Pharmacologic Approaches to Glycemic Treatment PDF (ADA Standards of Care 2025)

Diabetes Care Volume 48, Supplement 1, January 2025 S181 9. Pharmacologic Approaches to American Diabetes Association...

Diabetes Care Volume 48, Supplement 1, January 2025 S181 9. Pharmacologic Approaches to American Diabetes Association Professional Practice Committee* Glycemic Treatment: Standards of Care in Diabetes—2025 Diabetes Care 2025;48(Suppl. 1):S181–S206 | https://doi.org/10.2337/dc25-S009 Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S181/791515/dc25s009.pdf by guest on 17 January 2025 9. PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT The American Diabetes Association (ADA) “Standards of 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, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations 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 Treat most adults with type 1 diabetes with continuous subcutaneous insulin in- fusion or multiple daily doses of prandial (injected or inhaled) and basal insulin. A 9.2 For most adults with type 1 diabetes, insulin analogs (or inhaled insulin) are preferred over injectable human insulins to minimize hypoglycemia risk. A 9.3 Early use of continuous glucose monitoring is recommended for adults with type 1 diabetes to improve glycemic outcomes and quality of life and to minimize hypoglycemia. B 9.4 Automated insulin delivery systems should be offered to all adults with type 1 diabetes. A 9.5 To improve glycemic outcomes and quality of life and to minimize hypogly- cemia risk, most adults with type 1 diabetes should receive education on how *A complete list of members of the American to match mealtime insulin doses to carbohydrate intake and fat and protein in- Diabetes Association Professional Practice Committee take. They should also be taught how to modify the insulin dose (correction can be found at https://doi.org/10.2337/dc25-SINT. dose) based on concurrent glycemia, glycemic trends (if available), sick-day man- Duality of interest information for each author is agement, and anticipated physical activity. B available at https://doi.org/10.2337/dc25-SDIS. 9.6 Insulin treatment plan and insulin-taking behavior should be reevaluated Suggested citation: American Diabetes Association at regular intervals (e.g., every 3–6 months) and adjusted to incorporate spe- Professional Practice Committee. 9. Pharmacologic cific factors that impact choice of treatment and ensure achievement of indi- approaches to glycemic treatment: Standards of Care in Diabetes—2025. Diabetes Care 2025;48 vidualized glycemic goals. E (Suppl. 1):S181–S206 © 2024 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational Insulin Therapy and not for profit, and the work is not altered. Insulin treatment is essential for individuals with type 1 diabetes because the hallmark More information is available at https://www of type 1 diabetes is absent or near-absent b-cell function. In addition to hyperglycemia,.diabetesjournals.org/journals/pages/license. S182 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 48, Supplement 1, January 2025 insulinopenia can contribute to other met- abolic disturbances like hypertriglyceride- mia and ketoacidosis as well as tissue catabolism that can be life threatening. plans Severe metabolic decompensation can be, and was, mostly prevented with once- or twice-daily insulin injections for the six or seven decades after the discovery of insu- plans lin. Over the past four decades, evidence has accumulated supporting more inten- sive insulin replacement, using multiple daily injections of insulin or continuous subcutaneous administration through an Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S181/791515/dc25s009.pdf by guest on 17 January 2025 insulin pump, as providing the best com- bination 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). The study was carried out with short-acting (regular) and intermediate-acting (NPH) human insulins. In this landmark trial, lower A1C with intensive management Figure 9.1—Choices of insulin plans in people with type 1 diabetes. Continuous glucose moni- (7%) led to 50% reductions in micro- toring improves outcomes with injected or infused insulin and is superior to blood glucose vascular complications over 6 years of monitoring. Inhaled insulin may be used in place of injectable prandial insulin in the U.S. The treatment. However, intensive therapy was number of plus or dollar signs is an estimate of relative association of the plan with greater associated with a higher rate of severe flexibility, lower risk of hypoglycemia, and higher costs between the different