2 Oral Therapy for Type 2 Diabetes Investigations • Innovation • Clinical ApplicationNew Frontiers and Advances inOral Therapy for Type 2 DiabetesFocus on DPP-4 Inhibition andIncretin-Based Therapy (IBT)Program ChairmanCharles Faiman, MD, FRCPC,MACEPast ChairmanConsultant StaffDepartment of Endocrinology, Diabetes and MetabolismCleveland Clinic Foundation
3 Welcome and Program Overview CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Bristol-Myers Squibb and AstraZeneca Partnership Faculty disclosures: Listed in program syllabus
4 Program Faculty Program Chairman Alexander Turchin, MD, MS Charles Faiman, MD, FRCPC,MACEPast ChairmanConsultant StaffDepartment of Endocrinology, Diabetesand MetabolismCleveland Clinic FoundationSamir Malkani, MDDirector, Adult Diabetes Clinic, University CampusUMass Memorial Medical Center Clinical Associate Professor of MedicineUniversity of Massachusetts MedicalSchoolUMASS Memorial Medical CenterWorcester, MAAlexander Turchin, MD, MSAssistant ProfessorHarvard Medical SchoolBrigham and Women's HospitalBoston, MADerek LeRoith, MD, PhD, FACPChief, Division of Endocrinology, Diabetes and Bone DiseaseDirector, Metabolism Institute,Mount Sinai School of MedicineNew York, NY
5 Type 2 Diabetes 2010: New Frontiers New Frontiers and Advances inOral Therapy for Type 2 DiabetesType 2 Diabetes 2010: New FrontiersProgram ChairmanCharles Faiman, MD, FRCPC,MACEPast ChairmanConsultant StaffDepartment of Endocrinology, Diabetes and MetabolismCleveland Clinic Foundation
6 Number of People with Diabetes (20-79 years) 2010 and 2030Country/Territory2010 MillionsIndia50.8China43.2United States26.8Russian Federation9.6Brazil7.6Germany7.5Pakistan7.1JapanIndonesia7.0Mexico6.8Country/Territory2030 MillionsIndia87.0China62.6United States36.0Pakistan13.8Brazil12.7Indonesia12.0Mexico11.9Bangladesh10.4Russian Federation10.3Egypt8.6IDF Diabetes Atlas, 4th ed. International Diabetes Federation, 2009
7 At a Glance: World At a Glance 2010 2030 Total world population (billions)7.08.4Adult population (20-79 yrs, billions)4.35.6Diabetes (20-79 Years)Global prevalence (%)6.67.8Comparative prevalence (%)6.47.7Number of people with diabetes (millions)285438IGT (20-79 years)7.9Number of people with IGT (millions)344472
8 Number of People with Diabetes by Age Group, 2010 and 2030 Millions
9 Number of People with Impaired Glucose Tolerance by Age Group, 2010 and 2030 Millions
10 North America and Caribbean Region At a Glance20102030Total population (millions)477555Adult population (20-79 yrs, millions)320390Diabetes (20-79 Years)Regional prevalence (%)11.713.6Comparative prevalence (%)10.212.1Number of people with diabetes (millions)37.453.2IGT (20-79 years)11.412.610.411.6Number of people with IGT (millions)36.649.1
11 North America and Caribbean Region At a Glance20102030Type 1 diabetes (0-14 years)Number of children with type 1 diabetes (thousands)96.7Number of newly-diagnosed cases per year (thousands)14.7Diabetes mortality (20-79 years)Number of deaths, male (thousands)141.0Number of deaths, female (thousands)172.2Health expenditure for diabetes (USD)Total health expenditure, R=2 (billions)214.2288.7
12 Highest Prevalence Diabetes Pacific Island - 43%Arab Gulf States (U.A.E.) - 19%U.S.A. / Canada- Natives- Blacks / Hispanics
13 United States $198 billion World $376 billion Costs for DM Care: 2010United States $198 billionWorld $376 billion
16 Types Of Diabetes Type 1 (Juvenile-Onset) Type 2 (Adult-Onset) Other types including:- Gestational diabetes- MODY (maturity onset diabetes of the young)- LADA (latent auto-immune diabetes of adults)- Others
17 Auto-immune destruction of insulin-producing β-cells in the pancreas Cause of Type 1 DMAuto-immune destruction ofinsulin-producing β-cells inthe pancreas
18 Cause of Type 2 DM Insulin resistance (genetics) - aggravated by obesity- aggravated by lack of exercise“Exhaustion” of insulin-producing β-cells
19 Major Metabolic Defects in Type 2 Diabetes Peripheral insulin resistance in muscle and fatDecreased pancreatic insulin secretionIncreased hepatic glucose outputThe endocrine characteristics of type 2 diabetes include peripheral insulin resistance in muscle and fat tissue, decreased pancreatic insulin secretion, and increased hepatic glucose output.Haffner SM, et al. Diabetes Care, 1999
