noted in islet destruction. Given the potential 9.10 In patients with type 2 diabetes,
Table 4.1, examination of insulin injec- adverse effects of immunosuppressive a glucagon-like peptide 1 recep-
tion sites for the presence of lipohyper- therapy, pancreas transplantation should tor agonist is preferred to in-
trophy, as well as assessment of injection be reserved for patients with type 1 dia- sulin when possible. A
device use and injection technique, are betes undergoing simultaneous renal trans- 9.11 Recommendation for treatment
key components of a comprehensive plantation, following renal transplantation, intensification for patients not
diabetes medical evaluation and treat- or for those with recurrent ketoacidosis meeting treatment goals should
ment plan. Proper insulin injection tech- or severe hypoglycemia despite intensive not be delayed. A
nique may lead to more effective use glycemic management (34).S114 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 44, Supplement 1, January 2021
Care” (https://doi.org/10.2337/dc21-S011) consider a drug from another class de-
9.12 The medication regimen and
have recommendations for the use of picted in Fig. 9.1. When A1C is $1.5%
medication-taking behavior
glucose-lowering drugs in the manage- (12.5 mmol/mol) above the glycemic
should be reevaluated at regular
ment of cardiovascular and renal disease, target (see Section 6 “Glycemic Targets,”
intervals (every 3–6 months) and
respectively. https://doi.org/10.2337/dc21-S006,
adjusted as needed to incorpo-
for appropriate targets), many patients
rate specific factors that impact
Initial Therapy will require dual combination therapy
choice of treatment (Fig. 4.1 and
Metformin should be started at the time to achieve their target A1C level (42).
Table 9.1). E
type 2 diabetes is diagnosed unless there Insulin has the advantage of being effec-
9.13 Clinicians should be aware of
are contraindications; for many patients tive where other agents are not and
the potential for overbasaliza-
this will be monotherapy in combination should be considered as part of any
tion with insulin therapy. Clinical
with lifestyle modifications. Additional combination regimen when hyperglyce-
signals that may prompt evalu-
and/or alternative agents may be con- mia is severe, especially if catabolic fea-
ation of overbasalization include
tures (weight loss, hypertriglyceridemia,
basal dose more than ;0.5 IU/ sidered in special circumstances, such
as in individuals with established or in- ketosis) are present. It is common practice
kg, high bedtime-morning or
creased risk of cardiovascular or renal to initiate insulin therapy for patients who
post-preprandial glucose differ-
complications (see Section 10 “Cardio- present with blood glucose levels $300
ential, hypoglycemia (aware or
vascular Disease and Risk Management,” mg/dL (16.7 mmol/L) or A1C .10% (86
unaware), and high variability.
https://doi.org/10.2337/dc21-S010, and mmol/mol) or if the patient has symptoms
Indication of overbasalization
Fig. 9.1). Metformin is effective and safe, of hyperglycemia (i.e., polyuria or poly-
should prompt reevaluation to
is inexpensive, and may reduce risk of dipsia) or evidence of catabolism (weight
further individualize therapy. E
cardiovascular events and death (37). loss) (Fig. 9.2). As glucose toxicity resolves,
Metformin is available in an immediate- simplifying the regimen and/or changing
The American Diabetes Association/
release form for twice-daily dosing or as to oral agents is often possible. However,
European Association for the Study of
there is evidence that patients with un-
Diabetes consensus report “Management an extended-release form that can be
given once daily. Compared with sulfo- controlled hyperglycemia associated with
of Hyperglycemia in Type 2 Diabetes,
nylureas, metformin as first-line therapy type 2 diabetes can also be effectively
2018” and the 2019 update (35,36)
has beneficial effects on A1C, weight, and treated with a sulfonylurea (43).
recommend a patient-centered approach
to choosing appropriate pharmacologic cardiovascular mortality (38); there is Combination Therapy
treatment of blood glucose. This includes little systematic data available for other Because type 2 diabetes is a progressive
consideration of efficacy and key patient oral agents as initial therapy of type 2 disease in many patients, maintenance of
factors: 1) important comorbidities such diabetes. glycemic targets with monotherapy is
as atherosclerotic cardiovascular disease The principal side effects of metformin often possible for only a few years, after
(ASCVD) and indicators of high ASCVD are gastrointestinal intolerance due to which combination therapy is necessary.
