S98 Diabetes Care Volume 43, Supplement 1, January 2020

This article includes updates in the form of annotations as of June 2020. See page S101.

9. Pharmacologic Approaches to American Diabetes Association Glycemic Treatment: Standards of Medical Care in Diabetesd2020 Diabetes Care 2020;43(Suppl. 1):S98–S110 | https://doi.org/10.2337/dc20-S009

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence- grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to com- ment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES

Recommendations

9. PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT 9.1 Mostpeoplewithtype1diabetesshouldbetreatedwithmultipledailyinjections of prandial and basal , or continuous subcutaneous insulin infusion. A 9.2 Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk. A 9.3 Patients with type 1 diabetes should be trained to match prandial insulin doses to carbohydrate intake, premeal blood glucose, and anticipated physical activity. C

Insulin Therapy Because the hallmark of type 1 diabetes is absent or near-absent b-cell function, insulin treatment is essential for individuals with type 1 diabetes. In addition to hyperglycemia, insulinopenia can contribute to other metabolic disturbances like hypertriglyceridemia and ketoacidosis as well as tissue catabolism that can be life threatening. Severe metabolic decompensation can be, and was, mostly pre- vented 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 supporting more intensive insulin replacement, using multiple daily injections of Suggested citation: American Diabetes Associa- insulin or continuous subcutaneous administration through an insulin pump, as tion. 2. Pharmacologic approaches to glycemic providing the best combination of effectiveness and safety for people with type 1 treatment: StandardsofMedicalCareinDiabetesd diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that 2020. Diabetes Care 2020;43(Suppl. 1):S98–S110 intensive therapy with multiple daily injections or continuous subcutaneous insulin © 2019 by the American Diabetes Association. infusion (CSII) reduced A1C and was associated with improved long-term outcomes Readers may use this article as long as the work – is properly cited, the use is educational and not (1 3). The study was carried out with short-acting (regular) and intermediate-acting for profit, and the work is not altered. More infor- (NPH) human . In this landmark trial, lower A1C with intensive control (7%) mation is available at http://www.diabetesjournals led to ;50% reductions in microvascular complications over 6 years of treatment. .org/content/license. care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S99

However, intensive therapy was associ- meta-analysis concluded that pump ther- Typical multidose regimens for pa- ated with a higher rate of severe hypo- apy has modest advantages for lowering tients with type 1 diabetes combine glycemiathanconventional treatment (62 A1C (–0.30% [95% CI –0.58 to –0.02]) and premeal use of shorter-acting insulins compared with 19 episodes per 100 pa- for reducing severe hypoglycemia rates with a longer-acting formulation, usually tient-years of therapy). Follow-up of sub- in children and adults (11). However, there at night. The long-acting basal dose is jects from the DCCT more than 10 years is no consensus to guide the choice of titrated to regulate overnight, fasting after the active treatment component of injection or pump therapy in a given glucose. Postprandial glucose excur- the study demonstrated less macrovas- patient, and research to guide this sions are best controlled by a well-timed cular as well as less microvascular com- decision-making is needed (12). The arrival injection of prandial insulin. The opti- plications in the group that received of continuous glucose monitors to clinical mal time to administer prandial insulin intensive treatment. practice has proven beneficial in specific varies, based on the Over the last 25 years, rapid-acting and circumstances. Reduction of nocturnal of the formulation (regular, RAA, in- long-acting insulin analogs have been hypoglycemia in people with type 1 di- haled), the premeal blood glucose level, developed that have distinct pharmaco- abetes using insulin pumps with glucose and carbohydrate consumption. Recom- kinetics compared with recombinant hu- sensors is improved by automatic sus- mendations for prandial insulin dose man insulins: basal insulin analogs have pension of insulin delivery at a preset administration should therefore be indi- longer duration of action with flatter, glucose level (12–14). The U.S. Food and vidualized. Physiologic insulin secretion more constant plasma concentrations Drug Administration (FDA) has also ap- varies with glycemia, meal size, and tissue and activity profiles than NPH insulin; proved the first hybrid closed-loop pump demands for glucose. To approach this rapid-acting analogs (RAA) have a quicker system. The safety and efficacy of hybrid variability in people using insulin treat- onset and peak and shorter duration of closed-loop systems has been supported ment, strategies have evolved to adjust action than regular human insulin. In in the literature in adolescents and adults prandial doses based on predicted needs. people with type 1 diabetes, treatment with type 1 diabetes (15,16), and recent Thus, education of patients on how to with analog insulins is associated with less evidence suggests that a closed-loop adjust prandial insulin to account for hypoglycemia and weight gain as well as system is superior to sensor-augmented carbohydrate intake, premeal glucose lower A1C compared with human insu- pump therapy for glycemic control levels, and anticipated activity can be lins (4–6). More recently, two new insulin and reduction of hypoglycemia over 3 effective and should be offered to most formulations with enhanced rapid action months of comparison in children and patients (20,21). For individuals in whom profiles have been introduced. Inhaled adults with type 1 diabetes (17). Intensive carbohydrate counting is effective, esti- human insulin has a rapid peak and insulinmanagementusingaversionofCSII mates of the fat and protein content of shortened duration of action compared and continuous glucose monitoring should meals can be incorporated into their with RAA and may cause less hypogly- be considered in most patients. See Sec- prandial dosing for added benefit (22). cemia and weight gain (7), and faster- tion 7 “Diabetes Technology” (https://doi acting may reduce prandial .org/10.2337/dc20-S007) for a full discus- Insulin Injection Technique excursions better than RAA (8); further sion of insulin delivery devices. Ensuring that patients and/or caregivers investigationisneededtoestablishaclear In general, patients with type 1 di- understand correct insulin injection tech- place for these agents in diabetes man- abetes require 50% of their daily insulin nique is important to optimize glucose agement. In addition, new longer-acting as basal and 50% as prandial. Total daily control and insulin use safety. Thus, it is basal analogs (U-300 glargine or degludec) insulin requirements can be estimated important that insulin be delivered into may confer a lower hypoglycemia risk based on weight, with typical doses the proper tissue in the right way. Rec- compared with U-100 glargine in patients ranging from 0.4 to 1.0 units/kg/day. ommendations have been published else- with type 1 diabetes (9,10). Despite the Higher amounts are required during pu- where outlining best practices for insulin advantages of insulin analogs in patients berty, pregnancy, and medical illness. injection (23). Proper insulin injection tech- with type 1 diabetes, for some patients the The American Diabetes Association/ nique includes injecting into appropriate expense and/or intensity of treatment JDRF Type 1 Diabetes Sourcebook notes body areas, injection site rotation, ap- required for their use is prohibitive. There 0.5 units/kg/day as a typical starting dose propriate care of injection sites to avoid are multiple approaches to insulin treat- in patients with type 1 diabetes who are infection or other complications, and avoid- ment, and the central precept in the metabolically stable, with half adminis- ance of intramuscular (IM) insulin delivery. management of type 1 diabetes is tered as prandial insulin given to control Exogenous-delivered insulin should be that some form of insulin be given in blood glucose after meals and the other injected into subcutaneous tissue, not a planned regimen tailored to the in- half as basal insulin to control glycemia intramuscularly. Recommended sites for dividual patient to keep them safe, out of in the periods between meal absorption insulin injection include the abdomen, diabetic ketoacidosis, and avoid signifi- (18); this guideline provides detailed in- thigh, buttock, and upper arm. Because cant hypoglycemia, with every effort formation on intensification of therapy insulin absorption from IM sites differs made to reach the patient’s glycemic to meet individualized needs. In addi- according to the activity of the muscle, targets. tion, the American Diabetes Association inadvertent IM injection can lead to un- Most studies comparing multiple daily position statement “Type 1 Diabetes predictable insulin absorption and vari- injections with CSII have been rela- Management Through the Life Span” able effects on glucose, with IM injection tively small and of short duration. How- provides a thorough overview of type 1 being associated with frequent and unex- ever, a recent systematic review and diabetes treatment (19). plained hypoglycemia in several reports. S100 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

