Diabetes Research and CareThrough the AgesDiabetes Care 2017;40:1302–1313 | https://doi.org/10.2337/dci17-0042

As has been well established, the Diabetes Care journal’s most visible signatureevent is the Diabetes Care Symposium held each year during the American DiabetesAssociation’s Scientific Sessions. Held this past year on 10 June 2017 in San Diego,California, at the 77th Scientific Sessions, this event has become one of the mostattended sessions during the Scientific Sessions. Each year, in order to continue tohave the symposiumgenerate interest,we revise the format and content of this event.For this past year, our 6th annual symposium, I felt it was time to provide a compre-hensive overview of our efforts in diabetes care to determine, first and foremost, howwe arrived at our current state of management. I also felt the narrative needed toinclude the current status of management, especially with a focus toward cardiovas-cular disease, and finally, we wanted to ask what the future holds. Toward this goal, Iasked four of the most noted experts in the world to provide their opinion on thistopic. The symposium started with a very thoughtful presentation by Dr. Jay Skylerentitled “A Look Back as to HowWeGot Here.” Thatwas followed by two lectures oncurrent concepts by Dr. Bernard Zinman entitled “Current Treatment ParadigmsTodaydHow Well Are We Doing?” and by Dr. Matthew Riddle entitled “EvolvingConcepts and FutureDirections for CardiovascularOutcomes Trials.” Thefinal lecturefor the symposium was delivered by Dr. Ele Ferrannini and was entitled “What Doesthe Future Hold?” As always, a well-attended and well-received symposium is nowthe norm for our signature event and our efforts were rewarded by the enthusiasmof the attendees. This narrative summarizes the lectures held at the symposium.

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

I. A LOOK BACK AS TO HOW WE GOT HERE

A polyuric state, presumably diabetes, was describedmore than 3,500 years ago, beingnoted by the physician Hesy-Ra in an Egyptian papyrus (from approximately 1500 B.C.)found by George Ebers. The sweetness of urine was noted by the Hindu physiciansCharaka and Sushruta around 400–500 B.C. (1). Apollonius of Memphis (around250 B.C.) used the term “diabetes” (from the Greek for siphon), and Aretaeus ofCappadocia (A.D. 30–90) described what is likely type 1 diabetes (T1D) as a meltingdown of flesh into urine, with short survival (2). The sugary nature of the urine alsowasnoted by Zhen Li-Yan in China in the 7th century A.D., by the Arabian Avicenna (A.D.980–1037), and indetail by ThomasWillis in 1675,who labeled it the “pissing evil” (1,3).John Rollo in 1797 applied the descriptor “mellitus” (from the Latin for honey) (4,5).

Dietary ManipulationsAs elegantly catalogued in the classic 1919monograph “Total Dietary Regulation in theTreatment of Diabetes” (6), the treatment of diabetes for centuries was empiric andfundamentally one of dietary restrictions andmanipulations, with the addition of varioussubstances, some of which might be considered drugs. Aretaeus recommended a

1Lunenfeld-Tanenbaum Research Institute,Mount Sinai Hospital, University of Toronto,Toronto, Ontario, Canada2Diabetes Research Institute, University of Mi-ami, Miami, FL3Division of Endocrinology, Diabetes & ClinicalNutrition, Oregon Health & Science University,Portland, OR4CNR Institute of Clinical Physiology, and theDepartment of Clinical and Experimental Medicine,University of Pisa, Pisa, Italy

Corresponding author: Matthew C. Riddle,riddlem@ohsu.edu.

Received 26 July 2017 and accepted 26 July 2017.

© 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 notaltered.More infor-mationisavailableathttp://www.diabetesjournals.org/content/license.

Bernard Zinman,1 Jay S. Skyler,2

Matthew C. Riddle,3 and Ele Ferrannini 4

1302 Diabetes Care Volume 40, October 2017

DIABETES

CARESYMPOSIUM

“non-irritating diet” of milk and carbohy-dratesandhiera,nardum,mastix,andtheriakas drugs. Aetius of Amida (A.D. 550) intro-duced bleeding, emetics, and narcotics,which were used long after. Avicennaused a treatment consisting of powdersof fenugreek, lupin, and wormseed indosages up to 45 g/day (6).Thomas Willis said that “treatment

should aim to thicken the blood and sup-ply salts” and recommended “milk, rice,and starchy and gummy foods” (6). Helimited patients to a diet of milk and bar-ley water boiled with bread and thus be-came the author of the first carbohydrateor undernutrition care (6). He also initi-ated opium treatment (3).Thomas Sydenhamprescribed narcotics

and theriak and said, “Let the patient eatfood easy of digestion, such as veal, mut-ton, and the like, and abstain from allsorts of fruits and garden stuff” (6).John Rollo began treatment with

bleeding. He ordered “confinement . . .preferably to one room, with the utmostpossible quiet and avoidance of exercise”(6). A diet of animal food, as rancid aspossible, was also proposed. Drugs werechosen to produce anorexia and nausea,including ammonium sulfide, wine of an-timony, tincture of opium, digitalis, andtobacco (4–6).Apollinaire Bouchardat in France resur-

rected and transformed the Rollo treat-ment (7,8). Some consider him the fatherof diabetology. He was the first to insiston individualized treatment for patients.He disapproved the rancid character ofthe fats in the Rollo diet but substitutedfat and alcohol for carbohydrate in thediet (6). He forbade milk because of itscarbohydrate content, and he “urgedthat patients eat as little as possible,andmasticate carefully” (6). He introducedfasting to control glycosuria and recom-mended green vegetables to provide“little sugar, a little protein and fat, butespecially potassium, organic acids, andvarious salts” (6). He also first introducedthe intelligent use of exercise in the treat-ment of diabetes and advocated dailyurine testing “to keep track of the toler-ance and to guard against a return ofsugar without the patient’s knowledge”(6). He prescribed sodium bicarbonate,chalk, magnesia, citrates, tartrates, andammonium and potassium salts.Sir HenryMarsh criticized the Rollo diet

as “impossible to follow because ofthe indigestion and repugnance to food

resulting,” but he used the Bouchardatplan with the addition of vegetables andrestriction of fluid intake as well as exer-cise, warm clothing, and baths (6).