plans. LAA, hypoglycemia than conventional treat- long-acting insulin analog; MDI, multiple daily injections; RAA, rapid-acting insulin analog; URAA, ultra-rapid-acting insulin analog. Adapted from Holt et al. (4). ment (62 compared with 19 episodes per 100 person-years of therapy) (1). Follow- up of participants from the DCCT demon- analog (URAA) insulin formulations are given in a defined treatment plan tailored strated fewer macrovascular and micro- available that contain excipients that ac- to the individual to prevent diabetic ke- vascular complications in the group that celerate absorption and provide more ac- toacidosis (DKA) and minimize clinically received intensive treatment. Achieving tivity in the first portion of their profile relevant hypoglycemia while achieving the intensive glycemic goals during the active compared with the other RAA (8,9). In- individual’s glycemic goals. The impact of treatment period of the study had a per- haled human insulin has a rapid peak and the introduction of interchangeable biosi- sistent beneficial impact over the 20 years shortened duration of action compared milars and unbranded versions of some after the active treatment component of with RAA (10) (see also subsection ALTERNA- analog products as well as current and up- the study ended (1–3). TIVE INSULIN ROUTES IN PHARMACOLOGIC THERAPY FOR coming price reductions on insulin access Insulin replacement plans typically con- ADULTS WITH TYPE 2 DIABETES). These newer for- need to be evaluated. Reassessment of in- sist of basal insulin, mealtime insulin, and mulations may cause less hypoglycemia sulin-taking behavior and adjustment of correction insulin (Fig. 9.1) (4). Basal insu- while improving postprandial glucose treatment plans to account for specific fac- lin includes NPH insulin, long-acting insu- excursions and administration flexibility (in tors, including cost, that impact choice of lin analogs, and continuous delivery of relation to prandial intake) compared with treatment is recommended at regular in- rapid-acting insulin via an insulin pump. RAA (10–12). In addition, longer-acting tervals (every 3–6 months). Basal insulin analogs have longer duration basal analogs (U-300 glargine or deglu- Most studies comparing multiple daily of action with flatter, more constant and dec) may confer a lower hypoglycemia injections with CSII have been relatively consistent plasma concentrations and risk compared with U-100 glargine in in- small and of short duration. A systematic activity profiles than NPH insulin; rapid- dividuals with type 1 diabetes (13,14). review and meta-analysis concluded that acting analogs (RAA) have a quicker onset Despite the advantages of insulin ana- CSII via pump therapy has modest advan- and peak and shorter duration of action logs in individuals with type 1 diabetes, tages for lowering A1C ( 0.30% [95% CI than regular human insulin. In people the expense and/or complexity of treat- 0.58 to 0.02]) and for reducing severe with type 1 diabetes, treatment with ana- ment required for their use may be pro- hypoglycemia rates in children and adults log insulins is associated with less hypo- hibitive (Table 9.1). There are multiple (15). Use of CSII is associated with im- glycemia and weight gain and lower A1C approaches to insulin treatment. The cen- provement in quality of life, particularly in compared with injectable human insulins tral precept in the management of type 1 areas related to fear of hypoglycemia and (5–7). Two injectable ultra-rapid-acting diabetes is that some form of insulin be diabetes distress, compared with multiple Table 9.1—Examples of subcutaneous insulin treatment plans Plans Timing and distribution Advantages Disadvantages Adjusting doses Plans that more closely mimic normal insulin secretion Insulin pump therapy (also including Basal delivery of URAA or RAA; Can adjust basal rates for varying Most expensive plan. Mealtime insulin: if carbohydrate AID systems: hybrid closed- generally 30–50% of TDD. insulin sensitivity by time of Must continuously wear one or more counting is accurate, change ICR if diabetesjournals.org/care loop, low-glucose suspend, Mealtime and correction: URAA or day, for exercise, and for sick devices. glucose after meal consistently out CGM-augmented open-loop, RAA by bolus based on ICR days. Risk of rapid development of ketosis or of target. BGM-augmented open-loop) and/or ISF and target glucose, Flexibility in meal timing and DKA with interruption of insulin Correction insulin: adjust ISF and/or with premeal insulin 15 min content. delivery. target glucose if correction does before eating. Pump can deliver insulin in Potential reactions to adhesives and not consistently bring glucose into increments of fractions of units. site infections. range. Potential for integration with CGM Most technically complex approach Basal rates: adjust based on overnight, for AID systems. (harder for people with lower fasting or daytime glucose outside TIR % highest and TBR % lowest numeracy or literacy skills). of activity of URAA/RAA bolus. with: hybrid closed-loop > low- AID systems: carbohydrate ratio, insulin glucose suspend > CGM- on board, targets, and/or ISF may augmented open-loop > BGM- be adjusted, depending on the augmented open-loop. system. Make sure to review and adjust manual mode settings, if available. 