PathophysiologicApproach to Therapyin Patients With Newly DiagnosedType 2 DiabetesRALPH A. DEFRONZO, MD

ROY ELDOR, MD, PHD

MUHAMMAD ABDUL-GHANI, MD, PHD

Two general approaches to the treat-ment of type 2 diabetes mellitus(T2DM) have been advocated. 1) A

“guideline” approach that advocates se-quential addition of antidiabetes agentswith “more established use” (1); this ap-proach more appropriately should becalled the “treat to failure” approach,and deficiencies with this approach havebeen discussed (2). And 2) a “pathophys-iologic” approach using initial combina-tion therapy with agents known to correctestablished pathophysiologic defects inT2DM (3). Within the pathophysiologicapproach, choice of antidiabetes agentsshould take into account the patient’sgeneral health status and associated med-ical disorders. This individualized ap-proach, which we refer to as the ABCD(E)of diabetes treatment (4), has been incor-porated into the updated American Diabe-tes Association (ADA) guidelines (5).

A = AgeB = Body weightC = Complications (microvascular and

macrovascular)D = Duration of diabetesE = Life ExpectancyE = Expense

Even though physicians must be cogni-zant of these associated conditions(ABCDE) when initiating therapy in newlydiagnosed T2DM patients, we believe thatthe most important consideration is to

select antidiabetes agents that correctspecific pathophysiologic disturbancespresent in T2DM and that have comple-mentary mechanisms of action. Althoughit has been argued that the pathogenesis ofT2DM differs in different ethnic groups(6), evidence to support this is weak. Al-though the relative contributions of b-cellfailure and insulin resistance to develop-ment of glucose intolerance may differ indifferent ethnic groups (6), the core de-fects of insulin resistance in muscle/liver/adipocytes and progressive b-cell failure(3) are present in virtually all T2DM pa-tients and must be treated aggressively toprevent the relentless rise in HbA1c that ischaracteristic of T2DM.

In subsequent sections, we provide areview of the natural history of T2DM,specific pathophysiologic abnormalitiesresponsible for T2DM, currently availableantidiabetes agents and their mechanismof action, recommended glycemic goals,and use of combination therapy basedupon reversal of pathophysiologic defectspresent in T2DM. We will not address ex-pense but recognize that this is an im-portant consideration in choosing anyantidiabetes regimen.

Overview of T2DM: pathophysiologyand general therapeutic approachT2DM is a complex metabolic/cardiovas-cular disorder with multiple pathophys-iologic abnormalities. Insulin resistance

in muscle/liver and b-cell failure repre-sent the core defects (7,8). b-Cell failureoccurs much earlier in the natural historyof T2DM and is more severe than previ-ously thought (9–12). Subjects in the up-per tertile of impaired glucose tolerance(IGT) are maximally/near-maximally in-sulin resistant and have lost .80% oftheir b-cell function. In addition to mus-cle, liver, and b-cells (“triumvirate”) (7),adipocytes (accelerated lipolysis), gas-trointestinal tract (incretin deficiency/resistance), a-cells (hyperglucagonemia),kidney (increased glucose reabsorption),and brain (insulin resistance and neuro-transmitter dysregulation) play importantroles in development of glucose intoler-ance in T2DM individuals (3). Collec-tively, these eight players comprise the“ominous octet” (Fig. 1) and dictate that1)multiple drugs used in combinationwillbe required to correct the multiple patho-physiological defects, 2) treatment shouldbe based upon reversal of known patho-genic abnormalities and not simply on re-ducing HbA1c, and 3) therapy must bestarted early to prevent/slow progressiveb-cell failure that is well established inIGT subjects. A treatment paradigm shiftis recommended in which combinationtherapy is initiated with agents that correctknown pathogenic defects in T2DM andproduce durable reduction in HbA1c

rather than just focusing on the glucose-lowering ability of the drug.

Natural history of T2DMIndividuals destined to develop T2DMinherit genes that make their tissues re-sistant to insulin (2,8,13–15). In liver, in-sulin resistance is manifested by glucoseoverproduction during the basal state de-spite fasting hyperinsulinemia (16) andimpaired suppression of hepatic glucoseproduction (HGP) by insulin (17), as oc-curs following a meal (18). In muscle(17,19,20), insulin resistance is manifestby impaired glucose uptake after carbo-hydrate ingestion, resulting in postpran-dial hyperglycemia (18). Although theorigins of insulin resistance can be tracedto their genetic background (8,14,15), thecurrent diabetes epidemic is related to the

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From the Diabetes Division, University of Texas Health Science Center, San Antonio, Texas.Corresponding author: Ralph A. DeFronzo, albarado@uthscsa.edu.This publication is based on the presentations from the 4thWorld Congress on Controversies to Consensus in

Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement weremade possible in part by unrestricted educational grants from Abbott, AstraZeneca, Boehringer Ingelheim,Bristol-Myers Squibb, Eli Lilly, Ethicon Endo-Surgery, Janssen, Medtronic, Novo Nordisk, Sanofi, andTakeda.

