TH E JOU RNAL OF CLI N ICAL AN D APPLI ED RESEARCH AN D EDUCATION
`
`VOLUME 39 | SUPPLEMENT 1
`
`WWW.DIABETES.ORG/DIABETESCARE
`
`JANUARY 2016
`
`L EM
`
`T1
`
`EN
`
`P
`
`U P
`S
`
`A M E R I C A N D I A B E T E S A S S O C I A T I O N
`
`STANDARDS OF
`MEDICAL CARE
`IN DIABETES—2016
`
`ISSN 0149-5992
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`JANUARY 2016
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`VOLUME 39 | SUPPLEMENT 1 | PAGES S1-S112
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`S52
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`Diabetes Care Volume 39, Supplement 1, January 2016
`
`7. Approaches to Glycemic
`Treatment
`
`Diabetes Care 2016;39(Suppl. 1):S52–S59 | DOI: 10.2337/dc16-S010
`
`American Diabetes Association
`
`Suggested citation: American Diabetes Associa-
`tion. Approaches to glycemic treatment. Sec. 7.
`In Standards of Medical Care in Diabetesd2016.
`Diabetes Care 2016;39(Suppl. 1):S52–S59
`
`© 2016 by the American Diabetes Association.
`Readers may use this article as long as the work
`is properly cited, the use is educational and not
`for profit, and the work is not altered.
`
`PHARMACOLOGICAL THERAPY FOR TYPE 1 DIABETES
`
`Recommendations
`c Most people with type 1 diabetes should be treated with multiple-dose insulin
`injections (three to four injections per day of basal and prandial insulin) or
`continuous subcutaneous insulin infusion. A
`c Consider educating individuals with type 1 diabetes on matching prandial insulin
`dose to carbohydrate intake, premeal blood glucose, and anticipated activity. E
`c Most individuals with type 1 diabetes should use insulin analogs to reduce
`hypoglycemia risk. A
`c Individuals who have been successfully using continuous subcutaneous insulin
`infusion should have continued access after they turn 65 years of age. E
`
`Insulin Therapy
`Insulin is the mainstay of therapy for individuals with type 1 diabetes. There are
`excellent reviews to guide the initiation and management of insulin therapy to
`achieve desired glycemic goals (1). Although most studies of multiple-dose insulin
`versus pump therapy have been small and of short duration, a systematic review and
`meta-analysis concluded that there are minimal differences between the two forms
`of intensive insulin therapy in A1C (combined mean between-group difference
`favoring insulin pump therapy 20.30% [95% CI 20.58 to 20.02]) and severe hypo-
`glycemia rates in children and adults (2). A large randomized trial in patients with
`type 1 diabetes with nocturnal hypoglycemia reported that sensor-augmented in-
`sulin pump therapy with the threshold suspend feature reduced nocturnal hypo-
`glycemia, without increasing glycated hemoglobin values (3). Intensive
`management through pump therapy/continuous glucose monitoring and active
`patient/family participation should be strongly encouraged (4–6). Selected
`individuals who have mastered carbohydrate counting should be educated that fat
`increases glucose concentrations and insulin requirements (7).
`The Diabetes Control and Complications Trial (DCCT) clearly showed that in-
`tensive insulin therapy (three or more injections per day of insulin) or continuous
`subcutaneous insulin infusion (CSII) (insulin pump therapy) was a key part of
`improved glycemia and better outcomes (8,9). The study was carried out with
`short-acting and intermediate-acting human insulins. Despite better microvascular,
`macrovascular, and all-cause mortality outcomes, intensive insulin therapy was as-
`sociated with a high rate of severe hypoglycemia (62 episodes per 100 patient-years
`of therapy). Since the DCCT, a number of rapid-acting and long-acting insulin analogs
`have been developed. These analogs are associated with less hypoglycemia in type 1
`diabetes, while matching the A1C lowering of human insulins (10,11).
`Rapid-acting inhaled insulin used before meals in type 1 diabetes leads to inferior
`A1C lowering when compared with aspart insulin, with less hypoglycemia across all
`A1C target categories (12).
`Postprandial glucose excursions can be better controlled by adjusting the timing
`of prandial (bolus) insulin dose administration. The optimal time to inject prandial
`insulin varies, based on the type of insulin injected (regular, rapid-acting analog,
`inhaled, etc.), the measured blood glucose level, timing of meals, and carbohydrate
`consumption. Recommendations for prandial insulin dose administration should
`therefore be individualized.
