7. Approaches to GlycemicTreatmentDiabetes Care 2016;39(Suppl. 1):S52–S59 | DOI: 10.2337/dc16-S010

PHARMACOLOGICAL THERAPY FOR TYPE 1 DIABETES

Recommendations

c Most people with type 1 diabetes should be treated with multiple-dose insulininjections (three to four injections per day of basal and prandial insulin) orcontinuous subcutaneous insulin infusion. A

c Consider educating individuals with type 1 diabetes onmatching prandial insulindose to carbohydrate intake, premeal blood glucose, and anticipated activity. E

c Most individuals with type 1 diabetes should use insulin analogs to reducehypoglycemia risk. A

c Individuals who have been successfully using continuous subcutaneous insulininfusion should have continued access after they turn 65 years of age. E

Insulin TherapyInsulin is the mainstay of therapy for individuals with type 1 diabetes. There areexcellent reviews to guide the initiation and management of insulin therapy toachieve desired glycemic goals (1). Although most studies of multiple-dose insulinversus pump therapy have been small and of short duration, a systematic review andmeta-analysis concluded that there are minimal differences between the two formsof intensive insulin therapy in A1C (combined mean between-group differencefavoring insulin pump therapy20.30% [95% CI20.58 to20.02]) and severe hypo-glycemia rates in children and adults (2). A large randomized trial in patients withtype 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). Intensivemanagement through pump therapy/continuous glucose monitoring and activepatient/family participation should be strongly encouraged (4–6). Selectedindividuals who have mastered carbohydrate counting should be educated that fatincreases 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 continuoussubcutaneous insulin infusion (CSII) (insulin pump therapy) was a key part ofimproved glycemia and better outcomes (8,9). The study was carried out withshort-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-yearsof therapy). Since the DCCT, a number of rapid-acting and long-acting insulin analogshave been developed. These analogs are associated with less hypoglycemia in type 1diabetes, 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 allA1C 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 prandialinsulin varies, based on the type of insulin injected (regular, rapid-acting analog,inhaled, etc.), the measured blood glucose level, timing of meals, and carbohydrateconsumption. Recommendations for prandial insulin dose administration shouldtherefore be individualized.

Suggested citation: American Diabetes Associa-tion. Approaches to glycemic treatment. Sec. 7.In Standards ofMedical 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 workis properly cited, the use is educational and notfor profit, and the work is not altered.

American Diabetes Association

S52 Diabetes Care Volume 39, Supplement 1, January 2016

7.APPROACHES

TOGLYCEM

ICTR

EATM

ENT

Recommended therapy for type 1 di-abetes consists of the following:

1. Multiple-dose insulin injections (threeto four injections per day of basal andprandial insulin) or CSII therapy.

2. Match prandial insulin to carbohy-drate intake, premeal blood glucose,and anticipated physical activity.

3. Formost patients (especially those atelevated risk of hypoglycemia), useinsulin analogs.

4. For patients with frequent nocturnalhypoglycemia, recurrent severe hy-poglycemia, and/or hypoglycemiaunawareness, a sensor-augmentedlow glucose threshold suspend pumpmay be considered.

PramlintidePramlintide, an amylin analog, is anagent that delays gastric emptying,blunts pancreatic secretion of glucagon,and enhances satiety. It is a U.S. Foodand Drug Administration (FDA)-approvedtherapy for use in adults with type 1 di-abetes. It has been shown to induceweight loss and lower insulin dose. Con-current reduction of prandial insulindosing is required to reduce the risk ofsevere hypoglycemia.

Pancreas and Islet Cell TransplantationPancreas and islet cell transplantationhave been shown to normalize glucoselevels but require lifelong immunosup-pression to prevent graft rejection andrecurrence of autoimmune islet destruc-tion. Given the potential adverse effectsof immunosuppressive therapy, pan-creas transplantation should be reservedfor patients with type 1 diabetes under-going simultaneous renal transplanta-tion, following renal transplantation,or for those with recurrent ketoacidosisor severe hypoglycemia despite aggres-sive glycemic management (13). Isletcell transplantation remains investiga-tional. Autoislet transplantation maybe considered for patients requiring to-tal pancreatectomy who meet eligibilitycriteria.