DOI: 10.2337/dcS13-2011© 2013 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 thework is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

See accompanying article, p. S139.

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epidemic of obesity and physical inactiv-ity (21), which are insulin-resistant states(22) and place stress on pancreatic b-cellsto augment insulin secretion to offset in-sulin resistance (2,3,8). As long as b-cellsaugment insulin secretion sufficiently tooffset the insulin resistance, glucose toler-ance remains normal (2,3,8,23–29). How-ever, with time b-cells begin to fail, andinitially postprandial plasma glucose lev-els and subsequently fasting plasma glu-cose begin to rise, leading to overt diabetes(2,3,8). Thus, it is progressive b-cell fail-ure that determines the rate of disease pro-gression. The natural history of T2DMdescribed above (2,3) is depicted by a pro-spective study carried out by DeFronzo

(3); Jallut, Golay, and Munger (30); andFelber et al. (31) (Fig. 2).

b-Cell functionAlthough the plasma insulin response toinsulin resistance is increased early in thenatural history of T2DM (Fig. 2), this doesnot mean that b-cells are functioning nor-mally (3). Simply measuring the plasmainsulin response to a glucose challengedoes not provide a valid index of b-cellfunction (32). b-Cells respond to an in-crement in glucose (ΔG) with an incre-ment in insulin (ΔI). Thus, a bettermeasure ofb-cell function isΔI/ΔG. How-ever, b-cells also increase insulin sectionto offset insulin resistance and maintainnormoglycemia (9,10,12,23,32,33). Thus,the gold standard measure of b-cell func-tion in vivo in man is the insulin secretion/insulin resistance (disposition) index(ΔI/ΔG 4 IR).

Figure 3 depicts the insulin secretion/insulin resistance index in normal glucosetolerant (NGT), IGT, and T2DM subjectsas a function of 2-h plasma glucose duringoral glucose tolerance test (OGTT)(2,9,10,12). Subjects in the upper tertileof NGT (2-h plasma glucose 120–139mg/dL) have lost.50% ofb-cell function,while subjects in upper tertile of IGT (2-hplasma glucose 180–199 mg/dL) have lost;80% of b-cell function (Fig. 3). Similarconclusions are evident from other publi-cations (24,27,34,35). The therapeuticimplications of these findings are obvious.When the diagnosis of diabetes is made,the patient has lost ;80% of their b-cell

function, and it is essential that physiciansintervene with therapies known to correctestablished pathophysiological disturbancesinb-cell function. Evenmore ominous areobservations of Butler et al. (36), whodemonstrated that as individuals progressfrom NGT to IFG, there is significant lossofb-cell mass that continues with progres-sion to diabetes. Similar results have beenpublished by others (37,38) and indicatethat significant loss of b-cells occurs longbefore onset of T2DM, according to cur-rent diagnostic criteria (1).

In summary, although insulin resis-tance in liver/muscle is well establishedearly in the natural history of T2DM, overtdiabetes does not occur in the absence ofprogressive b-cell failure.

Insulin resistanceThe liver and muscle are severely resistantto insulin in T2DM (rev. in 2,3,8).Liver. After an overnight fast, the liverproduces glucose at ;2 mg/kg/min(2,16). In T2DM, the rate of basal HGPis increased, averaging ;2.5 mg/kg/min(2,16). This amounts to addition of anextra 25–30 g glucose to the systemic cir-culation nightly and is responsible for theincreased fasting plasma glucose concen-tration. This hepatic overproduction ofglucose occurs despite fasting insulinlevels that are increased two- to three-fold, indicating severe hepatic insulinresistance.Muscle. With use of the euglycemic in-sulin clamp with limb catheterization(2,3,17,19,20,39,40), it has conclusivelybeen demonstrated that lean, as well asobese, T2DM individuals are severely re-sistant to insulin and that the primary siteof insulin resistance resides in muscle.Multiple intramyocellular defects in insu-lin action have been documented in

Figure 1dThe ominous octet (3) depicting the mechanism and site of action of antidiabetesmedications based upon the pathophysiologic disturbances present in T2DM.

Figure 2dNatural history of T2DM. Theplasma insulin response depicts the classicStarling’s Curve of the Pancreas. See text fora detailed explanation (7). Upper panel: In-sulin-mediated glucose disposal (insulin clamptechnique) and mean plasma insulin concen-tration during OGTT. Lower panel: Meanplasma glucose concentration during OGTT.DIAB, T2DM; Hi, high; Lo, low; OB, obese.

Figure 3dInsulin secretion/insulin resistance(disposition) index (DI/DG 4 IR) duringOGTT in individuals with NGT, IGT, andT2DM as a function of the 2-h plasma glucose(PG) concentration in lean and obese subjects(9–12).

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T2DM (rev. in 2,3,8,40), including im-paired glucose transport/phosphoryla-tion (17), reduced glycogen synthesis(39), and decreased glucose oxidation(17). However, more proximal insulinsignaling defects play a paramount rolein muscle insulin resistance (3,40–42).

