1302 Diabetes Care Volume 40, October 2017 SYMPOSIUM

Bernard Zinman,1 Jay S. Skyler,2 Diabetes Research and Care Matthew C. Riddle,3 and Ele Ferrannini 4 DIABETES CARE Through the Ages Diabetes Care 2017;40:1302–1313 | https://doi.org/10.2337/dci17-0042

As has been well established, the Diabetes Care journal’s most visible signature event is the Diabetes Care Symposium held each year during the American Diabetes Association’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 most attended sessions during the Scientific Sessions. Each year, in order to continue to have the symposium generate 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, how we arrived at our current state of management. I also felt the narrative needed to include 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, I asked four of the most noted experts in the world to provide their opinion on this topic. The symposium started with a very thoughtful presentation by Dr. Jay Skyler entitled “A Look Back as to How We Got Here.” That was followed by two lectures on current concepts by Dr. Bernard Zinman entitled “Current Treatment Paradigms TodaydHow Well Are We Doing?” and by Dr. Matthew Riddle entitled “Evolving Concepts and Future Directions for Cardiovascular Outcomes Trials.” The final lecture for the symposium was delivered by Dr. Ele Ferrannini and was entitled “What Does the Future Hold?” As always, a well-attended and well-received symposium is now the norm for our signature event and our efforts were rewarded by the enthusiasm of the attendees. This narrative summarizes the lectures held at the symposium. dWilliam T. Cefalu Chief Scientific, Medical & Mission Officer, American Diabetes Association

1Lunenfeld-Tanenbaum Research Institute, I. A LOOK BACK AS TO HOW WE GOT HERE Mount Sinai Hospital, University of Toronto, A polyuric state, presumably diabetes, was described more than 3,500 years ago, being Toronto, Ontario, Canada 2Diabetes Research Institute, University of Mi- noted by the physician Hesy-Ra in an Egyptian papyrus (from approximately 1500 B.C.) ami, Miami, FL found by George Ebers. The sweetness of urine was noted by the Hindu physicians 3Division of Endocrinology, Diabetes & Clinical Charaka and Sushruta around 400–500 B.C. (1). Apollonius of Memphis (around Nutrition, Oregon Health & Science University, 250 B.C.) used the term “diabetes” (from the Greek for siphon), and Aretaeus of Portland, OR 4 Cappadocia (A.D. 30–90) described what is likely type 1 diabetes (T1D) as a melting CNR Institute of Clinical Physiology, and the fl Department of Clinical and Experimental Medicine, down of esh into urine, with short survival (2). The sugary nature of the urine also was University of Pisa, Pisa, Italy noted by Zhen Li-Yan in China in the 7th century A.D., by the Arabian Avicenna (A.D. Corresponding author: Matthew C. Riddle, 980–1037), and in detail by Thomas Willis in 1675, who labeled it the “pissing evil” (1,3). [email protected]. “ ” John Rollo in 1797 applied the descriptor mellitus (from the Latin for honey) (4,5). Received 26 July 2017 and accepted 26 July 2017. Dietary Manipulations © 2017 by the American Diabetes Association. As elegantly catalogued in the classic 1919 monograph “Total Dietary Regulation in the Readers may use this article as long as the work ” is properly cited, the use is educational and not Treatment of Diabetes (6), the treatment of diabetes for centuries was empiric and for profit, and the work is not altered. More infor- fundamentally one of dietary restrictions and manipulations, with the addition of various mationisavailableathttp://www.diabetesjournals substances, some of which might be considered drugs. Aretaeus recommended a .org/content/license. care.diabetesjournals.org Zinman and Associates 1303

