S140
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`Diabetes Care Volume 46, Supplement 1, January 2023
`
`9. Pharmacologic Approaches to
`Glycemic Treatment: Standards
`ofCareinDiabetes—2023
`
`Diabetes Care 2023;46(Suppl. 1):S140–S157 | https://doi.org/10.2337/dc23-S009
`
`Nuha A. ElSayed, Grazia Aleppo,
`Vanita R. Aroda, Raveendhara R. Bannuru,
`Florence M. Brown, Dennis Bruemmer,
`Billy S. Collins, Marisa E. Hilliard,
`Diana Isaacs, Eric L. Johnson, Scott Kahan,
`Kamlesh Khunti, Jose Leon, Sarah K. Lyons,
`Mary Lou Perry, Priya Prahalad,
`Richard E. Pratley, Jane Jeffrie Seley,
`Robert C. Stanton, and Robert A. Gabbay,
`on behalf of the American Diabetes
`Association
`
`The American Diabetes Association (ADA) “Standards of Care in Diabetes” in-
`cludes the ADA’s current clinical practice recommendations and is intended to
`provide the components of diabetes care, general treatment goals and guide-
`lines, and tools to evaluate quality of care. Members of the ADA Professional
`Practice Committee, a multidisciplinary expert committee, are responsible for up-
`dating the Standards of Care annually, or more frequently as warranted. For a de-
`tailed description of ADA standards, statements, and reports, as well as the
`evidence-grading system for ADA’s clinical practice recommendations and a full
`list of Professional Practice Committee members, please refer to Introduction
`and Methodology. 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
`
`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-
`perglycemia, insulinopenia can contribute to other metabolic disturbances like hy-
`pertriglyceridemia and ketoacidosis as well as tissue catabolism that can be life
`threatening. Severe metabolic decompensation can be, and was, mostly prevented
`with once- or twice-daily injections for the six or seven decades after the discovery
`of insulin. However, over the past three decades, evidence has accumulated sup-
`porting more intensive insulin replacement, using multiple daily injections of insulin
`or continuous subcutaneous administration through an insulin pump, as providing
`the best combination of effectiveness and safety for people with type 1 diabetes.
`The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive
`therapy with multiple daily injections or continuous subcutaneous insulin infusion
`(CSII) reduced A1C and was associated with improved long-term outcomes (1–3).
`
`Disclosure information for each author is
`available at https://doi.org/10.2337/dc23-SDIS.
`
`Suggested citation: ElSayed NA, Aleppo G,
`Aroda VR, et al., American Diabetes Association.
`9. Pharmacologic approaches to glycemic treat-
`ment: Standards of Care in Diabetes—2023.
`Diabetes Care 2023;46(Suppl. 1):S140–S157
`
`© 2022 by the American Diabetes Association.
`Readers may use this article as long as the
`work is properly cited, the use is educational
`and not for profit, and the work is not altered.
`More information is available at https://www.
`diabetesjournals.org/journals/pages/license.
`
`9.PHARMACOLOGICAPPROACHESTOGLYCEMICTREATMENT
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`The study was carried out with short-
`acting (regular) and intermediate-acting
`(NPH) human insulins. In this landmark
`trial, lower A1C with intensive control
`(7%) led to 50% reductions in micro-
`vascular complications over 6 years of
`treatment. However,
`intensive therapy
`was associated with a higher rate of se-
`vere hypoglycemia than conventional
`treatment (62 compared with 19 epi-
`sodes per 100 patient-years of therapy).
`Follow-up of subjects from the DCCT
`more than 10 years after the active treat-
`ment component of the study demon-
`strated fewer macrovascular as well as
`fewer microvascular complications in the
`group that received intensive treatment
`(2,4).
`Insulin replacement regimens typically
`consist of basal insulin, mealtime insulin,
`and correction insulin (5). Basal
`insulin
`includes NPH insulin, long-acting insulin
`analogs, and continuous delivery of rapid-
`acting insulin via an insulin pump. Basal
`insulin analogs have longer duration of
`action with flatter, more constant plasma
`concentrations and activity profiles than
`NPH insulin; rapid-acting analogs (RAA)
`have a quicker onset and peak and shorter
`duration of action than regular human in-
`sulin. In people with type 1 diabetes, treat-
`ment with analog insulins is associated
`with less hypoglycemia and weight gain as
`well as lower A1C compared with human
`insulins (6–8). More recently, two inject-
`able insulin formulations with enhanced
`rapid-action profiles have been introduced.
