Basal Glucose Can Be Controlled,but the Prandial ProblemPersistsdIt’s the Next Target!Diabetes Care 2017;40:291–300 | DOI: 10.2337/dc16-2380

Both basal and postprandial elevations contribute to the hyperglycemic exposure ofdiabetes, but current therapies are mainly effective in controlling the basal compo-nent. Inability to control postprandial hyperglycemia limits success in maintainingoverall glycemic control beyond the first 5 to 10 years after diagnosis, and it is alsorelated to the weight gain that is common during insulin therapy. The “prandialproblem”dcomprising abnormalities of glucose and othermetabolites, weight gain,and risk of hypoglycemiaddeservesmore attention. Several approaches to prandialabnormalities have recently been studied, but thepatient populations forwhich theyare best suited and the best ways of using them remain incompletely defined.Encouragingly, several proof-of-concept studies suggest that short-acting glucagon-like peptide 1 agonists or the amylin agonist pramlintide can be very effective incontrolling postprandial hyperglycemia in type 2 diabetes in specific settings. Thisarticle reviews these topics and proposes that a greater proportion of availableresources be directed to basic and clinical research on the prandial problem.

Widespread self-testing of blood glucose and, more recently, continuous glucose mon-itoring (CGM) have drawn attention to the daily patterns of blood glucose in both type 1and type 2 diabetes. Seeing thesepatternshas allowed separate consideration of fasting(basal) hyperglycemia and after-meal (postprandial) increments of glucose above basallevels. In entirely healthy individuals, fasting plasma glucose is rarely .100 mg/dL(5.5mmol/L). Peak values after meals are,140mg/dL (7.8 mmol/L) and return quicklyto basal levels. In the early stages of dysglycemia, high basal glucose (described asimpaired fasting glucose) is the main abnormality for some people, whereas for othershyperglycemia after meals or an oral glucose load (impaired glucose tolerance) is moreevident. These differences reflect varying mechanisms, may predict specific responsesto initial treatments, and deserve further study. However, both basal and postprandialhyperglycemia are routinely present later in the natural history of type 2 diabetes, inpart because sustained hyperglycemia can impair both the secretion and the variousactions of insulin. Both are always present in type 1 diabetes. In the last 25 years wehave become very successful in managing basal hyperglycemia, but postprandial hy-perglycemia and its associated abnormalities remain untamed.

STUDIES OF BASAL GLYCEMIC THERAPIES IN TYPE 2 DIABETES

In untreated type 2 diabetes, basal hyperglycemia is usually quantitatively greater thanfurther elevation of glucose after meals, especially when A1C is.8.0% (64mmol/mol)(1–4). This is fortunate becausemost treatments for type 2 diabetes aremore effectivein controlling basal hyperglycemia. Metformin, sulfonylureas, thiazolidinediones, andbasal insulins (human NPH and insulins glargine, detemir, and degludec) all have rel-ativelymodest effects on postprandial hyperglycemia. The same is true for most of the

Division of Endocrinology, Diabetes & ClinicalNutrition, Oregon Health & Science University,Portland, OR

Corresponding author:MatthewC. Riddle, riddlem@ohsu.edu.

Received 7 November 2016 and accepted 10December 2016.

© 2017 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. More infor-mation is available at http://www.diabetesjournals.org/content/license.

Matthew C. Riddle

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newer agents, including dipeptidyl pepti-dase 4 inhibitors, sodium–glucose co-transporter blockers, and longer-actingglucagon-like peptide 1 (GLP-1) receptoragonists. Consequently, in a mixed popu-lation of type 2 diabetes, glycemic expo-sure from basal hyperglycemia is typicallydominant when A1C is high, and whencontrol is improved by treatment, thecontribution from postprandial hypergly-cemia becomesmore prominent (5). Evenwhen dietary or pharmacological treat-ment maintains A1C values below the7.0% (53mmol/mol) target, residual post-prandial hyperglycemia commonly limitsattainment of A1C,6.5%, the upper endof the normal range (4,6). Persistence ofpostprandial hyperglycemia is most evi-dent when long-acting (basal) insulin isadded to one or more oral agents andsystematically titrated to a fasting glucosetarget. An analysis of self-measured glu-cose profiles in type 2 diabetes no longerwell controlled with oral agents, pooledfrom six studies, found that 79% of theglucose elevation .100 mg/dL was dueto basal hyperglycemia (7). Six monthsafter initiation of basal insulin, 34% ofthe hyperglycemic burden was basal and66% was postprandial. In studies of thiskind, average fasting glucose after optimi-zation of basal insulin generally rangesbetween 100 and 130 mg/dL (6.6 and7.3 mmol/L) and mean A1C is close to7.0% (53mmol/mol). Evenwhen basal in-sulin is expertly titrated, significant pran-dial hyperglycemia may persist. Forexample, an experienced research groupshowed that for 61 patients whose meanbaseline A1Cwas 9.5% (80mmol/mol) onone or two oral agents, 36 weeks of titra-tion of insulin glargine with continuationof metformin led to excellent controlof fasting glucose (mean 104 mg/dL[5.75 mmol/L]). However, the mean A1Cwas 7.14% (54 mmol/mol), and half thegroup still had A1C.7%, mainly becauseof daytime hyperglycemia (8).Attainment of A1C levels ,7.0% is