“non-irritating diet” of milk and carbohy- resulting,” but he used the Bouchardat fruits and garden stuff.” He also proposed drates and hiera, nardum, mastix, and theriak plan with the addition of vegetables and to “avoid worry and lead an even, quiet as drugs. Aetius¨ of Amida (A.D. 550) intro- restriction of fluid intake as well as exer- life” in an equitable climate, use flannel or duced bleeding, emetics, and narcotics, cise, warm clothing, and baths (6). silk near the skin, take a cold bath daily which were used long after. Avicenna Arnoldo Cantani established a new and a Turkish bath occasionally, and get used a treatment consisting of powders strict level of treatment (9). He isolated moderate exercise or massage. He noted of fenugreek, lupin, and wormseed in his patients “under lock and key, and al- that “no one drug has directly curative dosages up to 45 g/day (6). lowed them absolutely no food but lean influence” but that “opium alone stands Thomas Willis said that “treatment meat and various fats. In the less severe the test of experience as a remedy should aim to thicken the blood and sup- cases, eggs, liver, and shell-fish were per- capable of limiting the progress of the ply salts” and recommended “milk, rice, mitted. For drink the patients received disease.” He wrote that other “effective” and starchy and gummy foods” (6). He water, plain or carbonated, and dilute al- agents included potassium bromide, lac- limited patients to a diet of milk and bar- cohol for those accustomed to liquors, tic acid, arsenicals, creosote, and lithium ley water boiled with bread and thus be- the total fluid intake being limited to salts. came the author of the first carbohydrate one and one-half to two and one-half li- or undernutrition care (6). He also initi- ters per day” (6). Insulin Era ated opium treatment (3). Bernhard Naunyn encouraged a strict In 1889, Josef von Mering and Oskar Thomas Sydenham prescribed narcotics carbohydrate-free diet (6,10). He locked Minkowski reported that total pancrea- andtheriakandsaid,“Let the patient eat patients in their rooms for 5 months tectomy in dogs resulted in severe diabe- food easy of digestion, such as veal, mut- when necessary for “sugar-freedom” (6). tes in the dog (14,15). In 1893, Gustave ton, and the like, and abstain from all When sugar-freedom was not attained Edouard Laguesse (16) deduced that the sorts of fruits and garden stuff” (6). through the withdrawal of carbohydrate, pancreatic islands described by Paul John Rollo began treatment with protein was reduced as low as 40–50 g/day Langerhans in 1869 (17) as a “little heap bleeding. He ordered “confinement . . . and the calories were also diminished. of cells” produced an internal secretion preferably to one room, with the utmost Occasional fast days were advised as that regulated glucose metabolism. In possible quiet and avoidance of exercise” necessary. 1901, Eugene L. Opie reported that de- (6). A diet of animal food, as rancid as KarlvonNoordenused1or2fastdays, generation of the “islets of Langerhans” possible, was also proposed. Drugs were with the only food being alcohol (up to was associated with diabetes (18,19). All chosen to produce anorexia and nausea, 200–250 mL cognac). As soon as gly- of these events contributed to the search including ammonium sulfide, wine of an- cosuria and acidosis were partially con- for the hypothetical hormone that Jean timony, tincture of opium, digitalis, and trolled, he quickly provided an “oat-cure” De Meyer in 1909 dubbed “insuline” tobacco (4–6). (6). (20). Edward Sharpey-Shafer in 1916 Apollinaire Bouchardat in France resur- Frederick M. Allen of the hospital of coined “insulin” as a single substance rected and transformed the Rollo treat- The Rockefeller Institute for Medical Re- from the pancreas responsible for diabetes. ment (7,8). Some consider him the father search was one of the first to appreciate Meanwhile, multiple people (Table 1) of diabetology. He was the first to insist that diabetes involves total metabolism around the world were attempting the on individualized treatment for patients. rather than carbohydrate metabolism extraction of insulin. These are chronicled He disapproved the rancid character of alone (6,11). He studied a detailed regi- in detail in Michael Bliss’sbookThe Dis- the fats in the Rollo diet but substituted men that involved fasting 2–10 days to covery of Insulin and will not be reviewed fat and alcohol for carbohydrate in the clear glycosuria, followed by a restricted- here (21). diet (6). He forbade milk because of its calorie diet that provided mainly fat and It was in 1921 that Frederick Banting carbohydrate content, and he “urged protein (especially eggs) with the smallest and Charles Best, working in the laboratory of that patients eat as little as possible, amount of carbohydrates (mostly vegeta- J.J.R. Macleod at the University of Toronto, and masticate carefully” (6). He introduced bles) necessary to sustain life. If glycosuria successfully extracted insulin. It was first used fasting to control glycosuria and recom- appeared, fasting was resumed for 1–2 as treatment in January 1922 (22) and was a mended green vegetables to provide days. The regimen essentially starved truly life-saving achievement. Unselfishly, “little sugar, a little protein and fat, but people with severe diabetes in order to the University of Toronto made their especially potassium, organic acids, and control the disease. achievement available to companies various salts” (6). He also first introduced Elliot P. Joslin embraced the Allen ap- around the world so that insulin could the intelligent use of exercise in the treat- proach but also used a treatment that be widely used. Initial improvements in ment of diabetes and advocated daily began by withdrawing only fat (12). isolation and purification were made by urine testing “to keep track of the toler- J.B. (Bert) Collip and George H.A. Clowes. anceandtoguardagainstareturnof Pre–Insulin Therapy Insulin launched a new era of diabetes sugar without the patient’sknowledge” In addition to the various dietary manipu- management. Elliot P. Joslin noted, how- (6). He prescribed sodium bicarbonate, lations described, other nonpharmacologic ever, that “the disease . . . was far from chalk, magnesia, citrates, tartrates, and and pharmacologic approaches were pro- solved by insulin. Insulin marked the end ammonium and potassium salts. posed. In his 1892 textbook (13), William of one era in diabetes management, not Sir Henry Marsh criticized the Rollo diet Osler recommended a dietary prescrip- the end of diabetes” (23). as “impossible to follow because of tion 65% fat, 32% protein, and 3% carbo- The way that insulin was used differed the indigestion and repugnance to food hydrate, including abstaining from “all widely. One U.K. specialist in 1924 asserted 1304 Diabetes Research and Care Through the Ages Diabetes Care Volume 40, October 2017

