Reviews/Commentaries/ADA Statements REVIEW ARTICLE

Incretin-Based Therapies for the Treatment of Type 2 : Evaluation of the Risks and Benefits

1 4 DANIEL J. DRUCKER, MD RICHARD M. BERGENSTAL, MD ure, weight gain, and, in some analyses, 2 3 STEVEN I. SHERMAN, MD ROBERT S. SHERWIN, MD increased mortality with modest benefit 3 5 FRED S. GORELICK, MD JOHN B. BUSE, MD, PHD on rates of myocardial infarction. This has led to a re-examination of treatment recommendations to minimize the risk ype 2 diabetes is a complex meta- currently available agents exhibit the ideal of cardiovascular morbidity and mortal- bolic disorder characterized by profile of exceptional -lowering ity (3,4) and specifically an interest in T hyperglycemia arising from a com- efficacy to safely achieve target levels of incretin-based therapies in this regard. bination of insufficient secretion glycemia in a broad range of patients. together with resistance to insulin action. Hence, highly efficacious agents that ex- Incretin-based therapies: The incidence and prevalence of type 2 hibit unimpeachable safety, excellent tol- mechanisms of action and benefits diabetes are rising steadily, fuelled in part erability, and ease of administration to The two most recently approved classes of by a concomitant increase in the world- ensure long-term adherence and that also therapeutic agents for the treatment of wide rates of obesity. As longitudinal clearly reduce common comorbidities type 2 diabetes, -like -1 studies of type 2 diabetes provide evi- and complications of diabetes are clearly (GLP-1) receptor (GLP-1R) agonists and dence linking improved glycemic control needed (Fig. 1). Furthermore, most pa- dipeptidyl peptidase-4 inhibitors (DPP- with a reduction in the rates of diabetes- tients require combination therapy to 4i), exert their actions through potentia- associated complications, there is consid- achieve effective control of their disease tion of incretin receptor signaling. erable interest in the therapy of type 2 (3). Recommended initial therapy gener- Incretins are gut-derived hormones, prin- diabetes (Fig. 1), with a focus on the de- ally includes comprehensive lifestyle cipally GLP-1 and glucose-dependent in- velopment and use of new agents that ex- management and patient education com- sulinotropic peptide (GIP), that are hibit improved efficacy and safety relative bined with metformin therapy. Although secreted at low basal levels in the fasting to current available medicines. metformin is widely accepted as the pre- state. Circulating levels increase rapidly Although the number of patients with ferred agent for the initial treatment of and transiently following food ingestion. type 2 diabetes that successfully achieve type 2 diabetes, there remains consider- As native GLP-1 displays a very short cir- target levels of A1C is steadily improving, able uncertainty and lack of consensus in culating half-life due to renal clearance a substantial number of subjects continue regard to choice of additional agents that and NH2-terminal degradation by the to fall short of acceptable treatment goals, need to be added to metformin to opti- enzyme DPP-4, degradation-resistant leaving them at high risk for development mize glycemic control. GLP-1R agonists have been developed. of diabetes-associated complications (1). Recent recommendations have high- Exendin-4, a GLP-1R agonist structurally More importantly, a large number of sub- lighted the use of insulin, sulfonylureas, related to the native gut peptide, was ap- jects with type 2 diabetes fail to achieve and thiazolidinediones as second-line proved for the treatment of type 2 diabe- target values for glucose, lipids, and blood therapies because of their proven efficacy tes in the U.S. in April 2005 and is pressure, with only 12.2% of patients in long-term outcome studies. Neverthe- currently administered as a subcutaneous meeting target values despite recent im- less, more recent studies involving in- injection (10 ␮g twice daily) for use as provements in therapeutic agents target- tensive use of these therapies in patients monotherapy in subjects not achieving ing hyperglycemia, dyslipidemia, and with clinical cardiovascular disease or adequate glycemic control on lifestyle hypertension (2). The development of multiple risk