Ominous octetIn addition to the triumvirate (b-cell fail-ure and insulin resistance in muscle andliver), at least five other pathophysiologicabnormalities contribute to glucose intol-erance in T2DM (3) (Fig. 1): 1) adipocyteresistance to insulin’s antilipolytic effect,leading to increased plasma FFA concen-tration and elevated intracellular levels oftoxic lipidmetabolites in liver/muscle andb-cells that cause insulin resistance andb-cell failure/apoptosis (17); 2) decreasedincretin (glucagon-like peptide [GLP]-1/glucose-dependent insulinotropic poly-peptide [GIP]) effect resulting from impairedGLP-1 secretion (43) but, more impor-tantly, severe b-cell resistance to the stim-ulatory effect of GLP-1 and GIP (44,45);3) increased glucagon secretion by a-cellsand enhanced hepatic sensitivity to gluca-gon, leading to increased basal HGP andimpaired HGP suppression by insulin(46,47); 4) enhanced renal glucose reab-sorption contributing to maintenance ofelevated plasma glucose levels (48,49);and 5) central nervous system resistanceto the anorectic effect of insulin and al-tered neurosynaptic hormone secretioncontributing to appetite dysregulation,weight gain, and insulin resistance inmus-cle/liver (50–52).

Implications for therapyThe preceding review of pathophysiologyhas important therapeutic implications:1) effective treatment will require multi-ple drugs in combination to correct themultiple pathophysiological defects, 2)treatment should be based upon estab-lished pathogenic abnormalities and notsimply on HbA1c reduction, and 3) ther-apy must be started early in the naturalhistory of T2DM to prevent progressiveb-cell failure.

Figure 1 displays therapeutic optionsas they relate to key pathophysiologicalderangements in T2DM (Fig. 1). In liver,both metformin (53–55) and thiazolidi-nediones (TZDs) (56–62) are potent in-sulin sensitizers and inhibit the increasedrate of HGP. In muscle, TZDs are potentinsulin sensitizers (56–58,61,63), whereasmetformin is, at best, a weak insulin sen-sitizer (53,55,64). Since TZDs work

through the insulin signaling pathway(65), whereas metformin works throughthe AMP kinase pathway (66), combina-tion TZD/metformin therapy gives a com-pletely additive effect to reduce HbA1c

(67–72). Further, hypoglycemia is notencountered because these drugs are in-sulin sensitizers and do not augment in-sulin secretion. In adipocytes, TZDs areexcellent insulin sensitizers and potentinhibitors of lipolysis (73). TZDs alsomobilize fat out of muscle, liver, andb-cells, thereby ameliorating lipotoxicity(57,62,63,74–76).

Although weight loss has the poten-tial to improve both the defects in insulinsensitivity and insulin secretion (77), twometa-analyses involving 46 publishedstudies demonstrated that the ability tomaintain the initial weight loss is difficult(78,79). In the following sections, wewill focus on pharmacologic agentsdasmonotherapy and combination therapydthat have been proven to reverse patho-physiologic abnormalities in T2DM.

In the b-cell, sulfonylureas and glinidesaugment insulin secretion (80), but onlyTZDs (81–83) and GLP-1 analogs (84–86)improve and preserve b-cell functionand demonstrate durability of glycemiccontrol (70,82–85,87–93). Importantly,TZDs and GLP-1 analogs cause durableHbA1c reduction for up to 5 and 3.5 years,respectively (82,93). Although dipeptidylpeptidase inhibitors (DPP4i) augment in-sulin secretion (94), their b-cell effect isweak compared with GLP1 analogs andthey begin to lose efficacy (manifested byrising HbA1c) within 2 years after initia-tion of therapy (95,96). Despite the potenteffects of TZDs and GLP-1 agonists onb-cells, the two most commonly pre-scribed drugs in the U.S. and worldwideare sulfonylureas and metformin, neitherof which exerts any b-cell protective ef-fect. This is a major concern, since pro-gressive b-cell failure is the primarypathogenic abnormality responsible fordevelopment of T2DM and progressiveHbA1c rise (Fig. 3).

GLP-1 analogs augment and preserveb-cell function for at least 3 years (84).This protective effect has its onset within24 h (86) and persists as long as GLP-1therapy is continued (84,85,93). Further,both exenatide and liraglutide promoteweight loss, inhibit glucagon secretion,and delay gastric emptying, reducingpostprandial hyperglycemia (45,93,97–99). Weight loss depletes lipid from mus-cle and liver, improving muscle andhepatic insulin sensitivity (84,85). GLP-1