Table 1—Attempts at insulin extraction was meant to be a standard concentration, Table 2—Insulins with extended action 1892 Capparelli although U-500 had been available since Protamine insulinate, 1936 1892 Comby the early 1950s for special circumstances. Protamine zinc insulin, 1936 1892 Minkowski Preparations were either of mixed beef Surfen insulin, 1938 1893 Bathistini and pork origin, pure beef, or pure pork. Globin insulin, 1939 1893 White There were progressive improvements in Phenylcarbamoyl insulin, 1944 the purity of preparations as chemical 1895 Vanni Isophane (NPH) insulin, 1946 techniques improved. Prior to 1972, con- 1897 Hougounena and Doyou Lente insulins, 1951 ventional preparations contained 8% non- 1898 Blumenthal insulin proteins. 1898 Hedon In the early 1980s, “human” insulins metformin was studied, approved, and – 1903 1907 Zuelzer were introduced (26). These were made introduced in the U.S. in 1995. 1905 Gley either by recombinant DNA technology Sulfonylureas 1906 De Witt in bacteria (Escherichia coli)oryeast(Sac- Celestino Ruiz of Argentina noted hypogly- 1907 Rennie and Frazer charomyces cerevisiae) or by enzymatic cemic action of some sulfonamides in 1930 1908 Siorqvist conversion of pork insulin to human in- (28). Subsequently, Auguste Loubatieres` 1909 Lepine sulin, since pork differed by only one of France discovered the hypoglycemic 1910 Pratt amino acid from human insulin. action of a prototype sulfonylurea in 1911 Knowlton and Starling The powerful nature of recombinant 1942 and worked extensively on under- 1912 Massaglia and Zannini DNA technology also led to the develop- standing its mechanism of action (29). 1912 Scott ment of insulin analogs designed for spe- The first sulfonylurea, carbutamide, was fi 1913 Murlin and Krammer ci c effects. These include rapid-acting introduced in 1955, followed by tolbuta- 1916 Clark insulin analogs and basal insulin analogs. mide in 1957 and chlorpropamide in 1919 Kleiner and Meltzer 1960. Subsequently, a variety of other sul- 1916–1921 Paulescu Oral Therapies fonylureas were introduced, including 1921–1922 Banting and Best Biguanides acetohexamide, tolazamide, glipizide, In medieval Europe, Galega officinalis glyburide (glybenclamide), gliclazide, (goat’s rue or French lilac) was used as a and glimiperide. that “essential parts of the treatment treatment for diabetes (27). The active Until 1996, the only oral medications with insulin were ‘slowing the metabo- component of G. officinalis is guanidine. available were biguanides and sulfonyl- ’ lism by rest in bed for a month at least In 1926, in Germany, a biguanide deriva- ureas. Since that time, there has been at the beginning of treatment, and careful tive (synthalin) was introduced, but it was an explosion of new classes of oral and eradication of septic foci” (24). In contrast, withdrawn because of toxicity. In the late parenteral preparations. in 1923 in Cleveland an outpatient clinic 1950s, three other buguanides were was established that included individual developeddmetformin, phenformin, II. CURRENT TREATMENT and group education by a physician, a di- and buformin. Phenformin was the only PARADIGMS TODAYdHOW WELL etitian giving food demonstrations, and biguanide introduced in the U.S. Unfortu- ARE WE DOING? a social worker who made sure patients nately, it was associated with induction of The Current Management of Type 2 came, investigated home conditions, and lactic acidosis, which often was fatal. Con- Diabetes kept records (24). sequently, in 1977 the U.S. Food and Drug The management of type 2 diabetes (T2D) The initial preparations of insulin were Administration (FDA), using the “clear has undergone rapid change with the extracted from beef and pork pancreata and imminent danger” provision of the introduction of several new classes of obtained at the slaughterhouse. The ini- Food and Drug Act, ordered phenformin glucose-lowering therapies. This increase tial preparations contained 10 (U-10) or withdrawn from the U.S. market. This in diabetes therapy options represents 20 (U-20) units of insulin per mL. The represents the only time the FDA has both an opportunity, with the expansion “unit” dosing was originally based on ever withdrawn a drug from the U.S. mar- of the tool kit to optimize treatment, and the dose required to induce hypoglycemic ket. Many drugs have been withdrawn by the uncertainty as to deciding on the cor- convulsions in laboratory rabbits. manufacturersdusually with prodding rect treatment interventions in a timely The characteristics of insulin prepara- by the FDAdbut in the case of phenfor- manner. In fact, the treatment guidelines tions include the purity of the prepara- min, the manufacturer declined to act. are generally clear in the context of using tion, the concentration of insulin, the Meanwhile, metformin was widely used metformin as the first oral medication species of origin, and the time course of around the world. Unfortunately, how- for T2D and present a menu approach action (onset, peak, duration) (25). From ever, its patent had expired by the time with respect to the second and third the 1930s to the early 1950s, one of the phenformin was withdrawn. Thus, there glucose-lowering medication (30–32). In major efforts made was to develop an in- was not a pathway to license and com- order to facilitate this decision, the sulin with extended action (Table 2). Most mercialization of metformin until the guidelines list the characteristics of each preparations contained 40 (U-40) or Hatch-Waxman Act was passed by Con- medication including side effects and cost, 80 (U-80) units of insulin per mL, with gress in 1984. That law gave limited ex- and the health care provider is expected to U-10 and U-20 eliminated in the early clusivity in the market for new chemical make a choice that would be most suited 1940s. U-100 was introduced in 1973 and entities approved by the FDA. Subsequently, for patient comorbidities and health care care.diabetesjournals.org Zinman and Associates 1305