`Inhaled human insulin has a rapid peak
`and shortened duration of action com-
`pared with RAA and may cause less hypo-
`glycemia and weight gain (9) (see also
`subsection ALTERNATIVE INSULIN ROUTES in
`PHARMACOLOGIC THERAPY FOR ADULTS WITH TYPE 2
`DIABETES), and faster-acting insulin aspart
`and insulin lispro-aabc may reduce pran-
`dial excursions better than RAA (10–12).
`In addition, longer-acting basal analogs
`(U-300 glargine or degludec) may confer
`a lower hypoglycemia risk compared with
`U-100 glargine in individuals with type 1
`diabetes (13,14). Despite the advantages
`of insulin analogs in individuals with type 1
`diabetes, for some individuals the expense
`and/or intensity of treatment required for
`their use is prohibitive. There are multiple
`approaches to insulin treatment, and the
`central precept in the management of
`type 1 diabetes is that some form of insu-
`lin be given in a planned regimen tailored
`
`to the individual to keep them safe and
`out of diabetic ketoacidosis and to avoid
`significant hypoglycemia, with every ef-
`fort made to reach the individual’s gly-
`cemic targets.
`Most studies comparing multiple daily
`injections with CSII have been relatively
`small and of short duration. However, a
`systematic review and meta-analysis con-
`cluded that CSII via pump therapy has
`modest advantages for lowering A1C
`(0.30% [95% CI 0.58 to 0.02]) and
`for reducing severe hypoglycemia rates
`in children and adults (15). However,
`there is no consensus to guide the choice
`of injection or pump therapy in a given
`individual, and research to guide this deci-
`sion-making is needed (16). The arrival of
`continuous glucose monitors (CGM) to
`clinical practice has proven beneficial in
`people using insulin therapy.
`Its use is
`now considered standard of care for most
`people with type 1 diabetes (5) (see Sec-
`tion 7, “Diabetes Technology”). Reduction
`of nocturnal hypoglycemia in individuals
`with type 1 diabetes using insulin pumps
`with CGM is improved by automatic sus-
`pension of insulin delivery at a preset glu-
`cose level (16–18). When choosing among
`insulin delivery systems, individual pref-
`erences, cost, insulin type and dosing
`regimen, and self-management capabili-
`ties should be considered (see Section 7,
`“Diabetes Technology”).
`The U.S. Food and Drug Administra-
`tion (FDA) has now approved multiple
`hybrid closed-loop pump systems (also
`called automated insulin delivery [AID]
`systems). The safety and efficacy of hybrid
`closed-loop systems has been supported
`in the literature in adolescents and adults
`with type 1 diabetes (19,20), and evi-
`dence suggests that a closed-loop system
`is superior to sensor-augmented pump
`therapy for glycemic control and reduction
`of hypoglycemia over 3 months of com-
`parison in children and adults with type 1
`diabetes (21). In the International Diabe-
`tes Closed Loop (iDCL) trial, a 6-month
`trial in people with type 1 diabetes at
`least 14 years of age, the use of a closed-
`loop system was associated with a greater
`percentage of time spent in the target gly-
`cemic range, reduced mean glucose and
`A1C levels, and a lower percentage of time
`spent in hypoglycemia compared with use
`of a sensor-augmented pump (22).
`Intensive insulin management using a
`version of CSII and continuous glucose
`
`monitoring should be considered in most
`individuals with type 1 diabetes. AID sys-
`tems may be considered in individuals
`with type 1 diabetes who are capable of
`using the device safely (either by them-
`selves or with a caregiver) in order to
`improve time in range and reduce A1C
`and hypoglycemia (22). See Section 7,
`“Diabetes Technology,” for a full discus-
`sion of insulin delivery devices.
`In general, individuals with type 1 dia-
`betes require 50% of their daily insulin
`as basal and 50% as prandial, but this is
`dependent on a number of factors, in-
`cluding whether the individual consumes
`lower or higher carbohydrate meals. To-
`tal daily insulin requirements can be esti-
`mated based on weight, with typical
`doses ranging from 0.4 to 1.0 units/kg/
`day. Higher amounts are required during
`puberty, pregnancy, and medical
`illness.