factors to achieve lower modification alone or one or more oral multiple new agents for the treatment of target glucose levels were associated agents. is an investigational type 2 diabetes has broadened the options with hypoglycemia, bone fractures, human acylated GLP-1R agonist ap- for patient-specific therapy. However, no hospitalization for congestive heart fail- proved in Europe that binds nonco- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● valently to albumin and exhibits a more From the 1Department of Medicine, Samuel Lunenfeld Research Institute, University of Toronto, Toronto, prolonged duration of action suitable for Ontario; 2The University of Texas M.D. Anderson Cancer Center, Houston, Texas; the 3Department of once daily administration. A longer- Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; the 4International acting microsphere preparation of ex- 5 Diabetes Center, Minneapolis, Minnesota; and the Division of Endocrinology, University of North enatide suitable for once weekly Carolina School of Medicine, Chapel Hill, North Carolina. Corresponding author: Daniel J. Drucker, [email protected]. administration, (once weekly), Received 20 August 2009 and accepted 17 October 2009. has also been studied in controlled clini- DOI: 10.2337/dc09-1499 cal trials and appears to be somewhat © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly more effective compared with exenatide cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. org/licenses/by-nc-nd/3.0/ for details. twice daily (5). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby Sitagliptin was the first DPP-4i ap- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. proved in the U.S. in October 2006. It See accompanying editorial, p. 453. exerts its glucoregulatory actions through

428 DIABETES CARE, VOLUME 33, NUMBER 2, FEBRUARY 2010 care.diabetesjournals.org Drucker and Associates

Figure 1—Relative comparison of properties exhibited by different classes of agents approved for the treatment of type 2 diabetes. CVD, cardio- vascular disease; TG, triglycerides; CHF, congestive heart failure. A1C reduction depends on starting A1C. prevention of incretin degradation, lead- gastric emptying and reduces food intake, and liraglutide therapy are nausea and ing to potentiation of GLP-1 and GIP ac- leading to weight loss in the majority of vomiting, which generally diminish over tion (6). Sitagliptin is administered as a treated subjects (8). The GLP-1R is ex- time (13). Analysis of the antidiabetic ac- single 100-mg daily tablet either as mono- pressed in cardiomyocytes and endothe- tions pursuant to GLP-1 administration therapy or in combination therapy with lial cells, and preclinical studies has demonstrated that activation of the oral antidiabetic agents. Sitagliptin is well demonstrate that GLP-1R activation is as- GLP-1R for 24 h provides more sustained tolerated and is not associated with nau- sociated with substantial cardioprotec- and potent control of glycemia relative to sea or vomiting as the levels of endoge- tion and reduced infarct size in shorter periods of GLP-1R agonism (16). nous intact GLP-1 achieved following experimental models of coronary artery In contrast, sustained GLP-1R activation DPP-4 inhibition are at the upper limit of ischemia (9,10). Limited evidence sug- may be associated with a modest reduc- the normal physiological range; hence, it gests that GLP-1 may also preserve ven- tion in control of postprandial glycemia is not sufficient to induce an aversive re- tricular function and improve outcomes (5,13), observations of interest to scien- sponse. Conversely, DPP-4i therapy is not in human subjects with heart failure or tists studying the link between postpran- associated with inhibition of gastric emp- myocardial infarction (11,12). Moreover, dial glucose and the development of tying or weight loss, and the available data both exenatide and liraglutide reduce cardiovascular morbidity and mortality. suggest that long-acting GLP-1R agonists blood pressure, body weight, and plasma As exenatide requires twice daily admin- achieve more potent control of glycemia, lipid profiles in subjects with type 2 dia- istration and does not provide 24-h relative to DPP-4i, due to more potent and betes (13), raising the hope that long- GLP-1R activation, there