analogs also correct multiple cardiovascu-lar risk factors (rev. in 100) and, thus,have the potential to reduce cardiovascu-lar events (101,102). Although DPP4ishare some characteristics with GLP-1 an-alogs, they do not raise plasma GLP-1 lev-els sufficiently to offset b-cell resistance toGLP-1 (103). Not surprisingly, their abil-ity to augment insulin secretion and re-duce HbA1c is considerably less thanGLP-1 analogs (94,104,105), and theydo not promote weight loss (94). In a1-year study involving 665 metformin-treated T2DM patients, HbA1c reductionwith sitagliptin (0.9%) was significantlyless than liraglutide dosed at 1.2 mg/day(ΔHbA1c = 1.2%) or 1.8 mg/day(ΔHbA1c = 1.8%) (105). In a short-term,mechanism-of-action, crossover study,exenatide was far superior to sitagliptinin reducing glucose area under the curveand 2-h glucose after a meal, increasinginsulin secretion, inhibiting glucagon se-cretion, and promoting weight loss (104).Metformin increases GLP-1 secretion byintestinal L-cells (106–108), and the com-bination of metformin plus DPP4i mayexert a more durable effect on b-cell func-tion. The major mechanism of action ofDPP4i to improve glycemic control is me-diated via inhibition of glucagon secretionwith subsequent decline in HGP (109)

Although not yet approved by U.S.regulatory agencies, sodium glucose trans-porter 2 inhibitors (approved in Europe)demonstrate modest efficacy in reducingHbA1c, promote weight loss, reduce bloodpressure, and can be added to any antidia-betes agent (48,110).

Instituting therapy in newlydiagnosed T2DM patientsWhen initiating therapy in newly diag-nosed T2DM patients, the following con-siderations are of paramount importance:

1. Therapy should have the ability toachieve the desired level of glycemiccontrol, based upon starting HbA1c.According to the ADA, European As-sociation for the Study of Diabetes(EASD), and American Association ofClinical Endocrinologists (AACE), thedesired HbA1c is 6.5% (EASD andAACE) or 7.0% (ADA) (5,111). How-ever, we believe that in newly diagnoseddiabetic patients without cardiovascu-lar disease, the optimal HbA1c shouldbe #6.0%, while avoiding adverseevents, primarily hypoglycemia. Thisis consistent with the expanded ADA/EASD statement (5).

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2. In most newly diagnosed diabetic pa-tients, monotherapy will not reduceHbA1c,6.5–7.0% or, most optimally,,6.0%, and combination therapy willbe required.

3. Importantly, medications used incombination therapy should have anadditive effect, and individual drugsshould correct established pathophysi-ologic disturbances in T2DM. If anti-diabetes medications do not correctunderlying pathogenic abnormalities,long-term durable glycemic controlcannot be achieved.

4. Progressive b-cell failure is respon-sible for progressiveHbA1c rise inT2DM(3). Therefore, medications used totreat T2DM should preserve or im-proveb-cell function to ensure durableglycemic control.

5. Because insulin resistance is a coredefect in T2DM and exacerbates thedecline in b-cell function, medicationsalso should ameliorate insulin resis-tance in muscle/liver.

6. T2DM is associated with an increasedincidence of atherosclerotic cardio-vascular complications. Therefore, it isdesirable that drugs exert beneficialeffects on cardiovascular risk factorsand decrease cardiovascular events.

7. Since obesity is a major problem indiabetic individuals, combination ther-apy should be weight neutral and, ifpossible, promote weight loss.

8. Combination therapy should be safeand not exacerbate underlying medi-cal conditions.

No single antidiabetes agent can cor-rect all of the pathophysiologic distur-bances present in T2DM, and multipleagents, used in combination, will be re-quired for optimal glycemic control. Fur-ther, the HbA1c decrease produced by asingle antidiabetes agent, e.g., metformin,sulfonylurea, TZD, GLP-1 analog, is in therange of 1.0–1.5% depending upon thestarting HbA1c (5). Thus, in newly diag-nosed T2DM with HbA1c .8.0–8.5%, asingle agent is unlikely to achieve HbA1c

goal,6.5–7.0%, and virtually no onewillachieve HbA1c ,6.0%. When maximal-dose metformin, sulfonylurea, or TZD isinitiated asmonotherapy,,40%of newlydiagnosed T2DM subjects can be expec-ted to achieve HbA1c ,6.5–7.0%. Thus,most patients with HbA1c .8.0–8.5%will require initial combination therapyto reach HbA1c ,6.5–7.0%. Moreover,because different agents lower plasma glu-cose via different mechanisms, combination

therapy will have an additive effect to re-duce HbA1c compared with each agentalone. Simultaneous correction of theb-cell defect and insulin resistance ismore likely to cause durable HbA1c reduc-tion. Lastly, combination therapy allowsuse of submaximal doses of each antidia-betes agent, resulting in fewer side effects(112).

In summary, initiating therapy withmultiple antidiabetes agents in newly di-agnosed T2DM patients, especially thosewith HbA1c .8.0–8.5%, represents a ra-tional approach to achieve the targetHbA1c level while minimizing side effects.Indeed, AACE recommends startingnewly diagnosed diabetic subjects withHbA1c .7.5% on multiple antidiabetesagents (111).