`The American Diabetes Association/JDRF
`Type 1 Diabetes Sourcebook notes 0.5 units/
`kg/day as a typical starting dose in indi-
`viduals with type 1 diabetes who are
`metabolically stable, with half adminis-
`tered as prandial insulin given to control
`blood glucose after meals and the other
`half as basal insulin to control glycemia
`in the periods between meal absorption
`(23); this guideline provides detailed in-
`formation on intensification of therapy
`to meet individualized needs. In addi-
`tion, the American Diabetes Association
`(ADA) position statement “Type 1 Diabe-
`tes Management Through the Life Span”
`provides a thorough overview of type 1
`diabetes treatment (24).
`Typical multidose regimens for individ-
`uals with type 1 diabetes combine pre-
`meal use of shorter-acting insulins with a
`longer-acting formulation. The long-acting
`basal dose is titrated to regulate over-
`night and fasting glucose. Postprandial
`glucose excursions are best controlled
`by a well-timed injection of prandial in-
`sulin. The optimal time to administer
`prandial insulin varies, based on the phar-
`macokinetics of the formulation (regular,
`RAA, inhaled), the premeal blood glucose
`level, and carbohydrate consumption. Rec-
`ommendations for prandial
`insulin dose
`administration should therefore be individ-
`ualized. Physiologic insulin secretion varies
`with glycemia, meal size, meal composi-
`tion, and tissue demands for glucose. To
`approach this variability in people using
`insulin treatment, strategies have evolved
`to adjust prandial doses based on pre-
`dicted needs. Thus, education on how to
`
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`
`adjust prandial insulin to account for car-
`bohydrate intake, premeal glucose levels,
`and anticipated activity can be effective
`and should be offered to most individuals
`(25,26). For individuals in whom carbohy-
`drate counting is effective, estimates of
`the fat and protein content of meals can
`be incorporated into their prandial dos-
`ing for added benefit (27) (see Section 5,
`“Facilitating Positive Health Behaviors and
`Well-being to Improve Health Outcomes”).
`The 2021 ADA/European Association
`for the Study of Diabetes (EASD) consen-
`sus report on the management of type 1
`diabetes in adults summarizes different
`insulin regimens and glucose monitoring
`strategies in individuals with type 1 dia-
`betes (Fig. 9.1 and Table 9.1) (5).
`
`Insulin Injection Technique
`Ensuring that individuals and/or caregivers
`understand correct insulin injection tech-
`nique is important to optimize glucose
`control and insulin use safety. Thus, it is
`important that insulin be delivered into
`the proper tissue in the correct way. Rec-
`ommendations have been published else-
`where outlining best practices for insulin
`injection (28). Proper insulin injection tech-
`nique includes injecting into appropriate
`body areas, injection site rotation, appro-
`priate care of injection sites to avoid infec-
`tion or other complications, and avoidance
`of intramuscular (IM) insulin delivery.
`Exogenously delivered insulin should be
`injected into subcutaneous tissue, not in-
`tramuscularly. Recommended sites for in-
`sulin injection include the abdomen, thigh,
`buttock, and upper arm. Insulin absorption
`from IM sites differs from that in subcuta-
`neous sites and is also influenced by the
`activity of the muscle. Inadvertent IM in-
`jection can lead to unpredictable insulin
`absorption and variable effects on glucose
`and is associated with frequent and unex-
`plained hypoglycemia. Risk for IM insulin
`delivery is increased in younger, leaner
`individuals when injecting into the limbs
`rather than truncal sites (abdomen and
`buttocks) and when using longer needles.
`Recent evidence supports the use of short
`needles (e.g., 4-mm pen needles) as effec-
`tive and well tolerated when compared
`with longer needles, including a study per-
`formed in adults with obesity (29).
`Injection site rotation is additionally nec-
`essary to avoid lipohypertrophy, an accu-
`mulation of subcutaneous fat in response to
`
`the adipogenic actions of insulin at a site
`of multiple injections. Lipohypertrophy ap-
`pears as soft, smooth raised areas several
`centimeters in breadth and can contribute
`to erratic insulin absorption,
`increased
`glycemic variability, and unexplained
`hypoglycemic episodes. People treated
`with insulin and/or caregivers should
`receive education about proper injec-
`tion site rotation and how to recognize
`and avoid areas of lipohypertrophy. As
`noted in Table 4.1, examination of insu-
`lin injection sites for the presence of lipo-
`hypertrophy, as well as assessment of
`injection device use and injection tech-
`nique, are key components of a compre-
`hensive diabetes medical evaluation and
`treatment plan. Proper insulin injection
`technique may lead to more effective use
`of this therapy and, as such, holds the po-
`tential for improved clinical outcomes.
