7. Approaches to GlycemicTreatmentDiabetes Care 2015;38(Suppl. 1):S41–S48 | DOI: 10.2337/dc15-S010
PHARMACOLOGICAL THERAPY FOR TYPE 1 DIABETES
Recommendations
c Most people with type 1 diabetes should be treated with multiple-dose insulin(MDI) injections (three to four injections per day of basal and prandial insulin)or continuous subcutaneous insulin infusion (CSII). A
c Most people with type 1 diabetes should be educated in how to match pran-dial insulin dose to carbohydrate intake, premeal blood glucose, and antici-pated activity. E
c Most people with type 1 diabetes should use insulin analogs to reduce hypo-glycemia risk. A
Insulin TherapyThere are excellent reviews to guide the initiation and management of insulintherapy to achieve desired glycemic goals (1,2,3). Although most studies of MDIversus pump therapy have been small and of short duration, a systematic review andmeta-analysis concluded that there were no systematic differences in A1C or severehypoglycemia rates in children and adults between the two forms of intensive in-sulin therapy (4). A large randomized trial in type 1 diabetic patients with nocturnalhypoglycemia reported that sensor-augmented insulin pump therapy with thethreshold suspend feature reduced nocturnal hypoglycemia, without increasingglycated hemoglobin values (5). Overall, intensive management through pumptherapy/continuous glucose monitoring and active patient/family participationshould be strongly encouraged (6–8). For selected individuals who have masteredcarbohydrate counting, education on the impact of protein and fat on glycemicexcursions can be incorporated into diabetes management (9).The Diabetes Control and Complications Trial (DCCT) clearly showed that intensive
insulin therapy (three ormore injections per day of insulin) or CSII (insulin pump therapy)was a key part of improved glycemia and better outcomes (10,11). The studywas carriedout with short- and intermediate-acting human insulins. Despite better microvascularoutcomes, intensive insulin therapy was associated with a high rate of severe hypogly-cemia (62 episodes per 100 patient-years of therapy). Since the DCCT, a number of rapid-acting and long-acting insulin analogs havebeendeveloped. These analogs are associatedwith less hypoglycemia in type 1 diabetes, while matching the A1C lowering of humaninsulins (1,12).
Recommended therapy for type 1 diabetes consists of the following:1. Use MDI injections (three to four injections per day of basal and prandial insulin)
or CSII therapy.2. Match prandial insulin to carbohydrate intake, premeal blood glucose, and an-
ticipated physical activity.3. For most patients (especially those at an elevated risk of hypoglycemia), use
insulin analogs.4. For patients with frequent nocturnal hypoglycemia and/or hypoglycemia unawareness,
a sensor-augmented low glucose threshold suspend pump may be considered.
PramlintidePramlintide, an amylin analog, is an agent that delays gastric emptying, bluntspancreatic secretion of glucagon, and enhances satiety. It is a U.S. Food and Drug
Suggested citation: American Diabetes Associa-tion. Approaches to glycemic treatment. Sec. 7.In Standards ofMedical Care in Diabetesd2015.Diabetes Care 2015;38(Suppl. 1):S41–S48
Administration (FDA)-approved therapyfor use in type 1 diabetes. It has beenshown to induce weight loss and lowerinsulin dose; however, it is only indi-cated in adults. Concurrent reductionof prandial insulin dosing is required toreduce the risk of severe hypoglycemia.
Investigational AgentsMetformin
Adding metformin to insulin therapy mayreduce insulin requirements and improvemetabolic control in overweight/obesepatients with poorly controlled type 1diabetes. In a meta-analysis, metforminin type 1 diabetes was found to reduceinsulin requirements (6.6 U/day, P ,0.001) and led to small reductions inweight and total and LDL cholesterol butnot to improved glycemic control (abso-lute A1C reduction 0.11%, P5 0.42) (13).
Incretin-Based Therapies
Therapies approved for the treatment oftype 2 diabetes are currently being eval-uated in type 1 diabetes. Glucagon-likepeptide 1 (GLP-1) agonists and dipep-tidyl peptidase 4 (DPP-4) inhibitors arenot currently FDA approved for thosewith type 1 diabetes, but are being stud-ied in this population.