Arnoldo Cantani established a newstrict level of treatment (9). He isolatedhis patients “under lock and key, and al-lowed them absolutely no food but leanmeat and various fats. In the less severecases, eggs, liver, and shell-fish were per-mitted. For drink the patients receivedwater, plain or carbonated, and dilute al-cohol for those accustomed to liquors,the total fluid intake being limited toone and one-half to two and one-half li-ters per day” (6).

Bernhard Naunyn encouraged a strictcarbohydrate-free diet (6,10). He lockedpatients in their rooms for 5 monthswhen necessary for “sugar-freedom” (6).When sugar-freedom was not attainedthrough the withdrawal of carbohydrate,proteinwas reducedas lowas40–50g/dayand the calories were also diminished.Occasional fast days were advised asnecessary.

Karl von Noorden used 1 or 2 fast days,with the only food being alcohol (up to200–250 mL cognac). As soon as gly-cosuria and acidosis were partially con-trolled, he quickly provided an “oat-cure”(6).

Frederick M. Allen of the hospital ofThe Rockefeller Institute for Medical Re-search was one of the first to appreciatethat diabetes involves total metabolismrather than carbohydrate metabolismalone (6,11). He studied a detailed regi-men that involved fasting 2–10 days toclear glycosuria, followed by a restricted-calorie diet that provided mainly fat andprotein (especially eggs)with the smallestamount of carbohydrates (mostly vegeta-bles) necessary to sustain life. If glycosuriaappeared, fasting was resumed for 1–2days. The regimen essentially starvedpeople with severe diabetes in order tocontrol the disease.

Elliot P. Joslin embraced the Allen ap-proach but also used a treatment thatbegan by withdrawing only fat (12).

Pre–Insulin TherapyIn addition to the various dietary manipu-lationsdescribed, othernonpharmacologicand pharmacologic approaches were pro-posed. In his 1892 textbook (13), WilliamOsler recommended a dietary prescrip-tion 65% fat, 32% protein, and 3% carbo-hydrate, including abstaining from “all

fruits and garden stuff.”He also proposedto “avoid worry and lead an even, quietlife” in an equitable climate, use flannel orsilk near the skin, take a cold bath dailyand a Turkish bath occasionally, and getmoderate exercise or massage. He notedthat “no one drug has directly curativeinfluence” but that “opium alone standsthe test of experience as a remedycapable of limiting the progress of thedisease.” He wrote that other “effective”agents included potassium bromide, lac-tic acid, arsenicals, creosote, and lithiumsalts.

Insulin EraIn 1889, Josef von Mering and OskarMinkowski reported that total pancrea-tectomy in dogs resulted in severe diabe-tes in the dog (14,15). In 1893, GustaveEdouard Laguesse (16) deduced that thepancreatic islands described by PaulLangerhans in 1869 (17) as a “little heapof cells” produced an internal secretionthat regulated glucose metabolism. In1901, Eugene L. Opie reported that de-generation of the “islets of Langerhans”was associated with diabetes (18,19). Allof these events contributed to the searchfor the hypothetical hormone that JeanDe Meyer in 1909 dubbed “insuline”(20). Edward Sharpey-Shafer in 1916coined “insulin” as a single substancefromthepancreas responsible fordiabetes.

Meanwhile, multiple people (Table 1)around the world were attempting theextraction of insulin. These are chronicledin detail in Michael Bliss’s book The Dis-covery of Insulin and will not be reviewedhere (21).

It was in 1921 that Frederick BantingandCharlesBest,working in the laboratoryofJ.J.R. Macleod at the University of Toronto,successfully extracted insulin. Itwasfirstusedas treatment in January 1922 (22) andwas atruly life-saving achievement. Unselfishly,the University of Toronto made theirachievement available to companiesaround the world so that insulin couldbe widely used. Initial improvements inisolation and purification were made byJ.B. (Bert) Collip and George H.A. Clowes.

Insulin launched a new era of diabetesmanagement. Elliot P. Joslin noted, how-ever, that “the disease . . . was far fromsolved by insulin. Insulin marked the endof one era in diabetes management, notthe end of diabetes” (23).

The way that insulin was used differedwidely.OneU.K. specialist in 1924asserted

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that “essential parts of the treatmentwith insulin were ‘slowing the metabo-lism’ by rest in bed for a month at leastat the beginning of treatment, and carefuleradication of septic foci” (24). In contrast,in 1923 in Cleveland an outpatient clinicwas established that included individualand group education by a physician, a di-etitian giving food demonstrations, anda social worker who made sure patientscame, investigated home conditions, andkept records (24).The initial preparations of insulin were

extracted from beef and pork pancreataobtained at the slaughterhouse. The ini-tial preparations contained 10 (U-10) or20 (U-20) units of insulin per mL. The“unit” dosing was originally based onthedose required to inducehypoglycemicconvulsions in laboratory rabbits.The characteristics of insulin prepara-

tions include the purity of the prepara-tion, the concentration of insulin, thespecies of origin, and the time course ofaction (onset, peak, duration) (25). Fromthe 1930s to the early 1950s, one of themajor efforts made was to develop an in-sulinwith extended action (Table 2).Mostpreparations contained 40 (U-40) or80 (U-80) units of insulin per mL, withU-10 and U-20 eliminated in the early1940s. U-100 was introduced in 1973 and

wasmeant tobe a standard concentration,although U-500 had been available sincethe early 1950s for special circumstances.Preparations were either of mixed beefand pork origin, pure beef, or pure pork.There were progressive improvements inthe purity of preparations as chemicaltechniques improved. Prior to 1972, con-ventional preparations contained 8% non-insulin proteins.

In the early 1980s, “human” insulinswere introduced (26). These were madeeither by recombinant DNA technologyin bacteria (Escherichia coli) or yeast (Sac-charomyces cerevisiae) or by enzymaticconversion of pork insulin to human in-sulin, since pork differed by only oneamino acid from human insulin.