“Treat to fail” algorithmThe 2009 ADA/EASD algorithm (1) rec-ommended initiation of therapy withmetformin to achieve HbA1c ,7.0%, fol-lowed by, importantly, sequential addi-tion of a sulfonylurea. If sulfonylureaaddition failed to reduce HbA1c ,7.0%,addition of basal insulin was recommen-ded. Although the revised 2012 ADA/EASD algorithm (5) includes newer anti-diabetes agents (GLP-1 receptor agonists,DPP4i, and TZDs) as potential choices ifmetformin fails, the initial box in thetreatment algorithm still depicts sequen-tial addition of sulfonylurea and then in-sulin to maintain HbA1c ,7.0%. Thisalgorithm has little basis in pathophysiol-ogy and more appropriately should becalled the treat to fail algorithm. More-over, it does not consider the startingHbA1c or need for initial combinationtherapy in most newly diagnosed T2DMpatients, especially if HbA1c goal ,6.0–6.5% is desired, as suggested by us (4)and by the 2012 ADA/EASD consensusstatement (5). Because b-cell failure isprogressive (9–12,24–30,34,35,113,114)and results in loss of b-cell mass (36–38), it is essential to intervene withagents that normalize HbA1c and haltthe progressive b-cell demise (Fig. 3).Failure to do so will result in the major-ity of T2DM patients progressing to in-sulin therapy, as demonstrated in the UKProspective Diabetes Study (UKPDS)(113,114).Sulfonylureas/glinides: the treat to failapproach. Until recently (5), sulfonylur-eas have been considered the drug ofchoice for add-on therapy to metformin(1). In large part, this is attributed to theirlow cost and rapid onset of hypoglycemic

effect. However, they lack “glycemic du-rability” and within 1–2 years lose theirefficacy, resulting in steady HbA1c rise toor above pretreatment levels (107,108)(Figs. 4 and 5). Although long-term stud-ies examining glycemic durability withglinides (nateglinide, repaglinide) inT2DM are not available, nateglinide failedto prevent prediabetic (IGT) patientsfrom progressing to T2DM (115). In a2-year study in newly diagnosed T2DMsubjects, durability of netaglinide plusmetformin was comparable with glybur-ide plus metformin (116) and both groupsexperienced a small but progressive HbA1c

rise after the first year. Since deteriorationin glycemic control is largely accountedfor by progressive b-cell failure (3), it isclear that both sulfonylureas and gli-nides fail to prevent the progressive de-cline in b-cell function characteristic ofT2DM. Consistent with this, in vitro stud-ies have demonstrated a proapoptoticb-cell effect of sulfonylureas and glinides(117–120).

UKPDS conclusively demonstratedthat sulfonylureas exerted no b-cell pro-tective effect in newly diagnosed T2DMpatients (starting HbA1c = 7.0%) over a15-year follow-up (113,114). After aninitial HbA1c drop, sulfonylurea-treatedpatients experienced progressive deterio-ration in glycemic control that paralleledHbA1c rise in conventionally treated indi-viduals (Fig. 4). Moreover, some studieshave suggested that sulfonylureas mayaccelerate atherogenesis (121,122).Similarly, metformin-treated patients inUKPDS, after initial HbA1c decline (sec-ondary to inhibition of HGP), also expe-rienced progressive deterioration inglycemic control (123) (Fig. 4). With useof homeostasis model assessment of b-cellfunction, it was shown that the relentless

Figure 4dThe effect of sulfonylurea (gliben-clamide = glyburide) and metformin therapyon the plasma HbA1c concentration in newlydiagnosed T2DM subjects in UKPDS. Con-ventionally treated diabetic subjects receiveddiet plus exercise therapy (113,114).

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HbA1c rise observed with sulfonylureasand metformin resulted from progressivedecline in b-cell function and that within3–5 years, ;50% of diabetic patients re-quired an additional pharmacologic agentto maintain HbA1c ,7.0% (114,124–127). Although there is in vitro evidencethat metformin may improve b-cell func-tion (128,129), in vivo data from UKPDSand other studies (130) fail to supportany role for metformin in preservation ofb-cell function in humans. Metformin didreduce macrovascular events in UKPDS(123), although by today’s standards thenumber of metformin-treated subjects(n = 342) would be considered inadequateto justify any conclusions about cardio-vascular protection. Other than its effectto reduce the elevated rate of basal andpostprandial HGP (53,55,64), metformindoes not correct any other component ofthe ominous octet (Fig. 1), and even itsmuscle insulin-sensitizing effect is difficultto demonstrate in absence of weight loss(53,55,64).

UKPDS was designed as a monother-apy study. However, after 3 years it becameevident that monotherapy with neithermetformin nor sulfonylureas could pre-vent progressiveb-cell failure and stabilizeHbA1c at its starting level (113,114,123–127). Therefore, study protocol was al-tered to allow metformin addition tosulfonylurea and sulfonylurea additionto metformin. Although addition of asecond antidiabetes agent initially im-proved glycemic control, progressiveb-cell failure continued and HbA1c roseprogressively.