Investigational Agents

Metformin

Adding metformin to insulin therapy mayreduce insulin requirements and improvemetabolic control in overweight/obesepatients with poorly controlled type 1 di-abetes. In a meta-analysis, metformin intype 1 diabetes was found to reduce

insulin requirements (6.6 units/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) (14).

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 glucose re-absorption in the proximal renal tubuleby inhibiting SGLT2. These agentsprovide modest weight loss and bloodpressure reduction. There are threeFDA-approved agents for use in patientswith type 2 diabetes, but there are in-sufficient data to recommend treatmentin type 1 diabetes (15). The FDA recentlyissued 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 infectionsleading to urosepsis and pyelonephritismay also occur with SGLT2 inhibitors. Pa-tients should stop taking their SGLT2 in-hibitor and seek medical attentionimmediately if they have symptoms ofketoacidosis (16).

PHARMACOLOGICAL THERAPYFOR TYPE 2 DIABETES

Recommendations

c Metformin, if not contraindicatedand if tolerated, is the preferredinitial pharmacological agent fortype 2 diabetes. A

c Consider initiating insulin therapy(with or without additional agents)in patients with newly diagnosedtype2diabetes andmarkedly symp-tomatic and/or elevated blood glu-cose levels or A1C. E

c If noninsulin monotherapy at max-imum tolerated dose does notachieve or maintain the A1C targetover 3 months, then add a secondoral agent, a glucagon-like peptide1 receptor agonist, or basal insulin.A

c A patient-centered approachshould be used to guide the choiceof 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 diabeteswho are not achieving glycemicgoals, insulin therapy should notbe delayed. B

An American Diabetes Association/European Association for the Study ofDiabetes position statement (17) evalu-ated the data and developed recom-mendations, including advantages anddisadvantages, for antihyperglycemicagents for patients with type 2 diabetes.A patient-centered approach is stressed,including patient preferences, cost, andpotential side effects of each class, effectson body weight, and hypoglycemia risk.Lifestyle modifications that improvehealth (see Section 3 “Foundations ofCare and Comprehensive Medical Eval-uation”) should be emphasized alongwith any pharmacological therapy.

Initial TherapyMost patients should begin with life-style changes, which may include life-style counseling, setting a physicalactivity goal of 150min/weekminimum,andweight loss counseling to lose amin-imum of 7% of body weight (for detailson lifestyle therapy, see Section 6 “Obe-sity Management for the Treatment ofType 2 Diabetes”). When lifestyle effortsalone do not achieve or maintain glyce-mic goals, metformin monotherapyshould be added at, or soon after, diag-nosis, unless there are contraindicationsor intolerance. Metformin has a long-standing evidence base for efficacy andsafety, is inexpensive, and may reducerisk of cardiovascular events and death(18). Accumulating observational datasuggest that metformin may be safelycontinued down to glomerular filtrationrate (GFR) of 45 mL/min/1.73 m2 or even30 mL/min/1.73 m2 (19). If metformin isused in the lower GFR range, the doseshould be reduced and patients shouldbe advised to stop themedication for nau-sea, vomiting, and dehydration. In patientswith metformin intolerance or contraindi-cations, consider an initial drug from otherclasses depicted in Fig. 7.1 under “Dualtherapy” and proceed accordingly.

care.diabetesjournals.org Approaches to Glycemic Treatment S53

Combination TherapyAlthough there are numerous trialscomparing dual therapy with metforminalone, few directly compare drugs asadd-on therapy. A comparative effec-tiveness meta-analysis (20) suggeststhat overall each new class of noninsulinagents added to initial therapy lowersA1C around 0.9–1.1%. A comprehensivelisting, including the cost, is available inTable 7.1. The ongoing Glycemia Reduc-tion Approaches in Diabetes: A Compar-ative Effectiveness Study (GRADE) willcompare the effect of four major drugclasses (sulfonylurea, DPP-4 inhibitor,GLP-1 analog, and basal insulin) over4 years on glycemic control and other

medical, psychosocial, and health eco-nomic outcomes (21).