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 Flexibility in meal timing and Most costly insulins. counting is accurate, change ICR twice-daily dosing); generally content. Smallest increment of insulin is 1 unit if glucose after meal consistently 30–50% of TDD. Insulin analogs cause less (0.5 unit with some pens). out of target. Mealtime and correction: URAA or hypoglycemia than human LAAs may not cover strong dawn Correction insulin: adjust ISF and/or RAA based on ICR and/or ISF insulins. phenomenon (rise in glucose in target glucose if correction does and target glucose. early morning hours) as well as not consistently bring glucose pump therapy. into range. LAA: based on overnight or fasting glucose or daytime glucose outside of activity time course, or URAA or RAA injections. MDI plans 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 basal Pre-breakfast RAA: based on BGM after doses of N and RAA Pre-lunch: RAA 10% of TDD. carbohydrate count. deficit during day; may need 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 dinner or at bedtime. mealtimes and carbohydrate Evening N: based on fasting or intake. overnight BGM. Continued on p. S184 Pharmacologic Approaches to Glycemic Treatment S183 Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S181/791515/dc25s009.pdf by guest on 17 January 2025  S184 Table 9.1—Continued Plans Timing and distribution Advantages Disadvantages Adjusting doses Four injections daily with fixed Pre-breakfast: R 20% of TDD. May be feasible if unable to Greater risk of nocturnal Pre-breakfast R: based on BGM doses of N and R Pre-lunch: R 10% of TDD. carbohydrate count. hypoglycemia with N. after breakfast or before lunch. Pre-dinner: R 10% of TDD. R can be dosed based on ICR and Greater risk of delayed post-meal Pre-lunch R: based on BGM after Bedtime: N 50% of TDD. correction. hypoglycemia with R. lunch or before dinner. All meals have R coverage. Requires relatively consistent Pre-dinner R: based on BGM after Least expensive insulins. mealtimes and carbohydrate dinner or at bedtime. intake. Evening N: based on fasting or R must be injected at least 30 min overnight BGM. Pharmacologic Approaches to Glycemic Treatment before meal for better effect. Plans with fewer daily injections Three injections daily: N 1 R or Pre-breakfast: N 40% TDD 1 R or Morning insulins can be mixed in one Greater risk of nocturnal hypoglycemia Morning N: based on pre-dinner BGM. N 1 RAA RAA 15% TDD. syringe. with N than LAAs. Morning R: based on pre-lunch BGM. Pre-dinner: R or RAA 15% TDD. May be appropriate for those who Greater risk of delayed post-meal Morning RAA: based on post-breakfast Bedtime: N 30% TDD. cannot take injection in middle hypoglycemia with R than RAAs. or pre-lunch BGM. of day. Requires relatively consistent Pre-dinner R: based on bedtime BGM. Morning N covers lunch to some mealtimes and carbohydrate Pre-dinner RAA: based on post-dinner extent. intake. or bedtime BGM. Same advantages of RAAs over R. Coverage of post-lunch glucose often Evening N: based on fasting BGM. Least (N 1 R) or less expensive suboptimal. insulins than MDI with analogs. R must be injected at least 30 min before meal for better effect. Twice-daily “split-mixed”: N 1 R or Pre-breakfast: N 40% TDD 1 R or Least number of injections for people Risk of hypoglycemia in afternoon or Morning N: based on pre-dinner BGM. N 1 RAA RAA 15% TDD. with strong preference for this. middle of night from N. Morning R: based on pre-lunch BGM. Pre-dinner: N 30% TDD 1 R or RAA Insulins can be mixed in one syringe. Fixed mealtimes and meal content. Morning RAA: based on post-breakfast 15% TDD. Least (N 1 R) or less (N 1 RAA) Coverage of post-lunch glucose often or pre-lunch BGM. expensive insulins vs. analogs. suboptimal. Evening R: based on bedtime BGM. Eliminates need for doses during the Difficult to reach targets for blood Evening RAA: based on post-dinner or day. glucose without hypoglycemia. bedtime