Risk for IM insulin delivery is increased in to insulin therapy caused at treatment initiation to extend younger, leaner patients when injecting small (0.2%) reductions in A1C compared thetimetotreatmentfailure.A into the limbs rather than truncal sites with insulin alone in people with type 1 9.7 The early introduction of insulin (abdomen and buttocks) and when using diabetes and also reduced body weight should be considered if there is longer needles. Recent evidence supports by ;3 kg (29). Similarly, the addition evidence of ongoing catabolism the use of short needles (e.g., 4-mm pen of a sodium–glucose cotransporter 2 (weight loss), if symptoms of needles) as effective and well tolerated (SGLT2) inhibitor to insulin therapy has hyperglycemia are present, or when compared with longer needles, been associated with improvements in when A1C levels (.10% [86 including a study performed in obese A1C and body weight when compared mmol/mol]) or blood glucose lev- adults (24). with insulin alone (30,31); however, SGLT2 els ($300 mg/dL [16.7 mmol/L]) Injection site rotation is additionally inhibitor use in type 1 diabetes is associ- are very high. E necessary to avoid lipohypertrophy, an ated with a two- to fourfold increase 9.8 A patient-centered approach accumulation of subcutaneous fat in re- in ketoacidosis. The risks and benefits should be used to guide the sponse tothe adipogenicactions ofinsulin of adjunctive agents continue to be eval- choice of pharmacologic agents. at a site of multiple injections. Lipohyper- uated, but only is approved Considerations include cardiovas- trophy appears as soft, smooth raised for treatment of type 1 diabetes. cular comorbidities, hypoglycemia areas several centimeters in breadth risk,impactonweight,cost, riskfor and can contribute to erratic insulin ab- SURGICAL TREATMENT FOR TYPE 1 side effects, and patient preferen- sorption, increased glycemic variability, DIABETES ces (Table 9.2 and Figure 9.1). E and unexplained hypoglycemic episodes. Pancreas and Islet Transplantation 9.9 Among patients with type 2 di- Patients and/or caregivers should receive Successful pancreas and islet transplan- abetes who have established education about proper injection site ro- tation can normalize glucose levels and atherosclerotic cardiovascular tation and to recognize and avoid areas mitigate microvascular complications of disease or indicators of high risk, of lipohypertrophy. As noted in Table 4.1, type 1 diabetes. However, patients re- established kidney disease, or heart examination of insulin injection sites for ceiving these treatments require life- failure, a sodium–glucose cotrans- the presence of lipohypertrophy, as well long immunosuppression to prevent porter 2 inhibitor or glucagon-like as assessment of injection device use graft rejection and/or recurrence of peptide 1 receptor agonist with and injection technique, are key compo- autoimmune islet destruction. Given the demonstrated cardiovascular dis- nents of a comprehensive diabetes med- potential adverse effects of immunosup- ease benefit(Table 9.1, Table 10 ical evaluation and treatment plan. As pressive therapy, pancreas transplan- .3B,Table10.3C)isrecommended referenced above, there are now numer- tation should be reserved for patients as part of the glucose-lowering ous evidence-based insulin delivery rec- with type 1 diabetes undergoing si- regimen independent of A1C and ommendations that have been published. multaneous renal transplantation, fol- in consideration of patient-specific Proper insulin injection technique may lowing renal transplantation, or for those factors (Figure 9.1). A lead to more effective use of this therapy with recurrent ketoacidosis or severe 9.10 In patients with and, as such, holds the potential for im- hypoglycemia despite intensive glycemic who need greater glucose low- proved clinical outcomes. management (32). With the advent of ering than can be obtained with improved continuous glucose monitors, oral agents, glucagon-like pep- closed-loop pump-sensor systems, and Noninsulin Treatments for Type 1 tide 1 receptor agonists are pre- devices that offer alternative approaches Diabetes ferredtoinsulinwhenpossible.B Injectable and oral glucose-lowering for patients with hypoglycemia unaware- 9.11 Intensification of treatment for drugs have been studied for their efficacy ness, the role of pancreas transplantation patients with type 2 diabetes as adjuncts to insulin treatment of type 1 alone, as well as islet transplant, will need not meeting treatment goals diabetes. Pramlintide is based on the to be reconsidered. should not be delayed. B naturally occurring b-cell peptide 9.12 The medication regimen and and is approved for use in adults with PHARMACOLOGIC THERAPY FOR medication-taking behavior type 1 diabetes. Results from random- TYPE 2 DIABETES should be reevaluated at regular ized controlled studies show variable Recommendations intervals (every 3–6 months) and reductions of A1C (0–0.3%) and body 9.4 is the preferred ini- adjusted as needed to incorpo- weight (1–2 kg) with addition of pram- tial pharmacologic agent for rate specificfactorsthatimpact lintide to insulin (25,26). Similarly, re- the treatment of type 2 diabetes. choice of treatment (Fig. 4.1 and sults have been reported for several A Table 9.1). E agents currently approved only for 9.5 Once initiated, metformin should the treatment of type 2 diabetes. The be continued as long as it is tol- addition of metformin to adults with The American Diabetes Association/ erated and not contraindicated; type 1 diabetes caused small reductions European Association for the Study of other agents, including insulin, in body weight and lipid levels but did Diabetes consensus report “Manage- should be added to metformin. A not improve A1C (27,28). The addition ment of Hyperglycemia in Type 2 Di- 9.6 Early combination therapy can of the glucagon-like peptide 1 (GLP-1) abetes, 2018” and the 2019 update be considered in some patients receptor agonists (RAs) and (33,34) recommend a patient-centered aedaeejunl.r hraooi prahst lcmcTetetS101 Treatment Glycemic to Approaches Pharmacologic care.diabetesjournals.org Table 9.1—Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes

*For agent-specific dosing recommendations, please refer to the manufacturers’ prescribing information. †FDA approved for CVD benefit. ‡FDA-approved for heart failure indication; §FDA-approved for CKD indication. CV, cardiovascular; DPP-4, dipeptidyl peptidase 4; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; GLP-1 RAs, glucagon-like peptide 1 receptor agonists; HF, heart failure; NASH, nonalcoholic steatohepatitis; SGLT2, sodium–glucose cotransporter 2; SQ, subcutaneous; T2DM, type 2 diabetes. S102 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