`
`7.APPROACHESTOGLYCEMICTREATMENT
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`Approaches to Glycemic Treatment
`
`S53
`
`Recommended therapy for type 1 di-
`abetes consists of the following:
`
`1. Multiple-dose insulin injections (three
`to four injections per day of basal and
`prandial insulin) or CSII therapy.
`2. Match prandial insulin to carbohy-
`drate intake, premeal blood glucose,
`and anticipated physical activity.
`3. For most patients (especially those at
`elevated risk of hypoglycemia), use
`insulin analogs.
`4. For patients with frequent nocturnal
`hypoglycemia, recurrent severe hy-
`poglycemia, and/or hypoglycemia
`unawareness, a sensor-augmented
`low glucose threshold suspend pump
`may be considered.
`
`Pramlintide
`Pramlintide, an amylin analog, is an
`agent that delays gastric emptying,
`blunts pancreatic secretion of glucagon,
`and enhances satiety. It is a U.S. Food
`and Drug Administration (FDA)-approved
`therapy for use in adults with type 1 di-
`abetes. It has been shown to induce
`weight loss and lower insulin dose. Con-
`current reduction of prandial insulin
`dosing is required to reduce the risk of
`severe hypoglycemia.
`
`Pancreas and Islet Cell Transplantation
`Pancreas and islet cell transplantation
`have been shown to normalize glucose
`levels but require lifelong immunosup-
`pression to prevent graft rejection and
`recurrence of autoimmune islet destruc-
`tion. Given the potential adverse effects
`of immunosuppressive therapy, pan-
`creas transplantation should be reserved
`for patients with type 1 diabetes under-
`going simultaneous renal transplanta-
`tion, following renal transplantation,
`or for those with recurrent ketoacidosis
`or severe hypoglycemia despite aggres-
`sive glycemic management (13). Islet
`cell transplantation remains investiga-
`tional. Autoislet transplantation may
`be considered for patients requiring to-
`tal pancreatectomy who meet eligibility
`criteria.
`
`Investigational Agents
`
`Metformin
`Adding metformin to insulin therapy may
`reduce insulin requirements and improve
`metabolic control in overweight/obese
`patients with poorly controlled type 1 di-
`abetes. In a meta-analysis, metformin in
`type 1 diabetes was found to reduce
`
`insulin requirements (6.6 units/day, P ,
`0.001) and led to small reductions in
`weight and total and LDL cholesterol but
`not to improved glycemic control (abso-
`lute A1C reduction 0.11%, P 5 0.42) (14).
`
`Incretin-Based Therapies
`Therapies approved for the treatment of
`type 2 diabetes are currently being eval-
`uated in type 1 diabetes. Glucagon-like
`peptide 1 (GLP-1) agonists and dipep-
`tidyl peptidase 4 (DPP-4) inhibitors are
`not currently FDA approved for those
`with type 1 diabetes but are being stud-
`ied in this population.
`
`Sodium–Glucose Cotransporter 2
`Inhibitors
`Sodium–glucose cotransporter 2 (SGLT2)
`inhibitors provide insulin-independent
`glucose lowering by blocking glucose re-
`absorption in the proximal renal tubule
`by inhibiting SGLT2. These agents
`provide modest weight loss and blood
`pressure reduction. There are three
`FDA-approved agents for use in patients
`with type 2 diabetes, but there are in-
`sufficient data to recommend treatment
`in type 1 diabetes (15). The FDA recently
`issued a warning about the risk of keto-
`acidosis with SGLT2 inhibitors in individ-
`uals with type 1 or type 2 diabetes.
`Symptoms of ketoacidosis include nau-
`sea, vomiting, abdominal pain, tiredness,
`and dyspnea. Urinary tract infections
`leading to urosepsis and pyelonephritis
`may also occur with SGLT2 inhibitors. Pa-
`tients should stop taking their SGLT2 in-
`hibitor and seek medical attention
`immediately if they have symptoms of
`ketoacidosis (16).
