Is It Time to Change the Type 2Diabetes Treatment Paradigm?Yes! GLP-1 RAs Should ReplaceMetformin in the Type 2 DiabetesAlgorithmDiabetes Care 2017;40:1121–1127 | https://doi.org/10.2337/dc16-2368

Most treatment guidelines, including those from theAmericanDiabetes Association/European Association for the Study of Diabetes and the International DiabetesFederation, suggestmetformin be used as thefirst-line therapy after diet and exercise.This recommendation is based on the considerable body of evidence that hasaccumulatedover the last 30 years, but it is also supportedon clinical groundsbasedonmetformin’s affordability and tolerability. As such, metformin is the most commonlyused oral antihyperglycemic agent in the U.S. However, based on the release ofnewer agents over the recent past, some have suggested that the modern approachto disease management should be based upon identification of its etiology andcorrecting the underlying biological disturbances. That is, we should use interventionsthat normalize or at least ameliorate the recognized derangements in physiology thatdrive the clinical manifestation of disease, in this circumstance, hyperglycemia. Thus, itis argued that therapeutic interventions that target glycemia but do not correct theunderlying pathogenic disturbances are unlikely to result in a sustained benefit on thedisease process. In our field, there is an evolving debate regarding the suggested firststep in diabetes management and a call for a new paradigm. Given the current con-troversy, we provide a Point-Counterpoint debate on this issue. In the point narrativebelow that precedes the counterpoint narrative, Drs. Abdul-Ghani and DeFronzo pro-vide their argument that a treatment approach for type 2diabetes basedupon correct-ing the underlying pathophysiological abnormalities responsible for the developmentof hyperglycemia provides the best therapeutic strategy. Such an approach requires achange in the recommendation for first-line therapy from metformin to a GLP-1 re-ceptor agonist. In the counterpoint narrative that follows Drs. Abdul-Ghani andDeFronzo’s contribution, Dr. Inzucchi argues that, based on the medical community’sextensive experience and the drug’s demonstrated efficacy, safety, low cost, andcardiovascular benefits, metformin should remain the “foundation therapy” for allpatients with type 2 diabetes, barring contraindications.

dWilliam T. CefaluChief Scientific, Medical & Mission Officer, American Diabetes Association

The modern approach to disease management is based upon identification of itsetiology and correcting the underlying pathophysiological disturbances with interven-tions that ameliorate/normalize known defects responsible for the clinical manifesta-tion of the disease, i.e., hyperglycemia. Therapeutic interventions that simply targethyperglycemia but do not correct the underlying pathogenic disturbances are unlikely

1Division of Diabetes, University of Texas HealthScience Center at San Antonio, San Antonio, TX2Diabetes Research, Academic Health System,Hamad General Hospital, Doha, Qatar

Corresponding author: Muhammad Abdul-Ghani, abdulghani@uthscsa.edu.

M.A.-G. and R.A.D. contributed equally to thisarticle.

© 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 thework is not altered.More infor-mation is available at http://www.diabetesjournals.org/content/license.

See accompanying article, p. 1128.

Muhammad Abdul-Ghani1,2 and

Ralph A. DeFronzo1

Diabetes Care Volume 40, August 2017 1121

POINT-C

OUNTER

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https://doi.org/10.2337/dc16-2368http://crossmark.crossref.org/dialog/?doi=10.2337/dc16-2368&domain=pdf&date_stamp=2017-07-01mailto:abdulghani@uthscsa.eduhttp://www.diabetesjournals.org/content/licensehttp://www.diabetesjournals.org/content/license

to result in a sustained reduction inHbA1c. It is well established that type 2diabetes (T2D) is a complex metabolic/cardiovascular disorderwith at least eightdistinct pathophysiological disturbances,referred to as the Ominous Octet (1). Hy-perglycemia is a manifestation of theseeight pathophysiological abnormalities.Nonetheless, the current recommendedapproach in T2D management still fo-cuses on lowering the plasma glucoseconcentration rather than correcting theunderlying metabolic abnormalities thatcause the hyperglycemia (2–4). There-fore, it is not surprising that current ther-apeutic guidelines (2–4) do not result in asustained HbA1c reduction (5–8). In thisPoint-Counterpoint, we argue that it istime to apply the modern concepts ofclinical practice to diabetes managementand base therapy on pathophysiology.Thereby, GLP-1 receptor agonists (GLP-1RAs), which 1) correct six of the eightcomponents of the Ominous Octet, 2)prevent/reverse the progressive b-cellfailure and rise in HbA1c, and 3) lowercardiovascular risk in T2D independentof their glucose-lowering ability (9,10),should replace metformin as the recom-mended first-line therapy in newly diag-nosed T2D patients.