risk, chronic kidney disease (CKD), and bloating, abdominal discomfort, and di- Current recommendations have been to
heart failure (see Section 10 “Cardiovas- arrhea; these can be mitigated by gradual use stepwise addition of medications to
cular Disease and Risk Management,” dose titration. The drug is cleared by metformin to maintain A1C at target. This
https://doi.org/10.2337/dc21-S010, and renal filtration, and very high circulating allows a clearer assessment of the pos-
Section 11 “Microvascular Complications levels (e.g., as a result of overdose or itive and negative effects of new drugs
and Foot Care,” https://doi.org/10.2337/ acute renal failure) have been associated and reduces patient risk and expense
dc21-S011), 2) hypoglycemia risk, 3) ef- with lactic acidosis. However, the occur- (44); based on these factors, sequential
fects on body weight, 4) side effects, 5) rence of this complication is now known to addition of oral agents to metformin has
cost, and 6) patient preferences. Lifestyle be very rare, and metformin may be safely been the standard of care. However,
modifications that improve health (see used in patients with reduced estimated there are data to support initial combi-
Section 5 “Facilitating Behavior Change glomerular filtration rates (eGFR); the nation therapy for more rapid attain-
and Well-being to Improve Health FDA has revised the label for metformin ment of glycemic goals (45,46) and later
Outcomes,” https://doi.org/10.2337/ to reflect its safety in patients with combination therapy for longer durabil-
dc21-S005) should be emphasized along eGFR $30 mL/min/1.73 m2 (39). A ran- ity of glycemic effect (47). The VERIFY
with any pharmacologic therapy. Section 12 domized trial confirmed previous obser- (Vildagliptin Efficacy in combination with
“Older Adults” (https://doi.org/10.2337/ vations that metformin use is associated metfoRmIn For earlY treatment of type 2
dc21-S012) and Section 13 “Children and with vitamin B12 deficiency and wors- diabetes) trial demonstrated that initial
Adolescents” (https://doi.org/10.2337/ ening of symptoms of neuropathy (40). combination therapy is superior to se-
dc21-S013) have recommendations spe- This is compatible with a report from the quential addition of medications for ex-
cific for older adults and for children Diabetes Prevention Program Outcomes tending primary and secondary failure
and adolescents with type 2 diabetes, Study (DPPOS) suggesting periodic testing (48). In the VERIFY trial, participants
respectively. Section 10 “Cardiovascular of vitamin B12 (41). receiving the initial combination of met-
Disease and Risk Management” (https:// In patients with contraindications or formin and the dipeptidyl peptidase
doi.org/10.2337/dc21-S010) and Section intolerance to metformin, initial therapy 4 (DPP-4) inhibitor vildagliptin had
11 “Microvascular Complications and Foot should be based on patient factors; a slower decline of glycemic controlTable 9.1—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,
Pharmacologic Approaches to Glycemic Treatment
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 diabetes. *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.
S115S116
Pharmacologic Approaches to Glycemic Treatment
Figure 9.1—Glucose-lowering medication in type 2 diabetes: 2021 ADA Professional Practice Committee (PPC) adaptation of Davies et al. (35) and Buse et al. (36). For appropriate context, see Fig. 4.1. The 2021 ADA
Diabetes Care Volume 44, Supplement 1, January 2021
PPC adaptation of the Fig. 9.1 “Indicators of high-risk or established ASCVD, CKD, or HF” pathway has been adapted based on trial populations studied. ASCVD, atherosclerotic cardiovascular disease; CKD, chronic
kidney disease; CVD, cardiovascular disease; 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; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SU, sulfonylurea; T2D,
type 2 diabetes; TZD, thiazolidinedione.care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S117 Figure 9.2—Intensifying to injectable therapies. DSMES, diabetes self-management education and support; FPG, fasting plasma glucose; FRC, fixed-ratio combination; GLP-1 RA, glucagon-like peptide 1 receptor agonist; max, maximum; PPG, postprandial glucose. Adapted from Davies et al. (35).
S118 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 44, Supplement 1, January 2021
compared with metformin alone and consideration of patient-specific factors Cost for diabetes medicine has in-
with vildagliptin added sequentially to (Fig. 9.1). For patients without estab- creased dramatically over the past two
metformin. These results have not lished ASCVD, indicators of high ASCVD decades, and an increasing proportion
been generalized to oral agents other risk, heart failure, or CKD, the choice of is now passed on to patients and their
than vildagliptin, but they suggest that a second agent to add to metformin is families (61). Table 9.2 provides cost
more intensive early treatment has some not yet guided by empiric evidence com- information for currently approved
benefits and should be considered through paring across multiple classes. Rather, drug noninsulin therapies. Of note, prices
a shared decision-making process with choice is based on efficacy, avoidance listed are average wholesale prices
patients, as appropriate. Moreover, since of side effects (particularly hypoglycemia (AWP) (62) and National Average Drug
the absolute effectiveness of most oral and weight gain), cost, and patient pref- Acquisition Costs (NADAC) (63), separate
medications rarely exceeds 1%, initial com- erences (51). Similar considerations are measures to allow for a comparison of
bination therapy should be considered in applied in patients who require a third drug prices, but do not account for
patients presenting with A1C levels 1.5– agent to achieve glycemic goals. A recent discounts, rebates, or other price adjust-
2.0% above target. systematic review and network meta- ments often involved in prescription
Recommendations for treatment in- analysis suggests greatest reductions in sales that affect the actual cost incurred
tensification for patients not meeting A1C level with insulin regimens and specific by the patient. Medication costs can be a
treatment goals should not be delayed. GLP-1 RAs added to metformin-based back- major source of stress for patients with
Shared decision-making is important in ground therapy (52). In all cases, treatment diabetes and contribute to worse adher-
discussions regarding treatment intensi- regimens need to be continuously reviewed ence to medications (64); cost-reducing
fication. The choice of medication added for efficacy, side effects, and patient burden strategies may improve adherence in
to metformin is based on the clinical (Table 9.1). In some instances, patients will some cases (65).