`
`Noninsulin Treatments for Type 1
`Diabetes
`Injectable and oral glucose-lowering drugs
`have been studied for their efficacy as ad-
`juncts to insulin treatment of type 1 diabe-
`tes. Pramlintide is based on the naturally
`occurring b-cell peptide amylin and is ap-
`proved for use in adults with type 1 diabe-
`tes. Clinical trials have demonstrated a
`modest reduction in A1C (0.3–0.4%) and
`modest weight loss (1 kg) with pram-
`lintide (30–33). Similarly, results have been
`reported for several agents currently ap-
`proved only for the treatment of type 2 di-
`abetes. The addition of metformin in
`adults with type 1 diabetes caused small
`reductions in body weight and lipid lev-
`els but did not improve A1C (34,35). The
`largest clinical trials of glucagon-like pep-
`tide 1 receptor agonists (GLP-1 RAs) in
`type 1 diabetes have been conducted
`with liraglutide 1.8 mg daily, showing
`modest A1C reductions (0.4%), decreases
`in weight (5 kg), and reductions in insulin
`doses (36,37). Similarly, sodium–glucose co-
`transporter 2 (SGLT2) inhibitors have been
`studied in clinical trials in people with type 1
`diabetes, showing improvements in A1C, re-
`duced body weight, and improved blood
`pressure (38–40); however, SGLT2 inhibitor
`use in type 1 diabetes is associated with an
`increased rate of diabetic ketoacidosis. The
`risks and benefits of adjunctive agents
`continue to be evaluated, with consen-
`sus statements providing guidance on
`patient selection and precautions (41).
`
`SURGICAL TREATMENT FOR TYPE 1
`DIABETES
`Pancreas and Islet Transplantation
`Successful pancreas and islet transplan-
`tation can normalize glucose levels and
`mitigate microvascular complications of
`type 1 diabetes. However, people receiving
`these treatments require lifelong immuno-
`suppression to prevent graft rejection and/
`or recurrence of autoimmune islet destruc-
`tion. Given the potential adverse effects
`of immunosuppressive therapy, pancreas
`transplantation should be reserved for
`people with type 1 diabetes undergoing
`simultaneous renal transplantation, fol-
`lowing renal transplantation, or for those
`with recurrent ketoacidosis or severe
`hypoglycemia despite intensive glycemic
`management (42).
`The 2021 ADA/EASD consensus report
`on the management of type 1 diabetes
`in adults offers a simplified overview
`of indications for b-cell replacement
`therapy in people with type 1 diabetes
`(Fig. 9.2) (5).
`
`PHARMACOLOGIC THERAPY FOR
`ADULTS WITH TYPE 2 DIABETES
`
`Recommendations
`9.4a Healthy lifestyle behaviors, dia-
`betes self-management educa-
`tion and support, avoidance of
`clinical inertia, and social deter-
`minants of health should be con-
`sidered in the glucose-lowering
`management of type 2 diabetes.