The powerful nature of recombinantDNA technology also led to the develop-ment of insulin analogs designed for spe-cific effects. These include rapid-actinginsulin analogs and basal insulin analogs.

Oral Therapies

Biguanides

In medieval Europe, Galega officinalis(goat’s rue or French lilac) was used as atreatment for diabetes (27). The activecomponent of G. officinalis is guanidine.In 1926, in Germany, a biguanide deriva-tive (synthalin) was introduced, but it waswithdrawn because of toxicity. In the late1950s, three other buguanides weredevelopeddmetformin, phenformin,and buformin. Phenformin was the onlybiguanide introduced in the U.S. Unfortu-nately, it was associatedwith induction oflactic acidosis, which oftenwas fatal. Con-sequently, in 1977 theU.S. Food andDrugAdministration (FDA), using the “clearand imminent danger” provision of theFood and Drug Act, ordered phenforminwithdrawn from the U.S. market. Thisrepresents the only time the FDA hasever withdrawn a drug from the U.S. mar-ket. Many drugs have been withdrawn bymanufacturersdusually with proddingby the FDAdbut in the case of phenfor-min, the manufacturer declined to act.Meanwhile, metformin was widely usedaround the world. Unfortunately, how-ever, its patent had expired by the timephenformin was withdrawn. Thus, therewas not a pathway to license and com-mercialization of metformin until theHatch-Waxman Act was passed by Con-gress in 1984. That law gave limited ex-clusivity in the market for new chemicalentitiesapprovedby theFDA.Subsequently,

metformin was studied, approved, andintroduced in the U.S. in 1995.

Sulfonylureas

Celestino Ruiz of Argentina noted hypogly-cemic actionof somesulfonamides in 1930(28). Subsequently, Auguste Loubatieresof France discovered the hypoglycemicaction of a prototype sulfonylurea in1942 and worked extensively on under-standing its mechanism of action (29).The first sulfonylurea, carbutamide, wasintroduced in 1955, followed by tolbuta-mide in 1957 and chlorpropamide in1960. Subsequently, a variety of other sul-fonylureas were introduced, includingacetohexamide, tolazamide, glipizide,glyburide (glybenclamide), gliclazide,and glimiperide.

Until 1996, the only oral medicationsavailable were biguanides and sulfonyl-ureas. Since that time, there has beenan explosion of new classes of oral andparenteral preparations.

II. CURRENT TREATMENTPARADIGMS TODAYdHOW WELLARE WE DOING?

The Current Management of Type 2DiabetesThemanagement of type2 diabetes (T2D)has undergone rapid change with theintroduction of several new classes ofglucose-lowering therapies. This increasein diabetes therapy options representsboth an opportunity, with the expansionof the tool kit to optimize treatment, andthe uncertainty as to deciding on the cor-rect treatment interventions in a timelymanner. In fact, the treatment guidelinesare generally clear in the context of usingmetformin as the first oral medicationfor T2D and present a menu approachwith respect to the second and thirdglucose-lowering medication (30–32). Inorder to facilitate this decision, theguidelines list the characteristics of eachmedication including side effects and cost,and the health care provider is expected tomake a choice that would be most suitedfor patient comorbidities and health care

Table 2—Insulins with extended actionProtamine insulinate, 1936

Protamine zinc insulin, 1936

Surfen insulin, 1938

Globin insulin, 1939

Phenylcarbamoyl insulin, 1944

Isophane (NPH) insulin, 1946

Lente insulins, 1951

Table 1—Attempts at insulin extraction1892 Capparelli

1892 Comby

1892 Minkowski

1893 Bathistini

1893 White

1895 Vanni

1897 Hougounena and Doyou

1898 Blumenthal

1898 Hedon

1903–1907 Zuelzer

1905 Gley

1906 De Witt

1907 Rennie and Frazer

1908 Siorqvist

1909 Lepine

1910 Pratt

1911 Knowlton and Starling

1912 Massaglia and Zannini

1912 Scott

1913 Murlin and Krammer

1916 Clark

1919 Kleiner and Meltzer

1916–1921 Paulescu

1921–1922 Banting and Best

1304 Diabetes Research and Care Through the Ages Diabetes Care Volume 40, October 2017

circumstances. This can be confusing andcontributes to the clinical inertia charac-teristic of the usual management of T2D(33). Rather than revisiting this topic inthis narrative, it is felt we can all agreethat we are now in an era of diabetes ther-apy where the first choice of medicationsshould provide effective glucose-loweringwithout weight gain or hypoglycemia. Anexpanded list of the desirable characteris-tics of glucose-lowering therapies is pre-sented in Table 3. (34)In addition to effective glucose lower-

ing, low hypoglycemia risk, and noweightgain, the therapy should be able to becombined with other agents and providea complementary mechanism of action,provide durable control, and possess areasonable short- and long-term adverseeffects profile. As added value, relevantto the day-to-day management of T2D, amedication that preservesb-cell function,which invariably decreaseswith longer di-abetes duration, would be of particularinterest. In addition, given the increasedrisk of cardiovascular (CV) morbidity andmortality in T2D, a medication associatedwith reduced CV events would be partic-ularly noteworthy.