characteristics of the patient and their require medication reduction or discontin-
preferences. Important clinical charac- uation. Common reasons for this include Cardiovascular Outcomes Trials
teristics include the presence of estab- ineffectiveness, intolerable side effects, ex- There are now multiple large randomized
lished ASCVD or indicators of high ASCVD pense, or a change in glycemic goals (e.g., in controlled trials reporting statistically
risk, heart failure, CKD, other comorbid- response to development of comorbidities significant reductions in cardiovascular
ities, and risk for specific adverse drug or changes in treatment goals). Section 12 events in patients with type 2 diabetes
effects, as well as safety, tolerability, and “Older Adults” (https://doi.org/10.2337/ treated with an SGLT2 inhibitor (empa-
cost. Although there are numerous trials dc21-S012) has a full discussion of treat- gliflozin, canagliflozin, dapagliflozin) or
comparing dual therapy with metformin ment considerations in older adults, in GLP-1 RA (liraglutide, semaglutide, dula-
alone, there is little evidence to support whom changes of glycemic goals and glutide); see Section 10 “Cardiovascular
one combination over another. A com- de-escalation of therapy are common. Disease and Risk Management” (https://
parative effectiveness meta-analysis The need for the greater potency of doi.org/10.2337/dc21-S010) for details.
suggests that each new class of non- injectable medications is common, par- The subjects enrolled in the cardiovas-
insulin agents added to initial therapy ticularly in people with a longer duration cular outcomes trials using empagliflozin,
with metformin generally lowers A1C of diabetes. The addition of basal insulin, canagliflozin, dapagliflozin, liraglutide, and
approximately 0.7–1.0% (49,50). If the either human NPH or one of the long- semaglutide had A1C $6.5%, and more
A1C target is not achieved after approx- acting insulin analogs, to oral agent regi- than 70% were taking metformin at base-
imately 3 months, metformin can be mens is a well-established approach that line. Thus, a practical extension of these
combined with any one of the preferred is effective for many patients. In addition, results to clinical practice is to use these
six treatment options: sulfonylurea, thia- recent evidence supports the utility of drugs preferentially in patients with
zolidinedione, DPP-4 inhibitor, SGLT2 in- GLP-1 RAs in patients not at glycemic goal. type 2 diabetes and established ASCVD
hibitor, GLP-1 RA, or basal insulin; the While most GLP-1 RAs are injectable, an or indicators of high ASCVD risk. For these
choice of which agent to add is based on oral formulation of semaglutide is now com- patients, incorporating one of the SGLT2
drug-specific effects and patient factors mercially available (53). In trials comparing inhibitors or GLP-1 RAs that have been
(Fig. 9.1 and Table 9.1). the addition of an injectable GLP-1 RA or demonstrated to have cardiovascular dis-
For patients with established ASCVD insulin in patients needing further glu- ease benefit is recommended (Table 9.1).
or indicators of high ASCVD risk (such as cose lowering, glycemic efficacy of inject- In cardiovascular outcomes trials, em-
patients $55 years of age with coronary, able GLP-1 RA was similar or greater than pagliflozin, canagliflozin, dapagliflozin,
carotid, or lower-extremity artery steno- that of basal insulin (54–60). GLP-1 RAs in liraglutide, semaglutide, and dulaglutide
sis .50% or left ventricular hypertro- these trials had a lower risk of hypogly- all had beneficial effects on indices of
phy), heart failure, or CKD, an SGLT2 cemia and beneficial effects on body CKD, while dedicated renal outcomes
inhibitor or GLP-1 RA with demonstrated weight compared with insulin, albeit studies have demonstrated benefit of
CVD benefit (Table 9.1, Table 10.3B, with greater gastrointestinal side effects. specific SGLT2 inhibitors. See Section
Table 10.3C, and Section 10 “Cardiovas- Thus, trial results support GLP-1 RAs as the 11 “Microvascular Complications and
cular Disease and Risk Management,” preferred option for patients requiring Foot Care” (https://doi.org/10.2337/
https://doi.org/10.2337/dc21-S010) is the potency of an injectable therapy for dc21-S011) for discussion of how CKD
recommended as part of the glucose- glucose control (Fig. 9.2). However, high may impact treatment choices. Addi-
lowering regimen independent of A1C, costs and tolerability issues are impor- tional large randomized trials of other
independent of metformin use, and in tant barriers to GLP-1 RA use. agents in these classes are ongoing.care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S119
Table 9.2—Median monthly (30-day) AWP and NADAC of maximum approved daily dose of noninsulin glucose-lowering
agents in the U.S.