BGM. Evening N: based on fasting BGM. AID, automated insulin delivery; BGM, blood glucose monitoring; CGM, continuous glucose monitoring; ICR, insulin-to-carbohydrate ratio; ISF, insulin sensitivity factor; LAA, long-acting analog; MDI, mul- tiple daily injections; N, NPH insulin; R, short-acting (regular) insulin; RAA, rapid-acting analog; TBR, time below range; TDD, total daily insulin dose; TIR, time in range; URAA, ultra-rapid-acting analog (inhaled insulin may be considered if appropriate). Adapted from Holt et al. (4). Diabetes Care Volume 48, Supplement 1, January 2025 Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S181/791515/dc25s009.pdf by guest on 17 January 2025 diabetesjournals.org/care Pharmacologic Approaches to Glycemic Treatment S185 daily injections of insulin (16,17). How- can be estimated based on weight, with adjustment of prandial insulin dose for ever, there is no consensus to guide the typical doses ranging from 0.4 to 1 unit/ glycemic trends should be provided to in- choice of injection or pump therapy in a kg/day. Higher amounts may be required dividuals who are using CGM alone or an given individual, and research to guide during puberty, menses, and medical ill- AID system (59–62). Further adjustment this decision-making is needed (4). Inte- ness. The American Diabetes Association/ of prandial insulin doses for nutritional in- gration of continuous glucose monitoring JDRF Type 1 Diabetes Sourcebook notes take of protein and fat, in addition to car- (CGM) into the treatment plan soon after 0.5 units/kg/day as a typical starting dose bohydrates, is recommended but may be diagnosis improves glycemic outcomes, in adults with type 1 diabetes who are more feasible for individuals using CSII decreases hypoglycemic events, and im- metabolically stable, with approximately than for those using multiple daily injec- proves quality of life for individuals with one-half administered as prandial insulin tions (55). With some AID systems, use of type 1 diabetes (18–23). Its use is now given to manage blood glucose after meals a simplified meal announcement method considered standard of care for most peo- and the remaining portion as basal insulin may be an alternative for prandial insulin ple with type 1 diabetes (4) (see Section 7, to manage glycemia in the periods be- Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S181/791515/dc25s009.pdf by guest on 17 January 2025 dosing (31,63). Assessment and educa- “Diabetes Technology”). Reduction of noc- tween meal absorption (49). Starting doses tion tailored to improve health literacy turnal hypoglycemia in individuals with and those soon after diagnosis may be and numeracy may be necessary for indi- type 1 diabetes using insulin pumps with higher, if an individual presents with ketoa- viduals to effectively use various insulin CGM is improved by automatic suspen- cidosis, or lower (0.2–0.6 units/kg), particu- dosing strategies and tools (64,65) (see sion of insulin delivery at a preset glucose larly in young children and those with Section 5, “Facilitating Positive Health level, with further improvements when continued endogenous insulin production Behaviors and Well-being to Improve using devices with predictive low-glucose (during the partial remission phase or Health Outcomes,” and Section 7, “Diabetes insulin delivery suspension (24,25). “honeymoon period,” or in people who Technology”). Automated insulin delivery (AID) sys- present with type 1 diabetes in adult- The 2021 ADA/European Association tems are safe and effective for people hood) (49–51). This guideline provides for the Study of Diabetes (EASD) consen- with type 1 diabetes. Randomized con- detailed information on intensification sus report on the management of type 1 trolled trials and real-world studies have of therapy to meet individualized needs. diabetes in adults summarizes different in- demonstrated the ability of commercially In addition, the American Diabetes Asso- sulin plans and glucose monitoring strate- available systems to improve achievement ciation (ADA) position statement “Type 1 gies in individuals with type 1 diabetes of glycemic goals while reducing the risk of Diabetes Management Through the Life (Fig. 9.1 and Table 9.1) (4). hypoglycemia (26–31). Data are emerging Span” provides a thorough overview of on the safety and effectiveness of do-it- type 1 diabetes treatment (52). Insulin Administration Technique yourself systems (32,33). Evidence sug- Typical multidose treatment plans for Ensuring that individuals and/or caregivers gests that an AID hybrid closed-loop sys- individuals with type 1 diabetes combine understand