approach to choosing appropriate phar- very high circulating levels (e.g., as a re- positive and negative effects of new drugs macologic treatment of blood glucose sult of overdose or acute renal failure) and reduces patient risk and expense (42); (Fig. 9.1). This includes consideration of have been associated with lactic acidosis. based on these factors, sequential addi- efficacy and key patient factors: 1)im- However, the occurrence of this compli- tion of oral agents to metformin has been portant comorbidities such as atheroscle- cation is now known to be very rare, and the standard of care. However, there is rotic cardiovascular disease (ASCVD) and metformin may be safely used in patients data to support initial combination ther- indicators of high ASCVD risk, chronic with reduced estimated glomerular filtra- apyfor morerapidattainment of glycemic kidney disease (CKD), and heart failure tion rates (eGFR); the FDA has revised the goals (43,44), and a recent clinical trial (HF) (see Section 10 “Cardiovascular Dis- label for metformin to reflect its safety in has demonstrated that this approach is ease and Risk Management,” https://doi patients with eGFR $30 mL/min/1.73 m2 superior to sequential addition of medica- .org/10.2337/dc20-S010, and Section 11 (37). A recent randomized trial confirmed tionsforextendingprimary andsecondary “Microvascular Complications and Foot previousobservations that metforminuse failure (45). In the VERIFY trial, partic- Care,” https://doi.org/10.2337/dc20-S011), is associated with vitamin B12 deficiency ipants receiving the initial combination of 2) hypoglycemia risk, 3) effects on body and worsening of symptoms of neurop- metformin and the dipeptidyl peptidase 4 weight, 4) side effects, 5) cost, and 6) athy (38). This is compatible with a recent (DPP-4) inhibitor vildagliptin had a slower patient preferences. Lifestyle modifica- report from the Diabetes Prevention Pro- decline of glycemic control compared tions that improve health (see Section gramOutcomesStudy(DPPOS)suggesting with metformin alone and to vildagliptin 5 “Facilitating Behavior Change and periodic testing of vitamin B12 (39). added sequentially to metformin. These Well-being to Improve Health Outcomes,” In patients with contraindications or results have not been generalized to oral https://doi.org/10.2337/dc20-S005) should intolerance to metformin, initial therapy agents other than vildagliptin, but they be emphasized along with any pharma- should be based on patient factors; suggest that more intensive early treat- cologic therapy. Section 12 “Older Adults” consider a drug from another class de- ment has some benefits and should be (https://doi.org/10.2337/dc20-S012)andSec- picted in Fig. 9.1. When A1C is $1.5% considered through a shared decision- tion 13 “Children and Adolescents” (12.5 mmol/mol) above the glycemic making process with patients, as appropriate. (https://doi.org/10.2337/dc20-S013) target (see Section 6 “Glycemic Targets,” Moreover, since the absolute effectiveness have recommendations specific for older https://doi.org/10.2337/dc20-S006, for of most oral medications rarely exceeds adults and for children and adolescents selecting appropriate targets), many pa- 1%, initial combination therapy should be with type 2 diabetes, respectively; Sec- tients will require dual combination ther- considered in patients presenting with tion 10 “Cardiovascular Disease and Risk apy to achieve their target A1C level (40). A1C levels 1.5–2.0% above target. Management” (https://doi.org/10.2337/ Insulin has the advantage of being effec- The choice of medication added to dc20-S010) and Section 11 “Microvascular tive where other agents are not and should metformin is based on the clinical char- Complications and Foot Care” (https://doi be considered as part of any combination acteristics of the patient and their pref- .org/10.2337/dc20-S011)haverecommen- regimen when hyperglycemia is severe, erences. Important clinical characteristics dations for the use of glucose-lowering especially if catabolic features (weight include the presence of established drugs in the management of cardiovascular loss, hypertriglyceridemia, ketosis) are ASCVD or indicators of high ASCVD risk, and renal disease, respectively. present. It is common practice to initiate other comorbidities, and risk for specific insulin therapy for patients who present adverse drug effects, as well as safety, Initial Therapy with blood glucose levels $300 mg/dL tolerability, and cost. Although there are Metformin should be started at the time (16.7 mmol/L) or A1C .10% (86 mmol/mol) numerous trials comparing dual therapy type 2 diabetes is diagnosed unless there or if the patient has symptoms of hy- with metformin alone, there is little ev- are contraindications; for many patients perglycemia (i.e., polyuria or polydipsia) idence to support one combination over this will be monotherapy in combination or evidence of catabolism (weight loss) another. A comparative effectiveness with lifestyle modifications. Metformin (Fig. 9.2). As glucose toxicity resolves, meta-analysis suggests that each new is effective and safe, is inexpensive, and simplifying the regimen and/or changing class of noninsulin agents added to initial may reduce risk of cardiovascular events to oral agents is often possible. However, therapy with metformin generally lowers and death (35). Metformin is available in there is evidence that patients with un- A1C approximately 0.7–1.0% (46,47). If the an immediate-release form for twice- controlled hyperglycemia associated with A1C target is not achieved after approxi- daily dosing or as an extended-release type 2 diabetes can also be effectively mately 3 months, metformin can be com- form that can be given once daily. Com- treated with a (41). bined with any one of the preferred six pared with , metformin as treatment options: sulfonylurea, thiazolidine- first-line therapy has beneficial effects on Combination Therapy dione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 A1C, weight, and cardiovascular mortal- Because type 2 diabetes is a progressive RA, or basal insulin; the choice of which agent ity (36); there is little systematic data disease in many patients, maintenance of to add is based on drug-specificeffectsand available for other oral agents as initial glycemic targets with monotherapy is patient factors (Fig. 9.1 and Table 9.1). therapy of type 2 diabetes. The principal often possible for only a few years, after Forpatients withestablished ASCVD or side effects of metformin are gastroin- which combination therapy is necessary. indicators of high ASCVD risk (such as testinal intolerance due to bloating, ab- Current recommendations have been to patients $55 years of age with coronary, dominal discomfort, and diarrhea; these use stepwise addition of medications carotid, or lower-extremity artery steno- canbemitigated bygradualdosetitration. tometformintomaintainA1Cattarget. sis .50% or left ventricular hypertro- The drug is cleared by renal filtration, and This allows a clearer assessment of the phy), established kidney disease, or heart aedaeejunl.r hraooi prahst lcmcTetetS103 Treatment Glycemic to Approaches Pharmacologic care.diabetesjournals.org

Figure 9.1—Glucose-lowering medication in type 2 diabetes: overall approach. For appropriate context, see Fig. 4.1. ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOTs, cardiovascular outcomes trials; DPP-4i, dipeptidyl peptidase 4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SU, sulfonylurea; TZD, . Adapted from Davies and colleagues (33,34). S104 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

Figure9.2—Intensifyingtoinjectabletherapies.DSMES,diabetesself-managementeducationandsupport;FPG,fastingplasmaglucose;FRC,fixed-ratio combination; GLP-1 RA, glucagon-like peptide 1 receptor agonist; max, maximum; PPG, postprandial glucose. Adapted from Davies et al. (33). care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S105

