Professional Documents
Culture Documents
Pharmacologic Treatment
Pharmacologic Treatment
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
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 hy- Disclosure information for each author is
perglycemia, insulinopenia can contribute to other metabolic disturbances like hy- available at https://doi.org/10.2337/dc23-SDIS.
pertriglyceridemia and ketoacidosis as well as tissue catabolism that can be life Suggested citation: ElSayed NA, Aleppo G,
threatening. Severe metabolic decompensation can be, and was, mostly prevented Aroda VR, et al., American Diabetes Association.
with once- or twice-daily injections for the six or seven decades after the discovery 9. Pharmacologic approaches to glycemic treat-
of insulin. However, over the past three decades, evidence has accumulated sup- ment: Standards of Care in Diabetes—2023.
Diabetes Care 2023;46(Suppl. 1):S140–S157
porting more intensive insulin replacement, using multiple daily injections of insulin
or continuous subcutaneous administration through an insulin pump, as providing © 2022 by the American Diabetes Association.
the best combination of effectiveness and safety for people with type 1 diabetes. Readers may use this article as long as the
work is properly cited, the use is educational
The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive and not for profit, and the work is not altered.
therapy with multiple daily injections or continuous subcutaneous insulin infusion More information is available at https://www.
(CSII) reduced A1C and was associated with improved long-term outcomes (1–3). diabetesjournals.org/journals/pages/license.
diabetesjournals.org/care Pharmacologic Approaches to Glycemic Treatment S141
The study was carried out with short- to the individual to keep them safe and monitoring should be considered in most
acting (regular) and intermediate-acting out of diabetic ketoacidosis and to avoid individuals with type 1 diabetes. AID sys-
(NPH) human insulins. In this landmark significant hypoglycemia, with every ef- tems may be considered in individuals
trial, lower A1C with intensive control fort made to reach the individual’s gly- with type 1 diabetes who are capable of
(7%) led to 50% reductions in micro- cemic targets. using the device safely (either by them-
vascular complications over 6 years of Most studies comparing multiple daily selves or with a caregiver) in order to
treatment. However, intensive therapy injections with CSII have been relatively improve time in range and reduce A1C
was associated with a higher rate of se- small and of short duration. However, a and hypoglycemia (22). See Section 7,
vere hypoglycemia than conventional systematic review and meta-analysis con- “Diabetes Technology,” for a full discus-
treatment (62 compared with 19 epi- cluded that CSII via pump therapy has sion of insulin delivery devices.
sodes per 100 patient-years of therapy). modest advantages for lowering A1C In general, individuals with type 1 dia-
Follow-up of subjects from the DCCT ( 0.30% [95% CI 0.58 to 0.02]) and betes require 50% of their daily insulin
as basal and 50% as prandial, but this is
adjust prandial insulin to account for car- the adipogenic actions of insulin at a site SURGICAL TREATMENT FOR TYPE 1
bohydrate intake, premeal glucose levels, of multiple injections. Lipohypertrophy ap- DIABETES
and anticipated activity can be effective pears as soft, smooth raised areas several Pancreas and Islet Transplantation
and should be offered to most individuals centimeters in breadth and can contribute Successful pancreas and islet transplan-
(25,26). For individuals in whom carbohy- to erratic insulin absorption, increased tation can normalize glucose levels and
drate counting is effective, estimates of glycemic variability, and unexplained mitigate microvascular complications of
the fat and protein content of meals can hypoglycemic episodes. People treated type 1 diabetes. However, people receiving
be incorporated into their prandial dos- with insulin and/or caregivers should these treatments require lifelong immuno-
ing for added benefit (27) (see Section 5, receive education about proper injec- suppression to prevent graft rejection and/
“Facilitating Positive Health Behaviors and tion site rotation and how to recognize or recurrence of autoimmune islet destruc-
Well-being to Improve Health Outcomes”). and avoid areas of lipohypertrophy. As tion. Given the potential adverse effects
of immunosuppressive therapy, pancreas
The 2021 ADA/European Association noted in Table 4.1, examination of insu-
transplantation should be reserved for
TIR % highest and TBR % lowest numeracy or literacy skills). glucose outside of activity of
with: hybrid closed-loop > low- URAA/RAA bolus.
glucose suspend > CGM-
augmented open-loop > BGM-
augmented open-loop.