correct insulin administration tem is superior to AID sensor-augmented premeal use of prandial insulins with a technique is important to optimize glyce- pump therapy for increased percentage longer-acting formulation. The long-acting mic management and insulin use safety. of time in range and reduction of hypogly- basal dose is titrated to regulate over- Recommendations have been published cemia (34,35). night and fasting glucose. Postprandial Intensive insulin management using a glucose excursions are best managed by a elsewhere outlining best practices for in- version of CSII and CGM should be con- well-timed injection or inhalation of pran- sulin administration (66). Proper insulin sidered in individuals with type 1 diabetes dial insulin. Prandial insulin should ideally administration technique includes the whenever feasible. AID systems are pre- be administered prior to meal consump- following: injection, insertion of patch or ferred and should be considered for indi- tion; however, the optimal time to admin- infusion (for CSII or AID systems) into ap- viduals with type 1 diabetes who are ister varies based on the pharmacokinetics propriate body areas, or oral inhalation capable of using the device safely (either of the formulation (regular, RAA, or inhaled), (inhaled human insulin); injection or in- by themselves or with a caregiver) to im- the premeal blood glucose level, and carbo- fusion site rotation; appropriate care of prove time in range and reduce A1C and hydrate consumption. Recommendations injection or infusion sites to avoid infec- hypoglycemia (26,28–31,36–42). When for prandial insulin dose administration tion or other complications; avoidance of choosing among insulin delivery systems, should therefore be individualized. Physi- intramuscular (IM) insulin delivery; and individual preferences, cost, insulin type, ologic insulin secretion varies with glyce- filling of the reservoir (for bolus patch, dosing plan, and self-management capabil- mia, meal size, meal composition, and CSII, or AID systems) or inhaler (for in- ities should be considered. See Section 7, tissue demand for glucose. To address haled human insulin) depending on the “Diabetes Technology,” for a full discussion this variability in people treated with insu- method of administration. Selection of of insulin delivery devices. lin, strategies have evolved to adjust method of administration (vial and sy- In general, individuals with type 1 dia- prandial doses based on predicted needs. ringe, insulin pen, insulin patch, inhaled betes require approximately 30–50% of Thus, education on how to adjust pran- insulin, connected insulin pens/devices, their daily insulin as basal and the remain- dial insulin to account for nutritional in- or insulin pumps) will depend on a vari- der as prandial (43). This proportion de- take and the correction dose based on ety of individual-specific factors and pends on several factors, including but premeal glucose levels, anticipated activ- needs, cost and coverage, and individual not limited to carbohydrate consumption, ity, and sick-day management can be ef- preferences. Reassessment of the appro- age, pregnancy status, and puberty stage fective and should be offered to most priate administration technique should (4,44–48). Total daily insulin requirements individuals (53–58). Education regarding be completed during routine follow-up. S186 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 48, Supplement 1, January 2025 Exogenously delivered insulin should loss (1 kg) with pramlintide (68). Similar delaying the progression of symptomatic be injected or infused into subcutaneous results have been reported for several type 1 diabetes. Higher C-peptide levels tissue, not intramuscularly. Recommended agents currently approved only for the have been associated with better A1C, sites for insulin administration include the treatment of type 2 diabetes. The addi- lower risk of retinopathy, lower risk of abdomen, thigh, buttock, and upper arm. tion of metformin in adults with type 1 nephropathy, and lower risk of severe Insulin absorption from IM sites differs diabetes was associated with small re- hypoglycemia (85). Various therapies, from that in subcutaneous sites and is also ductions in body weight, insulin dose, including verapamil, menin inhibitors, influenced by the activity of the muscle. and lipid levels but did not sustainably Janus kinase inhibitors, antithymocyte Inadvertent IM injection can lead to un- improve A1C (69,70). The largest clinical globulin, several monoclonal antibodies predictable insulin absorption and variable trials of glucagon-like peptide 