more likely when basal insulin is startedbefore A1C is markedly elevated. Analysisof data from .2,000 participants in12 studies showed that when baselineA1C was between 7 and 8% (mean 7.6%[60mmol/mol]), a level,7.0%wasreachedin 6 months by 75% of patients (9). TheOutcome ReductionWith Initial GlargineIntervention (ORIGIN) trial further veri-fied the safety and efficacy of timely ini-tiation of basal therapies (10).More than

12,500 patients with impaired fastingglucose, impaired glucose tolerance, ortype 2 diabetes treated with no morethan one oral agent (and also selectedfor high cardiovascular risk) were ran-domized to either stepwise oral therapy(in most cases metformin and glimepiride)or insulin glargine added to any prior oraltherapy and titrated to specific targets.For the 88% of patients in ORIGIN withovert diabetes at enrollment, themean du-ration of diabetes was 4 years and medianA1C was 6.6% (49 mmol/mol) (11). After7 years of treatment A1C was 6.6% withthe regimen based on oral therapy (with;10% needing to add insulin) and 6.3%(45 mmol/mol) with the basal insulin regi-men. Safety findings were reassuring evenin this high-risk population and similar be-tween the regimens except for a threefoldgreater frequency of hypoglycemia in thebasal insulin arm.

Hypoglycemia is associated with mor-bidity and mortality and is the leadinglimitation of basal insulin therapy. InORIGIN, younger age, lower BMI, andlower attained dosage of glargine as basalinsulin were independent predictors ofnonseverehypoglycemia (12). In contrast,and consistent with other studies, eventsrequiring assistance by another personwere associated with older age and evi-dence of renal or cognitive impairment(12,13). Although a causal relationshipbetween hypoglycemia and poor medicaloutcomes has been difficult to verify intype 2 diabetes, recurrent or severe hy-poglycemia calls for measures tomitigaterisks (13,14). The simplest such measureis relaxation of goals for A1C, typically byincreasing the target range from ,7.0%to between 7 and 8% for higher-risk pa-tients. Use of the new basal insulins (in-sulin degludec [Tresiba] and insulinglargine 300 units/mL [Toujeo]), both ofwhich have longer and flatter glucose-lowering profiles, may reduce the riskof hypoglycemia while maintainingdesired levels of glycemic control. Di-rect comparisons of degludec (15) andglargine 300 units/mL (16) with glargine100 units/mL (Lantus) as ongoing basaltherapy in type 2 diabetes have shown;30% lower risk of confirmed hypoglyce-mic events at night and smaller reduc-tions of hypoglycemia at any time ofday. Presumably, a subset of patientswould be especially likely to benefitfrom using one of the new basal insulins.The analysis of predictors of hypoglycemia

accompanying the use of glargine 100units/mL described above suggests thatindividuals who have low BMI and lowbasal insulin requirements might bemost likely to have more stable glycemiccontrol with a longer-acting insulin (12).When the risk of hypoglycemia is reduced,further titration of dosage during long-term follow-upmight favormore frequentattainment of A1C targets, but this expec-tation has been difficult to verify (17,18).

Long-acting GLP-1 receptor agonistsare an alternative to basal insulin for pa-tients with high risk of hypoglycemia andcan be combined with basal insulins toprovide further improvement of glycemiccontrol beyond what is possible with ei-ther component alone (19). They have afavorable effect on weight but, like basalinsulin, only a modest effect on incre-ments of glucose after meals (20,21).

In summary, with an array of oral andinjectable agents to control basal hyper-glycemia, as well as the recent additionof basal insulins with improved profilesof action, type 2 diabetes can usually bemanaged well for the first decade afterdiagnosis. In this time frame, the leadingbarriers to maintaining A1C ,7.0% aredelay in diagnosis, clinical inertia in ad-vancing therapy (22), and difficulty iden-tifying patients at greatest risk forhypoglycemia to allow use of alternativetreatment goals or methods.

THE PRANDIAL PROBLEM PERSISTS

After longer duration of type 2 diabetes(and for most patients with type 1 diabe-tes), control of postprandial hyperglyce-mia is the main unmet need, and it tendsto become more difficult over time. Be-cause type 2 diabetes is now often diag-nosed before age 40, increasing numbersof patients no longer maintain adequateglycemic control with basal therapiesalone at an age when they should haveseveral decades of productive life ahead,provided microvascular complicationscan be prevented.