MDI: LAA 1 flexible doses of URAA LAA once daily (insulin detemir or Can use pens for all components. At least four daily injections. Mealtime insulin: if carbohydrate
or RAA at meals insulin glargine may require twice- Flexibility in meal timing and Most costly insulins. counting is accurate, change ICR if
daily dosing); generally 50% of content. Smallest increment of insulin is glucose after meal consistently out
TDD. Insulin analogs cause less 1 unit (0.5 unit with some pens). of target.
Mealtime and correction: URAA or hypoglycemia than human insulins. LAAs may not cover strong dawn Correction insulin: adjust ISF and/or
RAA based on ICR and/or ISF and phenomenon (rise in glucose in target glucose if correction does
target glucose. early morning hours) as well as not consistently bring glucose into
pump therapy. range.
LAA: based on overnight or fasting
glucose or daytime glucose
outside of activity time course, or
URAA or RAA injections.
MDI regimens with less flexibility
Four injections daily with fixed Pre-breakfast: RAA 20% of TDD. May be feasible if unable to Shorter duration RAA may lead to Pre-breakfast RAA: based on BGM
doses of N and RAA Pre-lunch: RAA 10% of TDD. carbohydrate count. basal deficit during day; may need after breakfast or before lunch.
Pre-dinner: RAA 10% of TDD. All meals have RAA coverage. twice-daily N. Pre-lunch RAA: based on BGM after
Bedtime: N 50% of TDD. N is less expensive than LAAs. Greater risk of nocturnal hypoglycemia lunch or before dinner.
with N. Pre-dinner RAA: based on BGM after
Requires relatively consistent mealtimes dinner or at bedtime.
and carbohydrate intake. Evening N: based on fasting or
overnight BGM.
Continued on p. S145
Diabetes Care Volume 46, Supplement 1, January 2023
BGM, blood glucose monitoring; CGM, continuous glucose monitoring; ICR, insulin-to-carbohydrate ratio; ISF, insulin sensitivity factor; LAA, long-acting analog; MDI, multiple daily injections; N, NPH
insulin; 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).
Pharmacologic Approaches to Glycemic Treatment
S145
modifications and health behaviors that cologic approaches that provide the ef- Weight management is an impactful com-
improve health (see Section 5, “Facilitating ficacy to achieve treatment goals should ponent of glucose-lowering management
Positive Health Behaviors and Well-being be considered, such as metformin or other in type 2 diabetes (45,46). The glucose-
to Improve Health Outcomes”) should be agents, including combination therapy, that lowering treatment regimen should con-
emphasized along with any pharmacologic provide adequate efficacy to achieve and sider approaches that support weight
therapy. Section 13, “Older Adults,” and maintain treatment goals (45). In adults management goals, with very high ef-
Section 14, “Children and Adolescents,” with type 2 diabetes and established/high ficacy for weight loss seen with sema-
have recommendations specific for older risk of atherosclerotic cardiovascular disease glutide and tirzepatide (Fig. 9.3 and
adults and for children and adolescents (ASCVD), heart failure (HF), and/or chronic Table 9.2) (45).
with type 2 diabetes, respectively. Sec- kidney disease (CKD), the treatment regi- Metformin is effective and safe, is inex-
tion 10, “Cardiovascular Disease and Risk men should include agents that reduce cardi- pensive, and may reduce risk of cardiovas-
Management,” and Section 11, “Chronic orenal risk (see Fig. 9.3, Table 9.2, Section cular events and death (47). Metformin is
Kidney Disease and Risk Management,” 10, “Cardiovascular Disease and Risk available in an immediate-release form for
have recommendations for the use of glucose- Management,” and Section 11, “Chronic twice-daily dosing or as an extended-
lowering drugs in the management of cardio- Kidney Disease and Risk Management”). release form that can be given once daily.
vascular and renal disease, respectively. Pharmacologic approaches that provide the Compared with sulfonylureas, metformin
efficacy to achieve treatment goals should as first-line therapy has beneficial effects
Choice of Glucose-Lowering Therapy be considered, specified as metformin or on A1C, weight, and cardiovascular mor-
Healthy lifestyle behaviors, diabetes self- agent(s), including combination therapy, tality (48).