`
`PHARMACOLOGICAL THERAPY
`FOR TYPE 2 DIABETES
`
`Recommendations
`c Metformin, if not contraindicated
`and if tolerated, is the preferred
`initial pharmacological agent for
`type 2 diabetes. A
`c Consider initiating insulin therapy
`(with or without additional agents)
`in patients with newly diagnosed
`type 2 diabetes and markedly symp-
`tomatic and/or elevated blood glu-
`cose levels or A1C. E
`c If noninsulin monotherapy at max-
`imum tolerated dose does not
`achieve or maintain the A1C target
`over 3 months, then add a second
`oral agent, a glucagon-like peptide
`1 receptor agonist, or basal insulin. A
`
`c A patient-centered approach
`should be used to guide the choice
`of pharmacological agents. Con-
`siderations include efficacy, cost,
`potential side effects, weight, co-
`morbidities, hypoglycemia risk,
`and patient preferences. E
`c For patients with type 2 diabetes
`who are not achieving glycemic
`goals, insulin therapy should not
`be delayed. B
`
`An American Diabetes Association/
`European Association for the Study of
`Diabetes position statement (17) evalu-
`ated the data and developed recom-
`mendations, including advantages and
`disadvantages, for antihyperglycemic
`agents for patients with type 2 diabetes.
`A patient-centered approach is stressed,
`including patient preferences, cost, and
`potential side effects of each class, effects
`on body weight, and hypoglycemia risk.
`Lifestyle modifications that improve
`health (see Section 3 “Foundations of
`Care and Comprehensive Medical Eval-
`uation”) should be emphasized along
`with any pharmacological therapy.
`
`Initial Therapy
`Most patients should begin with life-
`style changes, which may include life-
`style counseling, setting a physical
`activity goal of 150 min/week minimum,
`and weight loss counseling to lose a min-
`imum of 7% of body weight (for details
`on lifestyle therapy, see Section 6 “Obe-
`sity Management for the Treatment of
`Type 2 Diabetes”). When lifestyle efforts
`alone do not achieve or maintain glyce-
`mic goals, metformin monotherapy
`should be added at, or soon after, diag-
`nosis, unless there are contraindications
`or intolerance. Metformin has a long-
`standing evidence base for efficacy and
`safety, is inexpensive, and may reduce
`risk of cardiovascular events and death
`(18). Accumulating observational data
`suggest that metformin may be safely
`continued down to glomerular filtration
`rate (GFR) of 45 mL/min/1.73 m2 or even
`30 mL/min/1.73 m2 (19). If metformin is
`used in the lower GFR range, the dose
`should be reduced and patients should
`be advised to stop the medication for nau-
`sea, vomiting, and dehydration. In patients
`with metformin intolerance or contraindi-
`cations, consider an initial drug from other
`classes depicted in Fig. 7.1 under “Dual
`therapy” and proceed accordingly.
`
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`S54 Approaches to Glycemic Treatment
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`Diabetes Care Volume 39, Supplement 1, January 2016
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`Figure 7.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations (17). The order in the chart was determined by historical
`availability and the route of administration, with injectables to the right; it is not meant to denote any specific preference. Potential sequences of
`antihyperglycemic therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although
`horizontal 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. 17 for description of efficacy categorization. †Consider starting at this stage when A1C is $9% (75 mmol/mol).
`‡Consider starting at this stage when blood glucose is $300–350 mg/dL (16.7–19.4 mmol/L) and/or A1C is $10–12% (86–108 mmol/mol), especially
`if symptomatic or catabolic features are present, 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. (17).
`
`Combination Therapy
`Although there are numerous trials
`comparing dual therapy with metformin
`alone, few directly compare drugs as
`add-on therapy. A comparative effec-
`tiveness meta-analysis (20) suggests
`that overall each new class of noninsulin
`agents added to initial therapy lowers
`A1C around 0.9–1.1%. A comprehensive
`listing, including the cost, is available in
`Table 7.1. The ongoing Glycemia Reduc-
`tion Approaches in Diabetes: A Compar-
`ative Effectiveness Study (GRADE) will
`compare the effect of four major drug
`classes (sulfonylurea, DPP-4 inhibitor,
`GLP-1 analog, and basal insulin) over
`4 years on glycemic control and other
`
`medical, psychosocial, and health eco-
`nomic outcomes (21).