Dosage strength/product Median AWP Median NADAC Maximum approved
Class Compound(s) (if applicable) (min, max)† (min, max)† daily dose*
Biguanides c Metformin 850 mg (IR) $108 ($6, $109) $3 2,550 mg
1,000 mg (IR) $87 ($4, $88) $2 2,000 mg
1,000 mg (ER) $242 ($242, $188 ($188, $572) 2,000 mg
$7,214)
Sulfonylureas (2nd c Glimepiride 4 mg $74 ($71, $198) $4 8 mg
generation) c Glipizide 10 mg (IR) $75 ($67, $97) $5 40 mg (IR)
10 mg (XL) $48 $11 20 mg (XL)
c Glyburide 6 mg (micronized) $52 ($48, $71) $10 12 mg (micronized)
5 mg $93 ($63, $103) $11 20 mg
Thiazolidinediones c Pioglitazone 45 mg $348 ($283, $349) $5 45 mg
c Rosiglitazone 4 mg $407 $330 8 mg
a-Glucosidase inhibitors c Acarbose 100 mg $106 ($104, $106) $28 300 mg
c Miglitol 100 mg $241 $311 300 mg
Meglitinides (glinides) c Nateglinide 120 mg $155 $31 360 mg
c Repaglinide 2 mg $878 ($162, $897) $38 16 mg
DPP-4 inhibitors c Alogliptin 25 mg $234 $175 25 mg
c Saxagliptin 5 mg $530 $424 5 mg
c Linagliptin 5 mg $555 $444 5 mg
c Sitagliptin 100 mg $568 $456 100 mg
SGLT2 inhibitors c Ertugliflozin 15 mg $354 $284 15 mg
c Dapagliflozin 10 mg $621 $496 10 mg
c Empagliflozin 25 mg $627 $501 25 mg
c Canagliflozin 300 mg $622 $499 300 mg
GLP-1 RAs c Exenatide (extended 2 mg powder for $882 $706 2 mg**
release) suspension or pen
c Exenatide 10 mg pen $752 $720 20 mg
c Dulaglutide 4.5/0.5 mL pen $957 $766 4.5 mg**
c Semaglutide 1 mg pen $973 $779 1 mg**
14 mg (tablet) $927 $738 14 mg
c Liraglutide 18 mg/3 mL pen $1,161 $930 1.8 mg
c Lixisenatide 300 mg/3 mL pen $774 N/A 20 mg
Bile acid sequestrant c Colesevelam 625 mg tabs $710 ($674, $712) $105 3.75 g
3.75 g suspension $804 $318 3.75 g
Dopamine-2 agonist c Bromocriptine 0.8 mg $960 $772 4.8 mg
Amylin mimetic c Pramlintide 120 mg pen $2702 $2,097 120 mg/injection††
AWP, average wholesale price; DPP-4, dipeptidyl peptidase 4; ER and XL, extended release; GLP-1 RA, glucagon-like peptide 1 receptor agonist; 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 [62] or NADAC [63] 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. **Administered once weekly. ††AWP and NADAC calculated based on 120 mg three times daily.
Insulin Therapy management is beneficial. For example, individualized titration over days to weeks
Many patients with type 2 diabetes instruction of patients in self-titration of as needed. The principal action of basal
eventually require and benefit from in- insulin doses based on glucose monitoring insulin is to restrain hepatic glucose pro-
sulin therapy (Fig. 9.2). See the section improves glycemic control in patients with duction and limit hyperglycemia overnight
INSULIN INJECTION TECHNIQUE, above, for guid- type 2 diabetes initiating insulin (66). Com- and between meals (67,68). Control of
ance on how to administer insulin safely prehensive education regarding self-mon- fasting glucose can be achieved with hu-
and effectively. The progressive nature of itoring of blood glucose, diet, and the man NPH insulin or a long-acting insulin
type 2 diabetes should be regularly and avoidance and appropriate treatment of analog. In clinical trials, long-acting basal
objectively explained to patients, and hypoglycemia are critically important in analogs (U-100 glargine or detemir) have
providers should avoid using insulin any patient using insulin. been demonstrated to reduce the risk of
as a threat or describing it as a sign of Basal Insulin symptomatic and nocturnal hypoglycemia
personal failure or punishment. Rather, Basal insulin alone is the most convenient compared with NPH insulin (69–74), al-
the utility and importance of insulin to initial insulin regimen and can be added though these advantages are modest and
maintain glycemic control once progres- to metformin and other oral agents. may not persist (75). Longer-acting basal
sion of the disease overcomes the effect Starting doses can be estimated based analogs (U-300 glargine or degludec) may
of other agents should be emphasized. on body weight (0.1–0.2 units/kg/day) convey a lower hypoglycemia risk com-
Educating and involving patients in insulin and the degree of hyperglycemia, with pared with U-100 glargine when used inS120 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 44, Supplement 1, January 2021
Table 9.3—Median cost of insulin products in the U.S. calculated as AWP (62) and NADAC (63) per 1,000 units of specified
dosage form/product
Median AWP Median
Insulins Compounds Dosage form/product (min, max)* NADAC*
Rapid-acting c Lispro follow-on product U-100 vial $157 $125
U-100 prefilled pen $202 $161
c Lispro U-100 vial $165† $132†
U-100 cartridges $408 $326
U-100 prefilled pen $212† $170†
U-200 prefilled pen $424 $339
c Lispro-aabc U-100 vial $330 N/A
U-100 prefilled pen $424 N/A
U-200 prefilled pen $424 N/A
c Glulisine U-100 vial $341 $272
U-100 prefilled pen $439 $350
c Aspart U-100 vial $174† $139†
U-100 cartridges $215 $344
U-100 prefilled pen $223† $179†
c Aspart (“faster acting U-100 vial $347 $278
product”) U-100 cartridge $430 N/A
U-100 prefilled pen $447 $356
c Inhaled insulin Inhalation cartridges $924 $606
Short-acting c human regular U-100 vial $165†† $133††
Intermediate-acting c human NPH U-100 vial $165†† $133††
U-100 prefilled pen $208 $167
Concentrated human regular c U-500 human regular U-500 vial $178 $143
insulin insulin U-500 prefilled pen $229 $183
Long-acting c Glargine follow-on product U-100 prefilled pen $190 (118, 261) $210
U-100 vial $190 (118, 261) N/A
c Glargine U-100 vial; U-100 prefilled pen $340 $272
U-300 prefilled pen $340 $272
c Detemir U-100 vial; U-100 prefilled pen $370 $296
c Degludec U-100 vial; U-100 prefilled pen; U-200 $407 $325
prefilled pen
Premixed insulin products c NPH/regular 70/30 U-100 vial $165†† $133††
U-100 prefilled pen $208 $167
c Lispro 50/50 U-100 vial $342 $273
U-100 prefilled pen $424 $338
c Lispro 75/25 U-100 vial $342 $274
U-100 prefilled pen $212 $340
c Aspart 70/30 U-100 vial $180 $144
U-100 prefilled pen $224 $179
Premixed insulin/GLP-1 RA c Glargine/Lixisenatide 100/33 prefilled pen $589 $471
products c Degludec/Liraglutide 100/3.6 prefilled pen $874 $701
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 9.2. †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.