circumstances. This can be confusing and Table 4—Potential causes of clinical inertia in T2D contributes to the clinical inertia charac- Failure of clinicians to fully appreciate the progressive nature of T2D consequent to b-cell failure teristic of the usual management of T2D Aclinician’s lack of understanding about the frequent failure of monotherapy and that most patients (33). Rather than revisiting this topic in will ultimately require combination therapy this narrative, it is felt we can all agree A clinician’s and/or patient’s fear of hypoglycemia and weight gain when intensifying therapy, that we are now in an era of diabetes ther- particularly with sulfonylureas or insulin apy where the first choice of medications Aclinician’slackofconfidence, particularly when working in the primary care setting, in using insulin should provide effective glucose-lowering Poor recognition, by clinicians, of the evidence that demonstrates the benefits of early glycemic without weight gain or hypoglycemia. An control expanded list of the desirable characteris- A clinician’s general reluctance to use combination therapy early after diagnosis tics of glucose-lowering therapies is pre- sented in Table 3. (34) In addition to effective glucose lower- that T2D is a progressive disease. T2D is name a fewdmust be taken into account ing, low hypoglycemia risk, and no weight associated with ongoing b-cell failure in determining an intervention strat- gain, the therapy should be able to be and, as a consequence, we can safely pre- egy (37). In addition, the body generally combined with other agents and provide dict that for the majority of patients, gly- has the ability to overcome a single- a complementary mechanism of action, cemic control will deteriorate with time pathway intervention because of built-in provide durable control, and possess a despite metformin therapy (35). Contin- redundancy. Thus, it is not surprising that reasonable short- and long-term adverse ued observation and reinforcement of monotherapy metformin failure rates effects profile. As added value, relevant the current therapeutic regimen is not with a starting HbA1c .7% are ;20% to the day-to-day management of T2D, a likely to be effective. As an example of peryear(35). b medication that preserves -cell function, real-life clinical inertia for patients with Table 5 summarizes the rationale for which invariably decreases with longer di- T2D on monotherapy metformin and an early/initial combination therapy. With abetes duration, would be of particular HbA1c of 7 to ,8%, it took on the average initial combination therapy, one can interest. In addition, given the increased 19 months before additional glucose- expect a more robust initial response risk of cardiovascular (CV) morbidity and lowering therapy was introduced (36). The and, since two medications are initiated, mortality in T2D, a medication associated fear of hypoglycemia and weight gain inertia is less of a problem. Although the with reduced CV events would be partic- are appropriate concerns for both patient reduction in b-cell glucose toxicity may ularly noteworthy. and physician, but with newer therapies have long-term beneficial effects on these undesirable effects are significantly b-cell function, this remains to be docu- Clinical Inertia diminished. In addition, health care pro- mented. In addition, complementary Perhaps the most frustrating barrier to viders must appreciate that achieving mechanisms of action and the elimination optimizing diabetes management is the early and sustained glycemic control has of early hyperglycemia, which may have frequent occurrence of clinical inertia been demonstrated to have long-term longer-term consequences, provide im- (whenever the health care provider benefits, as demonstrated in both the Di- portant benefits of early/initial combina- does not initiate or intensify therapy ap- abetes Control and Complications Trial tion therapy. propriately and in a timely fashion when (DCCT)/Epidemiology of Diabetes Inter- therapeutic goals are not reached). More ventions and Complications (EDIC) and CV Risk in T2D and Its Relationship to broadly, the failure to advance therapy in the UK Prospective Diabetes Study the Treatment of T2D an appropriate manner can be traced to (UKPDS) (metabolic memory), resulting As documented by the DCCT/EDIC and physician behaviors, patient factors, or el- in remarkable reduction in the risk of UKPDS, there is little question that the fi ements of the health care system. The subsequent microvascular (retinopathy, bene ts of optimizing glucose control as clinician-based issues that lead to clinical nephropathy, and neuropathy) complica- it relates to microvascular complications inertia are itemized in Table 4. Despite tions. Clinicians have been schooled in is substantial for both T1D and T2D. Sim- clear evidence from multiple studies, the notion of a stepwise approach to ther- ilarly, glycemic control, if initiated early in health care providers fail to fully appreciate apy and are reluctant to initiate combina- the course of diabetes and with long-term tion therapy early in the course of T2D, follow-up, can be shown to reduce CV even if the combination intervention is outcomes. Table 3—Desirable characteristics of formulated as a fixed-dose combination. However, as shown in Fig. 1, CV events, glucose-lowering therapies CV mortality, and heart failure were not Effective glucose-lowering action Rationale for Early/Initial Combination positively affected by intensive versus Low risk of hypoglycemia Therapy in T2D less intensive glycemic control in rather No weight gain The recognition that T2D is a disease with a short trials in T2D. In 2008, the FDA man- Complementary mechanism of action with complex underlying pathophysiology that dated that all new diabetes medications other therapies includes components of increased insulin demonstrate CV safety in dedicated CV Durability resistance, increased hepatic glucose safety trials. The first four of these trials Well tolerated production, b-cell failure, abnormalities (Evaluation of Lixisenatide in Acute Coronary Long-term safety in incretin action, enhanced renal sodium– Syndrome [ELIXA], Examination of Cardio- Added value, e.g., b-cell function, CV, etc. glucose cotransporter 2 (SGLT2) activity, and vascular Outcomes with Alogliptin versus abnormalities in glucagon physiologydto Standard of Care [EXAMINE], Saxagliptin 1306 Diabetes Research and Care Through the Ages Diabetes Care Volume 40, October 2017

– fl Table 5—Rationale for initial combination therapy in T2D [95% CI 1.41 2.75]) with canagli ozin Early robust lowering of HbA1c compared with placebo (45). Avoidance of clinical inertia associated with a stepwise approach to therapy These findings have changed the pre- Potential for early combination therapy to improve b-cell function scribing label and guideline recommenda- fl Initiation of therapeutic intervention with complementary mechanism of action tions for empagli ozin. Guidelines have fi Potential to use less than maximal doses of individual agents to minimize side effects also recognized the CV bene ts of liraglu- tide. Semaglutide is not currently an Avoiding long-term consequences of metabolic memory approved medication, and the CANVAS results have only recently been reported.