`Pharmacologic therapy should be
`guided by person-centered treat-
`ment factors,
`including comor-
`bidities and treatment goals. A
`9.4b In adults with type 2 diabetes
`and established/high risk of ath-
`erosclerotic cardiovascular disease,
`heart failure, and/or chronic kid-
`ney disease, the treatment regi-
`men should include agents that
`reduce cardiorenal risk (Fig. 9.3
`and Table 9.2). A
`9.4c Pharmacologic approaches that
`provide adequate efficacy to
`achieve and maintain treatment
`goals should be considered, such
`as metformin or other agents,
`including combination therapy
`(Fig. 9.3 and Table 9.2). A
`9.4d Weight management is an im-
`pactful component of glucose-
`lowering management in type 2
`diabetes. The glucose-lowering
`
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`
`S143
`
`for details on cardiovascular risk
`reduction recommendations). A
`9.10 In adults with type 2 diabetes,
`a glucagon-like peptide 1 recep-
`tor agonist is preferred to insu-
`lin when possible. A
`9.11 If insulin is used, combination
`therapy with a glucagon-like pep-
`tide 1 receptor agonist is recom-
`mended for greater efficacy,
`durability of treatment effect,
`and weight and hypoglycemia
`benefit. A
`9.12 Recommendation for treatment
`intensification for individuals not
`meeting treatment goals should
`not be delayed. A
`9.13 Medication regimen and med-
`ication-taking behavior should
`be reevaluated at regular in-
`tervals (every 3–6 months) and
`adjusted as needed to incorpo-
`rate specific factors that impact
`choice of treatment (Fig. 4.1
`and Table 9.2). E
`9.14 Clinicians should be aware of
`the potential for overbasaliza-
`tion with insulin therapy. Clini-
`cal signals that may prompt
`evaluation of overbasalization
`include basal dose more than
`0.5 units/kg/day, high bedtime–
`morning or postpreprandial glu-
`cose differential, hypoglycemia
`(aware or unaware), and high
`glycemic variability. Indication of
`overbasalization should prompt
`reevaluation to further individu-
`alize therapy. E
`
`The ADA/EASD consensus report “Manage-
`ment of Hyperglycemia in Type 2 Diabetes,
`2022” (43–45) recommends a holistic, mul-
`tifactorial person-centered approach ac-
`counting for the lifelong nature of type 2
`diabetes. Person-specific factors that affect
`choice of treatment include individualized
`glycemic and weight goals, impact on
`weight, hypoglycemia and cardiorenal pro-
`tection (see Section 10, “Cardiovascular
`Disease and Risk Management,” and Sec-
`tion 11 “Chronic Kidney Disease and Risk
`Management”), underlying physiologic fac-
`tors, side effect profiles of medications,
`complexity of regimen, regimen choice to
`optimize medication use and reduce treat-
`ment discontinuation, and access, cost,
`and availability of medication. Lifestyle
`
`Figure 9.1—Choices of insulin regimens in people with type 1 diabetes. Continuous glucose
`monitoring improves outcomes with injected or infused insulin and is superior to blood glucose
`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 in-
`creased flexibility, lower risk of hypoglycemia, and higher costs between the considered regi-
`mens. LAA, long-acting insulin analog; MDI, multiple daily injections; RAA, rapid-acting insulin
`analog; URAA, ultra-rapid-acting insulin analog. Reprinted from Holt et al. (5).
`
`9.6
`
`treatment regimen should con-
`sider approaches that support
`weight management goals (Fig.
`9.3 and Table 9.2). A
`9.5 Metformin should be contin-
`ued upon initiation of insulin
`therapy (unless contraindica-
`ted or not tolerated) for on-
`going glycemic and metabolic
`benefits. A
`Early combination therapy can be
`considered in some individuals
`at treatment initiation to extend
`the time to treatment failure. A
`The early introduction of in-
`sulin should be considered if
`there is evidence of ongoing
`catabolism (weight loss), if symp-
`toms of hyperglycemia are pre-
`sent, or when A1C levels (>10%
`[86 mmol/mol]) or blood glucose
`levels ($300 mg/dL [16.7 mmol/L])
`are very high. E
`9.8 A person-centered approach
`should guide the choice of phar-
`macologic agents. Consider the
`
`9.7
`
`effects on cardiovascular and re-
`nal comorbidities, efficacy, hypo-
`glycemia risk, impact on weight,
`cost and access, risk for side ef-
`fects, and individual preferences
`(Fig. 9.3 and Table 9.2). E
`9.9 Among individuals with type 2
`diabetes who have established
`atherosclerotic cardiovascular
`disease or indicators of high
`cardiovascular risk, established
`kidney disease, or heart failure,
`a sodium–glucose cotransporter
`2 inhibitor and/or glucagon-like
`peptide 1 receptor agonist with
`demonstrated cardiovascular dis-
`ease benefit (Fig. 9.3, Table 9.2,
`Table 10.3B, and Table 10.3C)
`is recommended as part of the
`glucose-lowering regimen and
`comprehensive cardiovascular
`risk reduction, independent of
`A1C and in consideration of
`person-specific factors (Fig. 9.3)
`(see Section 10, “Cardiovascular
`Disease and Risk Management,”
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`Continuedonp.S145
`
`overnightBGM.
`
`EveningN:basedonfastingor
`
`andcarbohydrateintake.
`
`dinneroratbedtime.
`
`Requiresrelativelyconsistentmealtimes
`
`Pre-dinnerRAA:basedonBGMafter
`
`withN.