failure, an SGLT-2 inhibitor or GLP-1 RA with preferred option for patients requiring Insulin Therapy demonstrated CVD benefit(Table 9.1, the potency of an injectable therapy for Many patients with type 2 diabetes even- Table 10.3B, Table 10.3C) is recommended glucose control (Fig. 9.2). However, high tually require and benefit from insulin as part of the glucose-lowering regimen costs and tolerability issues are impor- therapy (Fig. 9.2). See the section INSULIN independent ofA1C and in consideration of tant barriers to the use of GLP-1 RAs. INJECTION TECHNIQUE above, for guidance on patient-specificfactors(Figure 9.1). For Cost for diabetes medicine has in- how to administer insulin safely and patients without established ASCVD, indi- creased dramatically over the past two effectively. The progressive nature of catorsofhighASCVDrisk,HF,orCKD,the decades, and an increasing proportion is type 2 diabetes should be regularly choice of a second agent to add to met- now passed on to patients and their families and objectively explained to patients, formin is not yet guided by empiric evi- (53). Table 9.2 provides cost information for and providers should avoid using insulin dence. Rather, drug choice is based on currently approved noninsulin therapies. Of as a threat or describing it as a sign of avoidance of side effects, particularly hy- note, prices listed are average wholesale personal failure or punishment. Rather, poglycemia and weight gain, cost, and prices (AWP) (54) and National Average the utility and importance of insulin to patient preferences (48). Similar consider- Drug Acquisition Costs (NADAC) (55), sep- maintain glycemic control once progres- ations are applied in patients who require a arate measures to allow for a comparison of sion of the disease overcomes the effect of third agent to achieve glycemic goals; there drug prices but do notaccountfor discounts, other agents should be emphasized. Ed- is very little trial-based evidence to guide rebates, or other price adjustments often ucating and involving patients in insulin this choice. In all cases,treatment regimens involved in prescription sales that affect the management is beneficial. For example, need to be continuously reviewed for actual cost incurred by the patient. Med- instruction of patients in self-titration of efficacy, side effects, and patient burden ication costs can be a major source of stress insulin doses based on self-monitoring of (Table 9.1). In some instances, patients will for patients with diabetes and contribute to blood glucose improves glycemic control require medication reduction or discontin- worse adherence with medications (56); in patients with type 2 diabetes initiating uation. Common reasons for this include cost-reducing strategies may improve ad- insulin (58). Comprehensive education re- ineffectiveness, intolerable side effects, ex- herence in some cases (57). garding self-monitoring of blood glucose, pense, or a change in glycemic goals (e.g., in diet, and the avoidance and appropriate response to development of comorbidities Cardiovascular Outcomes Trials treatment of hypoglycemia are critically or changes in treatment goals). Section There are now multiple large randomized important in any patient using insulin. 12 “Older Adults”(https://doi.org/10.2337/ controlled trials reporting statistically dc20-S012) has a full discussion of treat- significant reductions in cardiovascular Basal Insulin ment considerations in older adults, a events in patients with type 2 diabetes Basal insulinalone isthe most convenient settingwhere changes of glycemic goals treated with an SGLT2 inhibitor (em- initial insulin regimen and can be added and de-escalation of therapy is common. pagliflozin, canagliflozin, dapagliflozin) to metformin and other oral agents. Although most patients prefer oral or GLP-1 RA (liraglutide, , Starting doses can be estimated based medications to drugs that need to be ); see Section 10 “Cardiovas- on body weight (0.1–0.2 units/kg/day) injected, the eventual need for the cular Disease and Risk Management” and the degree of hyperglycemia, with greater potency of injectable medica- (https://doi.org/10.2337/dc20-S010) for individualized titration over days to weeks tions is common, particularly in people details. The subjects enrolled in the cardio- as needed. The principal action of basal with a longer duration of diabetes. The vascular outcome trials using empagliflozin, insulinistorestrainhepaticglucosepro- addition of basal insulin, either human canagliflozin, liraglutide, and semaglutide duction and limit hyperglycemia overnight NPH or one of the long-acting insulin had A1C $7%, and more than 70% were and between meals (59,60). Control of analogs, to oral agent regimens is a well- taking metformin at baseline. Thus, a prac- fasting glucose can be achieved with established approach that is effective for tical extension of these results to clinical human NPH insulin or a long-acting insulin many patients. In addition, recent evi- practice is to use these drugs preferen- analog. In clinical trials, long-acting basal dence supports the utility of GLP-1 RAs in tially in patients with type 2 diabetes and analogs (U-100 glargine or detemir) have patients not reaching glycemic targets established ASCVD or indicators of high been demonstrated to reduce the risk of with use of non-GLP-1 RA oral agent ASCVD risk. For these patients, incorpo- symptomaticandnocturnalhypoglycemia regimens. While most GLP-1 RA products rating one of the SGLT2 inhibitors or compared with NPH insulin (61–66), al- are injectable, an oral formulation of GLP-1 RAs that have been demonstrated though these advantages are modest and semaglutide is now commercially avail- to have cardiovascular disease benefitis may not persist (67). Longer-acting basal able (49). In trials comparing the ad- recommended (Table 9.1). In cardiovascular analogs (U-300 glargine or degludec) may dition of an injectable GLP-1 RAs or outcomes trials, empagliflozin, canagliflozin, convey a lower hypoglycemia risk com- insulin in patients needing further glu- dapagliflozin, liraglutide, semaglutide, and pared with U-100 glargine when used in cose lowering, the efficacy of the two dulaglutide all had beneficial effects on combination with oral agents (68–74). treatments was similar (50–52). How- indices of CKD. See Section 11 “Microvas- Despite evidence for reduced hypoglyce- ever, GLP-1 RAs in these trials had a cular Complications and Foot Care”(https:// mia with newer, longer-acting basal in- lower risk of hypoglycemia and beneficial doi.org/10.2337/dc20-S011) for a detailed sulin analogs in clinical trial settings, in effects on body weight compared with discussion on how CKD may impact treat- practice these effects may be modest insulin, albeit with greater gastroin- ment choices. Additional large randomized compared with NPH insulin (75). testinal side effects. Thus, trial results trials of other agents in these classes are The cost of insulin has been rising support injectable GLP-1 RAs as the ongoing. steadily over the past two decades, at S106 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

Table 9.2—Median monthly (30-day) cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S. Dosage strength/product Median AWP Median NADAC Maximum approved Class Compound(s) (if applicable) (min, max)† (min, max)† daily dose* c Metformin 500 mg (IR) $84 ($4, $85) $2 2,000 mg 850 mg (IR) $108 ($6, $109) $3 2,550 mg 1,000 mg (IR) $87 ($4, $88) $2 2,000 mg 500 mg (ER) $89 ($87, $7,412) $5 ($5, $988) 2,000 mg 750 mg (ER) $74 ($65, $74) $4 1,500 mg 1,000 mg (ER) $242 ($242, $7,214) $224 ($224, $910) 2,000 mg Sulfonylureas (2nd c 4 mg $74 ($71, $198) $4 8 mg generation) c 10 mg (IR) $75 ($67, $97) $5 40 mg (IR) 10 mg (XL) $48 $15 20 mg (XL) c Glyburide 6 mg (micronized) $50 ($48, $71) $4 12 mg (micronized) 5 mg $93 ($63, $103) $11 20 mg c 45 mg $348 ($283, $349) $4 45 mg c 4 mg $407 $330 8 mg a-Glucosidase c 100 mg $106 ($104, $106) $23 300 mg inhibitors c 100 mg $241 $311 300 mg (glinides) c 120 mg $155 $39 360 mg c 2 mg $878 ($162, $897) $39 16 mg DPP-4 inhibitors c 25 mg $234 $168 25 mg c 5 mg $505 $403 5 mg c 5 mg $523 $419 5 mg c 100 mg $541 $433 100 mg SGLT2 inhibitors c Ertugliflozin 15 mg $338 $271 15 mg c Dapagliflozin 10 mg $591 $473 10 mg c Empagliflozin 25 mg $591 $473 25 mg c Canagliflozin 300 mg $593 $475 300 mg GLP-1 RAs c Exenatide (extended release) 2 mg powder for $840 $672 2 mg** suspension or pen c Exenatide 10 mg pen $876 $730 20 mg c Dulaglutide 1.5/0.5 mL pen $911 $730 1.5 mg** c Semaglutide 1 mg pen $927 $745 1 mg** 14 mg (tablet) $927 N/A 14 mg c Liraglutide 18 mg/3 mL pen $1,106 $886 1.8 mg c 300 mg/3 mL pen $744 N/A 20 mg Bile acid sequestrant c Colesevelam 625 mg tabs $712 ($674, $712) $177 3.75 g 3.75 g suspension $675 $415 3.75 g Dopamine-2 agonist c 0.8 mg $906 $729 4.8 mg Amylin mimetic c Pramlintide 120 mg pen $2,623 $2,097 120 mg/injection††† AWP, average wholesale price; DPP-4, dipeptidyl peptidase 4; ER and XL, extended release; GLP-1 RA, glucagon-like peptide 1 receptor agonist; IR, immediate release; N/A, data not available; NADAC, National Average Drug Acquisition Cost; SGLT2, sodium–glucose cotransporter 2. †Calculated for30-day supply (AWP[54]orNADAC[55]unitprice3 numberof dosesrequiredtoprovidemaximumapproveddailydose3 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.