20 Development and Progression of Type 2 Diabetes*3/27/2017 9:33 PMNGT ® Insulin ® IGT/ IFG ® Type 2 Diabetes ResistancePostprandial glucoseGlucoseFasting glucose-10-551015202530Development and Progression of Type 2 DiabetesSpeaker notesThis conceptual diagram shows a recently proposed paradigm on the development and progression of pathophysiology in type 2 diabetes.The horizontal axis in the figure shows the years from diagnosis of diabetes.Insulin resistance rises during disease development and continues to rise during impaired glucose tolerance (IGT). Over time, insulin resistance remains stable during the progression of type 2 diabetes.1,2The insulin secretion rate increases, to compensate for the decrease in insulin effectiveness due to insulin resistance. This increase is often misperceived as an increase in beta-cell function. Thus, beta-cell function can decrease even as insulin secretion increases. Over time, beta-cell compensatory function deteriorates and insulin secretion decreases. Beta-cell function progressively fails.Initially, fasting glucose is maintained in near-normal ranges. The pancreatic beta cells compensate by increasing insulin levels, leading to hyperinsulinemia. This compensation keeps glucose levels normalized for a time, but as beta cells begin to fail, IGT develops with mild postprandial hyperglycemia. As the disease progresses, the beta cells continue to fail, resulting in higher postprandial glucose levels. With further loss of insulin secretory capacity, fasting glucose and hepatic glucose production increase.Once beta cells cannot secrete sufficient insulin to maintain normal glycemia at the fasting or postprandial stage, type 2 diabetes (hyperglycemia) becomes evident.Insulin resistance and beta-cell dysfunction are established well before type 2 diabetes is diagnosed.1,3Relative ActivityPurpose:To address the common misconception that an increase in insulin secretion (hyperinsulinemia) connotes an improvement in beta-cell function.Takeaway:Both insulin resistance and beta-cell dysfunction start early–and well before diabetes isdiagnosed–leading to rises in fasting and postprandial glucose levels.Insulin resistance —hepatic and peripheralInsulin levelBeta-cell function–10–551015202530Years from Diabetes Diagnosis*Conceptual representation.NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose.Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, 2006.; and Ramlo-Halsted et al. Prim Care. 1999;26:771–789.References1. Ferrannini E. Symposium: When does hyperglycemia become diabetes? Impaired β-cell function. Presentation at 65th ADA in Washington, DC, Available at Accessed October 2006.2. Ramlo-Halsted BA, Edelman SV. The natural history of type 2 diabetes. Implications for clinical practice. Prim Care. 1999;26:771–789.3. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia. 2003;46:3–19.
21 Functional Defects in ß-Cells in the Development of Diabetes Progressive decrease in b-cell insulin secretion in response to nutrientsFirst manifested as a decrease in early or acute insulin secretion (decreased first phase insulin secretion)Loss of normal minute-by-minute pulsatile insulin secretion and daily ultradian rhythm of secretionDecreases in insulin processing with increased proinsulin:insulin ratioFunctional Defects in b-Cells in the Development of DiabetesSeveral functional defects in b-cells insulin secretion occur prior to the onset of diabetes.First, there is a decrease in early or acute insulin secretion following meals or a glucose challenge.There is a disruption in the normal pulsatile insulin secretion and the ultradian variation in serum insulin levels. Insulin is secreted in a pulsatile manner over short time periods. There is also a variation in the amount of insulin secreted during the day, due to factors related to diet, changes in counter regulatory hormones, and other factors.The increased demand for insulin could cause a decrease in the time insulin is available to processing machinery, resulting in decreased C-peptide cleavage and an increase in the proinsulin/insulin ratio.