has been consid- sustained GLP-1R activation. Vildaglip- term treatment with these agents may erable interest in development of GLP-1R tin, a second DPP-4i, is approved in reduce the incidence of cardiovascular analogues with more prolonged durations Europe and other countries, while saxa- events. Intriguingly, the GLP-1 metabo- of action (Fig. 2) suitable for once-daily or gliptin has recently been approved in the lite, GLP-1 (9–36), also exerts cardiopro- once-weekly administration (17). Consis- U.S. and several other DPP-4i are under tective actions in preclinical studies tent with the notion that continuous regulatory review. through mechanisms independent of the GLP-1R activation is required for optimal GLP-1R agonists control blood glu- known GLP-1R (14); hence, ongoing re- glucoregulation, liraglutide administered cose through regulation of islet function, search is directed at understanding the once daily and exenatide administered principally with the stimulation of insulin complexity of incretin biology in the car- once weekly appear to be more potent and inhibition of glucagon secretion (7). diovascular system and the potential for glucose-lowering agents, relative to twice- Notably, these GLP-1R–dependent ac- incretin-based therapies to differentially daily exenatide (5,13). Furthermore, they tions are glucose dependent, thereby modulate cardioprotective signals in the seem to be associated with better tolera- minimizing the risk of hypoglycemia in diabetic heart and blood vessel in vivo bility and patient-reported outcomes as the absence of concomitant sulfonylurea (15). The principal treatment-related ad- well as trends toward greater benefit on therapy. GLP-1R activation also inhibits verse events associated with exenatide cardiovascular disease risk factors (Fig. care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 2, FEBRUARY 2010 429 Incretin therapies: risks and benefits

Figure 2—Comparison of features associated with exenatide twice daily versus the properties of the emerging class of long-acting GLP-1R agonists that achieve more prolonged and sustained GLP-1R activation. CVD, cardiovascular disease.

2). There are now over a dozen long- (with the exception of alcohol and smok- reported to the FDA in patients who pre- acting investigational GLP-1R agonists ing), although they have the theoretical viously used exenatide and similar cases being developed for the treatment of type potential to do so. Numerous animal but no deaths have been reported in pa- 2 diabetes (8). Several recent reviews have models for pancreatitis have been devel- tients treated with sitagliptin (19). A re- emphasized the mechanisms of action oped; however, drugs that are associated cent study used insurance records to and clinical results obtained in trials ex- with pancreatitis in humans rarely cause determine that the risk of pancreatitis for amining the efficacy of incretin-based disease in rodents. Whether these spe- subjects followed up to a year was 0.12% therapies (8,17). Herein we examine ad- cies-specific observations reflect differ- and 0.13% with sitagliptin and exenatide, verse events and safety concerns associ- ences in drug metabolism, pancreatitis respectively (20). These relative risks did ated with these agents. responses including inflammation, or the not differ from a control cohort treated fact that some drugs may act as sensitizers with metformin or glyburide. Data from Adverse events associated with GLP- and require other factors to cause disease, the manufacturer of liraglutide reported a 1R agonists remains unclear. low incidence of acute pancreatitis (0.8 Acute pancreatitis. Pancreatitis has Clinical data relating GLP-1R agonists cases/1,000 patient-years). Notably, anal- been reported as a rare side effect of ex- and DPP-4i to pancreatitis come from a ysis of pancreatitis in subjects with type 2 enatide therapy principally through post- limited number of case reports, the U.S. diabetes suggests that their risk is in- marketing surveillance. There are many Food and Drug Administration’s (FDA) creased threefold over nondiabetic sub- risk factors and predisposing causes for adverse event reporting system, and clin- jects (21). Since only a fraction of this risk acute pancreatitis, as well as over 200 ical trial records from pharmaceutical could be attributed to biliary pancreatitis, drugs linked to the development of acute companies. A summary of initial 30 cases it seems likely that other factors such as pancreatitis. The incidence of pancreatitis of individuals taking exenatide who de- obesity and hypertriglyceridemia might varies considerably among drugs, being veloped acute pancreatitis was published contribute to the increased risk in this relatively common for individuals taking in 2008 (18). The authors noted that in population. 