a pace several fold that of other medical familiar with its use (75). Human regular patient needs (see Figure 9.2). People expenditures (76). This expense contrib- insulin, NPH, and 70/30 NPH/regular prod- with type 2 diabetes are generally more utes significant burden to patients as ucts can be purchased for considerably insulin resistant than those with type 1 insulin has become a growing “out-of- less than the AWP and NADAC prices listed diabetes, require higher daily doses (;1 pocket” cost for people with diabetes, in Table 9.3 at select pharmacies. unit/kg), and have lower rates of hypo- and direct patient costs contribute to glycemia (77). Titration can be based treatment nonadherence (76). Therefore, Prandial Insulin on home glucose monitoring or A1C. consideration of cost is an important com- Many individuals with type 2 diabetes With significant additions to the prandial ponent of effective management. For require doses of insulin before meals, in insulin dose, particularly with the evening many patients with type 2 diabetes addition to basal insulin, to reach glyce- meal, consideration should be given to (e.g., individuals with relaxed A1C goals, mic targets. A dose of 4 units or 10% of decreasing basal insulin. Meta-analyses low rates of hypoglycemia, and prominent the amount of basal insulin at the largest of trials comparing rapid-acting insulin insulin resistance, as well as those with meal or the meal with the greatest post- analogs with human in cost concerns), human insulin (NPH and prandial excursion is a safe estimate for patients with type 2 diabetes have not regular) may be the appropriate choice initiating therapy. The prandial insulin reported important differences in A1C of therapy, and clinicians should be regimen can then be intensified based on or hypoglycemia (78,79). care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S107

Table 9.3—Median cost of insulin products in the U.S. calculated as AWP (54) and NADAC (55) per 1,000 units of specified dosage form/product Insulins Compounds Dosage form/product Median AWP (min, max)* MedianNADAC(min, max)* Rapid-acting c Lispro follow-on U-100 vial $157 $126 product U-100 prefilled pen $202 $162 c Lispro U-100 vial $330 $264 U-100 3 mL cartridges $408 $327 U-100 prefilled pen; U-200 $424 $340 prefilled pen c Glulisine U-100 vial $341 $273 U-100 prefilled pen $439 $353 c Aspart U-100 vial $347† $278† U-100 3 mL cartridges $430 $345 U-100 prefilled pen $447† $358† c Inhaled insulin Inhalation cartridges $924 $606 Short-acting c human regular U-100 vial $165 ($165, $178)†† $134 ($134, $146)†† Intermediate-acting c human NPH U-100 vial $165 ($165, $178)†† $135 ($135, $146)†† U-100 prefilled pen $377 $304 Concentrated human c U-500 human regular U-500 vial $178 $144 regular insulin insulin U-500 prefilled pen $230 $184 Long-acting c Glargine follow-on U-100 prefilled pen $261 $210 product c Glargine U-100 vial; U-100 prefilled pen $340 $272 U-300 prefilled pen $346 $280 c Detemir U-100 vial; U-100 prefilled pen $370 $295 c Degludec U-100 vial; U-100 prefilled pen; $407 $326 U-200 prefilled pen Premixed insulin products c NPH/regular 70/30 U-100 vial $165 ($165, $178) $134 ($134, $145) U-100 prefilled pen $377 $303 c Lispro 50/50 U-100 vial $342 $274 U-100 prefilled pen $424 $338 c Lispro 75/25 U-100 vial $342 $274 U-100 prefilled pen $424 $340 c Aspart 70/30 U-100 vial $360 $289 U-100 prefilled pen $447 $358 Premixed insulin/GLP-1 RA c Glargine/Lixisenatide 100/33 prefilled pen $565 $454 products c Degludec/Liraglutide 100/3.6 prefilled pen $832 $668 AWP, average wholesale price; GLP-1, glucagon-like peptide 1; NADAC, National Average Drug Acquisition Cost. *AWP or NADAC calculated as in Table 9.2. †Inclusive of both the original and “faster-acting” products. ††AWP and NADAC data presented do not include vials of regular human insulin and NPH available at Walmart for approximately $25/vial; median listed alone when only one product and/or price.

Concentrated Insulins units/mL).Theseconcentrated preparations hypoglycemia or weight gain (83), al- Several concentrated insulin prepara- maybemoreconvenientandcomfortable though results from a larger study are tions are currently available. U-500 reg- for patients to inject and may improve needed for confirmation. Inhaled insulin ular insulin is, by definition, five times adherence in those with insulin resistance is contraindicated in patients with chronic more concentrated than U-100 regular who require large doses of insulin. While lung disease, such as asthma and chronic insulin. Regular U-500 has distinct phar- U-500 regular insulin is available in both obstructive pulmonary disease, and is not macokinetics with delayed onset and prefilled pens and vials (a dedicated syringe recommended in patients who smoke or longer duration of action, has character- was approved in July 2016), other concen- who recently stopped smoking. All pa- istics more like an intermediate-acting trated insulins are available only in prefilled tients require spirometry (FEV1) testing to (NPH) insulin, and can be used as two or pens to minimize the risk of dosing errors. identify potential lung diseaseprior to and three daily injections (80). U-300 glargine after starting inhaled insulin therapy. and U-200 degludec are three and two Inhaled Insulin times as concentrated as their U-100 Inhaled insulin is available for prandial Combination Injectable Therapy formulations, and allow higher doses use with a limited dosing range; studies in If basal insulin has been titrated to an of basal insulin administration per vol- people with type 1diabetes suggest rapid acceptable fasting blood glucose level (or ume used. U-300 glargine has a longer pharmacokinetics (7). A pilot study found if the dose is .0.5 units/kg/day) and A1C duration of action than U-100 glargine evidence that compared with injectable remains above target, consider advancing but modestly lower efficacy per unit rapid-acting insulin, supplemental doses to combination injectable therapy (Fig. administered (81,82). The FDA has also of inhaled insulin taken based on post- 9.2). This approach can use a GLP-1 RA approved a concentrated formulation of prandial glucose levels may improve blood added to basal insulin or multiple doses of rapid-acting , U-200 (200 glucose management without additional insulin. The combination of basal insulin S108 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