Numerous long-term (.1.5 years)active-comparator or placebo-controlledstudies have demonstrated inability ofsulfonylureas to produce durable HbA1c

reduction in T2DM patients. These studies(70,83,87–92,113,131–133) showed that

after initial HbA1c decline, sulfonylureas(glyburide, glimepiride, and gliclazide)were associated with progressive declinein b-cell function with accompanyingloss of glycemic control (Fig. 5). Thereare no exceptions to this consistent lossof glycemic control with sulfonylureas af-ter the initial 18 months of therapy. Thus,evidence-based medicine demonstratesthat the glucose-lowering effect of sulfo-nylureas is not durable and that loss ofglycemic control is associated with pro-gressive b-cell failure.

Sulfonylurea treatment does not cor-rect any pathophysiologic component ofthe ominous octet (3) (Fig. 1) and is as-sociated with significant weight gain andhypoglycemia (89,90). Although nostudy has clearly implicated sulfonylureaswith an increased incidence of cardio-vascular events, a deleterious effect ofglibenclamide (glyburide) on the cardi-oprotective process of ischemic precon-ditioning has been demonstrated (134),while some (121,122,135–142) but notall (143,144) studies have suggested apossible association between sulfonylureasand adverse cardiovascular outcomes.Since metformin was the comparator inmany of these studies (121,122,137,138,140–142), it is difficult to determinewhether sulfonylureas increased or metfor-min decreased cardiovascular morbidity/mortality. In the study by Sillars et al. (143)the increased cardiovascular mortality/morbidity disappeared after adjusting forconfounding variables, and failure to doso in other sulfonylurea studies may haveclouded their interpretation. Among thesulfonylurea studies, the older sulfonylureas(i.e., glibenclamide)more commonly havebeen associated with increased adversecardiovascular outcomes than the newersulfonylurea agents (i.e., gliclazide and gli-meperide) (139,144–146).

In summary, we believe that currentlyavailable insulin secretagogues (sulfony-lureas and glinides) represent a pooroption as add-on therapy to metformin.However, in many countries newer anti-diabetes agents are not available or areexpensive (ABCDE) (4). In such circum-stances, sulfonylureas may be the onlyoption.

Antidiabetes agents known toreverse pathophysiologic defectsPioglitazone: unique benefits, uniqueside effects. Rosiglitazone has been re-moved from the market or its use severelyrestricted because of cardiovascular safetyconcerns (147). Therefore, pioglitazone is

the only representative TZD. Pioglitazoneis unique in that it both exerts b-cellprotective effects (81) and is a powerfulinsulin sensitizer in muscle and liver(56–61,65,74–76) Thus, it is the only an-tidiabetes agent that corrects the core de-fects of insulin resistance and b-cell failurein T2DM. Not surprisingly, it has a dura-ble effect to reduce HbA1c with low risk ofhypoglycemia.

Eight long-term (.1.5 years) studieswith TZDs (70,82,81–92) (Fig. 6) havedemonstrated that, after initial decline inHbA1c, durability of glycemic control ismaintained because of preservation ofb-cell function in T2DM patients. Fur-ther, five studies demonstrate that TZDsprevent progression of IGT to T2DM(148–152). All five studies showed that,in addition to their insulin-sensitizing ef-fect, TZDs had a major action to preserveb-cell function. In Actos Now for Preven-tion of Diabetes (ACT NOW), improvedinsulin secretion/insulin resistance (dispo-sition) index was shown both with OGTTand frequently sampled intravenous glu-cose tolerance test. Similar results weredocumented in Troglitazone in Preventionof Diabetes (TRIPOD) and Pioglitazone inPrevention of Diabetes (PIPOD)(148,151). Many in vivo and in vitro stud-ies with human and rodent islets havedemonstrated that TZDs exert a b-cell–protective effect (153–157).

Pioglitazone has additional beneficialpleiotropic properties, including in-creased HDL cholesterol, reduced plasmatriglyceride, decreased blood pressure,improved endothelial dysfunction, anti-inflammatory effects (76,158–161), andamelioration of nonalcoholic steatohe-patitis (75). In addition to reduced car-diovascular events in PROactive and U.S.

Figure 5dDurability of glycemic control withsulfonylureas. Summary of studies examiningthe effect of sulfonylurea treatment versus pla-cebo or versus active comparator on HbA1c inT2DM. See text for a more detailed discussion(70,82,87–92,113,114,124–127,131,132).

Figure 6dDurability of glycemic control withTZDs. Summary of studies examining the effectof TZDs versus placebo or versus active com-parator on HbA1c in T2DM subjects. See text fora more detailed discussion (70,82,87–92). Pio,pioglitazone; Rosi, rosiglitazone.

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phase 3 trials (162,163), pioglitazoneslows progression of carotid intimal-media thickness (87,152) and reducescoronary atheroma volume (88).