The usual recommendation for treat-ment intensification in this setting hasbeen to start basal-bolus insulin therapyor at least twice-daily injection of pre-mixed insulins. However, several lines ofevidence suggest this may no longer bethebest approach. First, population-basedstudies in the U.S. show that although theproportions of patients who are able tomaintain desired A1C levels by usinglifestyle alone or with oral agents have

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increased in the last decade, insulin-treat-ed patients continue to have poor control(23). Second, in the Action to Control Car-diovascular Risk in Diabetes (ACCORD)trial and the Veterans Affairs Diabetes Trial(VADT), which enrolled patients with long-duration type 2 diabetes and high cardio-vascular risk, seeking excellent glycemiccontrol with extensive use of basal-bolusinsulin had mixed results. Microvascularoutcomes and some nonfatal cardiovascu-lar events were reduced (24,25), but all-cause mortality increased 20% duringintensive glycemic therapy in ACCORD(25) and significant hypoglycemia andweight gain occurred in both studies.Third, studies comparing ways of intensi-fying insulin therapy for type 2 diabeteshave shown that basal-bolus treatmentoffers little further improvement of A1Cwhen compared with simpler insulin regi-mens (26,27). For all these reasons, it istime to reconsider the prandial problemin type 2 diabetes, which includes interre-lated difficulties with hyperglycemia, hy-poglycemia, and weight control.

PRANDIAL PHYSIOLOGY ANDPATHOPHYSIOLOGY

Growing knowledge of the mechanismsthat normally regulate plasma glucosehas clarified the problems posed by bothbasal and postprandial hyperglycemia(28–30). Fasting glucose is tightly con-trolled through regulation of hepatic glu-cose production by variable release ofinsulin into the portal vein, with modula-tion of insulin’s hepatic effects by glucagonand free fatty acids (FFA). In type 2 diabe-tes, basal insulin secretion is impaired andFFA and glucagon levels are high duringfasting. Injection of long-acting insulin sup-presses hepatic glucose production by act-ing directly on the liver and indirectly byreducing FFA release from adipose tissues.In type 1 diabetes, abnormalities of basalglucose regulation are more marked anddelivery of basal insulin that closelymatches physiological needs is mandatoryfor good control. Analogs of human insulinand improved delivery devices havegreatly helped in meeting this need.A more complex set of mechanisms

comes into play after meals. Insulin secre-tion rapidly and markedly increases, ac-companied by cosecretion of amylin (theother b-cell hormone), which suppressesglucagon, slows gastric emptying, andacutely signals satiety. Various other gas-trointestinal peptides are modulated by

meals, among them GLP-1, which alsosuppresses glucagon, slows gastric empty-ing, and provides amore sustained satietysignal. Neural factorsmay further regulatehepatic glucose production andperipheralinsulin sensitivity. In type 2 diabetes, peaklevels of insulin are lower than normal andoccur 90–120 min after the meal beginsrather than in the first 30 min. The rise ofamylin is also delayed and reduced andthus may fail to suppress glucagon, regu-late gastric emptying, and limit food in-take during the usual duration of themeal. Secretion or action of GLP-1 mayalso be impaired. As for basal glucose,mechanisms for controlling postprandialglucose are more severely disturbed intype 1 diabetes. When both endogenousinsulin and amylin are entirely lacking,prandial insulin treatment faces seriouschallenges.

In both type 1 diabetes and type 2 di-abetes requiring prandial therapy, the sizeand timing of a prandial insulin doseshould match the needs posed by eachmeal. However, meals differ widely incomposition, size, and timing. Faulty dos-ing decisions lead to a mismatch betweenthe meal and the profile of insulin deliv-ered, and either marked postprandial hy-perglycemia or later hypoglycemia canoccur. Even when prandial insulin dosingis accurate, the resulting smaller increaseof glucosemay lead to further suppressionof endogenous insulin and amylin, favor-ing reduced satiety and thus continuedcalorie intake. These difficulties contributeto the postprandial hyperglycemia, laterhypoglycemia, and continuing weightgain that are commonly seen duringbasal-bolus insulin treatment. In addition,frequent testing of glucose (or CGM) toguide prandial dosing and the multiple in-jections needed are burdens that hinderregimen adherence.