PATHOPHYSIOLOGY OF T2D

Theetiology of T2D is complex and involvesmultiple pathophysiological disturbancesinvolving multiple organs (1) (Fig. 1).

Insulin resistance in skeletal muscle, liver,and adipocytes (11–15) and b-cell dys-function (16–22) remain the major coredefects responsible for the developmentand progression of hyperglycemia. Insulinresistance is also associated withmultiplemetabolic abnormalities, e.g., hyperten-sion, dyslipidemia, endothelial dysfunc-tion, procoagulant state, inflammation,and visceral obesity, which collectivelyare known as the insulin resistance (met-abolic) syndrome (23–25). Each individualcomponent of the insulin resistance syn-drome, as well as the basic molecularetiology of the insulin resistance (25), iscausally related to the development ofatherosclerotic cardiovascular disease(CVD) and contributes to the increasedrisk for CVD in T2D patients.

Because progressive b-cell failure isthe principal factor responsible for thedevelopment and progression of hyper-glycemia in T2D patients (1,16–19), onlytherapies that halt/reverse the progres-sive b-cell failure will be effective in low-ering and maintaining HbA1c at the targetlevel, and ideally this should be ac-complished without increasing the riskof hypoglycemia.

In addition to insulin resistance andb-cell dysfunction, impaired incretineffect in T2D plays a major role in theprogression of b-cell failure and hyper-glycemia (26,27). Further, T2D patientshave elevated fasting plasma glucagonlevels that fail to suppress normally after

a meal and enhanced hepatic sensitivityto glucagon (28,29), in part due to resis-tance to GLP-1 (26,30); these pathophys-iological abnormalities can be reversedwith GLP-1 RA therapy (26,31).

BIOLOGICAL ACTIONSOF GLP-1 RAs

Activation of GLP-1 receptors in theb-cellamplifies glucose-stimulated insulin se-cretion but only under conditions of hy-perglycemia (26,32), whereas in thea-cell, GLP-1 suppresses glucagon secre-tion, leading to correction of postmealhyperglycemia in T2D (26,27,30). GLP-1RAs improve b-cell function by enhancingb-cell responsiveness to glucose, i.e., im-proving b-cell glucose sensitivity; thisbeneficial effect on the b-cell can be ob-served within 8 h after a single injectionof the GLP-1 RA (liraglutide) (33), is main-tained at 3 months (semaglutide) (34),and persists for at least 3 years (exenatide)(35). Thus, GLP-1 RAs produce a rapid anddurable reduction in HbA1c with low riskof hypoglycemia (36,37).

GLP-1 also exerts multiple nonglyce-mic actions, all of which improve meta-bolic control in T2D patients (Table 1),including 1) delayed gastric emptying,which slows the absorption of ingestedglucose (32), 2) appetite suppression,which promotes weight loss (26,38,39),3) reduction of hepatic and visceral fatcontent (40), making them an attractiveintervention to prevent/reverse non-alcoholic fatty liver disease/nonalcoholicsteatohepatitis (41), and 4) preventionof diabetic nephropathy in Liraglutide Ef-fect and Action in Diabetes: Evaluation ofCardiovascular Outcome ResultsdA LongTerm Evaluation (LEADER) (42). Recent ev-idence suggests that gut stimulationof GLP-1 secretion by the L cells is an im-portant mechanism via which metforminsuppresses hepatic glucose production(43,44).