and GLP-1 RA has potent glucose-lower- in type 1 diabetic participants of the Diabetes 15. Bergenstal RM, Garg S, Weinzimer SA, et al. ing actions and less weight gain and hypo- Control and Complications Trial/Epidemiology of Safety of a hybrid closed-loop insulin delivery fi Diabetes Interventions and Complications (DCCT/ system in patients with type 1 diabetes. JAMA glycemia compared with intensi ed insulin – – – EDIC) study. Diabetes 2006;55:3556 3565 2016;316:1407 1408 regimens (84 86). Two different once-daily 2. Nathan DM, Cleary PA, Backlund J-YC, et al.; 16. Garg SK, Weinzimer SA, Tamborlane WV, fixed-dual combination products contain- Diabetes Control and Complications Trial/ et al. Glucose outcomes with the in-home use of a ing basal insulin plus a GLP-1 RA are Epidemiology of Diabetes Interventions and hybrid closed-loop insulin delivery system in ado- available: plus lixisenatide Complications (DCCT/EDIC) Study Research Group. lescents and adults with type 1 diabetes. Diabetes – and plus liraglutide. Intensive diabetes treatment and cardiovascular Technol Ther 2017;19:155 163 disease in patients with type 1 diabetes. N Engl J fi 17. Tauschmann M, Thabit H, Bally L, et al.; Intensi cation of insulin treatment can Med 2005;353:2643–2653 APCam11 Consortium. Closed-loop insulin de- be done by adding doses of prandial to 3. Diabetes Control and Complications Trial livery in suboptimally controlled type 1 diabetes: basal insulin. Starting with a single pran- (DCCT)/Epidemiology of Diabetes Interventions a multicentre, 12-week randomised trial. Lancet dial dose with the largest meal of the day and Complications (EDIC) Study Research Group. 2018;392:1321–1329 Mortality in type 1 diabetes in the DCCT/EDIC is simple and effective, and it can be 18. Peters A, Laffel L (Eds.). American Diabetes versus the general population. Diabetes Care Association/JDRF Type 1 Diabetes Sourcebook. advanced to a regimen with multiple 2016;39:1378–1383 Alexandria, VA, American Diabetes Association, prandial doses if necessary (87). Alter- 4. Tricco AC, Ashoor HM, Antony J, et al. Safety, 2013 natively, in a patient on basal insulin in effectiveness, and cost effectiveness of long 19. Chiang JL,KirkmanMS,LaffelLMB,PetersAL; whom additional prandial coverage is acting versus intermediate acting insulin for pa- Type 1 Diabetes Sourcebook Authors. Type 1 di- tients with type 1 diabetes: systematic review desired, the regimen can be converted abetes through the life span: a position state- and network meta-analysis. BMJ 2014;349:g5459 ment of the American Diabetes Association. to two doses of a premixed insulin. Each 5. Bartley PC, Bogoev M, Larsen J, Philotheou A. Diabetes Care 2014;37:2034–2054 approach has advantages and disadvan- Long-term efficacy and safety of 20. Bell KJ, Barclay AW, Petocz P, Colagiuri S, tages. For example, basal/prandial regi- compared to Neutral Protamine Hagedorn in- Brand-Miller JC. Efficacy of carbohydrate count- mens offer greater flexibility for patients sulin in patients with type 1 diabetes using a ing in type 1 diabetes: a systematic review and treat-to-target basal-bolus regimen with insulin who eat on irregular schedules. On the meta-analysis. Lancet Diabetes Endocrinol 2014; aspart at meals: a 2-year, randomized, controlled 2:133–140 other hand, two doses of premixed in- trial. Diabet Med 2008;25:442–449 21. Vaz EC, Porf´ırio GJM, Nunes HRC, Nunes- sulin is a simple, convenient means of 6. DeWitt DE, Hirsch IB. Outpatient insulin ther- Nogueira VDS. Effectiveness and safety of car- spreading insulin across the day. More- apy in type 1 and type 2 diabetes mellitus: bohydrate counting in the management of adult over, humaninsulins,separately,self-mixed, scientific review. JAMA 2003;289:2254–2264 patients with type 1 diabetes mellitus: a system- 7. BodeBW,McGillJB,LorberDL,GrossJL,Chang or as premixed NPH/regular (70/30) atic review and meta-analysis. Arch Endocrinol PC, Bregman DB; Affinity 1 Study Group. Inhaled Metab 2018;62:337–345 formulations, are less costly alternatives technosphere insulin compared with injected 22. Bell KJ, Smart CE, Steil GM, Brand-Miller JC, to insulin analogs. Figure 9.2 outlines prandial insulin in type 1 diabetes: a randomized King B, Wolpert HA. Impact of fat, protein, and these options, as well as recommendations 24-week trial. Diabetes Care 2015;38:2266–2273 glycemic index on postprandial glucose control in for further intensification, if needed, to 8. Russell-Jones D, Bode BW, De Block C, et al. type 1 diabetes: implications for intensive diabetes Fast-acting insulin aspart improves glycemic con- achieve glycemic goals. When initiating management in the continuous glucose monitor- trol in basal-bolus treatment for type 1 diabetes: ing era. Diabetes Care 2015;38:1008–1015 combination injectable therapy, metformin results of a 26-week multicenter, active-controlled, 23. Frid AH, Kreugel G, Grassi G, et al. New insulin therapy should be maintained while sulfo- treat-to-target, randomized, parallel-group trial delivery recommendations. Mayo Clin Proc nylureas and DPP-4 inhibitors are typically (onset 1). Diabetes Care 2017;40:943–950 2016;91:1231–1255 discontinued. In patients with suboptimal 9. Lane W, Bailey TS, Gerety G, et al.; Group 24. Bergenstal RM, Strock ES, Peremislov D, Information; SWITCH 1. Effect of insulin degludec blood glucose control, especially those re- Gibney MA, Parvu V, Hirsch LJ. Safety and ef- vs insulin glargine U100 on hypoglycemia in ficacy of insulin therapy delivered via a 4mm pen quiring large insulin doses, adjunctive use patients with type 1 diabetes: the SWITCH 1 needle in obese patients with diabetes. Mayo of a thiazolidinedione or an SGLT2 inhibitor randomized clinical trial. JAMA 2017;318:33–44 Clin Proc 2015;90:329–338 mayhelptoimprovecontrol and reduce the 10. Home PD, Bergenstal RM, BolliGB, et al. New 25. RatnerRE,DickeyR, FinemanM,et al.Amylin amountofinsulin needed,though potential insulin glargine 300 units/mL versus glargine replacement with pramlintide as an adjunct to 100 units/mL in people with type 1 diabetes: side effects should be considered. Once a insulin therapy improves long-term glycaemic a randomized, phase 3a, open-label clinical and weight control in type 1 diabetes mellitus: basal/bolus insulin regimen is initiated, trial (EDITION 4). Diabetes Care 2015;38:2217– a1-year,randomizedcontrolledtrial.DiabetMed dose titration is important, with adjust- 2225 2004;21:1204–1212 ments made in both mealtime and basal 11. Yeh H-C, Brown TT, Maruthur N, et al. 26. Edelman S, Garg S, Frias J, et al. A double-blind, insulins based on the blood glucose levels Comparative effectiveness and safety of meth- placebo-controlled trial assessing pramlintide treat- ods of insulin delivery and glucose monitoring for and an understanding of the pharma- ment in the setting of intensive insulin therapy in diabetes mellitus: a systematic review and meta- type 1 diabetes. Diabetes Care 2006;29:2189–2195 codynamic profile of each formulation analysis. Ann Intern Med 2012;157:336–347 27. Meng H,ZhangA, LiangY,Hao J,Zhang X,Lu J. (pattern control). As people with type 2 12. Pickup JC. The evidence base for diabetes Effect of metformin on glycaemic control in diabetes get older, it may become necessary technology: appropriate and inappropriate meta- patients with type 1 diabetes: a meta-analysis – to simplify complex insulin regimens be- analysis. J Diabetes Sci Technol 2013;7:1567 1574 of randomized controlled trials. Diabetes Metab 13. Bergenstal RM, Klonoff DC, Garg SK, et al.; Res Rev 2018;34:e2983 cause of a decline in self-management ASPIRE In-Home Study Group. Threshold-based 28. Petrie JR, Chaturvedi N, Ford I, et al.; RE- ability (see Section 12 “Older Adults,” insulin-pump interruption for reduction of hy- MOVAL Study Group. Cardiovascular and met- https://doi.org/10.2337/dc20-S012). poglycemia. N Engl J Med 2013;369:224–232 abolic effects of metformin in patients with 14. Buckingham BA, Raghinaru D, Cameron F, type 1 diabetes (REMOVAL): a double-blind, et al.; In Home Closed Loop Study Group. Predictive randomised, placebo-controlled trial. Lancet Di- References low-glucose insulin suspension reduces duration of abetes Endocrinol 2017;5:597–609 1. Cleary PA, Orchard TJ, Genuth S, et al.; DCCT/ nocturnal hypoglycemia in children without in- 29. Wang W, Liu H, Xiao S, Liu S, Li X, Yu P. Effects EDIC Research Group. The effect of intensive creasing ketosis. Diabetes Care 2015;38:1197– of insulin plus glucagon-like peptide-1 receptor glycemic treatment on coronary artery calcification 1204 agonists (GLP-1RAs) in treating type 1 diabetes care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S109