Sodium–Glucose Cotransporter 2 Inhibitors
Sodium–glucose cotransporter 2 (SGLT2)inhibitors provide insulin-independentglucose lowering by blocking glucosereabsorption in the proximal renal tubuleby inhibiting SGLT2. These agents providemodest weight loss and blood pressurereduction. Although there are two FDA-approved agents for use in patients withtype 2 diabetes, there are insufficientdata to recommend clinical use in type 1diabetes at this time (14).
PHARMACOLOGICAL THERAPY FORTYPE 2 DIABETES
Recommendations
c Metformin, if not contraindicatedand if tolerated, is the preferredinitial pharmacological agent fortype 2 diabetes. A
c In patients with newly diagnosedtype2 diabetes andmarkedly symp-tomatic and/or elevated blood glu-cose levels or A1C, consider initiatinginsulin therapy (with or withoutadditional agents). E
c If noninsulin monotherapy at max-imum tolerated dose does not
achieve or maintain the A1C targetover 3 months, add a second oralagent, a GLP-1 receptor agonist, orbasal insulin. A
c A patient-centered approachshould be used to guide choiceof pharmacological agents. Con-siderations inc lude efficacy,cost, potential side effects, weight,comorbidities, hypoglycemia risk,and patient preferences. E
c Due to the progressive nature oftype 2 diabetes, insulin therapy iseventually indicated for many pa-tients with type 2 diabetes. B
An updated American Diabetes Asso-ciation/European Association for theStudy of Diabetes position statement(15) evaluated the data and developedrecommendations, including advan-tages and disadvantages, for antihyper-glycemic agents for type 2 diabeticpatients. A patient-centered approachis stressed, including patient prefer-ences, cost and potential side effectsof each class, effects on body weight,and hypoglycemia risk. Lifestyle modifi-cations that improve health (see Section4. Foundations of Care) should be em-phasized along with any pharmacologi-cal therapy.
Initial TherapyMost patients should begin with life-style changes (lifestyle counseling,weight-loss education, exercise, etc.).When lifestyle efforts alone have notachieved or maintained glycemic goals,metformin monotherapy should beadded at, or soon after, diagnosis, un-less there are contraindications or intol-erance. Metformin has a long-standingevidence base for efficacy and safety, isinexpensive, and may reduce risk of car-diovascular events (16). In patients withmetformin intolerance or contraindica-tions, consider an initial drug from otherclasses depicted in Fig. 7.1 under “Dualtherapy” and proceed accordingly.
Combination TherapyAlthough there are numerous trialscomparing dual therapy with metforminalone, few directly compare drugs asadd-on therapy. A comparative effec-tiveness meta-analysis (17) suggeststhat overall each new class of noninsulinagents added to initial therapy lowers
A1C around 0.9–1.1%. A comprehensivelisting, including the cost, is available inTable 7.1.
If the A1C target is not achieved afterapproximately 3 months, consider acombination of metformin and one ofthese six treatment options: sulfonyl-urea, thiazolidinedione, DPP-4 inhibi-tors, SGLT2 inhibitors, GLP-1 receptoragonists, or basal insulin (Fig. 7.1).Drug choice is based on patient prefer-ences as well as various patient, disease,and drug characteristics, with the goal ofreducing blood glucose levels whileminimizing side effects, especially hypo-glycemia. Figure 7.1 emphasizes drugscommonly used in theU.S. and/or Europe.
Rapid-acting secretagogues (megliti-nides) may be used instead of sulfonyl-ureas in patients with irregular mealschedules or who develop late post-prandial hypoglycemia on a sulfonyl-urea. Other drugs not shown in thefigure (e.g., a-glucosidase inhibitors, co-lesevelam, bromocriptine, pramlintide)may be tried in specific situations, butare generally not favored due to modestefficacy, the frequency of administra-tion, and/or side effects.
For all patients, consider initiatingtherapy with a dual combination whenA1C is $9% to more expeditiouslyachieve the target A1C level. Insulinhas the advantage of being effectivewhere other agents may not be andshould be considered as part of anycombination regimen when hyperglyce-mia is severe, especially if symptoms arepresent or any catabolic features(weight loss, ketosis) are in evidence.Consider initiating combination insulininjectable therapy when blood glucoseis$300–350 mg/dL (16.7–19.4 mmol/L)and/or A1C is $10–12%. As the pa-tient’s glucose toxicity resolves, theregimen can, potentially, be subse-quently simplified.