combination with oral agents (76–82). Indication of overbasalization should prompt (e.g., individuals with relaxed A1C goals,
Despite evidence for reduced hypogly- reevaluation to further individualize ther- low rates of hypoglycemia, and prom-
cemia with newer, longer-acting basal apy (84). inent insulin resistance, as well as those
insulin analogs in clinical trial settings, in The cost of insulin has been rising with cost concerns), human insulin (NPH
practice these effects may be modest steadily over the past two decades, at a and regular) may be the appropriate
compared with NPH insulin (83). Clini- pace several fold that of other medical choice of therapy, and clinicians should
cians should be aware of the potential for expenditures (85). This expense contrib- be familiar with its use (83). Human regular
overbasalization with insulin therapy. utes significant burden to patients as insulin, NPH, and 70/30 NPH/regular prod-
Clinical signals that may prompt evalu- insulin has become a growing “out-of- ucts can be purchased for considerably
ation of overbasalization include basal pocket” cost for people with diabetes, less than the AWP and NADAC prices
dosegreaterthan;0.5IU/kg,highbedtime- and direct patient costs contribute to listed in Table 9.3 at select pharmacies.
morning or post-preprandial glucose differ- treatment nonadherence (85). Therefore,
ential (e.g. bedtime-morning glucose dif- consideration of cost is an important Prandial Insulin
ferential $50 mg/dL), hypoglycemia component of effective management. Many individuals with type 2 diabetes
(aware or unaware), and high variability. For many patients with type 2 diabetes require doses of insulin before meals, incare.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S121
addition to basal insulin, to reach glyce- evidence that compared with injectable 30) formulations, are less costly alterna-
mic targets. A dose of 4 units or 10% of rapid-acting insulin, supplemental doses tives to insulin analogs. Figure 9.2 outlines
the amount of basal insulin at the largest of inhaled insulin taken based on post- these options as well as recommendations
meal or the meal with the greatest post- prandial glucose levels may improve for further intensification, if needed, to
prandial excursion is a safe estimate for blood glucose management without achieve glycemic goals. When initiating
initiating therapy. The prandial insulin additional hypoglycemia or weight gain combination injectable therapy, metfor-
regimen can then be intensified based on (92), although results from a larger study min therapy should be maintained, while
patient needs (see Fig. 9.2). People with are needed for confirmation. Inhaled sulfonylureas and DPP-4 inhibitors are
type 2 diabetes are generally more in- insulin is contraindicated in patients with typically weaned or discontinued. In pa-
sulin resistant than those with type 1 chronic lung disease, such as asthma and tients with suboptimal blood glucose
diabetes, require higher daily doses (;1 chronic obstructive pulmonary disease, control, especially those requiring large
unit/kg), and have lower rates of hypo- and is not recommended in patients who insulin doses, adjunctive use of a thia-
glycemia (86). Titration can be based on smoke or who recently stopped smoking. zolidinedione or an SGLT2 inhibitor
home glucose monitoring or A1C. With All patients require spirometry (forced may help to improve control and reduce
significant additions to the prandial in- expiratory volume in 1 s [FEV1]) testing to the amount of insulin needed, though
sulin dose, particularly with the evening identify potential lung disease prior to potential side effects should be consid-
meal, consideration should be given to and after starting inhaled insulin therapy. ered. Once a basal/bolus insulin regimen
decreasing basal insulin. Meta-analyses is initiated, dose titration is important,
of trials comparing rapid-acting insulin Combination Injectable Therapy with adjustments made in both mealtime
analogs with human regular insulin in If basal insulin has been titrated to an and basal insulins based on the blood
patients with type 2 diabetes have not acceptable fasting blood glucose level (or glucose levels and an understanding of
reported important differences in A1C or if the dose is .0.5 units/kg/day with the pharmacodynamic profile of each for-
hypoglycemia (87,88). indications of need for other therapy) mulation (pattern control). As people with
Concentrated Insulins
and A1C remains above target, consider type 2 diabetes get older, it may become
Several concentrated insulin prepara- advancing to combination injectable necessary to simplify complex insulin regi-
tions are currently available. U-500 reg- therapy (Fig. 9.2). This approach can use a mens because of a decline in self-manage-
ular insulin is, by definition, five times GLP-1 RA added to basal insulin or multi- ment ability (see Section 12 “Older
more concentrated than U-100 regular ple doses of insulin. The combination of Adults,” https://doi.org/10.2337/dc21-
insulin. Regular U-500 has distinct phar- basal insulin and GLP-1 RA has potent S012).