Clinical InertiaPerhaps the most frustrating barrier tooptimizing diabetes management is thefrequent occurrence of clinical inertia(whenever the health care providerdoes not initiate or intensify therapy ap-propriately and in a timely fashion whentherapeutic goals are not reached). Morebroadly, the failure to advance therapy inan appropriate manner can be traced tophysician behaviors, patient factors, or el-ements of the health care system. Theclinician-based issues that lead to clinicalinertia are itemized in Table 4. Despiteclear evidence from multiple studies,health careproviders fail to fully appreciate

that T2D is a progressive disease. T2D isassociated with ongoing b-cell failureand, as a consequence, we can safely pre-dict that for the majority of patients, gly-cemic control will deteriorate with timedespite metformin therapy (35). Contin-ued observation and reinforcement ofthe current therapeutic regimen is notlikely to be effective. As an example ofreal-life clinical inertia for patients withT2D on monotherapy metformin and anHbA1c of 7 to,8%, it took on the average19 months before additional glucose-lowering therapy was introduced (36). Thefear of hypoglycemia and weight gainare appropriate concerns for both patientand physician, but with newer therapiesthese undesirable effects are significantlydiminished. In addition, health care pro-viders must appreciate that achievingearly and sustained glycemic control hasbeen demonstrated to have long-termbenefits, as demonstrated in both the Di-abetes Control and Complications Trial(DCCT)/Epidemiology of Diabetes Inter-ventions and Complications (EDIC) andthe UK Prospective Diabetes Study(UKPDS) (metabolic memory), resultingin remarkable reduction in the risk ofsubsequent microvascular (retinopathy,nephropathy, and neuropathy) complica-tions. Clinicians have been schooled inthenotionof a stepwise approach to ther-apy and are reluctant to initiate combina-tion therapy early in the course of T2D,even if the combination intervention isformulated as a fixed-dose combination.

Rationale for Early/Initial CombinationTherapy in T2DThe recognition that T2D is a diseasewith acomplex underlying pathophysiology thatincludes components of increased insulinresistance, increased hepatic glucoseproduction, b-cell failure, abnormalitiesin incretin action, enhanced renal sodium–

glucose cotransporter 2 (SGLT2) activity, andabnormalities in glucagon physiologydto

name a fewdmust be taken into accountin determining an intervention strat-egy (37). In addition, the body generallyhas the ability to overcome a single-pathway intervention because of built-inredundancy. Thus, it is not surprising thatmonotherapy metformin failure rateswith a starting HbA1c .7% are ;20%per year (35).

Table 5 summarizes the rationale forearly/initial combination therapy. Withinitial combination therapy, one canexpect a more robust initial responseand, since two medications are initiated,inertia is less of a problem. Although thereduction in b-cell glucose toxicity mayhave long-term beneficial effects onb-cell function, this remains to be docu-mented. In addition, complementarymechanisms of action and the eliminationof early hyperglycemia, which may havelonger-term consequences, provide im-portant benefits of early/initial combina-tion therapy.

CV Risk in T2D and Its Relationship tothe Treatment of T2DAs documented by the DCCT/EDIC andUKPDS, there is little question that thebenefits of optimizing glucose control asit relates to microvascular complicationsis substantial for both T1D and T2D. Sim-ilarly, glycemic control, if initiated early inthe courseof diabetes andwith long-termfollow-up, can be shown to reduce CVoutcomes.

However, as shown in Fig. 1, CV events,CV mortality, and heart failure were notpositively affected by intensive versusless intensive glycemic control in rathershort trials in T2D. In 2008, the FDA man-dated that all new diabetes medicationsdemonstrate CV safety in dedicated CVsafety trials. The first four of these trials(EvaluationofLixisenatide inAcuteCoronarySyndrome [ELIXA], Examination of Cardio-vascular Outcomes with Alogliptin versusStandard of Care [EXAMINE], Saxagliptin

Table 3—Desirable characteristics ofglucose-lowering therapiesEffective glucose-lowering action

Low risk of hypoglycemia

No weight gain

Complementary mechanism of action withother therapies

Durability

Well tolerated

Long-term safety

Added value, e.g., b-cell function, CV, etc.

Table 4—Potential causes of clinical inertia in T2DFailure of clinicians to fully appreciate the progressive nature of T2D consequent to b-cell failure

A clinician’s lack of understanding about the frequent failure of monotherapy and thatmost patientswill ultimately require combination therapy

A clinician’s and/or patient’s fear of hypoglycemia and weight gain when intensifying therapy,particularly with sulfonylureas or insulin

A clinician’s lack of confidence, particularly when working in the primary care setting, in using insulin

Poor recognition, by clinicians, of the evidence that demonstrates the benefits of early glycemiccontrol

A clinician’s general reluctance to use combination therapy early after diagnosis

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Assessment of Vascular OutcomesRecorded in Patients with DiabetesMellitus–Thrombolysis in MyocardialInfarction 53 [SAVOR-TIMI 53], and TrialEvaluating Cardiovascular OutcomesWith Sitagliptin [TECOS]) met this impor-tant safety requirement (38–41). Subse-quently, the BI 10773 (Empagliflozin)Cardiovascular Outcome Event Trialin Type 2 Diabetes Mellitus Patients(EMPA-REG OUTCOME) and LiraglutideEffect and Action in Diabetes: Evaluationof Cardiovascular Outcome ResultsdALong Term Evaluation (LEADER) trialsdemonstrated not only safety but also areduction in the primaryMACE (CV death,nonfatal myocardial infarction [MI],

nonfatal stroke) outcome and robust re-ductions in CV death and hospitalizationfor heart failure with empagliflozin(42,43). More recently, the Trial to Evalu-ate Cardiovascular and Other Long-termOutcomes With Semaglutide in SubjectsWith Type 2 Diabetes (SUSTAIN-6) alsodocumented a reduction in MACE butnot in CV death or heart failure (44).The Canagliflozin Cardiovascular Assess-ment Study (CANVAS) is the secondSGLT2 trial to report a benefit in the pri-mary MACE outcome and hospitalizationfor heart failure but failed to demonstratea reduction in CV mortality. In addition,CANVAS reported an increase in lower-limb amputation (hazard ratio [HR] 1.97

[95% CI 1.41–2.75]) with canagliflozincompared with placebo (45).

These findings have changed the pre-scribing label and guideline recommenda-tions for empagliflozin. Guidelines havealso recognized the CV benefits of liraglu-tide. Semaglutide is not currently anapproved medication, and the CANVASresults have only recently been reported.

An Approach to Diabetes TherapyIf we eliminate cost issues and drug planrestrictions, can we develop an approachto the management of T2D that betterreflects modern therapy and current evi-dence? As previously indicated, the pri-mary focus should be on therapies notassociated with hypoglycemia or weightgain. Weight loss and evidence for a re-duction in CV outcomes, even in a subsetof patients with previous CV events,would be viewed positively.