Assessment of Vascular Outcomes nonfatal stroke) outcome and robust re- An Approach to Diabetes Therapy Recorded in Patients with Diabetes ductions in CV death and hospitalization If we eliminate cost issues and drug plan Mellitus–Thrombolysis in Myocardial for heart failure with empagliflozin restrictions, can we develop an approach Infarction 53 [SAVOR-TIMI 53], and Trial (42,43). More recently, the Trial to Evalu- to the management of T2D that better Evaluating Cardiovascular Outcomes ate Cardiovascular and Other Long-term reflects modern therapy and current evi- With Sitagliptin [TECOS]) met this impor- Outcomes With Semaglutide in Subjects dence? As previously indicated, the pri- tant safety requirement (38–41). Subse- With Type 2 Diabetes (SUSTAIN-6) also mary focus should be on therapies not quently, the BI 10773 (Empagliflozin) documented a reduction in MACE but associated with hypoglycemia or weight Cardiovascular Outcome Event Trial not in CV death or heart failure (44). gain. Weight loss and evidence for a re- in Type 2 Diabetes Mellitus Patients The Canagliflozin Cardiovascular Assess- duction in CV outcomes, even in a subset (EMPA-REG OUTCOME) and Liraglutide ment Study (CANVAS) is the second of patients with previous CV events, Effect and Action in Diabetes: Evaluation SGLT2 trial to report a benefitinthepri- wouldbeviewedpositively. of Cardiovascular Outcome ResultsdA mary MACE outcome and hospitalization In this context, initial combinations with Long Term Evaluation (LEADER) trials for heart failure but failed to demonstrate metformin (i.e., metformin/dipeptidyl demonstrated not only safety but also a a reduction in CV mortality. In addition, peptidase 4 [DPP-4] inhibitor, metformin/ reduction in the primary MACE (CV death, CANVAS reported an increase in lower- SGLT2 inhibitor, or DPP-4 inhibitor/SGLT2 nonfatal myocardial infarction [MI], limb amputation (hazard ratio [HR] 1.97 inhibitor) 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. care.diabetesjournals.org Zinman and Associates 1307

context of individualizing therapy, a history severity of hyperglycemia (48,49). Reti- in populations with low CV risk, further of pancreatitis (avoid DPP-4 inhibitors), nopathy often begins before the diagno- studies were designed to study patients renal impairment, or recurrent genital in- sis of diabetes and progresses steadily in with longer duration of diabetes who had fections (avoid SGLT2 inhibitors) and the first 10 years (50). CV disease may established CV disease or were at very other circumstances may determine the occur before the onset of diabetes, but high risk. These were the Action to Control specific combination. As another exam- more often it is not present at diagno- Cardiovascular Risk in Diabetes (ACCORD) ple, there are significant numbers of pa- sis. In the seminal Framingham Heart trial, the Veterans Affairs Diabetes Trial tients with gastrointestinal intolerance to Study, mortality from coronary heart (VADT), and the Action in Diabetes and metformin or reduced renal function con- disease increased gradually with dura- Vascular Disease: Preterax and Diamicron traindicating metformin use. The benefi- tion of observation over more than two MR Controlled Evaluation (ADVANCE) cial effects of glucagon-like peptide decades (51). The rate of increase for study (54–56). All reported some micro- 1 (GLP-1) receptor agonists and their menwithdiabeteswastwicethatof vascular benefits after ;5 years of ran- once-weekly formulations without weight men without diabetes and fourfold higher domized treatment, but despite including gain or risk of hypoglycemia make them for women, with the greater part of this enough events, they again found no an additional valuable component of a differential after 10 years of diabetes. consistent reduction of CV risk. Most combination approach. Although there Typically, clinically evident CV disease ap- significantly, a 20% increase of all-cause is reasonable rationale for this ap- pears more slowly than microvascular andCVmortalityoccurredinthein- proach, long-term studies documenting complications. tensive arm of ACCORD (53). This too the beneficial effects of newer combina- had a strong effect on clinical guidance. tions versus stepped approaches with Short-term Glycemic Intervention in It is now commonly advised to avoid these newer medications will have to Early Diabetes: DCCT and UKPDS seeking HbA1c levels ,7% in “high-risk” be documented. Such evidence prompted testing whether patients. To summarize the current status of T2D improved glycemic control can reduce at this time, it should be clearly empha- complications in people with newly diag- Long-term Follow-up of DCCT/EDIC sized that, first and foremost, T2D is char- nosed diabetes. Beginning in 1982, the and UKPDS acterized by a progressive deterioration DCCT enrolled patients with T1D with While ACCORD, VADT, and ADVANCE of glycemic control. A stepwise medica- mean duration of ;6years.From1977 were under way, long-term passive obser- tion introduction approach results in clin- on, the UKPDS enrolled patients shortly vation of the DCCT cohort (termed the ical inertia and frequently fails to meet after diagnosis of T2D. The main results EDIC study) and continued follow-up long-term treatment goals. Early/initial of these trials were reported in 1993 and of participants in the UKPDS added im- combination therapies that are not asso- 1998, respectively. portant new information. Follow-up in ciated with hypoglycemia and/or weight The DCCT showed that 6.5 years of EDIC showed that the risk of the original gainhavebeenshowntobesafeand treatment causing an ;2% mean reduc- composite primary CV end point was 42% effective. The added value of reducing tion of HbA1c led to 63% less progression lower in the previously intensively treat- CV outcomes with some of these newer of retinopathy and 54% less macroalbu- ed group than after standard therapy medications should elevate them to a minuria (52). A corresponding primary in the DCCT, and a composite of nonfatal more prominent place in the treatment analysis of the UKPDS, comparing insulin MI, stroke, or CV death was reduced paradigm. or sulfonylurea with conventional (life- 57% (57). When enough deaths had oc- style) therapy, showed that 10 years of curred to provide power for analysis in III. EVOLVING CONCEPTS AND ;1% mean reduction of HbA1c caused a EDIC, all-cause mortality was reduced by FUTURE DIRECTIONS FOR CV 25% reduction of combined microvascular 33% (58), and the investigators have pro- OUTCOMES TRIALS end points (53). Both studies had relative- vided evidence that adjusted mortality Compared with the treatment of cancer ly few CV events, and better glycemic con- rates in the DCCT/EDIC intensive group and CV disease, management of diabetes trol showed no significant effect on them. are no different from that of the general has been guided by relatively few large However, in a separate randomization in population in the U.S. (59). Similarly, clinical trials. Fortunately, recent evidence the UKPDS, participants treated with met- 10 years after the 10-year randomized is closing this gap. As described in the pre- formin had 36% lower all-cause mortality treatment period of the UKPDS, the inten- vious section, we have a growing array of than those allocated to lifestyle therapy sive group using insulin or sulfonylureas fi therapies for patients with diabetes and, (n = 50 of 342 vs. 89 of 411). had signi cant reductions of combined mi- as our understanding of the natural history crovascular end points (24%), MI (15%), of both microvascular and CV complica- Short-term Glycemic Intervention in and all-cause mortality (13%) (60). The tions improves, we are learning how best Diabetes With CV Disease: ACCORD, smaller intensive group using metformin fi to deploy these therapies. VADT, and ADVANCE had 16% (not statistically signi cant), Verification that improved glycemic con- 33%, and 27% reductions of the same Time Course of Microvascular and trol reduces microvascular complications end points. CV Disease in Diabetes had a profound effect on treatment Although limited by problems always Epidemiologic analyses show that risks of guidelines, but the limited CV effects present in passive follow-up studies, microvascular disease and CV disease in- were disappointing. To determine whether these consistent long-term observations crease with duration of time since the failure of glucose lowering to improve CV are highly provocative. They suggest what onset of diabetes (46,47) and also with outcomes was due to low statistical power the investigators of these studies have 1308 Diabetes Research and Care Through the Ages Diabetes Care Volume 40, October 2017