INFORMATION OBTAINED BY CGM

For clinical care, CGM facilitates individu-alized decisions on prandial dosing, andfor research, it offers new quantitativeend points for testing treatment regi-mens. Various formulas have been pro-posed to describe glycemic variability,and there is active debate about how touse them (31–33). Among the most ap-pealing is the “time in range.” An expertpanel recently proposed the percentageof measurements in a day between70 and 180 mg/dL (3.9 and 10.0 mmol/L)as a summary indicator of glycemic

control (34). Practice guidelines from theAmerican Diabetes Association alsosuggest ,180 mg/dL as a target for con-trol of glucose levels 1–2 h after a meal(35). Selection of 180 mg/dL (10 mmol/L)by both groups as the upper end of anominally desirable range speaks to thedifficulty of controlling postprandial hy-perglycemia with current methods. Anearly report of CGM measurements fora group of 15 patients with type 1 and15 with type 2 diabetes whose meanA1C was 7.5% (58 mmol/mol) found thatglucose was above 180 mg/dL 33% of thetime (36). In addition to limiting attain-ment of A1C targets, this much variabilitybeyond the desired range is suspected ofcontributing to both the microvascularand cardiovascular complications of dia-betes, independent of the mean level ofcontrol reflected by A1C (37).

TACTICS TO IMPROVE PRANDIALTHERAPY

Behavioral interventions for postpran-dial hyperglycemia and weight control,although centrally important, are be-yond the scope of this article. For thepresent discussion, several other ap-proaches deserve comment.

Metabolic SurgeryGastrointestinal procedures intended toalter food intake and absorption andotherwise improve prandial physiologyare now entering the mainstream oftreatment options (38). Themechanismsunderlying their effects are not well un-derstood (39), but a large body of infor-mation on short-term clinical outcomesis available. Diabetes cannot be said tobe cured by this approach, but very im-pressiveweight loss and improvement ofprandial and overall glycemic control arecommon (40). A recent joint statementby international diabetes organizationshas endorsed metabolic surgery as atreatment “recommended” for patientswith type 2 diabetes and BMI 40 kg/m2

or higher and “considered” under certainconditions for individuals with less se-vere obesity (41). However, long-termassessment of the risks versus benefitsof this approach is not yet available.

a-Glucosidase Inhibitorsa-Glucosidase inhibitors (AGIs) are notwidely used in the U.S. but have greateracceptance in someother countries. Theirleading drawbacks are gastrointestinalside effects, mainly flatulence and

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diarrhea. They can reduce postprandialhyperglycemia in type 2 diabetes by;50% and are effective in combinationwith therapies that target basal glucosecontrol (42). Secondary analyses of datafrom the Study to Prevent Non-Insulin-Dependent-Diabetes (STOP-NIDDM)suggested that acarbose might reducecardiovascular risk for patients with im-paired glucose tolerance or type 2 dia-betes (43). A large study testing thishypothesis is now underway (44). If car-diovascular benefit is confirmed, use ofAGIs for patients with type 2 diabetesand adequate basal control but persist-ing postprandial hyperglycemia shouldbe reconsidered.

Stepwise Addition of Prandial InsulinMany patients with type 2 diabetes ad-vised to use basal-bolus insulin therapydo not consistently follow the treatmentplan. To address this problem, a simpler,stepwise approach to adding prandial in-sulin to basal therapy has been proposed(45). Mean A1C reductions of 0.3% to0.5% after adding a single prandial injec-tion before breakfast or another impor-tant meal are typical and sometimessufficient (46). At the time of initiationof basal insulin for type 2 diabetes orsoon after, adding a single injection ofprandial insulin may be as effective asfull basal-bolus treatment and also as ef-fective as two injections of premixed in-sulin but with less risk of hypoglycemia(27,47). Of course, this approach is notappropriate for type 1 diabetes.

More Rapidly Absorbed PrandialInsulinsNormal secretion of endogenous insulinincreases plasma levels sooner after ameal than injection of the current gener-ation of “rapid-acting” insulin analogs.Hence, insufficiently rapid onset of pran-dial insulin has been proposed as themain limitation of basal-bolus therapy,whether by multiple injections or by con-tinuous subcutaneous insulin infusion(CSII). Also, the subcutaneous depot ofinsulins aspart, lispro, or glulisine maycontinue to increase plasma levels longerthan necessary to match needs aftersmall meals containing mainly refinedcarbohydrate. Insulin formulations thatare more rapidly absorbed after subcuta-neous injection are under study (48), andan inhalable formulation with rapid earlyuptake (49) is now available as well.Whether these modifications will lead to

sustained improvement of glycemic con-trol in routine management of either type1 or type 2 diabetes remains unknown.

Closed-Loop Insulin Delivery SystemsComputerized algorithms linking CSII toCGM are under intense scrutiny fortype 1 diabetes (50). The hardware andsoftware for such systems continue to im-prove, and there are encouraging reportsof their use for ambulatory patients(51,52). In addition to the pharmacoki-netics of currently used insulins, limita-tions of these systems include the costof the devices themselves and of clinicalsupport for their use, the risk of systemfailure, and observations that, to date,substantial glycemic variability related tomeals remains.Whether such systemswillbewidely acceptable for type 2 diabetes isunknown, as is whether weight gain asso-ciated with their use can be prevented.Systems supplementing insulin infusionwith timely delivery of subcutaneous glu-cagon to protect against hypoglycemiahave yielded promising early results (53).