22 Type 2 Diabetes: Pathogenesis in a Nutshell (cont.) Type 2 diabetes has been considered a PROGRESSIVE disease-cell dysfunction first leads to impaired glucose tolerance, which in some individuals progresses to type 2 diabetes-cell dysfunction starts long before blood glucose rises and worsens after diabetes developsHyperglycemia may cause additional defects in insulin secretion and insulin action (glucotoxicity)C (core) represents a core slide in this curriculum.Type 2 Diabetes: Pathogenesis in a Nutshell (cont.)Early in the natural history of type 2 diabetes, insulin resistance becomes established, but glucose tolerance remains normal because of an ability of the b-cells to compensate for insulin needs. As a result of several poorly understood mechanisms, b-cells lose their ability to compensate, leading to impaired glucose tolerance. Many (but not all) individuals continue to lose insulin secretory capacity, or have increases in insulin resistance and “fall further off the curve,” resulting in type 2 diabetes.Thus, type 2 diabetes is a progressive disease occurring in a gradual succession of stages of increasing glucose intolerance and insulin resistance.The hyperglycemia associated with type 2 diabetes can lead to additional effects on insulin secretion and insulin action by way of glucotoxicity. Glucotoxicity refers to the decreased sensitization of b-cells to the presence of glucose and the deleterious effects of accumulated fatty acids and their metabolic products on b-cells.Although some free fatty acids are needed for normal insulin secretion, prolonged increases result in b-cell dysfunction with decreased insulin secretion and impaired conversion of proinsulin to insulin. Buchanan TA. Clin Ther. 2003;25(suppl B):B32-B46.DeFronzo RA. Med Clin North Am. 2004;88:Kahn SE. J Clin Endocrinol Metab. 2001;86:Buchanan TA. Clin Ther. 2003;25(suppl B):B32-B46.DeFronzo RA. Med Clin North Am. 2004;88:Kahn SE. J Clin Endocrinol Metab. 2001;86:
23 UKPDS: Progressive Deterioration in Glycemic Control Over Time A1C9100880Median A1C (%)60b-cell function (%)7Conventional40Intensive206C (core) represents a core slide in this curriculum.UKPDS: Progressive Deterioration in Glycemic Control Over TimeThis slide demonstrates the progressive nature of hyperglycemia despite treatment in patients with established type 2 diabetes. It also demonstrates the loss of b-cell function as glucose levels rise.In the United Kingdom Prospective Diabetes Study (UKPDS), 3,867 subjects with symptomatic type 2 diabetes were randomized at entry to one of two treatment arms—conventional treatment with dietary therapy alone or intensive treatment with sulfonylurea or insulin.The glycemic goal of conventional treatment was fasting plasma glucose (FPG) <15 mmol/L (<270 mg/dL). Patients attended UKPDS clinics every 3 months; patients who eventually failed conventional diet treatment (FPG >15 mmol/L, >270 mg/dL) were subsequently randomized to one of the intensive treatment arms.The aim of the intensive treatment groups was FPG <6 mmol/L (<180 mg/dL). Although levels of A1C initially dropped in patients in the intensive treatment arm, eventually A1C deteriorated over time in all treatment groups, albeit the levels were significantly lower in the intensive treatment group compared with the conventional group.The figure on the right shows the change in b-cell function assessed by homeostasis model assessment (HOMA) measurements over time. The dashed line extrapolated from the plotted data suggests that deterioration in b-cell function may have begun from 10 to 12 years prior to the diagnosis of diabetes.Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25.UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:3691215-12-10-8-6-4-2246Time from randomization (y)Years from diagnosisHolman RR. Diabetes Res Clin Pract ;40(suppl):S21-S25.UKPDS Group. Lancet. 1998;352:
24 Mechanisms Responsible for Changes in Insulin Levels Normal b-cell adaptation to insulin resistanceIncreased secretion from each cellIncreased b-cell massImpaired b-cell adaptation in type 2 diabetes result ofDecreased secretion from each cellReduced b-cell massC (core) represents a core slide in this curriculum.Mechanisms Responsible for Changes in b-Cell FunctionNormal b-cell adaptation to insulin resistance can occur through increased secretion from each b-cell and/or an increase in the b-cell mass.Type 2 diabetes results from an inadequate insulin secretion from each b-cell or an inadequate b-cell mass for the levels of prevailing insulin sensitivity.This relates back to the concept of adaptation to acute or chronic changes in insulin sensitivity. An individual can have a reduced insulin secretion or reduced b-cell mass but can have normal glucose levels. These individuals have sufficient insulin sensitivity such that their insulin secretion is adequate.