1 receptor including teplizumab, and cell therapies, effects on glucose and is associated with agonists (GLP-1 RAs) in type 1 diabetes are currently under active investigation. frequent and unexplained hypoglycemia. have been conducted with liraglutide Risk for IM insulin delivery is increased in 1.8 mg daily, and results showed modest Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S181/791515/dc25s009.pdf by guest on 17 January 2025 SURGICAL TREATMENT OF TYPE 1 younger, leaner individuals when injecting A1C reductions (0.4%), decreases in DIABETES into the limbs rather than truncal sites weight (5 kg), and reductions in insulin Pancreas and Islet Transplantation (abdomen and buttocks) and when using doses (71,72). Liraglutide was also as- Successful pancreas and islet transplanta- longer needles. Recent evidence supports sessed for impact on C-peptide in individu- tion can normalize glucose levels and miti- the use of short needles (e.g., 4-mm pen als with type 1 diabetes and residual gate microvascular complications of type 1 needles) as effective and well tolerated b-cell function. During treatment there diabetes. However, people receiving these compared with longer needles, including was no impact, and with liraglutide dis- treatments require lifelong immunosup- a study performed in adults with obesity continuation there was worsening of C- pression to prevent graft rejection and/or (67). peptide loss compared with placebo recurrence of autoimmune islet destruc- Injection or infusion site rotation is ad- (73). Retrospective case series have re- tion. Given the potential adverse effects ditionally necessary to avoid lipohypertro- vealed potential benefits on body weight of immunosuppressive therapy, pancreas phy, an accumulation of subcutaneous fat and glycemic metrics with addition of transplantation should be reserved for in response to the adipogenic actions of semaglutide or tirzepatide for individuals people with type 1 diabetes undergoing insulin at a site of multiple injections. Lipo- with type 1 diabetes and obesity (74,75). simultaneous kidney transplantation, hypertrophy appears as soft, smooth raised Prospective studies using semaglutide following kidney transplantation, or for areas several centimeters in breadth and are ongoing (76,77). those with recurrent ketoacidosis or can contribute to erratic insulin absorption, Sodium–glucose cotransporter 2 (SGLT2) severe hypoglycemia despite optimized increased glycemic variability, and unex- inhibitors have been studied in clinical glycemic management (86). In much of plained hypoglycemic episodes. People trials in people with type 1 diabetes, and the world, allogenic islet transplantation treated with insulin and/or caregivers results showed improvements in A1C, re- is regulated as an organ transplant. How- should receive education about proper duced body weight, and improved blood ever, in the U.S., allogenic islet transplan- injection or infusion site rotation and how pressure (78); however, SGLT2 inhibitor tation is regulated as a cell therapy, and to recognize and avoid injecting in areas of use in type 1 diabetes was associated the first such allogeneic islet cell therapy, lipohypertrophy. As noted in Table 4.1, ex- with an increased rate of DKA (79). The donislecel-jujn, was approved in 2023. amination of insulin administration sites SGLT1/2 inhibitor sotagliflozin has been Donislecel is indicated for the treatment for the presence of lipohypertrophy, as studied in clinical trials in people with of adults with type 1 diabetes who are well as assessment of administration de- type 1 diabetes, and results showed im- unable to reach their A1C goals because of vice use and injection technique, are key provements in A1C and body weight (80); repeated episodes of severe hypoglyce- components of a comprehensive diabetes however, sotagliflozin use was associated mia despite intensive diabetes manage- medical evaluation and treatment plan. with an eightfold increase in DKA com- ment and education (87). Alternative Proper insulin injection, infusion, or inha- pared with placebo (81). The studies that islet sources are currently under active lation technique may lead to more effec- led to the approved indication for heart investigation. tive use of this therapy and, as such, failure (HF) excluded individuals with type 1 The 2021 ADA/EASD consensus report holds the potential for improved clinical diabetes or a history of DKA (82,83). See on the management of type 1 diabetes in outcomes. SGLT INHIBITION AND RISK OF KETOSIS, later in this adults offers a simplified overview of indi- section, and PREVENTION AND TREATMENT