termed a “legacy effect” or “metabolic Short-term Benefits From SpecificNew period of treatment with the SGLT2 memory” of prior glycemic control. That Therapies: EMPA-REG OUTCOME, blocker empagliflozin, during which risk is, a 6- to 10-year period of excellent gly- CANVAS, LEADER, and SUSTAIN-6 of the CV composite was reduced 14%, cemic control may leave a structural im- Prompted by concerns about increased CV CV mortality 38%, and all-cause mortality print on vascular and other tissues, risk attributed to treatment with rosiglita- 32%. The mechanisms of these effects are leading to clinical benefits more than zone, the FDA advised in 2008 that when not well understood, but two important 10 years later. A corollary of this idea is early studies of new drugs could not provide principles have been proved: drugs in that a harmful legacy effect may follow an strong evidence of CV safety, adequately these three classes do not seem to have early period of poor control, causing tis- powered CV outcomes trials should be short-term CV risks, and some have favor- sue injury that cannot be reversed by im- done. To limit the time and resources re- able effects beyond what can be attrib- proved control later on. Measures of quired for this purpose, subsequent trials of uted to metabolic improvements alone, glycemic control during the entire period DPP-4 inhibitors, GLP-1 receptor agonists, even in patients with established micro- of follow-up in DCCT/EDIC correlate and SGLT2 blockers have enrolled popula- vascular and CV complications of diabe- strongly with both microvascular and CV tionswithveryhighCVrisk(andanaverage tes. These recent findings, added to the outcomes (61,62), a finding consistent duration of diabetes .10 years), thereby older ones, have implications for both with long-lasting effects of hyperglycemia assuring high CV event rates. Of eight clinical practice and future research. during the early period of randomized such trials reported to date, four had neu- treatment. Potential mechanisms for leg- tral results for their primary composite CV Lessons for Clinical Practice acy effects are irreversible changes of col- end points, but four showed significant The concept of a positive legacy effect of lagen and other molecules in blood benefit of the drug tested. The drugs initially good metabolic control demands vessels by glycation or oxidative pathways shown to reduce CV risk were empagliflo- consideration of early diagnosis of di- (63). Furthermore, renal disease resulting zin (13), canagliflozin (45), liraglutide (14), abetes and strong efforts to obtain and from such mechanisms may itself become and semaglutide (15). The most dramatic maintain good control from the start. In an important CV risk factor. benefits were seen with a median 3.2-year addition 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 the period before diagnosis, risk factors for developing diabetes call for systematic screening to reduce the interval between onset and diagnosis, thereby reducing 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’s experience, often close to 10 years after diagnosis, more individualized therapy is likely to be needed, including consideration of newer therapeutic agents with nonglycemic effects that reduce the risk of CV events. GDM, gestational diabetes mellitus; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LADA, latent autoimmune diabetes in adults. care.diabetesjournals.org Zinman and Associates 1309