GLP-1 Receptor AgonistsMost studies of currently available GLP-1agonists have focused on the longer-acting products. Liraglutide (Victoza),extended-release exenatide (Bydureon),dulaglutide (Trulicity), and albiglutide(Tanzeum) all have relatively long dura-tion of action and greater effects on basalthan on postprandial glucose (54–57). Allare very effective in reducing A1C in pa-tients who start with high levels, and theyhave desirable effects on weight. Theirmain side effects are nausea and othergastrointestinal complaints, and up to20% of patients discontinue treatmentin clinical studies. They are strongly mar-keted as alternatives to basal insulin.

In contrast, the shorter-acting GLP-1agonists, unmodified exenatide (Byetta)and lixisenatide (Adlixin), have receivedlimited attention (58,59). When givenjust prior to a meal, both slow gastricemptying, prevent an inappropriate riseof glucagon, potentiate insulin secretion,and thereby markedly blunt postprandialhyperglycemia. They also favor weightloss. Dose-ranging studies have shownthat these agents can reducepostprandialhyperglycemia at low doses (e.g., 5 mgbefore a meal) that rarely cause gastroin-testinal side effects (60,61). In principle,their best use should be for patients withgood control of basal glucose but persist-ing postprandial hyperglycemia.

Amylin Receptor AgonistsEven less attention has been directed topramlintide (Symlin), an amylin analog(62). This agent is approved in the U.S.as an adjunct to basal-bolus treatmentof type 1 or type 2 diabetes. It is givenas fixed doses by subcutaneous injectionbefore meals, has a short duration of ac-tion, and markedly blunts postprandialhyperglycemia by suppressing glucagonand slowing gastric emptying. Like theGLP-1 agonists, it reduces food intakeand favors weight loss. Pramlintide’s dis-advantages for its current indications in-clude the need for several daily injectionsin addition to multiple injections of insu-lin, frequent dosing decisions, and in-creased risk of nausea or hypoglycemia.Because of these difficulties and limitedmarketing efforts, it is not widely used.

PROOF-OF-CONCEPT STUDIESFOR SHORT-ACTING GLP-1AGONISTS AND AN AMYLINRECEPTOR AGONIST

Recent studiesofGLP-1andamylin agonistsadded to basal insulin for type 2 diabeteshave been very encouraging. Key findingsfrom these are summarized in Table 1.

Exenatide Versus PlaceboIn one study (63), 261 patients withtype 2 diabetes with elevated A1C on oraltherapies plus insulin glargine (Lantus)were randomized to add twice-dailyexenatide (Byetta) or placebo injec-tions before breakfast and dinner(Fig. 1). Glargine was titrated during30 weeks of treatment. Mean baselineA1C was .8.0% in both groups, andthe reduction from baseline was 0.69%greater with exenatide. After treatment,A1C #7.0% was attained by 60% of thegroup assigned to exenatide and 35% ofthe placebo group. Body weight in-creased with placebo but decreasedwith exenatide, with a between-treatmentdifference of 2.7 kg. Gastrointestinal com-plaints were more frequent with exena-tide, but the frequency of hypoglycemiadid not differ. Most of the between-groupdifference in A1C was due to blunting ofthe postprandial increments of glucose af-ter the exenatide doses at breakfast anddinner.

Exenatide Versus Rapid-Acting InsulinAnother study directly compared basalinsulin plus twice-daily exenatide withconventional basal-bolus therapy oftype 2 diabetes (64). All patients had

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previously used insulin glargine (Lantus)with oral agents, and after 12 weeks oftitration of glargine dosage, 627 of themwere randomized to add either exena-tide (Byetta) or insulin lispro. Frommean baseline levels of 8.2% and 8.3%(66 and 67 mmol/mol), both treatmentsreduced A1C to 7.2% (55 mmol/mol).Weight increased with lispro but de-creased with exenatide, with a be-tween-treatment difference of 4.6 kg.Hypoglycemia was less frequent butgastrointestinal symptoms more com-mon with exenatide. Reduced postpran-dial increments accounted for most ofthe glycemic effect of both regimens.A smaller but similarly designed study