If the A1C target is not achieved afterapproximately 3 months, consider a com-bination ofmetformin and one of these sixtreatmentoptions: sulfonylurea, thiazolidi-nedione, DPP-4 inhibitors (22), SGLT2 in-hibitors, GLP-1 receptor agonists, or basalinsulin (Fig. 7.1). Drug choice is based onpatient preferences (23), as well as variouspatient, disease, and drug characteristics,with the goal of reducing blood glucoselevels while minimizing side effects, espe-cially hypoglycemia. Figure 7.1 emphasizesdrugs commonly used in the U.S. and/orEurope. Cost-effectiveness models havesuggested that some of the newer agents

may be low-value based on high cost andmoderate glycemic effect (24).

Rapid-acting secretagogues (megliti-nides) may be used instead of sulfonyl-ureas in patients with irregular mealschedules or those who develop latepostprandial hypoglycemia on a sulfo-nylurea. 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% (75 mmol/mol) to more

Figure 7.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations (17). 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. 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$300–350mg/dL (16.7–19.4mmol/L) and/or A1C is$10–12% (86–108mmol/mol), especiallyif symptomatic or catabolic features are present, in which case basal insulin 1 mealtime insulin is the preferred initial regimen. §Usually a basalinsulin (NPH, glargine, detemir, degludec). Adapted with permission from Inzucchi et al. (17).

S54 Approaches to Glycemic Treatment Diabetes Care Volume 39, Supplement 1, January 2016

Table

7.1—

Pro

pertiesofava

ilab

legluco

se-loweringagen

tsin

theU.S.andEuro

pethat

mayguideindividualize

dtreatm

entch

oicesin

patients

withtype2diabetes(17)

Class

Compound(s)

Cellularmechanism(s)

Prim

aryphysiologicalaction(s)

Advantages

Disadvantages

Cost*

Biguanides

cMetform

inActivates

AMP-kinase(?

other)

c↓Hep

aticglucose

production

cExtensive

experience

cGastrointestinalsideeffects

(diarrhea,abdominalcram

ping)

Low

cNohypoglycem

iacVitam

inB12defi

cien

cyc↓CVDeven

ts(UKP

DS)

cContraindications:CKD

,acidosis,

hypoxia,deh

ydration,etc.

cLacticacidosisrisk

(rare)

Sulfonylureas

2ndGen

eration

ClosesKATPchan

nelsonb-cell

plasm

amem

branes

c↑Insulin

secretion

cExtensive

experience

cHypoglycem

iaLow

cGlyburide/

gliben

clam

ide

c↓Microvascularrisk

(UKPD

S)c↑Weigh

t

cGlipizide

cGliclazide†

cGlim

epiride

Meglitinides

(glinides)

cRep

aglinide

ClosesKATPchan

nelsonb-cell

plasm

amem

branes

c↑Insulin

secretion

c↓Po

stprandialglucose

excursions

cHypoglycem

iaModerate

cNateglinide

cDosingflexibility

c↑Weigh

tcFreq

uen

tdosingsched

ule

TZDs

cPioglitazone‡

Activates

thenuclear

tran

scriptionfactorPP

AR-g

c↑Insulin

sensitivity

cNohypoglycem

iac↑Weigh

tLow

cRosiglitazone§

cDurability

cEdem

a/heartfailure

c↑HDL-C

cBonefractures

c↓Triglycerides

(pioglitazone)

c↑LD

L-C(rosiglitazone)

c?↓CVDeven

ts(PROactive,

pioglitazone)

c?↑MI(m

eta-an

alyses,

rosiglitazone)