In this context, initial combinations withmetformin (i.e., metformin/dipeptidylpeptidase 4 [DPP-4] inhibitor, metformin/SGLT2 inhibitor, or DPP-4 inhibitor/SGLT2inhibitor) seem like obvious choices. In the

Figure 1—CV risk in T2D: summary of large randomized trials with respect to CV events (MACE), CV mortality, and heart failure.

Table 5—Rationale for initial combination therapy in T2DEarly robust lowering of HbA1c

Avoidance of clinical inertia associated with a stepwise approach to therapy

Potential for early combination therapy to improve b-cell function

Initiation of therapeutic intervention with complementary mechanism of action

Potential to use less than maximal doses of individual agents to minimize side effects

Avoiding long-term consequences of metabolic memory

1306 Diabetes Research and Care Through the Ages Diabetes Care Volume 40, October 2017

context of individualizing therapy, a historyof pancreatitis (avoid DPP-4 inhibitors),renal impairment, or recurrent genital in-fections (avoid SGLT2 inhibitors) andother circumstances may determine thespecific combination. As another exam-ple, there are significant numbers of pa-tients with gastrointestinal intolerance tometformin or reduced renal function con-traindicating metformin use. The benefi-cial effects of glucagon-like peptide1 (GLP-1) receptor agonists and theironce-weekly formulationswithoutweightgain or risk of hypoglycemia make theman additional valuable component of acombination approach. Although thereis reasonable rationale for this ap-proach, long-term studies documentingthe beneficial effects of newer combina-tions versus stepped approaches withthese newer medications will have tobe documented.To summarize the current status of T2D

at this time, it should be clearly empha-sized that, first and foremost, T2D is char-acterized by a progressive deteriorationof glycemic control. A stepwise medica-tion introduction approach results in clin-ical inertia and frequently fails to meetlong-term treatment goals. Early/initialcombination therapies that are not asso-ciated with hypoglycemia and/or weightgain have been shown to be safe andeffective. The added value of reducingCV outcomes with some of these newermedications should elevate them to amore prominent place in the treatmentparadigm.

III. EVOLVING CONCEPTS ANDFUTURE DIRECTIONS FOR CVOUTCOMES TRIALS

Compared with the treatment of cancerand CV disease, management of diabeteshas been guided by relatively few largeclinical trials. Fortunately, recent evidenceis closing this gap. As described in the pre-vious section, we have a growing array oftherapies for patients with diabetes and,as our understanding of the natural historyof both microvascular and CV complica-tions improves, we are learning how bestto deploy these therapies.

Time Course of Microvascular andCV Disease in DiabetesEpidemiologic analyses show that risks ofmicrovascular disease and CV disease in-crease with duration of time since theonset of diabetes (46,47) and also with

severity of hyperglycemia (48,49). Reti-nopathy often begins before the diagno-sis of diabetes and progresses steadily inthe first 10 years (50). CV disease mayoccur before the onset of diabetes, butmore often it is not present at diagno-sis. In the seminal Framingham HeartStudy, mortality from coronary heartdisease increased gradually with dura-tion of observation over more than twodecades (51). The rate of increase formen with diabetes was twice that ofmenwithout diabetes and fourfold higherfor women, with the greater part of thisdifferential after 10 years of diabetes.Typically, clinically evident CV disease ap-pears more slowly than microvascularcomplications.

Short-term Glycemic Intervention inEarly Diabetes: DCCT and UKPDSSuch evidence prompted testing whetherimproved glycemic control can reducecomplications in people with newly diag-nosed diabetes. Beginning in 1982, theDCCT enrolled patients with T1D withmean duration of ;6 years. From 1977on, the UKPDS enrolled patients shortlyafter diagnosis of T2D. The main resultsof these trials were reported in 1993 and1998, respectively.

The DCCT showed that 6.5 years oftreatment causing an ;2% mean reduc-tion of HbA1c led to 63% less progressionof retinopathy and 54% less macroalbu-minuria (52). A corresponding primaryanalysis of the UKPDS, comparing insulinor sulfonylurea with conventional (life-style) therapy, showed that 10 years of;1% mean reduction of HbA1c caused a25% reduction of combined microvascularend points (53). Both studies had relative-ly fewCVevents, andbetter glycemic con-trol showed no significant effect on them.However, in a separate randomization intheUKPDS, participants treatedwithmet-formin had 36% lower all-cause mortalitythan those allocated to lifestyle therapy(n = 50 of 342 vs. 89 of 411).

Short-term Glycemic Intervention inDiabetes With CV Disease: ACCORD,VADT, and ADVANCEVerification that improved glycemic con-trol reduces microvascular complicationshad a profound effect on treatmentguidelines, but the limited CV effectswere disappointing. Todeterminewhetherfailure of glucose lowering to improve CVoutcomes was due to low statistical power

in populations with low CV risk, furtherstudies were designed to study patientswith longer duration of diabetes who hadestablished CV disease or were at veryhigh risk. These were the Action to ControlCardiovascular Risk in Diabetes (ACCORD)trial, the Veterans Affairs Diabetes Trial(VADT), and the Action in Diabetes andVascular Disease: Preterax and DiamicronMR Controlled Evaluation (ADVANCE)study (54–56). All reported some micro-vascular benefits after ;5 years of ran-domized treatment, but despite includingenough events, they again found noconsistent reduction of CV risk. Mostsignificantly, a 20% increase of all-causeand CV mortality occurred in the in-tensive arm of ACCORD (53). This toohad a strong effect on clinical guidance.It is now commonly advised to avoidseeking HbA1c levels ,7% in “high-risk”patients.