6-mercaptopurine and azathioprine (2– least 90% of these subjects, there were Several experimental studies have ex- 5%), but very uncommon for steroids and other factors that could predispose the in- amined the effects of incretin-based thiazide diuretics. The severity of the dis- dividuals to pancreatitis. Rechallenge, a agents on the in animal models. ease also varies; pancreatitis induced by standard measure for assigning causality Koehler et al. (22) found no evidence of 6-mercaptopurine is often quite severe, in drug-induced pancreatitis, was per- pancreatitis in mice treated with the while that caused by cholinesterase inhib- formed in only three patients but associ- GLP-1R agonist exendin-4 alone and no itors is usually mild. There are only two ated with recurrence of symptoms in GLP-1R–dependent enhancement of circumstances in which the mechanism of each. However, the recurrence of symp- pancreatitis responses in the caerulein- drug-induced disease is understood, toms with rechallenge was reported to oc- hyperstimulation model. In contrast, drugs that cause hypertriglyceridemia cur only after weeks in some patients. In Nachnani et al. (23) detected histological (e.g., some HIV-protease inhibitors, es- most patients with drug-induced pancre- evidence for acinar inflammation, cell trogens, isotrentinoin) and drugs that are atitis, rechallenge usually causes disease drop-out and possible fibrosis and in- mitochondrial toxins. Drugs are not within days. Subsequently, hemorrhagic creased levels of serum lipase in Sprague- thought to cause chronic pancreatitis pancreatitis and several deaths have been Dawley rats treated with exendin-4 for 75

430 DIABETES CARE, VOLUME 33, NUMBER 2, FEBRUARY 2010 care.diabetesjournals.org Drucker and Associates days. A study by Matveyenko et al. (24) Medullary cancer. Medullary ported, and some typical histological examined the effects of sitagliptin in hu- thyroid carcinoma (MTC) is an uncom- features of human MTC are generally man islet amyloid polypeptide (HIP) mon neuroendocrine malignancy with an lacking. Mice develop spontaneous MTC transgenic diabetic rats. The investigators estimated U.S. annual incidence of fewer less frequently, and most animal models reported that one of eight HIP rats receiv- than 1,000 persons and a lifetime risk of in use are either transgenic or xenografts ing the drug developed acute pancreatitis development of 0.013% (26). When diag- of the well-characterized TT cell line. and noted extensive pancreatic ductal nosed early and still confined to the thy- Food intake links incretin secretion proliferation and metaplasia and accom- roid gland, the long-term survival of MTC with stimulation of secretion in panying fibrosis in three HIP rats treated is nearly 100% (27). About 25% of MTCs rodents, potentially via GLP-1 receptors with sitagliptin. Some of the histological occur as part of an inherited autosomal expressed on rodent MTC cell lines, and findings from the latter two studies were dominant syndrome, either multiple en- GLP-1 stimulates calcitonin release in ro- very similar, and reminiscence of changes docrine neoplasia type II or familial MTC, dents in vivo (33–35). Analysis of data was seen with chronic pancreatitis. The and virtually all familial tumors are reported at the 2 April 2009 FDA Advi- animal studies raise several confounding caused by inherited mutations in the RET sory Committee review of liraglutide re- issues, namely might there be differences proto-oncogene. Of sporadic MTCs, at vealed that preclinical toxicology studies in pancreatitis responses between least 40% are associated with somatic mu- with liraglutide reported C-cell hyperpla- GLP-1R agonists and DPP-4i in humans tations and RET, and prognosis is worse in sia and MTC with