fi screening to identify it within a year of scienti c discovery). Genetics has been Table 6—Putative development of onset seems a good investment. If the disappointing for clinical diabetes as it major research areas emerging pattern of long-term outcomes shifted from the early T2D candidate Score* in DCCT/EDIC and the UKPDS continues, gene approach, which basically failed, to Value Speed marked reduction of the greater than genome-wide association scanning and twofold increase of CV risk accompanying genomics, which showed that dozens of Genome level 6 4 diabetes may be within reach, provided genes are involved in the predisposition to Genes – Epigenetics excellent metabolic control, perhaps with T2D (64 66). Furthermore, joint predispo- “omics” HbA ,7.0%, is maintained in the first sition to T2D and comorbidities (princi- 1c Tissue level 7 5 10 years. At the other end of the natural pally, obesity [67], hypertension [68], b-Cell plasticity history of diabetes, secondary interven- and dyslipidemia [69]) has raised the Adipose tissue plasticity tion for established CV disease in diabetes task of identifying the genetic makeup Gut factors (including should emphasize nonglycemic effects of of T2D to quasi-intractable levels of com- the microbiome) drugs rather than glucose lowering alone. plexity. However, epigenetics and the Organ level 9 5 Thus, evidence from these trials now sup- “omics” (mainly metabolomics and pro- Heart ports renewed clinical efforts before the teomics) are providing increasingly more Kidney Brain current diagnosis of diabetes, in the first “physiological” profiles of diabetic sub- 10 years after diagnosis, and after more phenotypes by using integrated network Environment 3 3 Diet and exercise than 10 years. These opportunities at all methodology (70). Understanding which Toxic factors stages of the natural history of T2D are gene variant controls the transcription of Infections illustrated in Fig. 2. which protein in which metabolic path- Pharmacology 6 7 way, resulting in which distinct, measur- New drugs Lessons for Future Clinical Trials able biochemical signature, currently Strategies The good news for pharmacologic re- appears to be a trajectory of slow but un- Information technology 2 9 search is that required safety studies of relenting progress (71,72). Sensors new agents can yield important new in- At the tissue level, classical studies of Electronic health records formation on both short-term risks and b-cell function are being refueled by the Big data short-term benefits. More problematic is increased availability of human islets. *On an ascending scale of 1 to 10. the reminder that a few years of observa- Thus, three-dimensional in situ and in tion cannot predict the legacy effects of vivo imaging has exposed the structure either metabolic changes or other effects of the human islet at an unprecedented acids [82], microbiota and their products of drugs that may emerge only decades level of resolution, highlighting the rela- [83]) and in the sparse endocrine section later. Notably, the impressive short- tive (i.e., as compared with rodent islets) (L and K cells and the panel of their in- term benefits of empagliflozin, and per- short total vessel network, the tight con- terrelated hormonal products) (84). haps other drugs of its class, cannot be nection between a-andb-cells, and the Thanks to ever more powerful in vivo assumed to be free of later harms. Also, presence of b-cell clusters within the islet imaging techniques (e.g., MRI and spec- the results these studies of very high-risk (73). With regard to the latter feature, troscopy, positron emission tomography patients cannot confidently be extrapo- brilliant work has recently discovered with multiple tracers), there is likely to lated to the entire range of patients seen “hubs” of b-cells that serve the function be a reprise of whole-organ studies jointly in clinical practice. Finally, to limit costs, of synchronizing insulin discharge across of structure, metabolism, and function the study of both short-term and long- the islet (74), a sort of specificconduction (85,86) (Fig. 3). Quantitation of regional term outcomes must be made more ef- system analogous to that of the heart. uptake of substrates and perfusion in the ficient by new trial designs and statistical The fundamental discovery of b-cell plas- liver (87), adipose tissue (88), and myo- methods, prospective data collection, ticity will add important details to the cardial muscle (89) and tissue perfusion/ and perhaps embedding of research processes of dedifferentiation and redif- metabolism matching (90) will enhance within health care systems. ferentiation of a-andb-cells (75–78). By our understanding of tissue energetics way of example, an antimalarial drug and their derangements in diabetes. The IV. WHAT DOES THE FUTURE class, the artemisinins, facilitate transdif- heart and the kidney will be in the front HOLD? ferentiation of a-tob-cells in a pathway line as ischemic heart disease, heart fail- To tackle the question of what the future involved in active GABAA receptor signal- ure, and renal insufficiency continue to holds, one might take two routes: one ing in neurons (79). These developments pose the major challenge to the survival deals with what is reasonable to expect will not only provide insight into the be- of T2D patients. The brain will steadily given current trends; the other is about havior of this diffuse organ but also ex- generate information on the neural con- what would be desirable to see in the tract molecular targets for intervention, trol of not just behavior but also metabolic future. with the use of drugs or by engineering functions (e.g., endogenous glucose pro- To begin with the reasonable, Table 6 synthetic gene circuits with CRISPR tech- ductionandinsulinaction[91,92]);even is a nonexhaustive list of research areas in nology (synthetic biology) (80). The gut is more impressively, the inherent links be- T2D that are evolving toward disruptively likely to yield much novel information both tween T2D and Alzheimer disease along new knowledge (indexed by a makeshift in the epithelial compartment (metabolic the aging process (93) will be elucidated, heuristic score of value and speed of effects of substrate transporters [81], bile and attempts at intervening jointly on 1310 Diabetes Research and Care Through the Ages Diabetes Care Volume 40, October 2017

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 normal subjects (left). The diffuse pattern of tracer uptake documents the absence of perfusion defects; quantification of these images measures insulin-mediated glucose uptake. In the insulin-resistant subject (right), tracer uptake is also diffuse but uniformly reduced, thereby demonstrating myocardial insulin resistance.