Long-term Follow-up of DCCT/EDICand UKPDSWhile ACCORD, VADT, and ADVANCEwereunderway, long-termpassive obser-vation of the DCCT cohort (termed theEDIC study) and continued follow-upof participants in the UKPDS added im-portant new information. Follow-up inEDIC showed that the risk of the originalcomposite primary CV end point was 42%lower in the previously intensively treat-ed group than after standard therapyin the DCCT, and a composite of nonfatalMI, stroke, or CV death was reduced57% (57). When enough deaths had oc-curred to provide power for analysis inEDIC, all-cause mortality was reduced by33% (58), and the investigators have pro-vided evidence that adjusted mortalityrates in the DCCT/EDIC intensive groupare no different from that of the generalpopulation in the U.S. (59). Similarly,10 years after the 10-year randomizedtreatment period of the UKPDS, the inten-sive group using insulin or sulfonylureashad significant reductions of combinedmi-crovascular end points (24%), MI (15%),and all-cause mortality (13%) (60). Thesmaller intensive group using metforminhad 16% (not statistically significant),33%, and 27% reductions of the sameend points.

Although limited by problems alwayspresent in passive follow-up studies,these consistent long-term observationsare highly provocative. They suggestwhatthe investigators of these studies have

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termed a “legacy effect” or “metabolicmemory” of prior glycemic control. Thatis, a 6- to 10-year period of excellent gly-cemic control may leave a structural im-print on vascular and other tissues,leading to clinical benefits more than10 years later. A corollary of this idea isthat a harmful legacy effectmay follow anearly period of poor control, causing tis-sue injury that cannot be reversed by im-proved control later on. Measures ofglycemic control during the entire periodof follow-up in DCCT/EDIC correlatestrongly with both microvascular and CVoutcomes (61,62), a finding consistentwith long-lasting effects of hyperglycemiaduring the early period of randomizedtreatment. Potential mechanisms for leg-acy effects are irreversible changes of col-lagen and other molecules in bloodvessels by glycationoroxidativepathways(63). Furthermore, renal disease resultingfrom suchmechanismsmay itself becomean important CV risk factor.

Short-term Benefits From Specific NewTherapies: EMPA-REG OUTCOME,CANVAS, LEADER, and SUSTAIN-6Prompted by concerns about increased CVrisk attributed to treatment with rosiglita-zone, the FDA advised in 2008 that whenearly studiesofnewdrugs couldnotprovidestrong evidence of CV safety, adequatelypowered CV outcomes trials should bedone. To limit the time and resources re-quired for this purpose, subsequent trials ofDPP-4 inhibitors, GLP-1 receptor agonists,and SGLT2 blockers have enrolled popula-tionswith very high CV risk (and an averageduration of diabetes .10 years), therebyassuring high CV event rates. Of eightsuch trials reported to date, four had neu-tral results for their primary composite CVend points, but four showed significantbenefit of the drug tested. The drugsshown to reduce CV risk were empagliflo-zin (13), canagliflozin (45), liraglutide (14),and semaglutide (15). The most dramaticbenefits were seenwith amedian 3.2-year

period of treatment with the SGLT2blocker empagliflozin, during which riskof the CV composite was reduced 14%,CV mortality 38%, and all-cause mortality32%. Themechanisms of these effects arenot well understood, but two importantprinciples have been proved: drugs inthese three classes do not seem to haveshort-term CV risks, and some have favor-able effects beyond what can be attrib-uted to metabolic improvements alone,even in patients with established micro-vascular and CV complications of diabe-tes. These recent findings, added to theolder ones, have implications for bothclinical practice and future research.

Lessons for Clinical PracticeThe concept of a positive legacy effect ofinitially good metabolic control demandsconsideration of early diagnosis of di-abetes and strong efforts to obtain andmaintain good control from the start. Inaddition to efforts to prevent diabetes,

Figure 2—Schematic depiction of three stages of the natural history of T2D, noting several opportunities for improvement of management. During theperiod before diagnosis, risk factors for developing diabetes call for systematic screening to reduce the interval between onset and diagnosis, therebyreducing an untreated interval of hyperglycemia. At diagnosis, specific subtypes of diabetes may be identified. During the early stages of T2D, evidence-based standard treatment algorithms may be effective in controlling glucose and reducing later complications. At some point in each individual’sexperience, often close to 10 years after diagnosis, more individualized therapy is likely to be needed, including consideration of newer therapeuticagentswith nonglycemic effects that reduce the risk of CV events. GDM, gestational diabetesmellitus; IFG, impaired fasting glucose; IGT, impaired glucosetolerance; LADA, latent autoimmune diabetes in adults.

1308 Diabetes Research and Care Through the Ages Diabetes Care Volume 40, October 2017

screening to identify it within a year ofonset seems a good investment. If theemerging pattern of long-term outcomesin DCCT/EDIC and the UKPDS continues,marked reduction of the greater thantwofold increase of CV risk accompanyingdiabetes may be within reach, providedexcellentmetabolic control, perhaps withHbA1c ,7.0%, is maintained in the first10 years. At the other end of the naturalhistory of diabetes, secondary interven-tion for establishedCVdisease in diabetesshould emphasize nonglycemic effects ofdrugs rather than glucose lowering alone.Thus, evidence from these trials now sup-ports renewed clinical efforts before thecurrent diagnosis of diabetes, in the first10 years after diagnosis, and after morethan 10 years. These opportunities at allstages of the natural history of T2D areillustrated in Fig. 2.

Lessons for Future Clinical TrialsThe good news for pharmacologic re-search is that required safety studies ofnew agents can yield important new in-formation on both short-term risks andshort-term benefits. More problematic isthe reminder that a few years of observa-tion cannot predict the legacy effects ofeither metabolic changes or other effectsof drugs that may emerge only decadeslater. Notably, the impressive short-term benefits of empagliflozin, and per-haps other drugs of its class, cannot beassumed to be free of later harms. Also,the results these studies of very high-riskpatients cannot confidently be extrapo-lated to the entire range of patients seenin clinical practice. Finally, to limit costs,the study of both short-term and long-term outcomes must be made more ef-ficient by new trial designs and statisticalmethods, prospective data collection,and perhaps embedding of researchwithin health care systems.