25 Potential Causes for Declining Insulin Secretion GlucotoxicityLipotoxicityb-cellApoptosisInsulin SecretionPrentki M et al. Diabetes. 2002;51(suppl 3):s405-s413.
26 Abnormalities of α-Cell Function in Type 2 Diabetes Elevated glucagon levelsLoss of insulin-induced suppressionLoss of glucose-induced suppressionIncreased stimulatory effect of arginineDunning BE et al. Diabetologia. 2005;48:
27 Summary Islets can adapt to insulin resistance Failure of adaptation results in impaired glucose tolerance and eventually, type 2 diabetesFailure appears to be due to reduced insulin secretion per islet and a reduction in the number of isletsIncreased glucagon contributes to hyperglycemia in type 2 diabetes
28 Global Cardiometabolic Risk* We have understood for decades the roles of ‘classical’ risk factors – elevated LDL-cholesterol, hypertension, elevated blood glucose and smoking – in the pathogenesis of cardiovascular disease. More recent research is continuing to define the contribution of emerging risk factors to the risk of developing type 2 diabetes and cardiovascular disease, particularly in the setting of insulin resistance. Abdominal obesity is associated with multiple cardiometabolic risk factors such as atherogenic elevated blood glucose (hypertriglyceridaemia and low HDL-cholesterol), elevated blood glucose and inflammation, which are major drivers of cardiovascular disease and type 2 diabetes. In addition, atherosclerosis is increasingly regarded as an inflammatory condition.* working definitionGelfand EV et al, 2006; Vasudevan AR et al, 2005Gelfand EV et al. Rimonabant: a cannabinoid receptor type 1 blocker for management of multiple cardiometabolic risk factors. J Am Coll Cardiol 2006:47(10):1919–26.Vasudevan AR, Ballantyne C et al, Cardiometabolic risk assessment: an approach to the prevention of cardiovascular disease and diabetes mellitus. Clin Cornerstone 2005; 7(2-3):7–16.
29 Differentiating Type 1 Vs. Type 2 DM Presentation with ketoacidosisAge at onsetTesting for C-peptide levelsTesting for antibodies- GAD-65- IA2- Insulin- Islet-cellTrial of oral agents
30 Other Kinds of Diabetes LADA (latent autoimmune disease of adults)MODY (maturity-onset diabetes of the young)Gestational diabetesStress-inducedPost-transplant
31 Complications of Diabetes Small Blood Vessel- eye (retina) – blindness- kidney failure – dialysisLarge Blood Vessel- heart attacks- strokes- peripheral vascular : amputationsNeuropathyErectile dysfunction (both vascular and nerve damage)
32 Avoiding Complications - I Diet / exercise‘Girth’ controlSugar controlLipid (cholesterol) controlBlood pressure control
33 Avoiding Complications - II Self-monitoring glucoseVisits to PCP – endocrinologist: goalsEye examsPodiatry examsPeriodic blood / urine lab testing
37 ConclusionsNo specific drugs or regimens seem to have a necessarily adverse effect on cardiovascular event rates despite expressed concerns about certain drugsA1C goal should be individualized<6.5% if healthy, and short duration diabetes and long life expectancy<7% average patient<7.5-8% medically complex, clinical cardiovascular disease, failed to achieve lower target with lifestyle, metformin and adequate doses of insulinThe future: continuing surveillance of newer classes of drugs for adverse – or beneficial – cardiovascular effects
38 Future Rx DM2 Longer acting GLP-1 analogues More DPP-IV inhibitors More TZD’sNewer drug classes : e.g., SGLT2-inhibitorsNOTE : FDA requires longer duration studies in DM2 to better understand risk / benefit before approval
39 Prevention of DM TYPE 1 - Immune modulation TYPE 2 - Diet/exercise - Drugs: MetforminTZD’sGlucosidase inhibitorsOthers?
40 Today’s Program Evolving science & medicine of incretin- based therapy Options, strategies and combinationsPractice – focused overviewT2DM Rx in 2010 – where are we?