mellitus: a systematic review and meta-analysis. than sequential add-on therapy in subjects adults with diabetes. Diabetes Res Clin Pract Diabetes Ther 2017;8:727–738 with new-onset diabetes. Results from the Effi- 2018;143:24–33 30. Dandona P, Mathieu C, Phillip M, et al.; cacy and Durability of Initial Combination Ther- 57. Patel MR, Piette JD, Resnicow K, Kowalski- DEPICT-1 Investigators. Efficacy and safety of apy for Type 2 Diabetes (EDICT): a randomized Dobson T, Heisler M. Social determinants of dapagliflozin in patients with inadequately con- trial. Diabetes Obes Metab 2015;17:268–275 health, cost-related nonadherence, and cost- trolled type 1 diabetes (DEPICT-1): 24 week 44. Phung OJ, Sobieraj DM, Engel SS, Rajpathak reducing behaviors among adults with diabetes: results from a multicentre, double-blind, phase SN. Early combination therapy for the treatment findings from the National Health Interview 3, randomised controlled trial. Lancet Diabetes of type 2 diabetes mellitus: systematic review Survey. Med Care 2016;54:796–803 Endocrinol 2017;5:864–876 and meta-analysis. Diabetes Obes Metab 2014; 58. Blonde L, Merilainen M, Karwe V, Raskin P; 31. Rosenstock J, Marquard J, Laffel LM, et al. 16:410–417 TITRATE Study Group. Patient-directed titration for Empagliflozin as adjunctive to insulin therapy in 45. Matthews DR, Paldanius´ PM, Proot P, Chiang achieving glycaemic goals using a once-daily basal type 1 diabetes: the EASE trials. Diabetes Care Y, Stumvoll M, Prato SD; VERIFY study group. insulin analogue: an assessment of two different 2018;41:2560–2569 Glycaemic durability of an early combination fasting plasma glucose targets - the TITRATE study. 32. Dean PG, Kukla A, Stegall MD, Kudva Y. therapy with vildagliptin and metformin versus Diabetes Obes Metab 2009;11:623–631 Pancreas transplantation. BMJ 2017;357:j1321 sequential metformin monotherapy in newly 59. Porcellati F, Lucidi P, Cioli P, et al. Pharma- 33. Davies MJ, D’Alessio DA, Fradkin J, et al. diagnosed type 2 diabetes (VERIFY): a 5-year, cokinetics and pharmacodynamics of insulin Management of hyperglycemia in type 2 diabe- multicentre, randomised, double-blind trial. Lan- glargine given in the evening as compared tes, 2018. A consensus report by the American cet 2019;394:1519–1529 with in the morning in type 2 diabetes. Diabetes Diabetes Association (ADA) and the European 46. Bennett WL, Maruthur NM, Singh S, et al. Care 2015;38:503–512 Association for the Study of Diabetes (EASD). Comparative effectiveness and safety of medi- 60. Wang Z, Hedrington MS, Gogitidze Joy N, et al. Diabetes Care 2018;41:2669–2701 cations for type 2 diabetes: an update including Dose-response effects of insulin glargine in type 34. Buse JB, Wexler DJ, Tsapas A, Rossing P, new drugs and 2-drug combinations. Ann Intern 2 diabetes. Diabetes Care 2010;33:1555–1560 Mingrone G, Mathieu C, et al. 2019 update to: Med 2011;154:602–613 61. Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett management of hyperglycemia in type 2 diabe- 47. Maloney A, Rosenstock J, Fonseca V. A H. Efficacy and safety of insulin analogues for tes, 2018: a consensus report by the American model-based meta-analysis of 24 antihypergly- the management of diabetes mellitus: a meta- Diabetes Association (ADA) and the European cemic drugs for type 2 diabetes: comparison of analysis. CMAJ 2009;180:385–397 Association for the Study of Diabetes (EASD). treatment effects at therapeutic doses. Clin 62. Horvath K, Jeitler K, Berghold A, et al. Long- Diabetes Care 19 December 2019 [Epub ahead of Pharmacol Ther 2019;105:1213–1223 acting insulin analogues versus NPH insulin (hu- print].DOI: 10.2337/dci19-0066 48. Vijan S, Sussman JB, Yudkin JS, Hayward RA. manisophane insulin) for type 2 diabetesmellitus. 35. Holman RR, Paul SK, Bethel MA, Matthews Effect of patients’ risks and preferences on Cochrane Database Syst Rev 2007 (2):CD005613 DR, Neil HAW. 10-year follow-up of intensive health gains with plasma glucose level lowering 63. Monami M, Marchionni N, Mannucci E. glucose control in type 2 diabetes. N Engl J Med in type 2 diabetes mellitus. JAMA Intern Med Long-acting insulin analogues versus NPH human 2008;359:1577–1589 2014;174:1227–1234 insulin in type 2 diabetes: a meta-analysis. Di- 36. Maruthur NM, Tseng E, Hutfless S, et al. 49. Pratley R, Amod A, Hoff ST, et al.; PIONEER abetes Res Clin Pract 2008;81:184–189 Diabetes medications as monotherapy or metfor- 4 investigators. Oral semaglutide versus sub- 64. Owens DR, Traylor L, Mullins P, Landgraf W. min-based combination therapy for type 2 diabe- cutaneous liraglutide and placebo in type 2 di- Patient-level meta-analysis of efficacy and hypo- tes: a systematic review and meta-analysis. Ann abetes (PIONEER 4): a randomised, double-blind, glycaemia in people with type 2 diabetes ini- Intern Med 2016;164:740–751 phase 3a trial. Lancet 2019;394:39–50 tiating insulin glargine 100U/mL or neutral 37. U.S. Food and Drug Administration. FDA 50. Singh S, Wright EE Jr, Kwan AYM, et al. protamine Hagedorn insulin analysed according Drug Safety Communication: FDA revises warn- Glucagon-like peptide-1 receptor agonists com- to concomitant oral antidiabetes therapy. Di- ings regarding use of the diabetes medicine pared with basal insulins for the treatment of abetes Res Clin Pract 2017;124(Supplement C): metformin in certain patients with reduced kid- type 2 diabetes mellitus: a systematic review and 57–65 ney function. Accessed 1 November 2019. Avail- meta-analysis. Diabetes Obes Metab 2017;19: 65. Riddle MC, Rosenstock J, Gerich J; Insulin able from http://www.fda.gov/Drugs/DrugSafety/ 228–238 Glargine 4002 Study Investigators. The treat-to- ucm493244.htm 51. Levin PA, Nguyen H, Wittbrodt ET, Kim SC. target trial: randomized addition of glargine or 38. Out M, Kooy A, Lehert P, Schalkwijk CA, Glucagon-like peptide-1 receptor agonists: human NPH insulin to oral therapy of type 2 Stehouwer CDA. Long-term treatment with met- a systematic review of comparative effectiveness diabetic patients. Diabetes Care 2003;26:3080– formin in type 2 diabetes and methylmalonic acid: research. Diabetes Metab Syndr Obes 2017;10: 3086 post hoc analysis of a randomized controlled 4.3year 123–139 66. Hermansen K, Davies M, Derezinski T, trial. J Diabetes Complications 2018;32:171–178 52. Abd El Aziz MS, Kahle M, Meier JJ, Nauck MA. Martinez Ravn G, Clauson P, Home P. A 39. Aroda VR, Edelstein SL, Goldberg RB, et al.; A meta-analysis comparing clinical effects of 26-week, randomized, parallel, treat-to-target Diabetes Prevention Program Research Group. short- or long-acting GLP-1 receptor agonists trial comparing insulin detemir with NPH insulin Long-term metformin use and vitamin B12 de- versus insulin treatment from head-to-head as add-on therapy to oral glucose-lowering drugs ficiency in the Diabetes Prevention Program studies in type 2 diabetic patients. Diabetes in insulin-naive people with type 2 diabetes. Outcomes Study. J Clin Endocrinol Metab Obes Metab 2017;19:216–227 Diabetes Care 2006;29:1269–1274 2016;101:1754–1761 53. Riddle MC, Herman WH. The cost of diabetes 67. Yki-Jarvinen¨ H, Kauppinen-Makelin¨ R, 40. Henry RR, Murray AV, Marmolejo MH, care-an elephant in the room. Diabetes Care Tiikkainen M, et al. Insulin glargine or NPH Hennicken D, Ptaszynska A, List JF. Dapagliflozin, 2018;41:929–932 combined with metformin in type 2 diabetes: metformin XR, or both: initial pharmacotherapy 54. Truven Health Analytics. Micromedex 2.0 the LANMET study. Diabetologia 2006;49:442– for type 2 diabetes, a randomised controlled Introduction to RED BOOK Online, 2018. Accessed 451 trial. Int J Clin Pract 2012;66:446–456 1 November 2019. Available from http://www 68. Bolli GB, Riddle MC, Bergenstal RM, et al.; on 41. Babu A, Mehta A, Guerrero P, et al. Safe and .micromedexsolutions.com/micromedex2/ behalf of the EDITION 3 study investigators. New simple emergency department discharge therapy 4.34.0/WebHelp/RED_BOOK/Introduction_to_ insulinglargine 300 U/mlcomparedwith glargine for patients with type 2 diabetes mellitus and severe REDB_BOOK_Online.htm 100 U/ml in insulin-na¨ıve people with type 2 hyperglycemia. Endocr Pract 2009;15:696–704 55. Centers for Medicare & Medicaid Services. diabetes on oral glucose-lowering drugs: a ran- 42. Cahn A, Cefalu WT. Clinical considerations NADAC (national average drug acquisition cost), domized controlled trial (EDITION 3). Diabetes for use of initial combination therapy in type 2 drug pricing and payment. Accessed 1 November Obes Metab 2015;17:386–394 diabetes. Diabetes Care 2016;39(Suppl. 2):S137– 2019. Available from https://data.medicaid.gov/ 69. Terauchi Y, Koyama M, Cheng X, et al. New S145 Drug-Pricing-and-Payment/NADAC-National-Average- insulin glargine 300 U/ml versus glargine 100 43. Abdul-Ghani MA, Puckett C, Triplitt C, et al. Drug-Acquisition-Cost-/a4y5-998d. U/ml in Japanese people with type 2 diabetes Initial combination therapy with metformin, 56. Kang H, Lobo JM, Kim S, Sohn M-W. Cost- using basal insulin and oral antihyperglycaemic pioglitazone and exenatide is more effective related medication non-adherence among U.S. drugs: glucose control and hypoglycaemia in a S110 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