Physicians must be cognizant of sideeffects associated with TZDs includingweight gain (81,164), fluid retention(162,165), bone fractures (166), and pos-sibly bladder cancer (162,167,168) (seearticle on peroxisome proliferator–activated receptors in this supplement[169]). The preferred starting dose of pio-glitazone is 15 mg/day titrated to 30 mg/day, which provides 70–80% of the glyce-mic efficacy with minimal side effects(170–174); titrating to 45 mg/day is notrecommended. HbA1c lowering has beenobserved with a pioglitazone dose of 7.5mg/day with minimal side effects. In a26-week study (172) involving a Caucasianpopulation, 7.5 mg/day pioglitazone re-duced the HbA1c by 0.9% compared withplacebo (P = 0.14), while 15 mg/day re-duced the HbA1c by 1.3% vs. placebo(P , 0.05). Similar HbA1c reduction withpioglitazone, 7.5 mg/day, has been ob-served in an Asian population (173,174).

In combination with metformin (in-hibits hepatic gluconeogenesis), pioglita-zone (improves insulin sensitivity in liver/muscle and preserves b-cell function) of-fers an effective, durable, and additivetherapy that retards progressive b-cellfailure with little risk of hypoglycemia.In a 6-month trial comparing fixed-dosecombination with pioglitazone (30 mg)/metformin (1,700 mg) in 600 drug-naïveT2DM patients, HbA1c declined by 1.8%(from baseline HbA1c 8.6%) and was sig-nificantly greater than the 1.0% reductionobserved with metformin alone or piogli-tazone alone (175). Similar results werereported by Rosenstock et al. (176) usinginitial combination therapy with rosiglita-zone (8 mg)/metformin (2,000 mg).

Combining pioglitazone with GLP-1analog curbs weight gain associated withthe TZD (177). Further, the natriureticeffect of GLP-1 analogs (178) mitigatesagainst fluid retention observed withTZDs. Therefore, we advocate combinedGLP-1 analog/pioglitazone therapy withor without metformin in newly diagnosedT2DM patients (3).Intensive therapy with insulin plusmetformin: reversal of metabolic de-compensation. Newly diagnosed T2DMpatients who present in poor metaboliccontrol are markedly resistant to insulinand have severely impairedb-cell function.Glucotoxicity (8), lipotoxicity (8,42,62),and multiple metabolic abnormalities (3)

play an important role in the insulin resis-tance and b-cell dysfunction. Institutionof intensive insulin therapy with or with-out other antidiabetes agents to correctthese many metabolic abnormalities,therefore, represents a rational approachto therapy based upon pathophysiology.After a period of sustained metabolic con-trol, the insulin therapy can be continuedor the patient can be switched to a non-insulin therapeutic regimen. This ap-proach has recently been examined byHarrison et al. (179). Fifty-eight newly di-agnosed T2DM patients in poor metaboliccontrol (HbA1c 10.8%) initially were trea-ted for 3 months with metformin plus in-sulin to reduce the HbA1c to 5.9%.Subjects then were randomized to contin-ued therapy with insulin-metformin com-bination therapy with pioglitazone/metformin/glyburide. During 3 years offollow-up, both groups maintained the re-duction in HbA1c, but the insulin dosehad to be increased, indicating that, de-spite excellent glycemic control, b-cellfailure continued in this group. Further,glycemic control in both groups wasachieved at the expense of a relativelyhigh rate of hypoglycemia and weightgain in the insulin/metformin group,consistent with multiple studiesdemonstrating a high incidence of hypo-glycemia in sulfonylurea-treated andinsulin-treated subjects.Metformin plus GLP-1 analog pluspioglitazone: a pathophysiologic op-tion that offers robust glycemic controland weight loss. The combination of

biguanide (metformin), TZD (pioglita-zone), and GLP-1 analog offers a rationaltreatment choice, targeting multiple path-ophysiologic abnormalities in T2DM:muscle insulin resistance (pioglitazone),adipocyte insulin resistance (pioglita-zone), pancreaticb-cell failure (GLP-1 an-alog, pioglitazone), hepatic insulinresistance (metformin, pioglitazone, andGLP-1 analog), and excessive glucagonsecretion (GLP-1 analog) (3) with weightloss (GLP-1 analog) and low risk of hypo-glycemia (93,97). Studies with exenatidehave demonstrated durable glycemic con-trol for 3 years (84,93). b-Cells in T2DMare blind to glucose, and GLP-1 analogshave the unique ability to restore b-cellglucose sensitivity (84–86) (Fig. 7) byaugmenting glucose transport, activatingglucokinase, increasing Pdx, and replen-ishing b-cell insulin stores (180,181).Because pharmacologic GLP-1 levels(;80–90 pmol/L) are achieved withGLP-1 analogs, they overcome b-cell in-cretin resistance and augment insulin se-cretion. Increased insulin and inhibitedglucagon secretion reduce basal HGP, re-ducing fasting plasma glucose concentra-tion and enhancing HGP suppressionafter a meal (98,99). Although GLP-1 ana-logs do not have a direct insulin-sensitizingeffect, they augment insulin-mediated glu-cose disposal secondary to weight loss(97). The combination of pioglitazoneplus exenatide reduces hepatic fat contentand markers of liver damage in T2DM(182). In T2DM patients treated with ro-siglitazone, exenatide, or both (as add-on

Figure 7dA single dose of liraglutide (Lira) (7.5 mg/kg or 0.75 mg for 100-kg person) ad-ministered acutely completely restores b-cell sensitivity to glucose using the graded glucose in-fusion technique to evaluate b-cell function (86).