Insulin TherapyMany patients with type 2 diabetes even-tually require and benefit from insulintherapy. Providers may wish to considerregimen flexibility when devising a planfor the initiation and adjustment of insu-lin therapy in people with type 2 diabetes(Fig. 7.2). The progressive nature of type2 diabetes and its therapies should beregularly and objectively explained to pa-tients. Providers should avoid using insu-lin as a threat or describing it as a failure
S42 Position Statement Diabetes Care Volume 38, Supplement 1, January 2015
or punishment. Equipping patients withan algorithm for self-titration of insulindoses based on self-monitoring of bloodglucose (SMBG) improves glycemic con-trol in type 2 diabetic patients initiatinginsulin (18).Basal insulin alone is the most conve-
nient initial insulin regimen, beginningat 10 U or 0.1–0.2 U/kg, depending onthe degree of hyperglycemia. Basal in-sulin is usually prescribed in conjunctionwith metformin and possibly one addi-tional noninsulin agent. If basal insulinhas been titrated to an acceptable fast-ing blood glucose level, but A1C remainsabove target, consider advancing to
combination injectable therapy (Fig. 7.2)to cover postprandial glucose excur-sions. Options include adding a GLP-1receptor agonist or mealtime insulin,consisting of one to three injections ofrapid-acting insulin analog (lispro, as-part, or glulisine) administered just be-fore eating. A less studied alternative,transitioning from basal insulin totwice-daily premixed (or biphasic) insu-lin analog (70/30 aspart mix, 75/25or 50/50 lispro mix), could also be con-sidered. Regular human insulin andhuman NPH-Regular premixed formula-tions (70/30) are less costly alternativesto rapid-acting insulin analogs and
premixed insulin analogs, respectively,but their pharmacodynamic profilesmake them suboptimal for the coverageof postprandial glucose excursions. Aless commonly used and more costlyalternative to “basal–bolus” therapywith multiple daily injections is CSII(insulin pump). In addition to the sug-gestions provided for determiningthe starting dose of mealtime insulinunder a basal–bolus regimen, anothermethod consists of adding up the totalcurrent insulin dose and then providingone-half of this amount as basal andone-half as mealtime insulin, the lattersplit evenly between three meals.
Figure 7.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations (15). The order in the chart was determined by historicalavailability and the route of administration, with injectables to the right; it is not meant to denote any specific preference. Potential sequences ofantihyperglycemic therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (althoughhorizontal movement within therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastro-intestinal; GLP-1-RA, GLP-1 receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea;TZD, thiazolidinedione. *See ref. 15 for description of efficacy categorization. †Consider starting at this stage when A1C is$9%. ‡Consider starting atthis stage when blood glucose is$300–350 mg/dL (16.7–19.4 mmol/L) and/or A1C is$10–12%, especially if symptomatic or catabolic features arepresent, in which case basal insulin 1 mealtime insulin is the preferred initial regimen. §Usually a basal insulin (NPH, glargine, detemir, degludec).Adapted with permission from Inzucchi et al. (15).
Figure 7.2 focuses solely on sequen-tial insulin strategies, describing thenumber of injections and the relativecomplexity and flexibility of each stage.Once an insulin regimen is initiated,dose titration is important, with adjust-ments made in both mealtime and basalinsulins based on the prevailing bloodglucose levels and an understanding ofthe pharmacodynamic profile of eachformulation (pattern control).Noninsulin agents may be continued,
although sulfonylureas, DPP-4 inhibitors,and GLP-1 receptor agonists are typicallystopped once more complex insulin regi-mens beyond basal are used. In patientswith suboptimal blood glucose control,especially those requiring increasing insu-lin doses, adjunctive use of thiazolidine-diones (usually pioglitazone) or SGLT2
inhibitors may be helpful in improvingcontrol and reducing the amount of in-sulin needed. Comprehensive educa-tion regarding SMBG, diet, exercise,and the avoidance of and response tohypoglycemia are critically important inany patient using insulin.