42 Investigations • Innovation • Clinical Application The Current Armamentarium of Oral Agents for Type 2 Diabetes Mellitus—Sequencing Oral TherapyWhen and Where Do We Start? When Do We Add? How Do The Guidelines Guide Us?Samir Malkani, MDDirector, Adult Diabetes Clinic, University CampusUMass Memorial Medical Center Clinical Associate Professor of MedicineUniversity of Massachusetts Medical SchoolUMASS Memorial Medical CenterWorcester, MA
43 Number and Percentage of U. S Number and Percentage of U.S. Population with Diagnosed Diabetes,MethodologyNumber and percent of the U.S. population with diagnosed diabetes were obtained from the National Health Interview Survey (NHIS, available at of the National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC) for years. Conducted continuously since 1957, the NHIS is a health survey of the civilian, noninstitutionalized population of the United States. The survey provides information on the health of the United States population, including information on the prevalence and incidence of disease, the extent of disability, and the utilization of health care services. The multistage probability design of the survey has been described elsewhere (1,2). Estimates for years were obtained from published data (3) and estimates from 1980 forward were derived directly from the NHIS survey data.References1. Massey JT, Moore TF, Parsons VL, Tadros W. Design and estimation for the National Health Interview Survey, Hyattsville, MD: National Center for Health Statistics. Vital and Health Statistics 1989;2(110).2. Botman SL, Moore TF, Moriarity CL, Parsons VL. Design and estimation for the National Health Interview Survey, 1995–2004. National Center for Health Statistics. Vital and Health Statistics 2000;2(130).3. Harris MI: Prevalence of noninsulin-dependent diabetes and impaired glucose tolerance. Chapter VI in Diabetes in America, Harris MI, Hamman RF, eds. NIH publ. no , 1985.CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at
45 U.S. Population with Diagnosed Diabetes, 1995-2008
46 U.S. Population with Diagnosed Diabetes, 1995-2008 2001
47 U.S. Population with Diagnosed Diabetes, 1995-2008
48 U.S. Population with Diagnosed Diabetes, 1995-2008 Too fatToo thin
49 Natural History of Type 2 Diabetes Insulin resistance100200300–10–551015202530Relative -cell function (%)At risk fordiabetesInsulin outputBeta-cell failureYears of diabetes50100200300Glucose (mg/dL)Post-meal glucoseFasting glucoseDiabetes
50 The Importance of ß-Cell Failure in the Development and Progression of Type 2 Diabetes Steven E KahnFIG. 7. Model for the relationship between b cell dysfunction and deterioration of glucose tolerance. As b cell function declines, glucose tolerance deteriorates so that the criteria for impaired fasting glucose and/or impaired glucose tolerance are reached.Subsequently, with a further loss of b cell function, diabetes developsbased on either or both the fasting and 2-h glucose levelsThe Journal of Clinical Endocrinology & Metabolism, September 2001, 86(9):4047–4058
52 Targets for Glycemia Control Recommendations for glycemia control from the American Diabetes Association and the American Association of Clinical Endocrinologists. *The glycated hemoglobin (HbA1c) goal for patients in general is less than 7.0%, while the HbA1c goal for selected patients is as close to normal (<6.0%) as possible without significant hypoglycemia. Sources: American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61; ACE/AACE Diabetes Road Map Task Force. Endocr Pract. 2007;13:
53 Dietary TherapyBest implemented by a registered dietitian experienced in behavioral modificationIndividualized diet based on weight, lipids, lifestyleTotal carbohydrates 45-65% of daily energy intakeAvoid sugars, increase complex carbohydrates, 50 gram of fiber dailyFat <30% calories (<7% saturated)Dietary therapy alone can reduce A1C by % or moreDiabetes Care, (Supp 1) S11-S48
54 Physical ActivityPerform at least 150 minutes of moderate-intensity* aerobic physical activity per weekIn the absence of contraindications, perform resistance training three times a weekDIAD study JAMA 2009 did not show any benefit of screening asymptomatic individuals with normal EKG* 50-70% of max heart rateDiabetes Care, (Supp 1) S11-S48
55 Patient Education in Diabetes Mellitus: 10 Content Areas Promoting Careprior to and duringPregnancyDiabetesDiseaseProcessIntegratingPsychosocialAdjustmentTo Daily LivingNutritionalManagementGoal setting forHealth &Daily LivingDiabetes Self-ManagementEducationPhysicalActivityPreventing,Detecting & TreatingChronic ComplicationsPreventing,Detecting & TreatingAcute ComplicationsUtilizingMedicationMonitoringBlood GlucoseFunnell et. al. Diabetes Care 2010:33 (Suppl1) S89-96