management, education, and support, that provide adequate efficacy to achieve The principal side effects of metfor-
avoidance of clinical inertia, and social and maintain treatment goals (Fig. 9.3 and min are gastrointestinal intolerance due
determinants of health should be consid- Table 9.2). In general, higher-efficacy ap- to bloating, abdominal discomfort, and
ered in the glucose-lowering manage- proaches have greater likelihood of achiev- diarrhea; these can be mitigated by grad-
ment of type 2 diabetes. Pharmacologic ing glycemic goals, with the following ual dose titration. The drug is cleared by
therapy should be guided by person- considered to have very high efficacy for renal filtration, and very high circulating
centered treatment factors, including glucose lowering: the GLP-1 RAs dulaglutide levels (e.g., as a result of overdose or
comorbidities and treatment goals. Phar- (high dose) and semaglutide, the gastric in- acute renal failure) have been associated
macotherapy should be started at the hibitory peptide (GIP) and GLP-1 RA tirze- with lactic acidosis. However, the occur-
time type 2 diabetes is diagnosed unless patide, insulin, combination oral therapy, rence of this complication is now known
there are contraindications. Pharma- and combination injectable therapy. to be very rare, and metformin may be
diabetesjournals.org/care
Figure 9.3—Use of glucose-lowering medications in the management of type 2 diabetes. ACEi, angiotensin-converting enzyme inhibitor; ACR, albumin-to-creatinine ratio; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardio-
vascular disease; CGM, continuous glucose monitoring; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase 4 inhibitor; eGFR, estimated glomeru-
lar filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalization for heart failure; MACE,
Pharmacologic Approaches to Glycemic Treatment
major adverse cardiovascular events; MI, myocardial infarction; SDOH, social determinants of health; SGLT2i, sodium-glucose cotransporter 2 inhibitor; T2D, type 2 diabetes; TZD, thiazolidinedione. Adapted from Davies et al. (45).
S147
CV, cardiovascular; CVOT, cardiovascular outcomes trial; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; DPP-4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; FDA,
U.S. Food and Drug Administration; GI, gastrointestinal; GIP, gastric inhibitory polypeptide; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; NASH, nonalcoholic steatohepatitis;
MACE, major adverse cardiovascular events; SGLT2, sodium–glucose cotransporter 2; SQ, subcutaneous; T2DM, type 2 diabetes mellitus. *For agent-specific dosing recommendations, please refer
Diabetes Care Volume 46, Supplement 1, January 2023
to manufacturers’ prescribing information. 1Tsapas et al. (62). 2Tsapas et al. (114). Reprinted from Davies et al. (45).
safely used in people with reduced esti- durability of glycemic effect (57). The Table 10.3C, and Section 10, “Cardiovascular
mated glomerular filtration rates (eGFR); VERIFY (Vildagliptin Efficacy in combina- Disease and Risk Management”) is recom-
the FDA has revised the label for metfor- tion with metfoRmln For earlY treatment mended as part of the glucose-lowering
min to reflect its safety in people with of type 2 diabetes) trial demonstrated regimen independent of A1C, independent
eGFR $30 mL/min/1.73 m2 (49). A ran- that initial combination therapy is supe- of metformin use and in consideration of
domized trial confirmed previous obser- rior to sequential addition of medications person-specific factors (Fig. 9.3). For peo-
vations that metformin use is associated for extending primary and secondary fail- ple without established ASCVD, indica-
with vitamin B12 deficiency and worsen- ure (58). In the VERIFY trial, participants tors of high ASCVD risk, HF, or CKD,
ing of symptoms of neuropathy (50). This receiving the initial combination of met- medication choice is guided by efficacy
is compatible with a report from the Di- formin and the dipeptidyl peptidase 4 in support of individualized glycemic and
abetes Prevention Program Outcomes (DPP-4) inhibitor vildagliptin had a slower weight management goals, avoidance of
Study (DPPOS) suggesting periodic test- decline of glycemic control compared with side effects (particularly hypoglycemia
metformin alone and with vildagliptin and weight gain), cost/access, and indi-
TO AVOID
THERAPEUTIC
Use principles in Figure 9.3, including reinforcement of behavioral INERTIA
REASSESS AND
interventions (weight management and physical activity) and provision MODIFY TREATMENT
of DSMES, to meet individualized treatment goals REGULARLY
(3–6 MONTHS)
Consider GLP-1 RA or GIP/GLP-1 RA in most individuals prior to insulin2 If already on GLP-1 RA or dual GIP
INITIATION: Initiate appropriate starting dose for agent selected (varies within class) and GLP-1 RA or if these are not
TITRATION: Titrate to maintenance dose (varies within class) appropriate OR insulin is preferred
If above A1C target and not already on a GLP-1 RA or dual GIP and GLP-1 RA,
consider these classes, either in free combination or fixed-ratio combination, with insulin.