BARIATRIC SURGERY
Recommendations
c Bariatric surgery may be con-sidered for adults with BMI .35kg/m2 and type 2 diabetes, espe-cially if diabetes or associated co-morbidities are difficult to controlwith lifestyle and pharmacologicaltherapy. B
c Patients with type 2 diabetes whohave undergone bariatric surgery
need lifelong lifestyle supportand medical monitoring. B
c Although small trials have shownglycemic benefit of bariatric surgeryin patients with type 2 diabetes andBMI 30–35 kg/m2, there is currentlyinsufficient evidence to generallyrecommend surgery in patientswith BMI,35 kg/m2. E
Bariatric and metabolic surgeries,either gastric banding or proceduresthat involve resecting, bypassing, ortransposing sections of the stomachand small intestine, can be effectiveweight-loss treatments for severeobesity when performed as part of acomprehensive weight-managementprogram with lifelong lifestyle support
Figure 7.2—Approach to starting and adjusting insulin in type 2 diabetes (15). FBG, fasting blood glucose; GLP-1-RA, GLP-1 receptor agonist; hypo,hypoglycemia; mod., moderate; PPG, postprandial glucose; #, number. Adapted with permission from Inzucchi et al. (15).
S46 Position Statement Diabetes Care Volume 38, Supplement 1, January 2015
andmedical monitoring. National guide-lines support consideration for bariatricsurgery for people with type 2 diabeteswith BMI .35 kg/m2.
AdvantagesTreatment with bariatric surgery hasbeen shown to achieve near- or com-plete normalization of glycemia 2 yearsfollowing surgery in 72% of patients(compared with 16% in a matched con-trol group treated with lifestyle andpharmacological interventions) (19). Astudy evaluated the long-term (3-year)outcomes of surgical intervention(Roux-en-Y gastric bypass or sleeve gas-trectomy) and intensive medical ther-apy (quarterly visits, pharmacologicaltherapy, SMBG, diabetes education, life-style counseling, and encouragement toparticipate in Weight Watchers) com-pared with just intensive medical ther-apy on achieving a target A1C #6%among obese patients with uncon-trolled type 2 diabetes (mean A1C9.3%). This A1C target was achieved by38% (P , 0.001) in the gastric bypassgroup, 24% (P5 0.01) in the sleeve gas-trectomy group, and 5% in those receiv-ing medical therapy (20). Diabetesremission rates tend to be higher withprocedures that bypass portions of thesmall intestine and lower with proce-dures that only restrict the stomach.Younger age, shorter duration of type
2 diabetes, lower A1C, higher serum in-sulin levels, and nonuse of insulin haveall been associated with higher remis-sion rates after bariatric surgery (21).Although bariatric surgery has been
shown to improve themetabolic profilesof morbidly obese patients with type 1diabetes, the role of bariatric surgery insuch patients will require larger and lon-ger studies (22).
DisadvantagesBariatric surgery is costly and has asso-ciated risks. Morbidity and mortalityrates directly related to the surgeryhave decreased considerably in recentyears, with 30-day mortality rates now0.28%, similar to those for laparoscopiccholecystectomy (23). Outcomes varydepending on the procedure and theexperience of the surgeon and center.Longer-term concerns include vitaminand mineral deficiencies, osteoporosis,and rare but often severe hypoglycemiafrom insulin hypersecretion. Cohort
studies attempting to match surgicaland nonsurgical subjects suggest thatthe procedure may reduce longer-termmortality rates (19). In contrast, a pro-pensity score-adjusted analysis of older,severely obese patients in Veterans Af-fairs Medical Centers found that bariatricsurgery was not associated with de-creased mortality compared with usualcare (mean follow-up 6.7 years) (24). Ret-rospective analyses and modeling studiessuggest that bariatric surgery may becost-effective for patients with type 2diabetes, but the results are largely de-pendent on assumptions about thelong-term effectiveness and safety ofthe procedures (25–27). Understandingthe long-term benefits and risks of bariat-ric surgery in individuals with type 2 diabe-tes, especially those who are not severelyobese, will require well-designed clinicaltrials, with optimal medical therapy asthe comparator (28). Unfortunately, suchstudies may not be feasible (29).
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S48 Position Statement Diabetes Care Volume 38, Supplement 1, January 2015