`If the A1C target is not achieved after
`approximately 3 months, consider a com-
`bination of metformin and one of these six
`treatment options: sulfonylurea, thiazolidi-
`nedione, DPP-4 inhibitors (22), SGLT2 in-
`hibitors, GLP-1 receptor agonists, or basal
`insulin (Fig. 7.1). Drug choice is based on
`patient preferences (23), as well as various
`patient, disease, and drug characteristics,
`with the goal of reducing blood glucose
`levels while minimizing side effects, espe-
`cially hypoglycemia. Figure 7.1 emphasizes
`drugs commonly used in the U.S. and/or
`Europe. Cost-effectiveness models have
`suggested that some of the newer agents
`
`may be low-value based on high cost and
`moderate glycemic effect (24).
`Rapid-acting secretagogues (megliti-
`nides) may be used instead of sulfonyl-
`ureas in patients with irregular meal
`schedules or those who develop late
`postprandial hypoglycemia on a sulfo-
`nylurea. Other drugs not shown in the
`figure (e.g., a-glucosidase inhibitors, co-
`lesevelam, bromocriptine, pramlintide)
`may be tried in specific situations, but
`are generally not favored due to modest
`efficacy, the frequency of administra-
`tion, and/or side effects.
`For all patients, consider initiating
`therapy with a dual combination when
`A1C is $9% (75 mmol/mol) to more
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`Approaches to Glycemic Treatment
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`S55
`
`Continuedonp.S56
`
`High
`
`High
`
`cRhinitis
`cFatigue
`cNausea
`cDizziness/syncope
`cGenerallymodestA1Cefficacy
`
`medications
`
`cMay↓absorptionofother
`c↑Triglycerides
`cConstipation
`cGenerallymodestA1Cefficacy
`c?↑Heartfailurehospitalizations
`c?Acutepancreatitis
`
`effects
`immune-mediateddermatological
`
`High
`
`cAngioedema/urticariaandother
`
`SafetyTrial)
`
`c?↓CVDevents(Cycloset
`cNohypoglycemia
`
`regulationofmetabolism
`ActivatesdopaminergicreceptorscModulateshypothalamic
`
`c↑Insulinsensitivity
`
`(quickrelease)§
`
`cBromocriptine
`
`Dopamine-2agonists
`
`c?↑Incretinlevels
`c?↓HepaticglucoseproductioncNohypoglycemia
`
`c↓LDL-C
`
`production
`increasinghepaticbileacid
`Bindsbileacidsinintestinaltract,
`
`cWelltolerated
`cNohypoglycemia
`cNonsystemic
`
`NIDDM)
`
`dependent)
`
`c↓Glucagonsecretion(glucose
`
`dependent)
`
`c↑Insulinsecretion(glucose
`
`(GLP-1,GIP)concentrations
`postprandialactiveincretin
`InhibitsDPP-4activity,increasing
`
`cColesevelam
`cAlogliptin
`cLinagliptin
`cSaxagliptin
`cVildagliptin†
`cSitagliptin
`
`Bileacidsequestrants
`
`DPP-4inhibitors
`
`cFrequentdosingschedule
`
`(flatulence,diarrhea)
`
`c?↓CVDevents(STOP-
`
`excursions
`
`moderate
`
`Lowto
`
`cGastrointestinalsideeffects
`cGenerallymodestA1Cefficacy
`
`c↓Postprandialglucose
`cNohypoglycemia
`
`digestion/absorption
`
`cSlowsintestinalcarbohydrate
`
`Inhibitsintestinala-glucosidase
`
`cMiglitol
`cAcarbose
`
`a-Glucosidaseinhibitors
`
`Low
`
`Moderate
`
`Low
`
`Low
`
`Cost*
`
`c↑Weight
`cHypoglycemia
`cLacticacidosisrisk(rare)
`
`hypoxia,dehydration,etc.