examined the effects of exenatide versusrapid-acting insulin on glucose profilesmeasured by CGM (65) (Fig. 2). After arun-in of 8 to 12 weeks on basal-bolusinsulin, 102 patients with long-duration(median 15 years) type 2 diabetes andhigh cardiovascular risk were randomizedto continue basal-bolus therapy or toswitch to insulin glargine (Lantus) plustwo or three mealtime doses of exena-tide (Byetta). Adjustment of medicationsduring 26 weeks of randomized treat-ment attained the intended goal ofequivalent A1C between 6.7 and 7.3%(50 and 56 mmol/mol) with each regi-men (final mean values 7.2% [55 mmol/mol] with basal-bolus insulin and 7.1%[54 mmol/mol] with basal insulin and

exenatide). Glycemic variability, definedas the coefficient of variation of glucoselevels measured by CGM, was the primaryend point. Variability was reduced morewith the exenatide-based regimen. Glu-cose values were in the 70–180 mg/dLrange 75% of the time with exenatide andbasal insulin and 71% of the time withbasal-bolus insulin. Weight was unchangedwith basal-bolus therapy but declinedwith exenatide and basal insulin, witha between-treatment difference of 5.5 kg.

Lixisenatide Versus PlaceboIn patients with type 2 diabetes previ-ously treated with basal insulin and oralagents, insulin glargine (Lantus) wastitrated for 12 weeks, and patients withA1C .7.0% (n = 446) were randomizedto add lixisenatide or placebo injectedonce-daily before breakfast (66). After24 weeks, mean A1C had declined from7.6 to 7.0% (60 to 53 mmol/mol) withlixisenatide and to 7.3% (56 mmol/mol)with placebo, with a difference of0.32%. Values of A1C #7.0% were at-tained by 56% of patients taking lixise-natide versus 39% of those assigned toplacebo. Gastrointestinal symptomsand hypoglycemia were more frequentwith lixisenatide.

Lixisenatide Versus Rapid-ActingInsulinThis head-to-head study examined 298patients with a mean duration of type 2

diabetes of 12 years who were previouslytaking basal insulin and oral agents. Afteroptimization of insulin glargine (Lantus)for 12 weeks, they were randomized toaddition of lixisenatide once daily, rapid-acting insulin once daily, or rapid-actinginsulin three times daily for 26 moreweeks (67). From a mean A1C of 7.6%(60 mmol/mol) after glargine titration,levels declined to 7.2, 7.2, and 7.0% (55,55, 53 mmol/mol) with lixisenatide andthe two rapid-acting insulin regimens, re-spectively. The change of weight duringrandomized treatment favored the lixise-natide arm versus the two insulin armsby21.7 and22.0 kg.

Pramlintide Versus Rapid-ActingInsulinA randomized, open-label comparison ofpramlintide with rapid-acting insulin, witheach of these prandial therapies added totitrated basal insulin, was performed in133 patients with type 2 diabetes (68) (Fig.3).After24weeks,A1Cwassimilarly reducedfrom8.2 and 8.3% (66 and 67mmol/mol) to7.2and7.0%(55and53mmol/mol)with thepramlintide and rapid-acting insulin regi-mens, respectively. Reductionsof fastingglu-cose and postprandial glucose incrementswere not significantly different betweenthe regimens. Weight increased with rapid-acting insulin but not pramlintide, with a dif-ference of 4.7 kg. Pramlintide caused morenausea but less hypoglycemia than rapid-acting insulin.

Table 1—Proof-of-concept studies of short-acting GLP-1 and amylin receptor agonists added to basal insulin for prandialtherapy

Authors (ref.)

Participants,N (duration

diabetes, years) Prior therapy ComparisonBaselineA1C (%)

AttainedA1C (%)

Δ Weight(kg) vs.

comparator Other comments

Buse et al. (63) 261 (mean 12) Oral agents +basal insulin

Exenatide b.i.d. vs.placebo b.i.d.

8.35, 8.53 6.6, 7.5 22.7 More nausea withexenatide

Diamant et al. (64) 627 (median11) Oral agents +basal insulin

Exenatide b.i.d. vs.rapid-acting insulin

t.i.d.

8.3, 8.2 7.2, 7.2 24.6 More nausea but lesshypoglycemia with

exenatide

FLAT-SUGAR TrialInvestigators (65)

102 (median15) Oral agents +basal-bolusinsulin

Exenatide b.i.d./t.i.d.vs. rapid-acting insulin

t.i.d.

7.3, 7.4 7.1, 7.2 25.45 Less glycemicvariability with

exenatide

Riddle et al. (66) 446 (mean 9) Oral agents +basal-bolusinsulin

Lixisenatide q.d. vs.placebo q.d.

7.6, 7.6 7.0, 7.3 20.9 More nausea andhypoglycemia with

lixisenatide

Rosenstock et al. (67) 298 (mean 12) Oral agents +basal-bolusinsulin

Lixisenatide q.d. vs.rapid-acting insulinq.d. vs. rapid-acting

insulin t.i.d.