IV. WHAT DOES THE FUTUREHOLD?

To tackle the question of what the futureholds, one might take two routes: onedeals with what is reasonable to expectgiven current trends; the other is aboutwhat would be desirable to see in thefuture.To begin with the reasonable, Table 6

is a nonexhaustive list of research areas inT2D that are evolving toward disruptivelynew knowledge (indexed by a makeshiftheuristic score of value and speed of

scientific discovery). Genetics has beendisappointing for clinical diabetes as itshifted from the early T2D candidategene approach, which basically failed, togenome-wide association scanning andgenomics, which showed that dozens ofgenes are involved in the predisposition toT2D (64–66). Furthermore, joint predispo-sition to T2D and comorbidities (princi-pally, obesity [67], hypertension [68],and dyslipidemia [69]) has raised thetask of identifying the genetic makeupof T2D to quasi-intractable levels of com-plexity. However, epigenetics and the“omics” (mainly metabolomics and pro-teomics) are providing increasingly more“physiological” profiles of diabetic sub-phenotypes by using integrated networkmethodology (70). Understanding whichgene variant controls the transcription ofwhich protein in which metabolic path-way, resulting in which distinct, measur-able biochemical signature, currentlyappears to be a trajectory of slow but un-relenting progress (71,72).

At the tissue level, classical studies ofb-cell function are being refueled by theincreased availability of human islets.Thus, three-dimensional in situ and invivo imaging has exposed the structureof the human islet at an unprecedentedlevel of resolution, highlighting the rela-tive (i.e., as compared with rodent islets)short total vessel network, the tight con-nection between a- and b-cells, and thepresence ofb-cell clusters within the islet(73). With regard to the latter feature,brilliant work has recently discovered“hubs” of b-cells that serve the functionof synchronizing insulin discharge acrossthe islet (74), a sort of specific conductionsystem analogous to that of the heart.The fundamental discovery of b-cell plas-ticity will add important details to theprocesses of dedifferentiation and redif-ferentiation of a- and b-cells (75–78). Byway of example, an antimalarial drugclass, the artemisinins, facilitate transdif-ferentiation of a- to b-cells in a pathwayinvolved in active GABAA receptor signal-ing in neurons (79). These developmentswill not only provide insight into the be-havior of this diffuse organ but also ex-tract molecular targets for intervention,with the use of drugs or by engineeringsynthetic gene circuits with CRISPR tech-nology (synthetic biology) (80). The gut islikely to yieldmuchnovel informationbothin the epithelial compartment (metaboliceffects of substrate transporters [81], bile

acids [82], microbiota and their products[83]) and in the sparse endocrine section(L and K cells and the panel of their in-terrelated hormonal products) (84).

Thanks to ever more powerful in vivoimaging techniques (e.g., MRI and spec-troscopy, positron emission tomographywith multiple tracers), there is likely tobe a reprise ofwhole-organ studies jointlyof structure, metabolism, and function(85,86) (Fig. 3). Quantitation of regionaluptake of substrates and perfusion in theliver (87), adipose tissue (88), and myo-cardial muscle (89) and tissue perfusion/metabolism matching (90) will enhanceour understanding of tissue energeticsand their derangements in diabetes. Theheart and the kidney will be in the frontline as ischemic heart disease, heart fail-ure, and renal insufficiency continue topose the major challenge to the survivalof T2D patients. The brain will steadilygenerate information on the neural con-trol of not just behavior but alsometabolicfunctions (e.g., endogenous glucose pro-duction and insulin action [91,92]); evenmore impressively, the inherent links be-tween T2D and Alzheimer disease alongthe aging process (93) will be elucidated,and attempts at intervening jointly on

Table 6—Putative development ofmajor research areas

Score*

Value Speed

Genome level 6 4GenesEpigenetics“omics”

Tissue level 7 5b-Cell plasticityAdipose tissue plasticityGut factors (including

the microbiome)

Organ level 9 5HeartKidneyBrain

Environment 3 3Diet and exerciseToxic factorsInfections

Pharmacology 6 7New drugsStrategies

Information technology 2 9SensorsElectronic health recordsBig data

*On an ascending scale of 1 to 10.

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metabolic control and cognitive functionwill proliferate (94).Much is already known about the en-

vironmental factors that impact on thenatural history of T2D: the roles of obe-sity, sedentariness (95), smoking, chemi-cal pollution (96), occupational changes,and infections on glucose tolerance andits main determinants (b-cell functionand insulin sensitivity) have been workedout well enough. Unfortunately, clinicalexperience with lifestyle modificationtypically is frustrating; in addition, ran-domized clinical trials have confirmedthe limited efficacy and the resourceintensity of lifestyle intervention (97).Concomitantly, several new classes of ef-ficacious and safe agents have been in-troduced in rapid sequence, which mayhave decreased the drive toward lifestyleintervention. The search for novel thera-peutic targets is very active (98), and thedevelopment of glucose-sensitive in-sulins (99), if successful, would be agame-changer as compared to the dual-hormone artificial pancreas (100). More-over, early use of drug combinations is verylikely to increase, especially with strategiesbased on complementary mechanisms

of action or chemical hybridization (101).In particular, in the future, insulin may bemostly used in combinations with agentsthat reduce the associated risk of hypo-glycemia and weight gain.

Application of information technologyto health care is already galloping, and itsrate of development may accelerate un-der heavy market pressure by corporategiants (Google, Facebook, etc.). Refinedsensors acquire all sorts of data (glycemia,heart rate, etc.), which are relayed tosmartphones/tablets/computersequippedwith feedback algorithms capable ofadjusting treatment (mobile health). In-creasing adoption of electronic healthrecords will facilitate planning bed occu-pancy and reduce in-hospital time. This,along with linking medical and adminis-trative databases, can help prioritize re-source allocation and cost assessment.The temptation, however, to mine theemerging humongous data pools to ex-tract counterfeit clinical guidance (102)will be increasingly difficult to resist. In-deed, means and strategies will have tobe deployed to deal with information fluxbecause the relationship between infor-mation supply and information handling

has longbeen known tohave an invertedUshape (103): above a certain range of in-formation load lie confusion and, worse,manipulation (Fig. 4). Additionally, somegovernance will have to be put in place toprevent fraudulent data hijacking and toprotect the privacy of medical data.