`
`cContraindications:CKD,acidosis,
`cVitaminB12deficiency
`
`(diarrhea,abdominalcramping)
`
`cGastrointestinalsideeffects
`
`(UKPDS)
`
`c↓Microvascularrisk
`cExtensiveexperience
`
`c↓CVDevents(UKPDS)
`cNohypoglycemia
`cExtensiveexperience
`
`Disadvantages
`
`Advantages
`
`c↑Insulinsecretion
`
`plasmamembranes
`ClosesKATPchannelsonb-cell
`
`c↓Hepaticglucoseproduction
`Primaryphysiologicalaction(s)
`
`ActivatesAMP-kinase(?other)
`
`cMetformin
`
`Cellularmechanism(s)
`
`Compound(s)
`
`Biguanides
`
`Class
`
`cNateglinide
`cRepaglinide
`cGlimepiride
`cGliclazide†
`cGlipizide
`
`glibenclamide
`
`cGlyburide/
`2ndGeneration
`
`Meglitinides(glinides)
`
`Sulfonylureas
`
`rosiglitazone)
`
`c?↑MI(meta-analyses,
`c↑LDL-C(rosiglitazone)
`cBonefractures
`cEdema/heartfailure
`c↑Weight
`cFrequentdosingschedule
`c↑Weight
`cHypoglycemia
`
`pioglitazone)
`(PROactive,
`
`c?↓CVDevents
`(pioglitazone)
`c↓Triglycerides
`c↑HDL-C
`cDurability
`cNohypoglycemia
`cDosingflexibility
`
`excursions
`
`c↓Postprandialglucose
`
`c↑Insulinsecretion
`
`plasmamembranes
`ClosesKATPchannelsonb-cell
`
`c↑Insulinsensitivity
`
`transcriptionfactorPPAR-g
`Activatesthenuclear
`
`cRosiglitazone§
`cPioglitazone‡
`
`TZDs
`
`Table7.1—Propertiesofavailableglucose-loweringagentsintheU.S.andEuropethatmayguideindividualizedtreatmentchoicesinpatientswithtype2diabetes(17)
`
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`high#
`
`Moderateto
`
`High
`
`High
`
`High
`
`Cost*
`
`cPulmonarytoxicity(inhaledinsulin)
`cInjectable(exceptinhaledinsulin)
`cPatientreluctance
`cTrainingrequirements
`c?Mitogeniceffects
`cWeightgain
`cHypoglycemia
`cTrainingrequirements
`cFrequentdosingschedule
`cInjectable
`
`simultaneouslyreduced
`
`cHypoglycemiaunlessinsulindoseis
`
`(nausea/vomiting)
`
`cGastrointestinalsideeffects
`cGenerallymodestA1Cefficacy
`cTrainingrequirements
`cInjectable
`
`thyroidtumorsinanimals
`
`cC-cellhyperplasia/medullary
`c?Acutepancreatitis
`c↑Heartrate
`
`(nausea/vomiting/diarrhea)
`cGastrointestinalsideeffects
`
`leadingtourosepsis,pyelonephritis
`
`cDKA,urinarytractinfections
`c↑Creatinine(transient)
`c↑LDL-C
`dizziness
`
`cVolumedepletion/hypotension/
`cPolyuria
`cGenitourinaryinfections
`
`subsequentstudy.§NotlicensedinEuropefortype2diabetes.#Costishighlydependentontype/brand(analogs.humaninsulins)anddosage.AdaptedwithpermissionfromInzucchietal.(17).
`Cyclosettrialofquick-releasebromocriptine(36).*Costisbasedonlowest-pricedmemberoftheclass(seeref.17).†NotlicensedintheU.S.‡Initialconcernsregardingbladdercancerriskaredecreasingafter
`PioglitazoneClinicalTrialinMacrovascularEvents(32);STOP-NIDDM,StudytoPreventNon-Insulin-DependentDiabetesMellitus(33);TZD,thiazolidinedione;UKPDS,UKProspectiveDiabetesStudy(34,35).