metabolic control and cognitive function of action or chemical hybridization (101). haslongbeenknowntohaveaninvertedU will proliferate (94). In particular, in the future, insulin may be shape (103): above a certain range of in- Much is already known about the en- mostly used in combinations with agents formation load lie confusion and, worse, vironmental factors that impact on the that reduce the associated risk of hypo- manipulation (Fig. 4). Additionally, some natural history of T2D: the roles of obe- glycemia and weight gain. governance will have to be put in place to sity, sedentariness (95), smoking, chemi- Application of information technology prevent fraudulent data hijacking and to cal pollution (96), occupational changes, to health care is already galloping, and its protect the privacy of medical data. and infections on glucose tolerance and rate of development may accelerate un- Turning to what is desirable, the an- its main determinants (b-cell function der heavy market pressure by corporate swer is straightforward (and nowadays and insulin sensitivity) have been worked giants (Google, Facebook, etc.). Refined “viral”): precision medicine. On the shoul- out well enough. Unfortunately, clinical sensors acquire all sorts of data (glycemia, ders of outstanding progress in diabetes experience with lifestyle modification heart rate, etc.), which are relayed to science, it should be possible to person- typically is frustrating; in addition, ran- smartphones/tablets/computers equipped alize diagnosis, prognosis, and treatment domized clinical trials have confirmed with feedback algorithms capable of for the individual patient by using a bat- the limited efficacy and the resource adjusting treatment (mobile health). In- tery of examinations (physical) and tests intensity of lifestyle intervention (97). creasing adoption of electronic health (in silico) as the patient first accesses the Concomitantly, several new classes of ef- records will facilitate planning bed occu- point of care. The patient would be clas- ficacious and safe agents have been in- pancy and reduce in-hospital time. This, sified into one of several subphenotypes troduced in rapid sequence, which may along with linking medical and adminis- (104,105), be given reliable quantitative have decreased the drive toward lifestyle trative databases, can help prioritize re- risk scores for complications, and walk intervention. The search for novel thera- source allocation and cost assessment. out with a tailored set of drug prescrip- peutic targets is very active (98), and the The temptation, however, to mine the tions (106), each complemented by a pre- development of glucose-sensitive in- emerging humongous data pools to ex- dicted rate of therapeutic response and sulins (99), if successful, would be a tract counterfeit clinical guidance (102) side effects. Years later, epidemiologists game-changer as compared to the dual- will be increasingly difficult to resist. In- and health care providers would proudly hormone artificial pancreas (100). More- deed, means and strategies will have to announce that the deadly gap in CV and over, early use of drug combinations is very be deployed to deal with information flux cancer morbidity/mortality between the likely to increase, especially with strategies because the relationship between infor- T2D segment and the background popu- basedoncomplementarymechanisms mation supply and information handling lation was canceled. This rosy prospect care.diabetesjournals.org Zinman and Associates 1311

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

Duality of Interest. B.Z. has served as consul- tant for and has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novo Nordisk, and Sanofi and has received grant sup- port from Boehringer Ingelheim, Novo Nordisk, and AstraZeneca. J.S.S. has acted as an advisor to ADOCIA, AstraZeneca, BD Technologies, Boehringer Ingelheim, Dance Biopharm, Diavacs, Elcelyx Therapeutics, Eli Lilly and Company, Ideal Life, ImmunoMolecular Therapeutics, Intarcia Therapeu- tics, Intrexon, Merck Sharp & Dohme, Orgenesis, Sanofi, Servier, vTv Therapeutics, Valeritas, and Viacyte; has received research funding from Mesoblast and Viacyte; is a member of the board of directors of Dexcom, Moerae Matrix, and VasoPrep Surgical; and has equity in Dance Bio- pharm, Dexcom, Ideal Life, Intrexon, Moerae Ma- trix, and VasoPrep Surgical. M.C.R. has received Figure 4—In learning machines and humans, the relationship between information load and in- honoraria for consulting from ADOCIA, Eleclyx, formation handling takes the shape of an inverted U (32). Sanofi, and Valeritas; for serving on a data safety monitoring committee for AstraZeneca and GlaxoSmithKline; for serving on a clinical trial would seem to be at hand, especially T2D (108) will capitalize on selective steering committee for Eli Lilly and Company since the pathophysiology of diabetes is screening (by age, family history, gesta- and Theracos; and for speaking at professional already known with enough detail to ac- tional diabetes mellitus, etc.) and power- meetings for Sanofi and has received research count for every milligram of circulating ful biomarker panels; treatment may support through his institution from AstraZeneca, Eli Lilly and Company, and Novo Nordisk. E.F. has glucose. There are, however, major hur- exploit the safer new drugs. Intervention been a speaker and consultant for AstraZeneca, dles. First, the sheer number of patients in prediabetes, however, must include Takeda, Novo Nordisk, Sanofi, Mitsubishi Tanabe, with known or unknown T2D, which is obesity, which remains the most power- Eli Lilly and Company, Boehringer Ingelheim, and climbing up to one-sixth of the general ful known risk factor for dysglycemia at all Merck Sharp & Dohme; has received research population (107), and the systemic nature latitudes. Bariatric surgery cogently dem- funds from Boehringer Ingelheim and Eli Lilly and Company; has done ad hoc consulting for of the disease once complications de- onstrates that, once stripped of weight Janssen and AstraZeneca; and is a member of velop will pose a hefty levy on health excess, T2D (but also hypertension and the scientific advisory board of Boehringer care. Second, given the geographic and dyslipidemia) undergoes prolonged re- Ingelheim/Eli Lilly and Company, Merck Sharp & socioeconomic distribution of T2D (107), mission or major improvement. Indeed, Dohme, and Sanofi. “ ” “ ” Prior Presentation. Parts of this article were most of the reasonably expected bene- lean or postobese T2D is where genetic presented at the 77th Scientific Sessions of the fit (Table 6) may go only to a fraction of predisposition is strongest and easiest to American Diabetes Association, San Diego, CA, the patientsdthose who have access to identify. Although obesity, by nature and 10 June 2017. and can afford the progress. Even these size, is also a social problem, science could happy few may experience a progressive contribute to its attenuation, if not solu- References erosion of physician contact as they be- tion, by building and testing a stepped 1. Tattersall RB. 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