a-Glucosidaseinhibitors

cAcarbose

Inhibitsintestinala-glucosidase

cSlowsintestinalcarbohydrate

digestion/absorption

cNohypoglycem

iacGen

erallymodestA1C

efficacy

Lowto

moderate

cMiglitol

c↓Po

stprandialglucose

excursions

cGastrointestinalsideeffects

(flatulence,d

iarrhea)

c?↓CVDeven

ts(STO

P-NIDDM)

cFreq

uen

tdosingsched

ule

cNonsystem

ic

DPP

-4inhibitors

cSitagliptin

InhibitsDPP

-4activity,increasing

postprandialactiveincretin

(GLP-1,G

IP)concentrations

c↑Insulin

secretion(glucose

dep

enden

t)cNohypoglycem

iacAngioed

ema/urticariaandother

immune-med

iateddermatological

effects

High

cVildagliptin†

c↓Glucagonsecretion(glucose

dep

enden

t)

cWelltolerated

c?Acute

pancreatitis

cSaxagliptin

c?↑Heartfailure

hospitalizations

cLinagliptin

cAlogliptin

Bile

acid

sequestran

tscColesevelam

Bindsbile

acidsinintestinaltract,

increasinghep

aticbile

acid

production

c?↓Hep

aticglucose

production

cNohypoglycem

iacGen

erallymodestA1C

efficacy

High

c?↑Incretin

levels

c↓LD

L-C

cConstipation

c↑Triglycerides

cMay

↓absorptionofother

med

ications

Dopam

ine-2agonists

cBromocriptine

(quickrelease)§

Activates

dopam

inergicreceptors

cModulateshypothalam

icregu

lationofmetab

olism

cNohypoglycem

iacGen

erallymodestA1C

efficacy

High

c↑Insulin

sensitivity

c?↓CVDeven

ts(Cycloset

Safety

Trial)

cDizziness/syncope

cNausea

cFatigue

cRhinitis

Con

tinuedon

p.S56

care.diabetesjournals.org Approaches to Glycemic Treatment S55

Table

7.1—

Continued

Class

Compound(s)

Cellularmechanism(s)

Prim

aryphysiologicalaction(s)

Advantages

Disad

vantages

Cost*

SGLT2inhibitors

cCan

aglifl

ozin

InhibitsSG

LT2in

theproximal

nep

hron

cBlocksglucose

reab

sorptionby

thekidney,increasing

glucosuria

cNohypoglycem

iacGen

itourinaryinfections

High

cDapagliflozin‡

c↓Weight

cPo

lyuria

cEm

paglifl

ozin

c↓Bloodpressure

cVolumedep

letion/hypotension/

dizziness

cEffectiveat

allstagesof

type2diabetes

c↑LD

L-C

cAssociated

withlower

CVDeven

trate

and

mortalityin

patients

withCVD(EMPA

-REG

OUTC

OME)

c↑Creatinine(transien

t)cDKA

,urinarytractinfections

lead

ingto

urosepsis,pyelonep

hritis

GLP-1

receptoragonists

cExen

atide

Activates

GLP-1

receptors

c↑Insulin

secretion(glucose

dep

enden

t)cNohypoglycem

iacGastrointestinalsideeffects

(nau

sea/vomiting/diarrhea)

High

cExen

atideextended

release

c↓Glucagonsecretion(glucose

dep

enden

t)

c↓Weight

c↑Heartrate

cLiraglutide

cSlowsgastricem

ptying

c↓Po

stprandialglucose

excursions

c?Acute

pan

creatitis

cAlbiglutide

c↑Satiety

c↓Somecardiovascular

risk

factors

cC-cellh

yperplasia/med

ullary

thyroid

tumors

inanim

als

cLixisenatide†

cInjectab

lecDulaglutide

cTrainingrequirem

ents

Amylin

mim

etics

cPram

lintide§

Activates

amylin

receptors

c↓Glucagonsecretion

c↓Po

stprandialglucose

excursions

cGen

erallymodestA1C

efficacy

High

cSlowsgastricem

ptying

c↓Weight

cGastrointestinalsideeffects

(nau

sea/vomiting)