OF cations for b-cell replacement therapy in Noninsulin Treatments for Type 1 HEART FAILURE in Section 10, “Cardiovascular people with type 1 diabetes (Fig. 9.2) (4). Diabetes Disease and Risk Management,” for infor- Injectable and oral noninsulin glucose- mation on risk mitigation with the use of PHARMACOLOGIC THERAPY FOR lowering medications have been studied SGLT inhibitors in those with type 1 dia- ADULTS WITH TYPE 2 DIABETES for their efficacy as adjuncts to insulin betes. The risks and benefits of adjunctive treatment of type 1 diabetes. Pramlintide agents continue to be evaluated, with Recommendations is based on the naturally occurring b-cell consensus statements providing guidance 9.7 Healthy behaviors, diabetes self- peptide amylin and is approved for use in on selection of candidates for treatment management education and support, adults with type 1 diabetes. Clinical trials and precautions (84). avoidance of therapeutic inertia, and have demonstrated a modest reduction There are currently no approved thera- social determinants of health should in A1C (0.3–0.4%) and modest weight pies for preservation of C-peptide or diabetesjournals.org/care Pharmacologic Approaches to Glycemic Treatment S187 mL/min/1.73 m2) Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S181/791515/dc25s009.pdf by guest on 17 January 2025 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 and islet cell transplantation. b-Cell replacement therapy can be combined with kidney trans- plantation if the individual has end-stage kidney disease, which may be performed simultaneously or after kidney transplantation. All decisions about transplantation must consider the surgical risk, metabolic need, and the choices of the individual with diabetes. GFR, glomerular filtration rate. Adapted from Holt et al. (4). be included in the glucose-lowering glycemic management and compre- events (Fig. 9.3). The glycemic benefits management of type 2 diabetes. A hensive cardiovascular risk reduction of SGLT2 inhibitors are reduced at 9.8 A person-centered shared decision- (irrespective of A1C) (Fig. 9.3 and eGFR 10% with any pharmacologic therapy. Section 13, (see Section 8, “Obesity and Weight Man- [>86 mmol/mol] or blood glucose “Older Adults,” and Section 14, “Children agement for the Prevention and Treat- $300 mg/dL [$16.7 mmol/L]). E and Adolescents,” have recommendations ment of Type 2 Diabetes”), mitigation of diabetesjournals.org/care Pharmacologic Approaches to Glycemic Treatment S189 metabolic dysfunction–associated liver dis- of eGFR to #30 mL/min/1.73 m2 which accessibility and affordability (108). In all ease (MASLD) or metabolic dysfunction– heightens the risk of lactic acidosis. Met- cases, treatment plans need to be contin- associated steatohepatitis (MASH) risk (see formin use is also associated with in- uously reviewed for efficacy, side effects, Section 4, “Comprehensive Medical Evalu- creased risk of vitamin B12 deficiency and hypoglycemia, and treatment burden ation and Assessment of Comorbidities”), worsening of symptoms of neuropathy (Table 9.2). and achievement and maintenance of (102,103), suggesting periodic testing of When A1C is $1.5% above the individ- individualized glycemic goals. In general, vitamin B12 levels (see Section 3, ualized glycemic goal (see Section 6, higher-efficacy approaches, including “Prevention or Delay of Diabetes and “Glycemic Goals and Hypoglycemia,” for combination therapy, have greater likeli- Associated Comorbidities”). appropriate goals), many individuals will hood of achieving treatment goals. Weight The comparative glucose-lowering effi- require dual-combination therapy or a management is a distinct treatment goal, cacy of different pharmacologic agents more potent glucose-lowering agent to along with glycemic management, as it has been examined primarily in network achieve and maintain their goal A1C level has multifaceted benefits, including reduc- meta-analyses, as few prospective clinical Downloaded from http://diabetesjournals.org/care/article-pdf/48/Supplement_1/S181/791515/dc25s009.pdf by guest on 17 January 2025 (89) (Fig. 9.3 and Table 9.2). Insulin tion of A1C, reduction in hepatic steatosis, trials have compared multiple drug clas- should be considered as part of any com- and improvement in cardiovascular risk ses head-to-head. In general, the largest bination medication plan when hypergly- factors (89–91). For individuals with type 2 reductions in A1C levels are achieved by cemia is severe, especially if catabolic diabetes who require initiation or intensi- treatment plans that include insulin, se- features (weight loss, hypertriglyceride- fication