If A1C remains above target:
1. Consider insulin as the first injectable if evidence of ongoing catabolism, symptoms of hyperglycemia are present, when A1C levels (>10% [86 mmol/mol]) or blood glucose levels
( 300 mg/dL [16.7 mmol/L]) are very high, or a diagnosis of type 1 diabetes is a possibility.
2. When selecting GLP-1 RA, consider individual preference, A1C lowering, weight-lowering effect, or fequency of injection. If CVD is present, consider GLP-1 RA with proven CVD benefit. Oral or
injectable GLP-1 RA are appropriate.
3. For people on GLP-1 RA and basal insulin combination, consider use of a fixed-ratio combination product (IDegLira or iGlarLixi).
4. Consider switching from evening NPH to a basal analog if the individual develops hypoglycemia and/or frequently forgets to administer NPH in the evening and would be better managed
with an A.M. dose of a long-acting basal insulin.
5. If adding prandial insulin to NPH, consider initiation of a self-mixed or premixed insulin regimen to decrease the number of injections required.
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).
diabetesjournals.org/care Pharmacologic Approaches to Glycemic Treatment S151
who are intensified to insulin therapy, provide the complementary outcomes analogs (U-100 glargine or detemir) have
combination therapy with a GLP-1 RA benefits associated with these classes been demonstrated to reduce the risk of
has been shown to have greater efficacy of medication (76). In cardiovascular symptomatic and nocturnal hypoglycemia
and durability of glycemic treatment ef- outcomes trials, empagliflozin, canagli- compared with NPH insulin (80–85), al-
fect, as well as weight and hypoglycemia flozin, dapagliflozin, liraglutide, semaglu- though these advantages are modest and
benefit, than treatment intensification tide, and dulaglutide all had beneficial may not persist (86). Longer-acting basal
with insulin alone (45). However, cost effects on indices of CKD, while dedicated analogs (U-300 glargine or degludec) may
and tolerability issues are important renal outcomes studies have demonstrated convey a lower hypoglycemia risk com-
considerations in GLP-1 RA use. benefit of specific SGLT2 inhibitors. See pared with U-100 glargine when used in
Costs for diabetes medications have Section 11, “Chronic Kidney Disease and combination with oral agents (87–93).
increased dramatically over the past two Risk Management,” for discussion of how Clinicians should be aware of the poten-
decades, and an increasing proportion is tial for overbasalization with insulin ther-
CKD may impact treatment choices. Ad-
apy. Clinical signals that may prompt
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) $106 ($5, $189) $2 2,550 mg
1,000 mg (IR) $87 ($3, $144) $2 2,000 mg
1,000 mg (ER) $242 ($242, $7,214) $32 ($32, $160) 2,000 mg
Sulfonylureas (2nd Glimepiride 4 mg $74 ($71, $198) $3 8 mg
generation) Glipizide 10 mg (IR) $70 ($67, $91) $6 40 mg
10 mg (XL/ER) $48 ($46, $48) $11 20 mg
Glyburide 6 mg (micronized) $52 ($48, $71) $12 12 mg
5 mg $79 ($63, $93) $9 20 mg
Thiazolidinedione Pioglitazone 45 mg $345 ($7, $349) $4 45 mg
AWP, average wholesale price; DPP-4, dipeptidyl peptidase 4; ER and XL, extended release; GIP, glucose-dependent insulinotropic polypeptide; GLP-1 RA,
glucagon-like peptide 1 receptor agonist; IR, immediate release; max, maximum; min, minimum; NA, data not available; NADAC, National Average Drug
Acquisition Cost; SGLT2, sodium-glucose cotransporter 2. †Calculated for 30-day supply (AWP [72] or NADAC [73] unit price × number of doses re-
quired 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 calculated based on 120 mg three times daily.