`GIP,glucose-dependentinsulinotropicpeptide;HDL-C,HDLcholesterol;LDL-C,LDLcholesterol;MI,myocardialinfarction;PPAR-g,peroxisomeproliferator–activatedreceptorg;PROactive,Prospective
`CKD,chronickidneydisease;CVD,cardiovasculardisease;DKA,diabeticketoacidosis;EMPA-REGOUTCOME,BI10773(Empagliflozin)CardiovascularOutcomeEventTrialinType2DiabetesMellitusPatients(31);
`
`Disadvantages
`
`Advantages
`
`Primaryphysiologicalaction(s)
`
`Cellularmechanism(s)
`
`Compound(s)
`
`glucosuria
`thekidney,increasing
`
`cBlocksglucosereabsorptionby
`
`nephron
`InhibitsSGLT2intheproximal
`
`cEmpagliflozin
`cDapagliflozin‡
`cCanagliflozin
`
`SGLT2inhibitors
`
`Class
`
`Table7.1—Continued
`
`riskfactors
`
`c↓Somecardiovascular
`
`excursions
`
`c↓Postprandialglucose
`c↓Weight
`cNohypoglycemia
`
`OUTCOME)
`withCVD(EMPA-REG
`mortalityinpatients
`CVDeventrateand
`
`cAssociatedwithlower
`
`type2diabetes
`
`cEffectiveatallstagesof
`c↓Bloodpressure
`c↓Weight
`cNohypoglycemia
`
`(UKPDS)
`
`c↓Microvascularrisk
`
`efficacy
`
`cTheoreticallyunlimited
`
`cSuppressesketogenesis
`
`response
`
`cNearlyuniversal
`
`c↓Hepaticglucoseproduction
`c↑Glucosedisposal
`
`types)
`
`cPremixed(several
`
`-Degludec†
`-Detemir
`-Glargine
`
`cBasalinsulinanalogs
`
`cIntermediate-acting
`
`-HumanNPH
`
`-HumanRegular
`
`cShort-acting
`
`-Inhaledinsulin
`-Glulisine
`-Aspart
`-Lispro
`
`cRapid-actinganalogsActivatesinsulinreceptors
`
`Insulins
`
`c↓Weight
`excursions
`
`c↓Postprandialglucose
`
`c↑Satiety
`cSlowsgastricemptying
`c↓Glucagonsecretion
`
`Activatesamylinreceptors
`
`cPramlintide§
`
`Amylinmimetics
`
`c↑Satiety
`cSlowsgastricemptying
`
`dependent)
`
`c↓Glucagonsecretion(glucose
`
`dependent)
`
`c↑Insulinsecretion(glucose
`
`ActivatesGLP-1receptors
`
`cDulaglutide
`cLixisenatide†
`cAlbiglutide
`cLiraglutide
`
`release
`
`cExenatideextended
`cExenatide
`
`GLP-1receptoragonists
`
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`Approaches to Glycemic Treatment
`
`S57
`
`Figure 7.2—Approach to starting and adjusting insulin in type 2 diabetes (17). 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. (17).
`
`expeditiously achieve the target A1C
`level. Insulin has the advantage of being
`effective where other agents may not be
`and should be considered as part of any
`combination regimen when hyperglyce-
`mia is severe, especially if symptoms are
`present or any catabolic features (weight
`loss, ketosis) are present. Consider ini-
`tiating combination insulin injectable
`therapy when blood glucose is $300–
`350 mg/dL (16.7–19.4 mmol/L) and/or
`A1C is $10–12% (86–108 mmol/mol). As
`the patient’s glucose toxicity resolves, the
`regimen may, potentially, be simplified.
`
`Insulin Therapy
`Consider initiating insulin therapy (with
`or without additional agents) in patients
`with newly diagnosed type 2 diabetes
`and markedly symptomatic and/or
`
`elevated blood glucose levels or A1C.
`Many patients with type 2 diabetes
`eventually require and benefit from in-
`sulin therapy. Providers may wish to
`consider regimen flexibility when de
`vising a plan for the initiation and ad-
`justment of insulin therapy in people
`with type 2 diabetes (Fig. 7.2). The pro-
`gressive nature of type 2 diabetes and
`its therapies should be regularly and ob-
`jectively explained to patients. For pa-
`tients with type 2 diabetes who are not
`achieving glycemic goals, providers should
`promptly initiate insulin therapy.
`Providers should avoid using insulin
`as a threat or describing it as a failure or
`punishment. Equipping patients with an
`algorithm for self-titration of insulin
`doses based on self-monitoring of blood
`glucose (SMBG) improves glycemic
`
`control in patients with type 2 diabetes
`initiating insulin (25).
`
`Basal Insulin
`Basal insulin alone is the most conve-
`nient initial insulin regimen, beginning
`at 10 units or 0.1–0.2 units/kg, depend-
`ing on the degree of hyperglycemia.
`Basal insulin is usually prescribed in con-
`junction with metformin and possibly
`one additional noninsulin agent. While
`there is evidence for reduced risk of hy-
`poglycemia with newer, longer-acting,
`basal insulin analogs, people with type
`2 diabetes without history of hypogly-
`cemia or severe hypoglycemia may use
`NPH safely at much lower cost (24,26).