macokinetics with delayed onset and glucose-lowering actions and less weight
longer duration of action, has character- gain and hypoglycemia compared with References
istics more like an intermediate-acting intensified insulin regimens (93–95), with 1. Cleary PA, Orchard TJ, Genuth S, et al.; DCCT/
one study suggesting greater durability EDIC Research Group. The effect of intensive
(NPH) insulin, and can be used as two or glycemic treatment on coronary artery calcifica-
three daily injections (89). U-300 glargine of glycemic effect compared with addi- tion in type 1 diabetic participants of the
and U-200 degludec are three and two tion of basal insulin alone (47). Two Diabetes Control and Complications Trial/
times as concentrated as their U-100 different once-daily, fixed dual-combination Epidemiology of Diabetes Interventions and
products containing basal insulin plus a Complications (DCCT/EDIC) study. Diabetes 2006;
formulations and allow higher doses of 55:3556–3565
basal insulin administration per volume GLP-1 RA are available: insulin glargine
2. Nathan DM, Cleary PA, Backlund J-YC, et al.;
used. U-300 glargine has a longer dura- plus lixisenatide and insulin degludec Diabetes Control and Complications Trial/
tion of action than U-100 glargine but plus liraglutide. Epidemiology of Diabetes Interventions and
modestly lower efficacy per unit admin- Intensification of insulin treatment can Complications (DCCT/EDIC) Study Research
be done by adding doses of prandial to Group. Intensive diabetes treatment and car-
istered (90,91). The FDA has also approved diovascular disease in patients with type 1
a concentrated formulation of rapid-acting basal insulin. Starting with a single pran-
diabetes. N Engl J Med 2005;353:2643–2653
insulin lispro, U-200 (200 units/mL) and dial dose with the largest meal of the day 3. Diabetes Control and Complications Trial
insulin lispro-aabc (U-200). These concen- is simple and effective, and it can be (DCCT)/Epidemiology of Diabetes Interventions
trated preparations may be more conve- advanced to a regimen with multiple and Complications (EDIC) Study Research Group.
prandial doses if necessary (96). Alter- Mortality in type 1 diabetes in the DCCT/EDIC
nient and comfortable for patients to inject versus the general population. Diabetes Care
and may improve adherence in those natively, in a patient on basal insulin in
2016;39:1378–1383
with insulin resistance who require large whom additional prandial coverage is 4. Writing Team for the Diabetes Control and
doses of insulin. While U-500 regular in- desired, the regimen can be converted to Complications Trial/Epidemiology of Diabetes
sulin is available in both prefilled pens and two doses of a premixed insulin. Each Interventions and Complications Research Group.
approach has advantages and disadvan- Effect of intensive therapy on the microvascular
vials, other concentrated insulins are avail- complications of type 1 diabetes mellitus. JAMA
able only in prefilled pens to minimize the tages. For example, basal/prandial regi- 2002;287:2563–2569
risk of dosing errors. mens offer greater flexibility for patients 5. Tricco AC, Ashoor HM, Antony J, et al. Safety,
who eat on irregular schedules. On the effectiveness, and cost effectiveness of long
Inhaled Insulin other hand, two doses of premixed in- acting versus intermediate acting insulin for
Inhaled insulin is available as a rapid- sulin is a simple, convenient means of patients with type 1 diabetes: systematic re-
view and network meta-analysis. BMJ 2014;
acting insulin; studies in people with spreading insulin across the day. More- 349:g5459
type 1 diabetes suggest rapid pharma- over, human insulins, separately, self- 6. Bartley PC, Bogoev M, Larsen J, Philotheou A.
cokinetics (8). A pilot study found mixed, or as premixed NPH/regular (70/ Long-term efficacy and safety of insulin detemirS122 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 44, Supplement 1, January 2021
compared to Neutral Protamine Hagedorn in- a multicentre, 12-week randomised trial. Lancet controlled type 1 diabetes (DEPICT-1): 24 week
sulin in patients with type 1 diabetes using a 2018;392:1321–1329 results from a multicentre, double-blind, phase
treat-to-target basal-bolus regimen with insulin 19. Brown SA, Kovatchev BP, Raghinaru D, et al.; 3, randomised controlled trial. Lancet Diabetes
aspart at meals: a 2-year, randomized, controlled iDCL Trial Research Group. Six-month random- Endocrinol 2017;5:864–876
trial. Diabet Med 2008;25:442–449 ized, multicenter trial of closed-loop control in 33. Rosenstock J, Marquard J, Laffel LM, et al.