address prandial control and to minimize with type 1 diabetes, require higher Concentrated Insulins
the risks of hypoglycemia and weight gain daily doses (1 unit/kg), and have lower Several concentrated insulin preparations
associated with insulin therapy (45). For rates of hypoglycemia (97). Titration can are currently available. U-500 regular
individuals who advance to prandial in- be based on home glucose monitoring or insulin is, by definition, five times more
sulin, a prandial insulin dose of 4 units or A1C. With significant additions to the pran- concentrated than U-100 regular insulin.
10% of the amount of basal insulin at the dial insulin dose, particularly with the eve- U-500 regular insulin has distinct phar-
largest meal or the meal with the great- ning meal, consideration should be macokinetics with delayed onset and
est postprandial excursion is a safe esti- given to decreasing basal insulin. Meta- longer duration of action, has charac-
mate for initiating therapy. The prandial analyses of trials comparing rapid-acting teristics more like an intermediate-acting
insulin regimen can then be intensified insulin analogs with human regular insu- (NPH) insulin, and can be used as two or
based on individual needs (Fig. 9.4). In- lin in type 2 diabetes have not reported three daily injections (100). U-300 glar-
dividuals with type 2 diabetes are gen- important differences in A1C or hypogly- gine and U-200 degludec are three and
erally more insulin resistant than those cemia (98,99). two times as concentrated as their U-100
diabetesjournals.org/care Pharmacologic Approaches to Glycemic Treatment S153
Table 9.4—Median cost of insulin products in the U.S. calculated as AWP (72) and NADAC (73) 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 $118 ($118, $157) $94
U-100 prefilled pen $151 $121
Lispro U-100 vial $99† $79†
U-100 cartridge $408 $326
U-100 prefilled pen $127† $102†
U-200 prefilled pen $424 $339
Lispro-aabc U-100 vial $330 $261
U-100 prefilled pen $424 $339
U-200 prefilled pen $424 NA
Glulisine U-100 vial $341 $272
formulations, respectively, and allow who require large doses of insulin. While pharmacokinetics (8). Studies comparing
higher doses of basal insulin adminis- U-500 regular insulin is available in both inhaled insulin with injectable insulin
tration per volume used. U-300 glargine prefilled pens and vials, other concen- have demonstrated its faster onset and
has a longer duration of action than trated insulins are available only in pre- shorter duration compared with rapid-
U-100 glargine but modestly lower efficacy filled pens to minimize the risk of dosing acting insulin lispro as well as clinically
per unit administered (101,102). The errors. meaningful A1C reductions and weight
FDA has also approved a concentrated reductions compared with insulin aspart
formulation of rapid-acting insulin lispro, Alternative Insulin Routes over 24 weeks (103–105). Use of in-
U-200 (200 units/mL), and insulin lispro- Insulins with different routes of admin- haled insulin may result in a decline in
aabc (U-200). These concentrated prepa- istration (inhaled, bolus-only insulin de- lung function (reduced forced expiratory
rations may be more convenient and livery patch pump) are also available volume in 1 s [FEV1]). Inhaled insulin is
comfortable for individuals to inject and (45). Inhaled insulin is available as a contraindicated in individuals with chronic
may improve treatment plan engage- rapid-acting insulin; studies in individu- lung disease, such as asthma and chronic
ment in those with insulin resistance als with type 1 diabetes suggest rapid obstructive pulmonary disease, and is not
S154 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 46, Supplement 1, January 2023
recommended in individuals who smoke options as well as recommendations for fur- 7. Bartley PC, Bogoev M, Larsen J, Philotheou A.