c↑Satiety

cHypoglycem

iaunlessinsulin

dose

issimultan

eouslyreduced

cInjectab

lecFreq

uen

tdosingsched

ule

cTrainingrequirem

ents

Insulins

cRapid-actinganalogs

Activates

insulin

receptors

c↑Glucose

disposal

cNearlyuniversal

response

cHypoglycem

iaModerateto

high#

-Lispro

-Aspart

-Glulisine

-Inhaled

insulin

cShort-acting

c↓Hep

aticglucose

production

cTheo

retically

unlim

ited

efficacy

cWeigh

tgain

-Human

Regular

cInterm

ediate-acting

cSuppresses

ketogenesis

c↓Microvascularrisk

(UKPD

S)

c?Mitogeniceffects

-Human

NPH

cBasalinsulin

analogs

cTrainingrequirem

ents

-Glargine

-Detem

ir-Degludec†

cPrem

ixed

(several

types)

cPatien

treluctan

cecInjectab

le(excep

tinhaled

insulin)

cPu

lmonarytoxicity

(inhaled

insulin)

CKD

,chronickidney

disease;CVD,cardiovasculardisease;D

KA,diabeticketoacidosis;EM

PA-REG

OUTC

OME,BI107

73(Empaglifl

ozin)C

ardiovascularOutcomeEven

tTrialinType2Diabetes

MellitusPatien

ts(31);

GIP,glucose-dep

enden

tinsulinotropicpep

tide;

HDL-C,H

DLcholesterol;LD

L-C,LDLcholesterol;MI,myocardialinfarction;PP

AR-g,p

eroxisomeproliferator–activatedreceptorg;PR

Oactive,P

rospective

PioglitazoneClinicalTrialinMacrovascularEven

ts(32);STOP-NIDDM,Studyto

Preven

tNon-Insulin-Dep

enden

tDiabetes

Mellitus(33);TZD,thiazolidined

ione;

UKP

DS,UKProspective

Diabetes

Study(34,35

).Cyclosettrialofquick-releasebromocriptine(36).*Costisbased

onlowest-pricedmem

ber

oftheclass(see

ref.17

).†Notlicen

sedintheU.S.‡Initialconcernsregardingbladder

cancerrisk

aredecreasingafter

subsequen

tstudy.§N

otlicen

sedin

Europefortype2diabetes.#C

ostishighlydep

enden

tontype/brand(analogs

.human

insulins)anddosage.Adap

tedwithpermissionfrom

Inzucchie

tal.(17).

S56 Approaches to Glycemic Treatment Diabetes Care Volume 39, Supplement 1, January 2016

expeditiously achieve the target A1Clevel. Insulin has the advantage of beingeffectivewhere other agents may not beand should be considered as part of anycombination regimen when hyperglyce-mia is severe, especially if symptoms arepresent or any catabolic features (weightloss, ketosis) are present. Consider ini-tiating combination insulin injectabletherapy when blood glucose is $300–350 mg/dL (16.7–19.4 mmol/L) and/orA1C is$10–12% (86–108 mmol/mol). Asthe patient’s glucose toxicity resolves, theregimen may, potentially, be simplified.

Insulin TherapyConsider initiating insulin therapy (withor without additional agents) in patientswith newly diagnosed type 2 diabetesand markedly symptomatic and/or

elevated blood glucose levels or A1C.Many patients with type 2 diabeteseventually require and benefit from in-sulin therapy. Providers may wish toconsider regimen flexibility when devising a plan for the initiation and ad-justment of insulin therapy in peoplewith type 2 diabetes (Fig. 7.2). The pro-gressive nature of type 2 diabetes andits therapies should be regularly and ob-jectively explained to patients. For pa-tients with type 2 diabetes who are notachieving glycemic goals, providers shouldpromptly initiate insulin therapy.

Providers should avoid using insulinas a threat or describing it as a failure orpunishment. Equipping patients with analgorithm for self-titration of insulindoses based on self-monitoring of bloodglucose (SMBG) improves glycemic

control in patients with type 2 diabetesinitiating insulin (25).