56 Type 2 Diabetes Medication Choices Experience and Potency RouteYearEfficacy as monotherapy: % in HgbA1cInsulins.c.19212.5SulfonylureasOral19461.5Glinides1997Metformin1995-glucosidase inhibitorsTZDs1999GLP analogue20050.6DPP-IV Inhibitors2006Amylin analogueColesevelam20080.5Bromocriptine mesylate2009
57 Type 2 Diabetes Medication Choices Experience and Potency RouteYearEfficacy as monotherapy: % in HgbA1cInsulins.c.19212.5SulfonylureasOral19461.5Glinides1997Metformin1995-glucosidase inhibitorsTZDs1999GLP analogue20050.6DPP-IV Inhibitors2006Amylin analogueColesevelam20080.5Bromocriptine mesylate2009
58 Mechanisms of Action of Pharmacologic Agents for Diabetes Improving Outcomes in Patients With Type 2 Diabetes Mellitus: Practical Solutions for Clinical ChallengesJames R. Gavin, III, MD, PhD; Mark W. Stolar, MD; Jeffrey S. Freeman, DO; Craig W. Spellman, DO, PhDJAOA • Vol 110 • No 5suppl6 • May 2010 • 2-14
59 Oral Medications for Type 2 Diabetes DrugInitial DoseMaximum DoseUsual DoseBiguanideMetformin500 mg bid2550 mg/dmg bidMetformin XR500 mg/d2000 mg/dmg/dSulfonylureaGlimepiride1-2 mg/d8 mg/d4 mg/dGlipizide2.5-5 mg/d40 mg/d10-20 mg/dGlipizide SR20 mg/d5-20 mg/dGlyburide5-10 mg/dGlyburide Micronizedmg/d12 mg/d3-12 mg/dThiazolidinedionePioglitazone15-30 mg/d45 mg/d15-45 mg/dRosiglitazone4-8 mg/da-Glucosidase inhibitorAcarbose25 mg tid100 mg tidmg tidMiglitolMetiglinideRepaglinide0.5 mg before meals4 mg before meals0.5-4 mg before mealsNateglinidemg tid before meals120 mg tid before mealsDPP4 InhibitorSitagliptin100 mg/dSaxagliptin2.5 mg/d5 mg/dBile Acid SequestrantsColesevelam375 mg/dayAdapted from: Annals of Internal Medicine, March 2010 “In the Clinic”
60 Type 2 Diabetes Medication Choices and Potency Higher baseline A1C levels predict greater drop in A1CShorter duration of diabetes predicts greater drop in A1C with any oral agentAll oral agents require presence of some endogenous b cell function, as they work by either increasing insulin sensitivity or augmenting b cell insulin releasePractical Tips!Sherifali et.al. Diabetes Care. 2010; 33:
61 Percentage of Individuals with A1C>7% NHANES surveys Hoerger TJ et. al. Diabetes Care. 2008; 31:81-86
63 Metformin - Drug Profile AdvantagesNo hypoglycemiaWeight lossCardiovascular benefitReduces LDL-C (approx 10 mg/dL), reduces TGDisadvantagesDiarrhea is commonContraindicated in renal impairment, liver failure, advanced cardiac failureRisk of lactic acidosis not increased in meta-analyses and systematic reviewsConcomitant use with other drugsCan be used as monotherapy and with all classes including insulin
64 Sulfonylureas - Drug Profile AdvantagesPotent glucose lowering effectFavorable adverse effect profileDisadvantagesHypoglycemia, more with GlyburideGlyburide contraindicated in renal impairment?Glyburide impairs ischemic preconditioning in heart (UKPDS did not reveal increased cardiac risk)Concomitant use with other drugsCan be used as monotherapy and with all classes including insulin
65 Repaglinide and Nateglinide: Drug Profiles AdvantagesLess hypoglycemia than sulfonylureasFavorable adverse effect profileDisadvantagesLess potent than sulfonylureas; target mainly post-prandial glucoseNateglinide less potent than RepaglinideConcomitant use with other drugsCan be used with all classes including insulin
66 Concomitant use with other drugs TZDs - Drug ProfileAdvantagesNo hypoglycemiaMay be useful in nonalcoholic fatty liver diseaseDisadvantagesIncreased fracture riskWeight gainEdema and exacerbation of CHF Rosiglitazone increases LDL-C (10mg/dL), TG (15-50mg/dL) and possible increase in MIConcomitant use with other drugsCan be used with other classes including insulin. Increased fluid retention and weight gain with insulin
67 Alpha Glucosidase Inhibitor (AGI) - Drug Profile AdvantagesNo hypoglycemiaWeight neutralDisadvantagesTargets only postprandial glucoseGI side effectsConcomitant use with other drugsCan be used as monotherapy and with all classes including insulin
68 DPP4 Inhibitors – Drug Profile AdvantagesWeight neutralFavorable adverse effect profileNo hypoglycemiaDisadvantagesLimited track recordNasopharyngitis, upper respiratory infectionsRare pancreatitisConcomitant use with other drugsCan be used as monotherapy and with SU, TZD, metformin (some have been studied with insulin)