or who recently stopped smoking. All ther intensification, if needed, to achieve Long-term efficacy and safety of insulin detemir
compared to neutral protamine Hagedorn insulin
individuals require spirometry (FEV1) glycemic goals. When initiating combination in patients with type 1 diabetes using a treat-
testing to identify potential lung disease injectable therapy, metformin therapy to-target basal-bolus regimen with insulin aspart
prior to and after starting inhaled insulin should be maintained, while sulfonylureas at meals: a 2-year, randomized, controlled trial.
therapy. and DPP-4 inhibitors are typically weaned Diabet Med 2008;25:442–449
8. DeWitt DE, Hirsch IB. Outpatient insulin
or discontinued. In individuals with sub- therapy in type 1 and type 2 diabetes mellitus:
Combination Injectable Therapy optimal blood glucose control, especially scientific review. JAMA 2003;289:2254–2264
If basal insulin has been titrated to an those requiring large insulin doses, ad- 9. Bode BW, McGill JB, Lorber DL, Gross JL, Chang
acceptable fasting blood glucose level junctive use of a thiazolidinedione or an PC; Affinity 1 Study Group. Inhaled technosphere
(or if the dose is >0.5 units/kg/day with SGLT2 inhibitor may help to improve con- insulin compared with injected prandial insulin
in type 1 diabetes: a randomized 24-week trial.
indications of need for other therapy) trol and reduce the amount of insulin Diabetes Care 2015;38:2266–2273
multicentre, 12-week randomised trial. Lancet controlled trial. Lancet Diabetes Endocrinol www.fda.gov/drugs/drug-safety-and-availability/fda-
2018;392:1321–1329 2017;5:597–609 drug-safety-communication-fda-revises-warnings-
22. Brown SA, Kovatchev BP, Raghinaru D, et al.; 36. Mathieu C, Zinman B, Hemmingsson JU, regarding-use-diabetes-medicine-metformin-certain
iDCL Trial Research Group. Six-month randomized, et al.; ADJUNCT ONE Investigators. Efficacy and 50. Out M, Kooy A, Lehert P, Schalkwijk CA,
multicenter trial of closed-loop control in type 1 safety of liraglutide added to insulin treatment in Stehouwer CDA. Long-term treatment with
diabetes. N Engl J Med 2019;381:1707–1717 type 1 diabetes: the ADJUNCT ONE treat-to-target metformin in type 2 diabetes and methylmalonic
23. Peters AL, Laffel L (Eds.). American Diabetes randomized trial. Diabetes Care 2016;39:1702– acid: post hoc analysis of a randomized controlled
Association/JDRF Type 1 Diabetes Sourcebook. 1710 4.3-year trial. J Diabetes Complications 2018;32:
Alexandria, VA, American Diabetes Association, 37. Ahren B, Hirsch IB, Pieber TR, et al.; ADJUNCT 171–178
2013 TWO Investigators. Efficacy and safety of liraglutide 51. Aroda VR, Edelstein SL, Goldberg RB, et al.;
24. Chiang JL, Kirkman MS, Laffel LMB; Type 1 added to capped insulin treatment in subjects with Diabetes Prevention Program Research Group.
Diabetes Sourcebook Authors. Type 1 diabetes type 1 diabetes: the ADJUNCT TWO randomized Long-term metformin use and vitamin B12 deficiency
through the life span: a position statement of the trial. Diabetes Care 2016;39:1693–1701 in the Diabetes Prevention Program Outcomes Study.