Basal Insulin

Basal insulin alone is the most conve-nient initial insulin regimen, beginningat 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 possiblyone additional noninsulin agent. Whilethere is evidence for reduced risk of hy-poglycemia with newer, longer-acting,basal insulin analogs, people with type2 diabetes without history of hypogly-cemia or severe hypoglycemia may useNPH safely at much lower cost (24,26).Concentrated preparation of basal in-sulin such as U-500 regular is five timesas potent per volume of insulin (i.e.,

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).

care.diabetesjournals.org Approaches to Glycemic Treatment S57

0.01 mL;5 units of U-100 regular) andhas a delayed onset and longerduration of action than U-100 regular.U-300 glargine and U-200 degludec arethree and two times, respectively, aspotent per volume, have a longer dura-tion of action, and may allow higherdoses of insulin administration insmaller volumes. These concentratedpreparations may be more comfortablefor the patient and allow better absorp-tion. However, they are more expen-sive, and accurate dosing may be morecomplicated.If basal insulin has been titrated to an

acceptable fasting blood glucose level,but A1C remains above target, consideradvancing to combination injectabletherapy (Fig. 7.2) to cover postprandialglucose excursions. Options includeadding a GLP-1 receptor agonist (27) ormealtime insulin, consisting of one tothree injections of rapid-acting insulinanalog (lispro, aspart, or glulisine) ad-ministered just before eating. A lessstudied alternative, transitioning frombasal 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 tocover postprandial glucose excursions.

Bolus Insulin

Some individuals with type 2 diabetesmay require bolus insulin dosing in ad-dition to basal insulin. Rapid-acting an-alogs are preferred due to their promptonset of action after dosing. The FDArecently approved a more concentratedformulation of rapid-acting insulin ana-log, U-200 (200 units/mL), dosed 15 minor immediately prior to a meal.Regular human insulin and human

NPH-Regular premixed formulations(70/30) are less costly alternatives torapid-acting insulin analogs and pre-mixed insulin analogs, respectively,but their pharmacodynamic profilesmake them suboptimal to cover post-prandial glucose excursions.

Continuous Subcutaneous Insulin Infusion

A less commonly used and more costlyalternative to “basal–bolus” therapywith multiple daily injections is CSII (in-sulin pump) (28,29). In addition to thesuggestions provided for determiningthe starting dose of mealtime insulinunder a basal–bolus regimen, anothermethod 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 threemeals. It is crit-ical that individuals who have been suc-cessfully using CSII should have continuedaccess after they turn 65 years of age (30).

Inhaled Insulin

Inhaled insulin is now available for pran-dial use with a more limited dosingrange and may require serial lung func-tion testing prior to and after startingtherapy.

Treatment Strategies

Figure 7.2 focuses solely on sequentialinsulin strategies, describing the num-ber of injections and the relative com-plexity and flexibility of each stage. Oncean insulin regimen is initiated, dose ti-tration is important, with adjustmentsmade in both mealtime and basal insu-lins based on the prevailing blood glu-cose levels and an understanding of thepharmacodynamic profile of each for-mulation (pattern control).

Noninsulin agents may be continued,although sulfonylureas, DPP-4 inhibi-tors, and GLP-1 receptor agonists aretypically stopped oncemore complex in-sulin regimens beyond basal are used. Inpatients with suboptimal blood glucosecontrol, especially those requiring in-creasing insulin doses, adjunctive useof thiazolidinediones (usually pioglita-zone) or SGLT2 inhibitors may be helpfulin improving control and reducing theamount of insulin needed. Comprehen-sive education regarding SMBG, diet, ex-ercise, and the avoidance of and responseto hypoglycemia are critically importantin any patient using insulin.

BARIATRIC SURGERY

Bariatric surgery also improves glycemiccontrol in type 2 diabetes. Its effects arediscussed in Section 6 “Obesity Man-agement for the Treatment of Type 2Diabetes.”

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