randomized controlled trial (EDITION JP 2). department visits or hospital admissions and units/mL in people with type 2 diabetes Diabetes Obes Metab 2016;18:366–374 with glycemic control in patients with type 2 using oral agents and basal insulin: glucose 70. Yki-Jarvinen¨ H, Bergenstal RM, Bolli GB, et al. diabetes. JAMA 2018;320:53–62 control and hypoglycemia in a 6-month ran- Glycaemic control and hypoglycaemia with new 76. Cefalu WT, Dawes DE, Gavlak G, et al.; Insulin domized controlled trial (EDITION 2). Diabetes insulin glargine 300 U/ml versus insulin glargine Access and Affordability Working Group. Con- Care 2014;37:3235–3243 100U/mlinpeoplewithtype 2 diabetes using basal clusions and recommendations. Diabetes Care 83. Akturk HK, Snell-Bergeon JK, Rewers A, et al. insulin and oral antihyperglycaemic drugs: the 2018;41:1299–1311 Improved postprandial glucose with inhaled EDITION 2 randomized 12-month trial including 77. McCall AL. Insulin therapy and hypoglycemia. technosphere insulin compared with insulin as- 6-month extension. Diabetes Obes Metab 2015;17: Endocrinol Metab Clin North Am 2012;41:57–87 part in patients with type 1 diabetes on multiple 1142–1149 78. Mannucci E, Monami M, Marchionni N. daily injections: the STAT study. Diabetes Technol 71. Marso SP, McGuire DK, Zinman B, et al.; Short-acting insulin analogues vs. regular human Ther 2018;20:639–647 DEVOTE Study Group. Efficacy and safety of insulin in type 2 diabetes: a meta-analysis. Di- 84. Diamant M, Nauck MA, Shaginian R, et al.; 4B degludec versus glargine in type 2 diabetes. N abetes Obes Metab 2009;11:53–59 Study Group. Glucagon-like peptide 1 receptor Engl J Med 2017;377:723–732 79. Heller S, Bode B, Kozlovski P, Svendsen AL. agonist or bolus insulin with optimized basal 72. Rodbard HW, Cariou B, Zinman B, et al.; Meta-analysis of insulin aspart versus regular insulin in type 2 diabetes. Diabetes Care 2014; BEGIN Once Long trial investigators. Compar- human insulin used in a basal-bolus regimen for 37:2763–2773 ison of insulin degludec with insulin glargine in the treatment of diabetes mellitus. J Diabetes 85. Eng C, Kramer CK, Zinman B, Retnakaran R. insulin-naive subjects with type 2 diabetes: a 2013;5:482–491 Glucagon-like peptide-1 receptor agonist and 2-year randomized, treat-to-target trial. Diabet 80. Wysham C, Hood RC, Warren ML, Wang T, basal insulin combination treatment for the Med 2013;30:1298–1304 Morwick TM, Jackson JA. Effect of total daily management of type 2 diabetes: a systematic 73. Wysham C, Bhargava A, Chaykin L, et al. dose on efficacy, dosing, and safety of 2 dose review and meta-analysis. Lancet 2014;384: Effect of insulin degludec vs insulin glargine U100 titration regimens of human regular U500 insu- 2228–2234 on hypoglycemia in patients with type 2 diabetes: lin in severely insulin-resistant patients with 86. Maiorino MI, Chiodini P, Bellastella G, the SWITCH 2 randomized clinical trial. JAMA 2017; type 2 diabetes. Endocr Pract 2016;22:653–665 Capuano A, Esposito K, Giugliano D. Insulin and 318:45–56 81. Riddle MC, Yki-Jarvinen¨ H, Bolli GB, et al. glucagon-like peptide 1 receptor agonist combi- 74. Zinman B, Philis-Tsimikas A, Cariou B, et al.; One-year sustained glycaemic control and less nation therapy in type 2 diabetes: a systematic NN1250-3579 (BEGIN Once Long) Trial Investi- hypoglycaemia with new insulin glargine 300 review and meta-analysis of randomized con- gators. Insulin degludec versus insulin glargine U/ml compared with 100 U/ml in people with trolled trials. Diabetes Care 2017;40:614–624 in insulin-naive patients with type 2 diabetes: type 2 diabetes using basal plus meal-time in- 87. Rodbard HW, Visco VE, Andersen H, Hiort a 1-year, randomized, treat-to-target trial (BEGIN sulin: the EDITION 1 12-month randomized trial, LC, Shu DHW. Treatment intensification with Once Long). Diabetes Care 2012;35:2464–2471 including 6-month extension. Diabetes Obes stepwise addition of prandial insulin aspart 75. Lipska KJ, Parker MM, Moffet HH, Huang ES, Metab 2015;17:835–842 boluses compared with full basal-bolus therapy Karter AJ. Association of initiation of basal in- 82. Yki-Jarvinen¨ H, Bergenstal R, Ziemen M, (FullSTEP Study): a randomised, treat-to-target sulin analogs vs neutral protamine Hagedorn et al.; EDITION 2 Study Investigators. New in- clinical trial. Lancet Diabetes Endocrinol 2014;2: insulin with hypoglycemia-related emergency sulin glargine 300 units/mL versus glargine 100 30–37