Turning to what is desirable, the an-swer is straightforward (and nowadays“viral”): precisionmedicine. On the shoul-ders of outstanding progress in diabetesscience, it should be possible to person-alize diagnosis, prognosis, and treatmentfor the individual patient by using a bat-tery of examinations (physical) and tests(in silico) as the patient first accesses thepoint of care. The patient would be clas-sified into one of several subphenotypes(104,105), be given reliable quantitativerisk scores for complications, and walkout with a tailored set of drug prescrip-tions (106), each complemented by a pre-dicted rate of therapeutic response andside effects. Years later, epidemiologistsand health care providers would proudlyannounce that the deadly gap in CV andcancer morbidity/mortality between theT2D segment and the background popu-lation was canceled. This rosy prospect

Figure 3—The use of a glucose analog (18F-deoxyglucose) and positron emission tomography images of the left ventricular wall of the heart of a normalsubjects (left). The diffuse pattern of tracer uptakedocuments the absenceof perfusion defects; quantification of these imagesmeasures insulin-mediatedglucose uptake. In the insulin-resistant subject (right), tracer uptake is also diffuse but uniformly reduced, thereby demonstrating myocardial insulinresistance.

1310 Diabetes Research and Care Through the Ages Diabetes Care Volume 40, October 2017

would seem to be at hand, especiallysince the pathophysiology of diabetes isalready known with enough detail to ac-count for every milligram of circulatingglucose. There are, however, major hur-dles. First, the sheer number of patientswith known or unknown T2D, which isclimbing up to one-sixth of the generalpopulation (107), and the systemic natureof the disease once complications de-velop will pose a hefty levy on healthcare. Second, given the geographic andsocioeconomic distribution of T2D (107),most of the “reasonably” expected bene-fit (Table 6) may go only to a fraction ofthe patientsdthose who have access toand can afford the progress. Even thesehappy few may experience a progressiveerosion of physician contact as they be-come identification numbers in a mecha-nized, automated, digitalized path. Butthe underprivileged many will still be inenvironments that preclude detailed phe-notyping, expensive drugs and devices,and connectivity. Finally, the explosionof diabetes care demand may enter intofierce competition with other resource-intensivediseases,e.g., cancerandAlzheimerdisease.At this juncture, a development that

is both reasonable and desirable is insight: prevention. The ongoing efforts toidentify subjects strongly predisposed to

T2D (108) will capitalize on selectivescreening (by age, family history, gesta-tional diabetes mellitus, etc.) and power-ful biomarker panels; treatment mayexploit the safer new drugs. Interventionin prediabetes, however, must includeobesity, which remains the most power-ful known risk factor for dysglycemia at alllatitudes. Bariatric surgery cogently dem-onstrates that, once stripped of weightexcess, T2D (but also hypertension anddyslipidemia) undergoes prolonged re-mission or major improvement. Indeed,“lean” or postobese T2D is where geneticpredisposition is strongest and easiest toidentify. Although obesity, by nature andsize, is also a social problem, science couldcontribute to its attenuation, if not solu-tion, by building and testing a steppedapproach using combinations of less inva-sive surgery (e.g., sleeve gastrectomy),drugs (e.g., GLP-1 receptor agonists,SGLT2 inhibitors), and “early” life-style counseling (i.e., in children andadolescents). This will remain an uphilltrajectorydbecause of the body’s attitudeto strenuously defend achieved weight(109)dbut one that goes straight to theroot of the problem. The increasingly “so-cial” dimension of diabetesddue to itssystemic and comorbid nature and its highprevalencedis likely to expand the diabe-tologist’s remit: from care to prevention,

from single point-of-care to networks,from individual education to public advo-cacy, from science translation to lobbying.A formidable prospect, particularly intimes of recurrent attacks on public healthcare, which still is a hallmark of civilization.

Duality of Interest. B.Z. has served as consul-tant for and has received honoraria fromAstraZeneca, Boehringer Ingelheim, Eli Lilly andCompany, Janssen, Merck Sharp & Dohme, NovoNordisk, and Sanofi and has received grant sup-port from Boehringer Ingelheim, Novo Nordisk,and AstraZeneca. J.S.S. has acted as an advisor toADOCIA, AstraZeneca, BD Technologies, BoehringerIngelheim, Dance Biopharm, Diavacs, ElcelyxTherapeutics, Eli Lilly and Company, Ideal Life,ImmunoMolecular Therapeutics, Intarcia Therapeu-tics, Intrexon, Merck Sharp & Dohme, Orgenesis,Sanofi, Servier, vTv Therapeutics, Valeritas, andViacyte; has received research funding fromMesoblast and Viacyte; is a member of the boardof directors of Dexcom, Moerae Matrix, andVasoPrep Surgical; and has equity in Dance Bio-pharm, Dexcom, Ideal Life, Intrexon, Moerae Ma-trix, and VasoPrep Surgical. M.C.R. has receivedhonoraria for consulting from ADOCIA, Eleclyx,Sanofi, and Valeritas; for serving on a data safetymonitoring committee for AstraZeneca andGlaxoSmithKline; for serving on a clinical trialsteering committee for Eli Lilly and Companyand Theracos; and for speaking at professionalmeetings for Sanofi and has received researchsupport through his institution from AstraZeneca,Eli Lilly and Company, and Novo Nordisk. E.F. hasbeen a speaker and consultant for AstraZeneca,Takeda, Novo Nordisk, Sanofi, Mitsubishi Tanabe,Eli Lilly and Company, Boehringer Ingelheim, andMerck Sharp & Dohme; has received researchfunds from Boehringer Ingelheim and Eli Lillyand Company; has done ad hoc consulting forJanssen and AstraZeneca; and is a member ofthe scientific advisory board of BoehringerIngelheim/Eli Lilly and Company, Merck Sharp &Dohme, and Sanofi.Prior Presentation. Parts of this article werepresented at the 77th Scientific Sessions of theAmerican Diabetes Association, San Diego, CA,10 June 2017.

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