`
`lunchorbeforedinner.
`
`Greaterriskofnocturnalhypoglycemia
`
`twice-dailyN.
`basaldeficitduringday;mayneed
`
`NislessexpensivethanLAAs.
`AllmealshaveRAAcoverage.
`
`carbohydratecount.
`
`ShorterdurationRAAmayleadto
`
`Maybefeasibleifunableto
`
`Bedtime:N50%ofTDD.
`Pre-dinner:RAA10%ofTDD.
`Pre-lunch:RAA10%ofTDD.
`Pre-breakfast:RAA20%ofTDD.
`
`dosesofNandRAA
`
`Fourinjectionsdailywithfixed
`
`MDIregimenswithlessflexibility
`
`Pre-lunchRAA:basedonBGMafter
`
`afterbreakfastorbeforelunch.
`Pre-breakfastRAA:basedonBGM
`
`URAAorRAAinjections.
`outsideofactivitytimecourse,or
`glucoseordaytimeglucose
`
`LAA:basedonovernightorfasting
`
`range.
`notconsistentlybringglucoseinto
`targetglucoseifcorrectiondoes
`Correctioninsulin:adjustISFand/or
`
`oftarget.
`glucoseaftermealconsistentlyout
`countingisaccurate,changeICRif
`
`Mealtimeinsulin:ifcarbohydrate
`
`pumptherapy.
`earlymorninghours)aswellas
`phenomenon(riseinglucosein
`LAAsmaynotcoverstrongdawn
`
`1unit(0.5unitwithsomepens).
`
`Smallestincrementofinsulinis
`Mostcostlyinsulins.
`Atleastfourdailyinjections.
`
`URAA/RAAbolus.
`glucoseoutsideofactivityof
`overnight,fastingordaytime
`
`numeracyorliteracyskills).
`(harderforpeoplewithlower
`
`Basalrates:adjustbasedon
`
`Mosttechnicallycomplexapproach
`
`range.
`notconsistentlybringglucoseinto
`targetglucoseifcorrectiondoes
`Correctioninsulin:adjustISFand/or
`
`oftarget.
`glucoseaftermealconsistentlyout
`countingisaccurate,changeICRif
`
`Mealtimeinsulin:ifcarbohydrate
`
`siteinfections.
`
`Potentialreactionstoadhesivesand
`
`delivery.
`orDKAwithinterruptionofinsulin
`Riskofrapiddevelopmentofketosis
`
`devices.
`
`Mustcontinuouslywearoneormore
`Mostexpensiveregimen.
`
`hypoglycemiathanhumaninsulins.
`
`Mealtimeandcorrection:URAAor
`
`targetglucose.
`RAAbasedonICRand/orISFand
`
`Insulinanalogscauseless
`
`content.
`
`Flexibilityinmealtimingand
`Canusepensforallcomponents.
`
`augmentedopen-loop.
`augmentedopen-loop>BGM-
`glucosesuspend>CGM-
`with:hybridclosed-loop>low-
`
`TIR%highestandTBR%lowest
`
`closed-loop.
`forlow-glucosesuspendorhybrid
`
`PotentialforintegrationwithCGM
`incrementsoffractionsofunits.
`
`Pumpcandeliverinsulinin
`
`content.
`
`Flexibilityinmealtimingand
`
`forexerciseandforsickdays.
`insulinsensitivitybytimeofday,
`
`Canadjustbasalratesforvarying
`
`TDD.
`dailydosing);generally50%of
`insulinglarginemayrequiretwice-
`
`orRAAatmeals
`
`LAAoncedaily(insulindetemiror
`
`MDI:LAA1flexibledosesofURAA
`
`beforeeating.
`pre-mealinsulin15min
`ISFandtargetglucose,with
`RAAbybolusbasedonICRand/or
`
`Mealtimeandcorrection:URAAor
`
`generally40–60%ofTDD.
`
`BasaldeliveryofURAAorRAA;
`
`open-loop)
`open-loop,BGM-augmented
`suspend,CGM-augmented
`closed-loop,low-glucose
`
`Insulinpumptherapy(hybrid
`
`Regimensthatmorecloselymimicnormalinsulinsecretion
`
`Adjustingdoses
`
`Disadvantages
`
`Advantages
`
`Timinganddistribution
`
`Regimen
`
`Table9.1—Examplesofsubcutaneousinsulinregimens
`
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`insulin;R,short-acting(regular)insulin;RAA,rapid-actinganalog;TDD,totaldailyinsulindose;URAA,ultra-rapid-actinganalog.ReprintedfromHoltetal.(5).