69 Colesevelam - Drug Profile AdvantagesNo hypoglycemiaReduces LDL-C (approx 10 mg/dL),DisadvantagesConstipation is commonIncrease in triglyceridesMalabsorption of fat soluble vitaminsConcomitant use with other drugsCan be used as combination therapy with metormin
71 ADA/EASD: Considerations for the Guidelines Use of information from clinical trials that address the efficacy and safety of different modalities of treatmentPaucity of high quality evidence was an impedimentClinical judgment of the panel participantsExtrapolation of UKPDS data that glucose lowering of drugs (metformin, sulfonylureas, insulin) predicted decrease in complications.Nonglycemic effects of medication, such as effect on CV risk, lipids, hypertension or insulin resistanceSafety, side effects, ease of use and expense
72 ADA Algorithm for Management of Diabetes Diabetes Care Tier 1: Well-validated core therapiesAt diagnosis:Lifestyle+MetforminLifestyle+Metformin+Basal InsulinLifestyle+Metformin+Intensive insulinLifestyle+Metformin+SulfonylureaStep 1Step 2Step 3Tier 2: less well-validatedtherapiesLifestyle+Metformin+PioglitazoneSulfonylureaLifestyle+Metformin+Pioglitazone(No hypoglycemia, edema,CHF, bone loss)*Useful when hypoglycemia is to be avoidedLifestyle+Metformin+GLP1(No hypoglycemia, wt loss,Nausea/vomiting)Lifestyle+Metformin+Basal InsulinAmylin agonists, GlinidesDPP-4 inhibitors may be appropriate in selected patients
73 ReviewAnnals of Internal MedicineSystematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes MellitusShari Bolen, MD, MPH; Leonard Feldman, MD; Jason Vassy, MD, MPH; Lisa Wilson, BS, ScM; Hsin-Chieh Yeh, PhD;Spyridon Marinopoulos, MD, MBA; Crystal Wiley, MD, MPH; Elizabeth Selvin, PhD; Renee Wilson, MS; Eric B. Bass, MD, MPH; and Frederick L. Brancati, MD, MHSBackground: As newer oral diabetes agents continue to emerge on the market, comparative evidence is urgently required to guide appropriate therapy.Purpose: To summarize the English-language literature on the benefits and harms of oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and -glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus.Conclusions: Compared with newer, more expensive agents (thiazolidinediones, aglucosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points.Ann Intern Med. 2007;147:
74 ReviewAnnals of Internal MedicineSystematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes MellitusShari Bolen, MD, MPH; Leonard Feldman, MD; Jason Vassy, MD, MPH; Lisa Wilson, BS, ScM; Hsin-Chieh Yeh, PhD;Spyridon Marinopoulos, MD, MBA; Crystal Wiley, MD, MPH; Elizabeth Selvin, PhD; Renee Wilson, MS; Eric B. Bass, MD, MPH; and Frederick L. Brancati, MD, MHSBackground: As newer oral diabetes agents continue to emerge on the market, comparative evidence is urgently required to guide appropriate therapy.Purpose: To summarize the English-language literature on the benefits and harms of oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and -glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus.Conclusions: Compared with newer, more expensive agents (thiazolidinediones, aglucosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points.Ann Intern Med. 2007;147:
75 Type 2 Diabetes: Assessing the Relative Risks and Benefits of Glucose-lowering MedicationsRichard M. Bergenstal, MD, Clifford J. Bailey, PhD David M. Kendall, MDInternational Diabetes Center, Minneapolis, Minn; Diabetes Research, Life and Health Sciences, Aston University, Birmingham, UK.The American Journal of Medicine (2010) 123, 374.Figure 4 Events per 1000 patient-years for representative endpoints. Black bars indicate excess risk of events in diabetes patients relative to nondiabetic subjects;19,75,85,86 gray bars indicate excess risk of events in patients treated with specific glucose- lowering medications relative to diabetic patients on other agents;2,25,41,54,60,61,74 and white bars indicate the decreased risk of events in patients undergoing intensive glucose control policies. Foley RN et al. J Am Soc Nephrol. 2005;16(2): ; b = 19Haffner SM et al. N Engl J Med.1998;339(4) ; c = 75Noel RA et al. Diabetes Care. 2009;32(5): ;d = 86Trautner C et al. Diabetes Care. 1997;20(7): ; e = 60,61HamptonT. JAMA. 2007;297(15):1645 and Meier C et al. Arch Intern Med. 2008;168(8): ; f = 41Lago RM et al. Lancet. 2007;370(9593): ; g = 25Patel A et al. N Engl J Med. 2008;358(24): ; h = 2Nissen SE, Wolski K. N Engl J Med. 2007;356(24) ; i = 54Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2006; j = 74Dore DD et al.