American Diabetes Association. Diabetes Care 38. Dandona P, Mathieu C, Phillip M, et al.; DEPICT-1 J Clin Endocrinol Metab 2016;101:1754–1761
2014;37:2034–2054 Investigators. Efficacy and safety of dapagliflozin in 52. Henry RR, Murray AV, Marmolejo MH,
and network meta-analysis. Ann Intern Med 77. Blonde L, Merilainen M, Karwe V; TITRATE 90. Marso SP, McGuire DK, Zinman B, et al.;
2020;173:278–286 Study Group. Patient-directed titration for achieving DEVOTE Study Group. Efficacy and safety of
63. Pratley R, Amod A, Hoff ST, et al.; PIONEER 4 glycaemic goals using a once-daily basal insulin degludec versus glargine in type 2 diabetes. N
investigators. Oral semaglutide versus subcutaneous analogue: an assessment of two different fasting Engl J Med 2017;377:723–732
liraglutide and placebo in type 2 diabetes (PIONEER plasma glucose targets–the TITRATE study. Diabetes 91. Rodbard HW, Cariou B, Zinman B, et al.; BEGIN
4): a randomised, double-blind, phase 3a trial. Lancet Obes Metab 2009;11:623–631 Once Long Trial Investigators. Comparison of insulin
2019;394:39–50 78. Porcellati F, Lucidi P, Cioli P, et al. Pharma- degludec with insulin glargine in insulin-naive
64. Singh S, Wright EE Jr, Kwan AYM, et al. cokinetics and pharmacodynamics of insulin subjects with type 2 diabetes: a 2-year randomized,
Glucagon-like peptide-1 receptor agonists compared glargine given in the evening as compared with treat-to-target trial. Diabet Med 2013;30:1298–
with basal insulins for the treatment of type 2 in the morning in type 2 diabetes. Diabetes Care 1304
diabetes mellitus: a systematic review and meta- 2015;38:503–512 92. Wysham C, Bhargava A, Chaykin L, et al. Effect
analysis. Diabetes Obes Metab 2017;19:228–238 79. Wang Z, Hedrington MS, Gogitidze Joy N, et al. of insulin degludec vs insulin glargine u100 on
65. Levin PA, Nguyen H, Wittbrodt ET, Kim SC. Dose-response effects of insulin glargine in type 2 hypoglycemia in patients with type 2 diabetes: the
Glucagon-like peptide-1 receptor agonists: a diabetes. Diabetes Care 2010;33:1555–1560 SWITCH 2 randomized clinical trial. JAMA 2017;
systematic review of comparative effectiveness 80. Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett 318:45–56
injections: the STAT study. Diabetes Technol Ther 108. Maiorino MI, Chiodini P, Bellastella G, Capuano to titrated insulin glargine on glycemic control in
2018;20:639–647 A, Esposito K, Giugliano D. Insulin and glucagon-like patients with type 2 diabetes: the SURPASS-5
104. Hoogwerf BJ, Pantalone KM, Basina M, Jones peptide 1 receptor agonist combination therapy in randomized clinical trial. JAMA 2022;327:534–
MC, Grant M, Kendall DM. Results of a 24-week type 2 diabetes: a systematic review and meta- 545
trial of technosphere insulin versus insulin aspart in analysis of randomized controlled trials. Diabetes 112. Taybani Z, B otyik B, Katk
o M, Gyimesi A,
type 2 diabetes. Endocr Pract 2021;27:38–43 Care 2017;40:614–624 Varkonyi T. Simplifying complex insulin regimens
105. Grant M, Heise T, Baughman R. Comparison 109. Aroda VR, Rosenstock J, Wysham C, et al.; while preserving good glycemic control in type 2
of pharmacokinetics and pharmacodynamics of LixiLan-L Trial Investigators. Efficacy and safety of diabetes. Diabetes Ther 2019;10:1869–1878
inhaled technosphere insulin and subcutaneous LixiLan, a titratable fixed-ratio combination of 113. Rodbard HW, Visco VE, Andersen H, Hiort LC,
insulin lispro in the treatment of type 1 diabetes insulin glargine plus lixisenatide in type 2 diabetes Shu DHW. Treatment intensification with
mellitus. Clin Pharmacokinet 2022;61:413–422 inadequately controlled on basal insulin and metformin: stepwise addition of prandial insulin aspart
106. Diamant M, Nauck MA, Shaginian R, et al.; the LixiLan-L randomized trial. Diabetes Care 2016; boluses compared with full basal-bolus therapy
4B Study Group. Glucagon-like peptide 1 receptor 39:1972–1980 (FullSTEP Study): a randomised, treat-to-target
agonist or bolus insulin with optimized basal 110. Lingvay I, Perez Manghi F, Garcıa-Hernandez clinical trial. Lancet Diabetes Endocrinol 2014;2:
insulin in type 2 diabetes. Diabetes Care 2014; P, et al.; DUAL V Investigators. Effect of insulin 30–37