GLP-1 RAs AND CVD

CVD is the leading cause of death in T2Dpatients (45), accounting for ;80% ofmortality, and T2D is best viewed as acardiometabolic disorder (25,46). Thus,reducing CVD risk is a high priority inT2Dmanagement, and reduction in bloodpressure and correction of diabetic dysli-pidemia are essential components ofdiabetes management. Considerable evi-dence documents that hyperglycemiais a weak risk factor for cardiovascular

Figure 1—GLP-1 RAs correct six components of the Ominous Octet, whereas metformin correctsonly one component.

1122 Point Diabetes Care Volume 40, August 2017

complications and improving glucosecontrol has little benefit on macrovascu-lar disease risk (UK Prospective DiabetesStudy [UKPDS], Action to Control Cardio-vascular Risk in Diabetes [ACCORD], Ac-tion in Diabetes and Vascular Disease:Preterax and Diamicron MR ControlledEvaluation [ADVANCE], Veterans AffairsDiabetes Trial [VADT]), especially when

it is well established. Numerous clinical tri-als have demonstrated that antidiabetesagents that reduceplasmaglucosewithoutaltering other cardiovascular risk factorsfail to reduce CVD risk in T2D patients.Conversely, antidiabetes medications thatin addition to lowering the plasma glu-cose concentration also improve car-diovascular risk factors, e.g., GLP-1 RAs(9,10), pioglitazone (47,48), and SGLT2inhibitors (49,50), significantly reducecardiovascular events in T2D with estab-lished CVD. Thus, these agents should befavored over agents that lower plasma glu-cose but have no effect on cardiovascularrisk factors or CVD, e.g., sulfonylureas(51,52), DPP-4 inhibitors (53–55), and in-sulin (56) (Fig. 2). GLP-1 RAs consistentlyhave been shown to reduce many CVDrisk factors (Table 2) (25,34,57–60).Thus, it is not surprising that two large,prospective, randomized, double-blind,placebo-controlled trials (9,10) havedem-onstrated that liraglutide and semaglu-tide significantly lower the incidence of3-pointMACE (major adverse cardiovascu-lar events), which includes nonfatal myo-cardial infarction, nonfatal stroke, andcardiovascular death, by 13% and 24%, re-spectively, in T2D patients with existingCVD. Of note, despite the high CVD riskin the patient populations in both LEADERand Trial to Evaluate Cardiovascular andOther Long-term Outcomes With Sema-glutide in Subjects With Type 2 Diabetes(SUSTAIN-6), all cardiovascular risk factors,including blood pressure and LDL choles-terol, were well controlled at baseline,

consistent with the high number of pa-tients receiving statins, ACE inhibitors, an-giotensin receptor blockers, and aspirintherapy. Addition of the GLP-1 RA to thepatients’ antidiabetes treatment resultedin onlymodest reductions in HbA1c (0.4%)and systolic bloodpressure (;2–3mmHg)in LEADER and SUSTAIN-6; these glucose-and blood pressure–lowering effects arequite modest and unlikely to explain theCVD benefit of liraglutide and semaglu-tide. This suggests the GLP-1 RAs mayhave a direct beneficial action to slow theatherosclerotic process, independent oftheir effect to reduceglycemiaand improvetraditional cardiovascular risk factors (59).

The above review demonstrates thatGLP-1RAsdirectly and/or indirectly correct/improve six of the eight pathophysiologicaldefects responsible for hyperglycemiain T2D, improve cardiovascular risk factors,and reduce MACE in two large, well-designed, prospective cardiovascular inter-vention trials.

GLP-1 RAs, NOT METFORMIN,SHOULD BE THE FIRST-LINETHERAPY IN T2D

GLP-1 RAs correct six members of theOminous Octet, whereas the only knownaction of metformin is to inhibit hepaticglucose production (61) (Fig. 1 and Table2). Contrary to common belief, metfor-min is not an insulin sensitizer in muscleor adipocytes (61–63) in the absence ofweight loss, which is a frequent occur-rence in patients treated with the bigua-nide (Fig. 3A). Consistent with this,following intravenous administration of11C-metformin, none of the biguanidecan be detected in muscle (64). Most im-portantly, and in direct contrast to theGLP-1 RAs, metformin lacks any effecton b-cell function (61,62) (Fig. 3B), whichis the primary pathophysiological distur-bance responsible for progressive hyper-glycemia in T2D patients (1). This is mostgraphically demonstrated in the UKPDS(65) and ADiabetesOutcome ProgressionTrial (ADOPT) (5) (Fig. 3D) in which, afteran initial decline during the first year,HbA1c rose progressively because of pro-gressive b-cell failure. This stands inmarked contrast to the GLP-1 RAs, whichexert a potent protective effect on theb-cell that persists for at least 3 years(34). Because the GLP-1 RAs cause signif-icant weight loss, they also improve insu-lin sensitivity in muscle. Thus, GLP-1 RAs,but not metformin, correct the two