`BGM,bloodglucosemonitoring;CGM,continuousglucosemonitoring;ICR,insulin-to-carbohydrateratio;ISF,insulinsensitivityfactor;LAA,long-actinganalog;MDI,multipledailyinjections;N,NPH
`
`EveningN:basedonfastingBGM.
`
`orbedtimeBGM.
`
`EveningRAA:basedonpost-dinner
`EveningR:basedonbedtimeBGM.
`
`breakfastorpre-lunchBGM.
`
`glucosewithouthypoglycemia.
`
`day.
`
`Difficulttoreachtargetsforblood
`
`Eliminatesneedfordosesduringthe
`
`suboptimal.
`
`expensiveinsulinsvsanalogs.
`
`MorningRAA:basedonpost-
`MorningR:basedonpre-lunchBGM.
`
`Coverageofpost-lunchglucoseoften
`Fixedmealtimesandmealcontent.
`
`Least(N1R)orless(N1RAA)
`Insulinscanbemixedinonesyringe.
`
`MorningN:basedonpre-dinner
`
`Riskofhypoglycemiainafternoonor
`
`Leastnumberofinjectionsforpeople
`
`BGM.
`
`middleofnightfromN.
`
`withstrongpreferenceforthis.
`
`beforemealforbettereffect.
`
`EveningN:basedonfastingBGM.
`
`Rmustbeinjectedatleast30min
`
`insulinsthanMDIwithanalogs.
`
`dinnerorbedtimeBGM.
`
`suboptimal.
`
`Pre-dinnerRAA:basedonpost-
`
`Coverageofpost-lunchglucoseoften
`
`Least(N1R)orlessexpensive
`SameadvantagesofRAAsoverR.
`
`BGM.
`
`Pre-dinnerR:basedonbedtime
`breakfastorpre-lunchBGM.
`
`MorningRAA:basedonpost-
`MorningR:basedonpre-lunchBGM.
`
`intake.
`mealtimesandcarbohydrate
`
`Requiresrelativelyconsistent
`
`hypoglycemiawithRthanRAAs.
`
`extent.
`
`MorningNcoverslunchtosome
`
`day.
`cannottakeinjectioninmiddleof
`
`Greaterriskofdelayedpost-meal
`
`Maybeappropriateforthosewho
`
`MorningN:basedonpre-dinner
`
`Greaterriskofnocturnal
`
`Morninginsulinscanbemixedinone
`
`BGM.
`
`hypoglycemiawithNthanLAAs.
`
`syringe.
`
`beforemealforbettereffect.
`
`overnightBGM.
`
`Rmustbeinjectedatleast30min
`
`EveningN:basedonfastingor
`
`dinneroratbedtime.
`
`intake.
`mealtimesandcarbohydrate
`
`Pre-dinnerR:basedonBGMafter
`
`Requiresrelativelyconsistent
`
`lunchorbeforedinner.
`
`hypoglycemiawithR.
`
`Leastexpensiveinsulins.
`AllmealshaveRcoverage.
`
`correction.
`
`Pre-lunchR:basedonBGMafter
`
`Greaterriskofdelayedpost-meal
`
`RcanbedosedbasedonICRand
`
`breakfastorbeforelunch.
`
`Pre-breakfastR:basedonBGMafter
`
`Adjustingdoses
`
`hypoglycemiawithN.
`Greaterriskofnocturnal
`
`Disadvantages
`
`carbohydratecount.
`
`Maybefeasibleifunableto
`
`Advantages
`
`RAA.
`
`Pre-dinner:30%N115%Ror
`Pre-breakfast:40%N115%Ror
`
`RAA.
`
`Twice-daily“split-mixed”:N1Ror
`
`N1RAA
`
`Bedtime:30%N.
`Pre-dinner:15%RorRAA.
`Pre-breakfast:40%N115%Ror
`
`RAA.
`
`N1RAA
`
`Threeinjectionsdaily:N1Ror
`Regimenswithfewerdailyinjections
`
`Bedtime:N50%ofTDD.
`Pre-dinner:R10%ofTDD.