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to metformin), improved b-cell functionand insulin sensitivity were noted, withweight loss in all exenatide-treated groups(177). Similar results have been reportedby others (182–185) with combinedGLP-1 analog/TZD therapy.

In an ongoing study, we comparedtriple combination therapy with pioglita-zone/metformin/exenatide with the stan-dard ADA approach (metformin followedby sequential addition of sulfonylureaand then basal insulin) in 134 newlydiagnosed T2DM patients with startingHbA1c 8.7% (186). After 2 years, HbA1c

reduction was greater in the triple therapyversus sequential ADA group (2.7 vs.2.2%, P , 0.01), triple therapy subjectslost 1.5 vs. 4.1 kg weight gain with theADA approach, and hypoglycemia inci-dence was 13.5-fold higher in the sequen-tial ADA group. These preliminary resultsindicate that a triple combination ap-proach focused on reversing underlyinginsulin resistance and b-cell dysfunctionis superior to sequential therapy (metfor-min, add sulfonylurea, add basal insulin)with agents that do not correct core path-ophysiologic defects in T2DM.DPP4i: weak but easy alternative toGLP-1 analogs. DPP4i have gained wide-spread use in combination with metfor-min because of their weight neutrality,modest efficacy, and safety (187,188).Metformin has a modest effect to increaseGLP-1 secretion (107,189). Thus, combi-nation metformin/DPP4i therapy may re-sult in increased GLP-1 levels (190) andan additive glucose-lowering effect(191,192). When used in triple combina-tion with metformin plus pioglitazone(30 mg/day), alogliptin resulted in betterglycemic control and fewer pioglitazonedose-dependent side effects (edema, weightgain) compared with metformin with ahigher pioglitazone dose (45 mg/day)(172). Because they correctmultiple compo-nents of the ominous octet, have superiorglucose-lowering efficacy, promote weightloss, and preserve b-cell function, we favorGLP-1 analogs over DPP4i in the triple ther-apy approach. Nonetheless, because of theirease of administration and safety, DPP4irepresent a reasonable alternative.

Conclusions and recommendationsT2DM is a multifactorial, multiorgan dis-ease, and antidiabetes medications shouldaddress underlying pathogenic mecha-nisms rather than solely reducing theblood glucose concentration. Emphasisshould be placed on medications thatameliorate insulin resistance and prevent

b-cell failure if durable HbA1c reduction isto be achieved. Further, the long-practicedglucocentric paradigm has become anti-quated. Diabetic patients are at high riskfor cardiovascular events, and compre-hensive evaluation/treatment of all cardio-vascular risk factors is essential. Simplyfocusing on glycemic control will nothave a major impact to reduce cardiovas-cular risk (113,123). Therefore, wefavor a therapeutic approach based notonly on the drug’s glucose-lowering effi-cacy/durability but also on its effect onweight, blood pressure, lipids, cardiovas-cular protection, and side effect profile,especially hypoglycemia.

Initial therapy in newly diagnosedT2DM patients without cardiovasculardisease should be capable of achievingthe desired glycemic goal, which shouldbe as close to normal as possible: HbA1c

#6.0%. This will require combinationtherapy in the majority of T2DM patients(3) (Fig. 1). While we favor the patho-physiologic approach, physicians mustbe cognizant of the ABCDE of diabetesmanagement (4). An approach that em-phasizes pathophysiology but allows forindividualized therapy will provide opti-mal results. Evidence-based medicine(UPKDS) has taught us that sequentialtherapy with metformin followed by sul-fonylurea addition with subsequent insu-lin addition represents the treat to failapproach, and we do not recommendthis approach unless cost is the overridingconcern.

AcknowledgmentsdR.A.D. is a member ofthe Bristol-Myers Squibb, Janssen, Amylin,Takeda, Novo Nordisk, and Lexicon advisoryboards; has received grants from Takeda,Amylin, and Bristol-Myers Squibb; and is amember of the following speakers bureaus:Bristol-Myers Squibb, Novo Nordisk, Janssen,and Takeda. No other potential conflicts ofinterest relevant to this article were reported.R.A.D. wrote the initial draft of the manu-

script. R.E. and M.A.-G. revised the manu-script. R.A.D. is the guarantor of this workand, as such, had full access to all the data inthe study and takes responsibility for the in-tegrity of the data and the accuracy of the dataanalysis.

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