Table 1—Metabolic actions ofGLP-1 RAsc PancreasPotentiate glucose-mediated insulin

secretionPreserve b-cell function/reverse b-cell

failureInhibit glucagon secretion in

a glucose-dependent fashion

c Cardiovascular systemReduce MACEReduce systolic blood pressureReduce pulmonary capillary wedge

pressureIncrease myocardial salvage following

myocardial infarctionImprove endothelial dysfunction

c GISlow gastric emptyingInhibit hepatic glucose productionDecrease liver fat contentDecrease visceral fat

c Central nervous systemSuppress appetite

c KidneyPreserve renal functionIncrease sodium excretion

c GeneralPromote weight loss

Figure 2—Not all antidiabetes agents are equal in their ability to reduce cardiovascular risk.

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major core defects in T2D patients, i.e.,b-cell dysfunction and muscle insulin re-sistance. The major mechanism of actionof metformin to reduce glycemia is in-hibition of hepatic gluconeogenesis(61,62) (Fig. 3C), whereas the GLP-1 RAsalso effectively reduce hepatic glucose

production but by multiple other mecha-nisms, i.e., inhibition of glucagon secre-tion, stimulation of insulin secretion,direct effect on the liver, and depletionof liver fat (26,27,30,59,66–68).

Although the UKPDS demonstratedthat metformin caused a reduction in

cardiovascular events in T2D patients(65), the patient population consistedof a small number of obese T2D subjects(n 5 342); these results, by today’s stan-dards, would never be accepted as evi-dence for a cardiovascular benefit ofthe biguanide. Moreover, a beneficial

Table 2—Benefits of GLP-1 RAs far outweigh those of metformin

GLP-1 RAs Metformin

Pathophysiological defects in T2D (see Fig. 1) Corrects six of the defects Corrects only one of the defects

Glucose-lowering efficacy Strong Strong

Durability of HbA1c reduction Strong None

Weight loss 3–4 kg 1–2 kg

Blood pressure ;2–3 mmHg reduction Neutral

Lipid profile Lowers triglycerides, increases HDL cholesterol Neutral

Cardiovascular protection (MACE) Reduction by 13–26% Neutral

Renal protection Reduction by 22% Neutral

Tolerability ;10–15% GI side effects ;10–15% GI side effects

Dosing Weekly subcutaneous injection Once to twice daily oral administration

Cost High Low

Figure 3—Effect of metformin on glycemic control, insulin secretion, and insulin sensitivity in T2D. A: Metformin does not improve muscle insulinsensitivity (measured with euglycemic insulin clamp) in T2D individuals (n5 20) in the absence ofweight loss (72).B:Metformin has no effect onb-cell function in T2D individuals (n5 14) (measured with an oral glucose tolerance test [OGTT] and hyperglycemic clamp) (73). C: The primary effectvia which metformin reduces the HbA1c in T2D is related to the suppression of hepatic glucose production (HGP) via inhibition ofgluconeogenesis (72). FPG, fasting plasma glucose. D: Effect of metformin on HbA1c. Because metformin does not affect muscle insulin sensitivity orb-cell function, following an initial decline after metformin administration, the HbA1c rises progressively in T2D patients (5,6,74). KPNW, Kaiser Perma-nente Northwest.