7. DeWitt DE, Hirsch IB. Outpatient insulin ther- type 1 diabetes. N Engl J Med 2019;381:1707– Empagliflozin as adjunctive to insulin therapy in
apy in type 1 and type 2 diabetes mellitus: 1717 type 1 diabetes: the EASE trials. Diabetes Care
scientific review. JAMA 2003;289:2254–2264 20. Peters AL, Laffel L (Eds.). American Diabetes 2018;41:2560–2569
8. Bode BW, McGill JB, Lorber DL, Gross JL, Chang Association/JDRF Type 1 Diabetes Sourcebook. 34. Dean PG, Kukla A, Stegall MD, Kudva YC.
PC, Bregman DB; Affinity 1 Study Group. Inhaled Alexandria, VA, American Diabetes Association, Pancreas transplantation. BMJ. 2017;357:j1321
technosphere insulin compared with injected 2013 35. Davies MJ, D’Alessio DA, Fradkin J, et al.
prandial insulin in type 1 diabetes: a randomized 21. Chiang JL, Kirkman MS, Laffel LMB, Peters AL; Management of hyperglycemia in type 2 diabe-
24-week trial. Diabetes Care 2015;38:2266–2273 Type 1 Diabetes Sourcebook Authors. Type 1 di- tes, 2018. A consensus report by the American
9. Russell-Jones D, Bode BW, De Block C, et al. abetes through the life span: a position state- Diabetes Association (ADA) and the European
Fast-acting insulin aspart improves glycemic ment of the American Diabetes Association. Association for the Study of Diabetes (EASD).
control in basal-bolus treatment for type 1 Diabetes Care 2014;37:2034–2054 Diabetes Care 2018;41:2669–2701
diabetes: results of a 26-week multicenter, 22. Bell KJ, Barclay AW, Petocz P, Colagiuri S, 36. Buse JB, Wexler DJ, Tsapas A, et al. 2019
active-controlled, treat-to-target, randomized, Brand-Miller JC. Efficacy of carbohydrate count- update to: management of hyperglycemia in
parallel-group trial (onset 1). Diabetes Care ing in type 1 diabetes: a systematic review and type 2 diabetes, 2018. A consensus report by the
2017;40:943–950 meta-analysis. Lancet Diabetes Endocrinol 2014; American Diabetes Association (ADA) and the
9a. Klaff L, Cao D, Dellva MA, et al. Ultra rapid 2:133–140 European Association for the Study of Diabetes
lispro improves postprandial glucose control 23. Vaz EC, Porfı́rio GJM, Nunes HRC, Nunes- (EASD). Diabetes Care 2020;43:487–493
compared with lispro in patients with type 1 Nogueira VDS. Effectiveness and safety of car- 37. Holman RR, Paul SK, Bethel MA, Matthews
diabetes: results from the 26-week PRONTO-T1D bohydrate counting in the management of adult DR, Neil HAW. 10-year follow-up of intensive
study. Diabetes Obes Metab 2020;22:1799–1807 patients with type 1 diabetes mellitus: a system- glucose control in type 2 diabetes. N Engl J Med
9b. Blevins T, Zhang Q, Frias JP, Jinnouchi H, atic review and meta-analysis. Arch Endocrinol 2008;359:1577–1589
Chang AM; PRONTO-T2D Investigators. Random- Metab 2018;62:337–345 38. Maruthur NM, Tseng E, Hutfless S, et al. Di-
ized double-blind clinical trial comparing ultra 24. Bell KJ, Smart CE, Steil GM, Brand-Miller JC, abetes medications as monotherapy or metformin-
rapid lispro with lispro in a basal-bolus regimen King B, Wolpert HA. Impact of fat, protein, and based combination therapy for type 2 diabetes:
in patients with type 2 diabetes: PRONTO-T2D. glycemic index on postprandial glucose control in a systematic review and meta-analysis. Ann In-
Diabetes Care 2020;43:2991–2998 type 1 diabetes: implications for intensive diabetes tern Med 2016;164:740–751
10. Lane W, Bailey TS, Gerety G, et al.; Group management in the continuous glucose monitor- 39. U.S. Food and Drug Administration. FDA
Information; SWITCH 1. Effect of insulin degludec ing era. Diabetes Care 2015;38:1008–1015 Drug Safety Communication: FDA revises warn-
vs insulin glargine U100 on hypoglycemia in patients 25. Frid AH, Kreugel G, Grassi G, et al. New insulin ings regarding use of the diabetes medicine
with type 1 diabetes: the SWITCH 1 randomized delivery recommendations. Mayo Clin Proc 2016; metformin in certain patients with reduced kidney
clinical trial. JAMA 2017;318:33–44 91:1231–1255 function. Accessed 6 March 2020. Available from
11. Home PD, Bergenstal RM, Bolli GB, et al. New 26. Bergenstal RM, Strock ES, Peremislov D, https://www.fda.gov/drugs/drug-safety-and-
insulin glargine 300 units/mL versus glargine Gibney MA, Parvu V, Hirsch LJ. Safety and efficacy availability/fda-drug-safety-communication-fda-