`Pre-lunch:R10%ofTDD.
`Pre-breakfast:R20%ofTDD.
`Timinganddistribution
`
`dosesofNandR
`
`Fourinjectionsdailywithfixed
`Regimen
`
`Table9.1—Continued
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`
`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 replace-
`ment therapy are whole-pancreas transplantation or islet cell transplantation. b-Cell replacement therapy can be combined with kidney transplan-
`tation if the individual has end-stage renal disease, which may be performed simultaneously or after kidney transplantation. All decisions about
`transplantation must balance the surgical risk, metabolic need, and the choice of the individual with diabetes. GFR, glomerular filtration rate. Re-
`printed from Holt et al. (5).
`
`modifications and health behaviors that
`improve health (see Section 5, “Facilitating
`Positive Health Behaviors and Well-being
`to Improve Health Outcomes”) should be
`emphasized along with any pharmacologic
`therapy. Section 13, “Older Adults,” and
`Section 14, “Children and Adolescents,”
`have recommendations specific for older
`adults and for children and adolescents
`with type 2 diabetes, respectively. Sec-
`tion 10, “Cardiovascular Disease and Risk
`Management,” and Section 11, “Chronic
`Kidney Disease and Risk Management,”
`have recommendations for the use of glucose-
`lowering drugs in the management of cardio-
`vascular and renal disease, respectively.
`
`Choice of Glucose-Lowering Therapy
`Healthy lifestyle behaviors, diabetes self-
`management, education, and support,
`avoidance of clinical
`inertia, and social
`determinants of health should be consid-
`ered in the glucose-lowering manage-
`ment of type 2 diabetes. Pharmacologic
`therapy should be guided by person-
`centered treatment factors, including
`comorbidities and treatment goals. Phar-
`macotherapy should be started at the
`time type 2 diabetes is diagnosed unless
`there are contraindications. Pharma-
`
`cologic approaches that provide the ef-
`ficacy to achieve treatment goals should
`be considered, such as metformin or other
`agents, including combination therapy, that
`provide adequate efficacy to achieve and
`maintain treatment goals (45). In adults
`with type 2 diabetes and established/high
`risk of atherosclerotic cardiovascular disease
`(ASCVD), heart failure (HF), and/or chronic
`kidney disease (CKD), the treatment regi-
`men should include agents that reduce cardi-
`orenal risk (see Fig. 9.3, Table 9.2, Section
`10, “Cardiovascular Disease and Risk
`Management,” and Section 11, “Chronic
`Kidney Disease and Risk Management”).
`Pharmacologic approaches that provide the
`efficacy to achieve treatment goals should
`be considered, specified as metformin or
`agent(s),
`including combination therapy,
`that provide adequate efficacy to achieve
`and maintain treatment goals (Fig. 9.3 and
`Table 9.2). In general, higher-efficacy ap-
`proaches have greater likelihood of achiev-
`ing glycemic goals, with the following
`considered to have very high efficacy for
`glucose lowering: the GLP-1 RAs dulaglutide
`(high dose) and semaglutide, the gastric in-
`hibitory peptide (GIP) and GLP-1 RA tirze-
`patide, insulin, combination oral therapy,
`and combination injectable therapy.
`
`Weight management is an impactful com-
`ponent of glucose-lowering management
`in type 2 diabetes (45,46). The glucose-
`lowering treatment regimen should con-
`sider approaches that support weight
`management goals, with very high ef-
`ficacy for weight loss seen with sema-
`glutide and tirzepatide (Fig. 9.3 and
`Table 9.2) (45).
`Metformin is effective and safe, is inex-
`pensive, and may reduce risk of cardiovas-
`cular events and death (47). Metformin is
`available in an immediate-release form for
`twice-daily dosing or as an extended-
`release form that can be given once daily.
`Compared with sulfonylureas, metformin
`as first-line therapy has beneficial effects
`on A1C, weight, and cardiovascular mor-
`tality (48).
`The principal side effects of metfor-
`min are gastrointestinal intolerance due
`to bloating, abdominal discomfort, and
`diarrhea; these can be mitigated by grad-
`ual dose titration. The drug is cleared by
`renal filtration, and very high circulating
`levels (e.g., as a result of overdose or
`acute renal failure) have been associated
`with lactic acidosis. However, the occur-
`rence of this complication is now known
`to be very rare, and metformin may be
`
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`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 filtrat