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effect on cardiovascular events was notobserved in other clinical studies with met-formin, i.e., the ADOPT study (5), whichincluded twice the number of patientsas the UKPDS (n5 818). To the contrary,subjects receiving metformin in ADOPTexperienced more cardiovascular eventsthan subjects receiving glyburide, al-though this difference was not statisti-cally significant. This emphasizes theproblemof interpreting results fromstud-ies that are markedly underpowered todetect clinically significant differences incardiac event rates. Conversely, the CVDbenefit of GLP-1 RAs has conclusivelybeen demonstrated in two very large,prospective cardiovascular interventiontrials, LEADER and SUSTAIN-6 (9,10).With regard to safety, both metformin

andGLP-1 RAs are associatedwith gastro-intestinal (GI) adverse events. Approxi-mately 15–20% of T2D patients do nottolerate metformin because of GI sideeffects (66). The incidence of GI side ef-fects with the long-acting GLP-1 RAs issimilar to that of metformin. Further,and unlike those with metformin, the GIside effects usually are mild to moderate,waning over the first 4–6 weeks of initi-ating therapy. The percentage of patientswho discontinue long-acting GLP-1 RAsbecause of GI side effects is signifi-cantly lower than that of metformin(67). Some postmarketing reports havesuggested an increased risk of acute pan-creatitis with GLP-1 RA use. However,three large, prospective, double-blind,placebo-controlled clinical trials including;20,000 patients followed for 2–4 yearshave demonstrated no increased risk ofacute pancreatitis with GLP-1 RA use(9,10,68).Metformin is administered orally ver-

sus via injection for GLP-1 RAs. However,intermediate-acting metformin requiresmultiple daily dosing, whereas two long-acting GLP-1 RAs (exenatide and dulaglu-tide) are available as weekly injectionsand a third (semaglutide) is under reviewby the U.S. Food and Drug Administra-tion. A subcutaneously implanted os-motic mini pump that continuouslydelivers exenatide for 6 months is ex-pected to be approved within the nextyear (69), and an oral formulation of theGLP-1 RA semaglutide is in phase 3 trials(70) and is anticipated to be availablewithin 3–4 years. These modern deliverymethodswill improve patient compliancefor GLP-1 RAs versus metformin.

Lastly, metformin is generic and inex-pensive, whereas GLP-1 RAs are still un-der patent and, therefore, expensive.However, most large health care planshave at least one GLP-1 RA on formularywith a modest copay. Moreover, lira-glutide (Victoza) is expected to becomegeneric by the end of 2017, and thisshould significantly reduce its cost. Acost-effective analysis is beyond thescope of this discussion, and the appro-priate long-term, clinical, real-world stud-ies to perform such an analysis are notavailable. However, a recent cost analysisfor the treatment of T2D patients in theU.S. by the American Diabetes Associa-tion (71) demonstrated that only a smallportion (12%) of the cost of T2D is due tothe direct cost of antihyperglycemic med-ications. The vast majority of the cost ofdiabetes care is related to the develop-ment of diabetic vascular complica-tions, with CVD disease contributing50% of that cost, and two recent stud-ies, LEADER and SUSTAIN-6, have de-monstrated that GLP-1 RAs decreasecardiovascular events. Further, the costof medications to treat the complica-tions of diabetes is 50% greater thanthe cost of antihyperglycemic medi-cations. It remains to be determinedwhether, on a long-term basis, the useof GLP-1 RAs, which in addition to causinga durable reduction in the plasma glu-cose concentration (thereby decreas-ing microvascular complications) alsoreduce cardiovascular events, will becost-effective.

In summary, the currently availableclinical and scientific evidence (Table 2)is overwhelmingly in favor of the useof GLP-1 RAs over metformin as first-line therapy in newly diagnosed T2D pa-tients.

Funding. M.A.-G. receives funding from theNational Institutes of Health (DK 097554-01)and the Qatar Foundation (National PrioritiesResearch Program 4-248-3-076), and R.A.D. re-ceives funding from the National Institutes ofHealth (DK 024092-42). R.A.D.’s salary is, in part,supported by the South Texas Veterans HealthCare System, Audie L. Murphy Division.Duality of Interest. R.A.D. is on the advisoryboard of AstraZeneca, Janssen, Novo Nordisk,Boehringer Ingelheim, and Intarcia. R.A.D. has re-ceived grants from AstraZeneca, Janssen, andBoehringer Ingelheim. R.A.D. is a member ofthe speakers’ bureau for AstraZeneca and NovoNordisk. No other potential conflicts of interestrelevant to this article were reported.

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