increasing exposure to versus rodents and in specific diabetic those mutated tumors. liraglutide. At the highest drug exposures, versus nondiabetic preclinical models? The histological precursors to MTC in MTC was reported in 14% of male and 6% Though the relevance of the HIP trans- the inherited syndromes are well de- of female Sprague-Dawley rats, which was genic rat model to human disease remains scribed, beginning with C-cell hyperpla- above the rates observed in untreated rat unclear, that study does suggest that sia, leading to nodular C-cell hyperplasia, controls. C-cell lesions were also reported DPP-4i might induce pancreatic metapla- and then eventually to MTC. However, to be more common with liraglutide in sia under specific experimental condi- among the sporadically occurring MTCs, CD-1 mice, albeit at much lower frequen- tions. In summary, the clinical and the role of this histological sequence is not cies; no C-cell lesions were described in experimental data linking GLP-1R ago- defined, and the exact distinction be- the cynomologous monkey. In contrast, nists and DPP-4i to pancreatitis are still tween neoplastic and non-neoplastic C- once-daily administration of exenatide in incomplete. More information is required cell hyperplasia is controversial (28,29). rodents is associated with a high fre- to allow one to determine whether these As a tumor derived from C-cells, MTCs quency of nodular C-cell lesions but no agents substantially increase the risk of generally secrete calcitonin, and high se- carcinomas were reported (36). In safety acute pancreatitis and whether such dis- rum levels of calcitonin (Ͼ100 pg/ml) are monitoring of multiple liraglutide clinical ease tends to be severe. However, patients nearly 100% specific for the presence of trials, many patients with undetectable receiving these medications will need to MTC (30,31). Nonetheless, the specificity calcitonin levels before initiation of inves- undergo continued surveillance for pan- of serum calcitonin concentrations be- tigational (liraglutide, placebo, or active creatitis and clinicians should carefully tween the upper end of the reference comparator) therapy were found to have exclude other causes of acute pancreatitis range and 100 pg/ml is considerably more levels that rose into the mid-reference when it occurs in subjects receiving these limited. Other etiologies of mild degrees normal range; rare patients developed drugs. Although the diagnosis of drug- of hypercalcitoninemia include lympho- mild hypercalcitoninemia during ther- induced pancreatitis would ideally be as- cytic thyroiditis, chronic renal insuffi- apy. Across the trials, six patients were sociated with confirmatory clinical data ciency, pancreatitis, hypercalcemia, found to have C-cell findings at thyroid- following drug rechallenge, physicians hypergastrinemia (of any etiology), and ectomy following therapy (36). Of these should exercise caution before consider- even the postprandial state (31,32). Stim- patients, four were in liraglutide treat- ing a trial of drug rechallenge. As GLP-1R ulation of calcitonin release with penta- ment arms, but three of these had elevated agonists may also affect smooth muscle infusion has long been used to calcitonin levels before initiation of treat- responses and may regulate cholangio- distinguish neoplastic from non- ment. The remaining two patients were in cyte function (25), their effects on the bil- neoplastic causes of mild hypercalci- the active comparator arms of trials, and iary tract and gallstone formation should toninemia; however, is no one had an elevated calcitonin level be- also be examined. longer available for human use in the fore treatment. This single patient had Issues linking these agents with pan- U.S., and the diagnostic accuracy of test- MTC and was treated with an active non- creatic metaplasia and chronic pancreati- ing with alternative stimulants such as GLP-1–based comparator; the patient tis, as now suggested by two experimental calcium infusion remains to be estab- had a markedly elevated calcitonin level studies, present a different challenge. lished (31). before initiating non-GLP-1–based com- Longer-term experimental studies using Animal models of MTC have limita- parator therapy. All of the remaining pa- different GLP-1R agonists