100 units/mL in people with type 1 diabetes: of insulin therapy delivered via a 4mm pen needle revises-warnings-regarding-use-diabetes-medicine-
a randomized, phase 3a, open-label clinical trial in obese patients with diabetes. Mayo Clin Proc metformin-certain
(EDITION 4). Diabetes Care 2015;38:2217–2225 2015;90:329–338 40. Out M, Kooy A, Lehert P, Schalkwijk CA,
12. Yeh H-C, Brown TT, Maruthur N, et al. 27. Ratner RE, Dickey R, Fineman M, et al. Amylin Stehouwer CDA. Long-term treatment with
Comparative effectiveness and safety of meth- replacement with pramlintide as an adjunct to metformin in type 2 diabetes and methylmalonic
ods of insulin delivery and glucose monitoring for insulin therapy improves long-term glycaemic acid: post hoc analysis of a randomized con-
diabetes mellitus: a systematic review and meta- and weight control in type 1 diabetes mellitus: trolled 4.3 year trial. J Diabetes Complications
analysis. Ann Intern Med 2012;157:336–347 a 1-year, randomized controlled trial. Diabet Med 2018;32:171–178
13. Pickup JC. The evidence base for diabetes 2004;21:1204–1212 41. Aroda VR, Edelstein SL, Goldberg RB, et al.;
technology: appropriate and inappropriate meta- 28. Edelman S, Garg S, Frias J, et al. A double- Diabetes Prevention Program Research Group.
analysis. J Diabetes Sci Technol 2013;7:1567–1574 blind, placebo-controlled trial assessing pramlin- Long-term metformin use and vitamin B12 de-
14. Bergenstal RM, Klonoff DC, Garg SK, et al.; tide treatment in the setting of intensive insulin ficiency in the diabetes prevention program out-
ASPIRE In-Home Study Group. Threshold-based therapy in type 1 diabetes. Diabetes Care 2006; comes study. J Clin Endocrinol Metab 2016;101:
insulin-pump interruption for reduction of hy- 29:2189–2195 1754–1761
poglycemia. N Engl J Med 2013;369:224–232 29. Meng H, Zhang A, Liang Y, Hao J, Zhang X, Lu J. 42. Henry RR, Murray AV, Marmolejo MH,
15. Buckingham BA, Raghinaru D, Cameron F, Effect of metformin on glycaemic control in Hennicken D, Ptaszynska A, List JF. Dapagliflozin,
et al.; In Home Closed Loop Study Group. Pre- patients with type 1 diabetes: a meta-analysis of metformin XR, or both: initial pharmacotherapy
dictive low-glucose insulin suspension reduces randomized controlled trials. Diabetes Metab for type 2 diabetes, a randomised controlled trial.
duration of nocturnal hypoglycemia in children Res Rev 2018;34:e2983 Int J Clin Pract 2012;66:446–456
without increasing ketosis. Diabetes Care 2015; 30. Petrie JR, Chaturvedi N, Ford I, et al.; RE- 43. Babu A, Mehta A, Guerrero P, et al. Safe and
38:1197–1204 MOVAL Study Group. Cardiovascular and meta- simple emergency department discharge therapy
16. Bergenstal RM, Garg S, Weinzimer SA, et al. bolic effects of metformin in patients with type 1 for patients with type 2 diabetes mellitus and severe
Safety of a hybrid closed-loop insulin delivery diabetes (REMOVAL): a double-blind, rando- hyperglycemia. Endocr Pract 2009;15:696–704
system in patients with type 1 diabetes. JAMA mised, placebo-controlled trial. Lancet Diabe- 44. Cahn A, Cefalu WT. Clinical considerations
2016;316:1407–1408 tes Endocrinol 2017;5:597–609 for use of initial combination therapy in type 2
17. Garg SK, Weinzimer SA, Tamborlane WV, 31. Wang W, Liu H, Xiao S, Liu S, Li X, Yu P. Effects diabetes. Diabetes Care 2016;39(Suppl. 2):S137–
et al. Glucose outcomes with the in-home use of insulin plus glucagon-like peptide-1 receptor S145
of a hybrid closed-loop insulin delivery system in agonists (GLP-1RAs) in treating type 1 diabetes 45. Abdul-Ghani MA, Puckett C, Triplitt C, et al.
adolescents and adults with type 1 diabetes. mellitus: a systematic review and meta-analysis. Initial combination therapy with metformin,
Diabetes Technol Ther 2017;19:155–163 Diabetes Ther 2017;8:727–738 pioglitazone and exenatide is more effective
18. Tauschmann M, Thabit H, Bally L, et al.; 32. Dandona P, Mathieu C, Phillip M, et al.; than sequential add-on therapy in subjects with
APCam11 Consortium. Closed-loop insulin de- DEPICT-1 Investigators. Efficacy and safety of new-onset diabetes. Results from the Efficacy
livery in suboptimally controlled type 1 diabetes: dapagliflozin in patients with inadequately and Durability of Initial Combination TherapyYou can also read