of glucose-lowering therapy to lect GLP-1 RAs (particularly semaglutide), mia, and ketosis) are present. It is com- achieve and/or maintain individualized and tirzepatide, while DPP-4 inhibitors re- mon practice to initiate insulin therapy glycemic goals and who do not have addi- sulted in the smallest reductions in A1C for people who present with blood glu- tional considerations informing choice of (104–106). In A Diabetes Outcome Progres- cose levels $300 mg/dL ($16.7 mmol/L) therapy beyond need for glucose lower- sion Trial (ADOPT), rosiglitazone monother- or A1C >10% (>86 mmol/mol) or if the ing, metformin is a commonly used apy was more effective than metformin individual has symptoms of hyperglyce- medication that historically has been the and glyburide monotherapies in achieving mia (i.e., polyuria or polydipsia) or evi- first-line treatment for type 2 diabetes and maintaining fasting plasma glucose dence of catabolism (unexpected weight (92,93). Metformin is effective and safe, below 180 mg/dL (10 mmol/L) among loss) (Fig. 9.4). As glucose toxicity re- is inexpensive and widely available, and recently diagnosed individuals with type 2 solves, simplifying the medication plan reduces risks of microvascular complica- diabetes whose baseline fasting plasma and/or changing to noninsulin agents is tions, cardiovascular events, and death glucose was 126–180 mg/dL (7–10 mmol/L), possible. Additionally, there is evidence (92,94,95). Metformin is available in an while glyburide was least effective (107). that people with type 2 diabetes and se- immediate-release form for twice-daily More recently, the Glycemia Reduction vere hyperglycemia can also be effectively dosing or as an extended-release form Approaches in Type 2 Diabetes: A Com- treated with a sulfonylurea, a GLP-1 RA, that can be given once daily. Compared parative Effectiveness (GRADE) trial com- or dual GIP and GLP-1 RA, though evi- with sulfonylureas, metformin as first-- pared use of insulin glargine U-100, dence is scarce for individuals with base- line therapy has beneficial effects on liraglutide, sitagliptin, and glimepiride as add- on treatments to metformin monotherapy line A1C above 10–12% (104,109–111). A1C, is weight neutral, does not cause hypoglycemia, and reduces cardiovascu- among individuals with type 2 diabetes GLP-1 RAs and tirzepatide have additional lar mortality (96). Metformin is also more and baseline A1C 6.8–8.5% (108). It found benefits over insulin and sulfonylureas, effective than dipeptidyl peptidase 4 that at 5 years, all therapies decreased specifically lower risks for hypoglycemia (DPP-4) inhibitors in lowering A1C and A1C levels but glargine and liraglutide (both) and favorable weight (both), car- weight when used as monotherapy (97). were modestly more effective in achiev- diovascular (GLP-1 RAs), kidney (GLP-1 The principal side effects of metfor- ing and maintaining A1C below 7%, while RAs), and liver (both) end points. min are gastrointestinal intolerance due sitagliptin was least effective. Severe hy- to bloating, abdominal discomfort, and poglycemia was significantly more com- Combination Therapy diarrhea; these can be mitigated by grad- mon in those prescribed glargine or Because type 2 diabetes is a progressive ual dose titration and/or using extended- glimepiride. An observational study that disease, maintenance of glycemic goals release formulation. The drug is cleared emulated many of GRADE’s design fea- often requires combination therapy. Tra- by kidney filtration, and metformin may tures and included canagliflozin as a com- ditional recommendations have called for be safely used in people with estimated parator arm, but did not include insulin the use of stepwise addition of medica- glomerular filtration rate $30 mL/min/ glargine, found that liraglutide was more tions to metformin to maintain A1C goals. 1.73 m2 (98). Very high circulating levels effective at achieving and maintaining The advantage of this is to provide a clear (e.g., as a result of overdose or acute kid- A1C below 7% than sitagliptin, canagliflo- assessment of the positive and negative ney injury) have been associated with lac- zin, or glimepiride, which all had compa- effects of new drugs and reduce potential tic acidosis (99). However, the occurrence rable effectiveness (108). side effects and expense (112). However, of this complication is very rare (100) and Thus, when choosing a glucose-lowering some data support initial combination primarily occurs when the estimated glo- medication to achieve individualized gly- therapy for more rapid attainment of glyce- merular filtration rate (eGFR) is