and DPP-4i in tions in regard to the biology and epide- tients who underwent for several species and experimental models miology of human MTC. Rats develop hypercalcitoninemia were reported to of diabetes need to be undertaken to help spontaneous age-related C-cell lesions at have C-cell hyperplasia. According to the clarify the importance of these findings. remarkably high frequency, especially FDA briefing documents, no cases of C-cell Hence, monitoring of pancreatic function nodular C-cell hyperplasia. Sporadic lesions have been documented by histol- and pancreatic disease in humans treated MTC occurs in 0.5–1% of most rat species ogy in patients treated with exenatide. with GLP-1R agonists and DPP-4i in on- evaluated, with increased frequency in Several cases of papillary thyroid cancer going long-term prospective controlled males and with advancing age; spontane- have also been reported in the liraglutide clinical trials seems prudent. ous RET mutations have not been re- clinical development program; however, care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 2, FEBRUARY 2010 431 Incretin therapies: risks and benefits the small number of cases, the incidental risk of acute pancreatitis in humans and Cancer Research; is a consultant to Bayer, Cel- histopathologic identification of the le- might not affect the risk at all. The rele- gene, Exelixis, Eli Lilly, Oxigene, Plexxikon, sions, together with the lack of biological vance to humans of the pancreatic meta- and Semafore; is on a speaker’s bureau for plausibility, suggest that this is an inci- plasia observed with these agents in two Genzyme; and has received honoraria from dental finding not directly related to ther- of the rodent studies is unknown. Contin- Genzyme and Exelixis. R.S.S. has stock op- tions for Insulet; serves on the scientific advi- apy with GLP-1R agonists. ued clinical monitoring and more re- sory boards or as a consultant for , In summary, rodents exposed to lira- search are required to clarify the actions of Boehringer Ingelheim, Biodel, Johnson & glutide and exenatide develop C-cell le- GLP-1R agonists and DPP-4i on the nor- Johnson, MannKind, Medtronic, Merck, and sions at relatively high frequency, mal and diabetic exocrine pancreas. Novartis. although the currently available data sug- GLP-1R activation stimulates calcito- No other potential conflicts of interest rele- gest that rodent MTC may be specific to nin secretion and promotes the develop- vant to this article were reported. long-acting GLP-1R agonists, likely due ment of C-cell hyperplasia and medullary to sustained GLP-1R activation. Because thyroid cancer in rodents but not in mon- of the historic difficulty of distinguishing keys, and the actions of GLP-1R agonists References neoplastic and non-neoplastic forms of C- on human C-cells remain uncertain. Be- 1. Hoerger TJ, Segel JE, Gregg EW, Saaddine cell hyperplasia in both rodents and hu- cause of the rarity of medullary carci- JB. Is glycemic control improving in U.S. mans, the diagnostic significance of C-cell adults? Diabetes Care 2008;31:81–86 noma of the thyroid and the lack of 2. Cheung BM, Ong KL, Cherny SS, Sham hyperplasia is unclear. Minimal eleva- specificity of clinical markers, screening PC, Tso AW, Lam KS. Diabetes preva- tions of calcitonin levels are very nonspe- strategies, except in the setting of famil- lence and therapeutic target achievement cific, and available methods of dynamic ial syndromes, almost certainly would in the United States, 1999 to 2006. Am J testing add little to clarify the etiologies. be associated with an increase in mor- Med 2009;122:443–453 Given the extreme rarity of MTC in hu- bidity and perhaps mortality as a result 3. Nathan DM, Buse JB, Davidson MB, Fer- mans, the numbers of patients who would of false positives. rannini E, Holman RR, Sherwin R, Zin- need to be treated for 10 years to yield one Taken together, the available evi- man B, American Diabetes Association, additional case of MTC may be extremely dence supports the use of incretin-based European Association for Study of Diabe- high (35–55,000 if risk is doubled; 10– therapies for patients requiring effective tes. Medical management of hyperglyce- 15,000 if risk is quintupled). Moreover, mia in type 2 diabetes: a consensus control of