7.8, 7.7, 7.8 7.2, 7.2, 7.0 21.7, 22.0 More nausea but lesshypoglycemia with

lixisenatide

Riddle et al. (68) 113 (mean 10) Oral agents6basal insulin

Pramlintide t.i.d. vs.rapid-acting insulin

t.i.d.

8.2, 8.3 7.2, 7.0 24.7 More nausea but lesshypoglycemia with

pramlintide

care.diabetesjournals.org Riddle 295

NEW PERSPECTIVES:REDIRECTING EFFORT FROMBASAL TO PRANDIAL CONTROL

The preceding discussion suggests thatbasal hyperglycemia is no longer themain problem. Instead, the prandialproblem deserves more attention, andthere are promising but incompletelyexplored options for addressing it.From both the commercial and the pub-lic health points of view, the return oninvestment could be improved by shift-ing effort and resources from basal toprandial therapy.

Immediate Clinical MeasuresTogetherwith earlier diagnosis and timelyinitiation of basal therapy for type 2 di-abetes, prandial treatment could beadded earlier than in the past. The glyce-mic increment persisting after optimizedbasal therapy could be blunted by adding,with one ormoremeals, an AGI, a dose ofrapid-acting or regular human insulin, or ashort-acting GLP-1 agonist. Progressingstepwise in this fashion from a basal-only regimen to basal plus prandialtherapy before attempting a full basal-prandial strategy is simpler and likely tobe better tolerated. At present, continu-ation of basal therapies used alone, evenwith appropriate titration of dose, typi-cally allows A1C levels to rise gradually tolevels well above 7.0% after 10 or moreyears while additional treatment to re-store A1C to the ,7.0% “target” is de-layed. A better approach might be toconsider 7% A1C a “ceiling” and to seekvalues below this level by timely additionof prandial therapy. Overtitration ofbasal insulin leading to hypoglycemiawould be less common if prandial ther-apy were regarded as easy and desirablerather than difficult and dangerous. Evenwithout incorporating newmethods, ear-lier prandial therapy might extend thetime excellent glycemic control is main-tained, leading to reduction of long-termmicrovascular and cardiovascular risks.

More Skillful Use of GLP-1 Agonists forType 2 DiabetesBetter awareness of the differences be-tween long-acting and short-acting drugsin this class is needed. Demonstration of a22% reduction of cardiovascularmortalitywith liraglutide (in the Liraglutide Effectand Action in Diabetes: Evaluation of car-diovascular outcomeResults [LEADER] trial[69]) has increased the attractiveness ofthis agent, but this GLP-1 agonist does

Figure 1—Comparison of treatment with basal insulin glargine plus either twice-daily injectionsof exenatide (black lines) or placebo (green lines), for type 2 diabetes previously treated withoral agents and basal insulin (adapted with permission from Buse et al. [63]). Dosage of glarginewas titrated during 30 weeks of randomized treatment. The figure shows responses of A1C (A),weight change from baseline (B), and 7-point self-measured glucose profiles before (dashedlines) and after (solid lines) treatment (C). Error bars display 95% CI. *P, 0.001 and †P, 0.01for between-treatment differences. PP, postprandial.

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not reliably control postprandial hyper-glycemia. Whether long-term use ofshort-acting GLP-1 agonists, which havebetter prandial effects (20,21), can alsoreduce cardiovascular risk in a similarpopulation is unknown, and no such

benefit was seen with once-daily lixise-natide in the very high-risk populationstudied in the Evaluation of Lixisenatidein Acute Coronary Syndrome (ELIXA) trial(70). However, the short-acting GLP-1agents might be an excellent option for

patients whose postprandial hyperglyce-mia seriously impairs attainment of A1Cgoals to limit microvascular risk. Exena-tide or lixisenatide should, for many pa-tientswith type 2 diabetes, be as effectiveas prandial insulinwithout causingweightgain and hypoglycemia. Gastrointestinalsymptoms could be limited byminimizingdoses. Delivery devices allowing selectionof doses between 2.5 and 10 mg wouldpermit the greatest flexibility, but theyhave not been made available. The bestresults are likely to derive from stepwiseaddition of up to three prandial doses(65). Pre- or postprandial glucose testswould not routinely be needed to guidedosing, allowing greater convenience andperhaps lower additional cost than pran-dial insulin. Further well-designed studiesof this approach are needed.