`Concentrated preparation of basal in-
`sulin such as U-500 regular is five times
`as potent per volume of insulin (i.e.,
`
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`Diabetes Care Volume 39, Supplement 1, January 2016
`
`0.01 mL ;5 units of U-100 regular) and
`has a delayed onset and longer
`duration of action than U-100 regular.
`U-300 glargine and U-200 degludec are
`three and two times, respectively, as
`potent per volume, have a longer dura-
`tion of action, and may allow higher
`doses of
`insulin administration in
`smaller volumes. These concentrated
`preparations may be more comfortable
`for the patient and allow better absorp-
`tion. However, they are more expen-
`sive, and accurate dosing may be more
`complicated.
`If basal insulin has been titrated to an
`acceptable fasting blood glucose level,
`but A1C remains above target, consider
`advancing to combination injectable
`therapy (Fig. 7.2) to cover postprandial
`glucose excursions. Options include
`adding a GLP-1 receptor agonist (27) or
`mealtime insulin, consisting of one to
`three injections of rapid-acting insulin
`analog (lispro, aspart, or glulisine) ad-
`ministered just before eating. A less
`studied alternative, transitioning from
`basal insulin to twice-daily premixed
`(or biphasic) insulin analogs (70/30 as-
`part mix, 75/25 or 50/50 lispro mix),
`could also be considered; pharmacody-
`namic profiles make them suboptimal to
`cover postprandial glucose excursions.
`
`Bolus Insulin
`Some individuals with type 2 diabetes
`may require bolus insulin dosing in ad-
`dition to basal insulin. Rapid-acting an-
`alogs are preferred due to their prompt
`onset of action after dosing. The FDA
`recently approved a more concentrated
`formulation of rapid-acting insulin ana-
`log, U-200 (200 units/mL), dosed 15 min
`or immediately prior to a meal.
`Regular human insulin and human
`NPH-Regular premixed formulations
`(70/30) are less costly alternatives to
`rapid-acting insulin analogs and pre-
`mixed insulin analogs, respectively,
`but their pharmacodynamic profiles
`make them suboptimal to cover post-
`prandial glucose excursions.
`
`Continuous Subcutaneous Insulin Infusion
`A less commonly used and more costly
`alternative to “basal–bolus” therapy
`with multiple daily injections is CSII (in-
`sulin pump) (28,29). In addition to the
`suggestions provided for determining
`the starting dose of mealtime insulin
`under a basal–bolus regimen, another
`method consists of adding up the total
`
`current insulin dose and then providing
`one-half of this amount as basal and
`one-half as mealtime insulin, the latter
`split evenly between three meals. It is crit-
`ical that individuals who have been suc-
`cessfully using CSII should have continued
`access after they turn 65 years of age (30).
`
`Inhaled Insulin
`Inhaled insulin is now available for pran-
`dial use with a more limited dosing
`range and may require serial lung func-
`tion testing prior to and after starting
`therapy.
`
`Treatment Strategies
`Figure 7.2 focuses solely on sequential
`insulin strategies, describing the num-
`ber of injections and the relative com-
`plexity and flexibility of each stage. Once
`an insulin regimen is initiated, dose ti-
`tration is important, with adjustments
`made in both mealtime and basal insu-
`lins based on the prevailing blood glu-
`cose levels and an understanding of the
`pharmacodynamic profile of each for-
`mulation (pattern control).
`Noninsulin agents may be continued,
`although sulfonylureas, DPP-4 inhibi-
`tors, and GLP-1 receptor agonists are
`typically stopped once more complex in-
`sulin regimens beyond basal are used. In
`patients with suboptimal blood glucose
`control, especially those requiring in-
`creasing insulin doses, adjunctive use
`of thiazolidinediones (usually pioglita-
`zone) or SGLT2 inhibitors may be helpful
`in improving control and reducing the
`amount of insulin needed. Comprehen-
`sive education regarding SMBG, diet, ex-
`ercise, and the avoidance of and response
`to hypoglycemia are critically important
`in any patient using insulin.
`
`BARIATRIC SURGERY
`
`Bariatric surgery also improves glycemic
`control in type 2 diabetes. Its effects are
`discussed in Section 6 “Obesity Man-
`agement for the Treatment of Type 2
`Diabetes.”
`
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