glycemia and body weight algorithm for the initiation and adjust- the differences in rodent versus human while minimizing the risk of hypoglyce- ment of therapy: a consensus statement of C-cell biology with regard to responsivity mia. Ongoing scrutiny and further studies the American Diabetes Association and to GLP-1R activation raise important are required to clarify the potential signif- the European Association for the Study of questions about the suitability of mice icance of reports of pancreatic injury, in- Diabetes. Diabetes Care 2009;32:193– and rats as models for understanding the cluding pancreatitis and metaplasia, and 203 effects of GLP-1R agonists on human rodent medullary thyroid cancer for hu- 4. Bergenstal RM, Bailey CJ, Kendall DM. C-cells. man subjects treated with GLP-1R ago- Therapeutic decision-making in type 2 di- nists and DPP-4i. abetes: assessing the relative risks and Summary and conclusions benefits of glucose lowering medications. Incretin-based therapies provide new op- Am J Med. In press 5. Drucker DJ, Buse JB, Taylor K, Kendall tions for the treatment of type 2 diabetes Acknowledgments— R.M.B.’s employer, DM, Trautmann M, Zhuang D, Porter L, and enable intensification of therapy Park Nicollet Institute, has contracted with a DURATION-1 Study Group. Exenatide while controlling body weight through variety of companies since 2002 for his ser- once weekly versus twice daily for the mechanisms associated with a low rate of vices as an investigator or consultant (with no treatment of type 2 diabetes: a random- hypoglycemia. Investigational long- personal income from these services going di- ised, open-label, non-inferiority study. acting GLP-1R agonists require less fre- rectly to R.M.B.) including Abbott, Amylin, Lancet 2008;372:1240–1250 quent administration and appear to be Bayer, Eli Lilly, Hygieia, Intuity, LifeScan, 6. Hansotia T, Baggio LL, Delmeire D, Hinke more potent with respect to A1C reduc- MannKind, Medtronic, Novo Nordisk, Na- SA, Yamada Y, Tsukiyama K, Seino Y, tion than twice-daily exenatide or once- tional Institutes of Health, Pfizer, ResMed, Holst JJ, Schuit F, Drucker DJ. Double in- Roche, sanofi-aventis, United Health Group, daily sitagliptin with respect to A1C cretin receptor knockout (DIRKO) mice and Valeritas. RMB holds stock in Merck (fam- reveal an essential role for the enteroinsu- reduction. These long-acting GLP-1R ily inheritance). J.B.B. is a shareholder in In- lar axis in transducing the glucoregulatory agonists have considerable potential as sulet. His employer, the University of North actions of DPP-IV inhibitors. Diabetes antidiabetic therapies as they not only Carolina, has contracted with a variety of com- 2004;53:1326–1335 lower glucose as or more effectively than panies since 2005 for his services as an inves- 7. Drucker DJ. The biology of incretin hor- other noninsulin antihyperglycemic ther- tigator and/or consultant including Amylin, mones. Cell Metab 2006;3:153–165 apies, they do so in concert with weight Bristol-Myers Squibb, Eli Lilly, GlaxoSmith- 8. Lovshin JA, Drucker DJ. Incretin-based loss, improvement in cardiovascular dis- Kline, Hoffman-La Roche, Merck, Novartis, therapies for type 2 diabetes mellitus. Nat ease risk factors, and with very low risk of Novo Nordisk, Pfizer, sanofi-aventis, and Rev Endocrinol 2009;5:262–269 hypoglycemia. However, two safety is- Wyeth. D.J.D. is a consultant to Amylin, 9. Timmers L, Henriques JP, de Kleijn DP, sues have been raised—pancreatitis and GlaxoSmithKline, Eli Lilly, Merck, Novo Nor- Devries JH, Kemperman H, Steendijk P, disk, and Roche and receives research support Verlaan CW, Kerver M, Piek JJ, Doeven- medullary carcinoma of the thyroid. for preclinical studies from Arena, Merck, dans PA, Pasterkamp G, Hoefer IE. Ex- The relationship between the use of Metabolex, Novo Nordisk, and Roche. S.I.S. enatide reduces infarct size and improves incretin therapy and the development of receives research support from Amgen, cardiac function in a porcine model of pancreatitis remains unclear. These AstraZeneca, Eisai, Genzyme, the National ischemia and reperfusion injury. J Am agents may not substantially increase the Cancer Institute, and The V Foundation for Coll Cardiol 2009;53:501–510

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