Coadministration of an AmylinAnalog With Insulin for Type 1DiabetesPerhaps themost remarkable opportunityis for development of a fixed-ratio formu-lation of an amylin analog with insulin.Under normal conditions, endogenous in-sulin and amylin are cosecreted by b-cellsin the same patterns during fasting andwith meals. Use of pramlintide (off-label)as the only prandial therapy supplement-ing newly initiated basal insulin in thestudy described above (66) is a significantproof of concept, but not likely to be ef-fective for longer-duration type 2 diabetesor type 1 diabetes. Especially in type 1diabetes, where little or no b-cell func-tion remains, coordinated replacementtherapy for this bihormonal deficiencydeserves further study. Preliminary re-ports show no obvious barriers to a com-bined formulation of pramlintide withregular human insulin for clinical use(71,72), and developing one could haveboth clinical and commercial appeal. Con-tinuous delivery of a coformulation mighthave several advantages. Titration deci-sionswould be simpler thanwith separatedosing. Postprandial hypoglycemia mightbe reduced, and weight control wouldsurely be improved comparedwith insulintherapy alone. Nausea might be less fre-quent thanwith intermittent use of pram-lintide. Combined with a closed-loopcontrol system, this approachmight attainnear-normal glycemic control more reli-ably than an insulin-only or insulin-with-glucagon system. These are testablehypotheses.

Figure 2—Comparison of treatment with either basal insulin glargine plus exenatide injectedtwo or three times daily or basal-bolus insulin plus metformin, for long-duration type 2 diabetespreviously stabilized on basal-bolus insulin (adapted with permission from FLAT-SUGAR TrialInvestigators [65]). During randomized treatment for 26 weeks the aim was to keep A1C be-tween 6.7 and 7.3%. The figure shows CGMmeasurements at baseline (black line) and 26 weeks(red line) for patients using basal-bolus insulin (A), CGM at baseline (black line) and 26 weeks(blue line) for those using basal insulin with exenatide (B), and weight changes during random-ized treatment (C). Mean weights and SE are shown.

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Development of Other Gut-PeptideRelated TherapiesThis topic deserves a separate review, butseveral points are clear. There are manygastrointestinal peptide hormones, somewith known structures and metabolicfunctions (73,74). Research on their rolesin health and disease will be central tounderstanding the genesis of obesityand diabetes and perhaps the links be-tween these and cardiovascular diseaseand cancer. Formulations of these pep-tides, or synthetic analogs, will becomeavailable for research and clinical use.Their dosing may be more flexible thanthat of insulin, allowing alternative (non-injection) routes of delivery.

ALLOCATION OF RESOURCES

Where can we find the resources forthese new efforts? Product developmentand basic research are expensive. How-ever, some of the resources now usedfor fine-tuning the treatment of basal hy-perglycemia may now be better used forthe prandial problem. We have multipleclasses of oral and injected agents withpowerful effects on basal glucose, aswell as many choices in each class. Ratherthan more of these redundant therapies,better ways to deliver prandial insulinsand short-acting GLP-1 agonists should

be studied, along with coformulation ofan amylin agonistwith insulin. In addition,investment in closed-loop delivery sys-tems and surgical modification of intesti-nal function should proceed but not beunlimited. They are what Lewis Thomascalled “half-way technologies” (75).Whileamazingdwe are lucky to have themtodaydthey will become obsolete (liketuberculosis sanatoria and iron lungs)when research uncovers the root causesof the problems they address. The pre-sent challenge is to focus use of closed-loop CSII and metabolic surgery onsubgroups of patients for whom they of-fer the best balance of benefit to cost andrisk. Other resources should be reservedto explore new insights into islet, gut, andbrain physiology (76) to produce the de-finitive therapies of the future. Regulatoryand financial incentives toward this endare needed. The prandial problemdincluding postprandial hyperglycemia,weight gain, and hypoglycemia caused byoverreliance on injected insulindis an en-docrine and neurologic puzzle that calls forfurther basic and clinical research.

Funding. Support for this work was from theRose Hastings and Russell Standley MemorialTrusts.

Duality of Interest. M.C.R. has received re-search grant support through Oregon Health &Science University from AstraZeneca, Eli Lilly,and Novo Nordisk and honoraria for consultingor speaking from AstraZeneca, Biodel, Elcelyx,Eli Lilly, GlaxoSmithKline, Sanofi, Theracos, andValeritas. These dualities of interest have beenreviewed and managed by Oregon Health & Sci-ence University. No other potential conflicts ofinterest relevant to this article were reported.

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Figure 3—Comparison of treatment with basal insulin glargine plus either prandial injections ofpramlintide (solid squares) or a rapid-acting insulin analog (open circles), for type 2 diabetespreviously treated with oral agents6 basal insulin (adapted with permission from Riddle et al.[68]). Dosage of glargine was titrated during 24 weeks of randomized treatment. The figureshows dosage of glargine with both regimens (solid lines) and rapid-acting insulin plus glargine inthe basal-bolus arm (dashed line) (A), responses of A1C (B), change of weight from baseline (C),and responses of fasting glucose (D). Means and SE are shown. ***P, 0.001 and **P, 0.01 forbetween-treatment differences.

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