76 Type 2 Diabetes: Assessing the Relative Risks and Benefits of Glucose-lowering Medications Richard M. Bergenstal, MD, Clifford J. Bailey, PhD David M. Kendall, MD International Diabetes Center, Minneapolis, Minn; Diabetes Research, Life and Health Sciences, Aston University, Birmingham, UK.Glucose-lowering medications have a favorable risk-benefit profileThe most common adverse event is hypoglycemia, particularly among patients receiving sulfonylureas or insulin.Metformin-associated lactic acidosis, exenatide-associated pancreatitis, and sitagliptin-associated hypersensitivity reactions appear to be rare.Increased risks of congestive heart failure and bone fractures in thiazolidinedione-treated patients, and reports of increased cardiovascular events in rosiglitazone-treated patients remain an issue.
77 Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy Steven E. Kahn, M.B., Ch.B., Steven M. Haffner, M.D., Mark A. Heise, Ph.D., William H. Herman, M.D., M.P.H., Rury R. Holman, F.R.C.P., Nigel P. Jones, M.A., Barbara G. Kravitz, M.S., John M. Lachin, Sc.D., M. Colleen O’Neill, B.Sc., Bernard Zinman, M.D., F.R.C.P.C., and Giancarlo Viberti, M.D., F.R.C.P., for the ADOPT Study Group *40Hazard ratio (95% CI)Rosiglitazone vs. metformin, 0.68 (0.55–0.85); P<0.001Rosiglitazone vs. glyburide, 0.37 (0.30–0.45); P<0.001Glyburide3020Cumulative Incidence of Monotherapy FailureMetforminRosiglitazone10YearsRosiglitazone139312071078957844324Metformin139712051076950818311Glyburide13371114958781617218Figure 2. Kaplan–Meier Estimates of the Cumulative Incidence of Monotherapy Failure at 5 Years.Treatment was considered to have failed if a patient had a confirmed or adjudicated level of fasting plasma glucose of more than 180 mg per deciliter. Risk reduction is listed for comparisons of pairwise groups from a baseline covariateadjusted Cox proportionalhazards model. Gray’s estimates of cumulative incidence adjusted for all deaths were smaller than Kaplan–Meier estimates of treatment failure: 10% in the rosiglitazone group, 15% in the metformin group, and 25% in the glyburide group. I bars indicate 95% CIs.N Engl J Med 2006;355:242743
79 AACE/ACE: Considerations for the Guidelines Minimizing risk and severity of hypoglycemiaMinimizing weight gainInclusion of all major classes of FDA-approved glycemic medicationsSelection of therapy stratified by hemoglobin A1C (A1C) and based on documented A1C lowering potentialConsideration of both fasting and postprandial glucose levels as end pointsConsideration of total cost of therapy to individual and society- includes cost of medication, glucose monitoring, hypoglycemic events, drug adverse events, and treatment of complications
80 LIFESTYLE MODIFICATION A1C %A1C %A1C >9%MonotherapyDual TherapyDrug naïve,No symptomsMETDPP4GLP1TZDAGIMET+GLP1 or DPP4 or TZDSU orGlinidesTriple TherapyMET+GLP1 or DPP4+SUTZD+TZDDual TherapyMET+GLP-1 or DPP4TZDGlinide or SUColesevelamAGITriple TherapyMET+GLP1 or DPP4+TZD+SUTZDSymptoms orunder treatmentTriple TherapyMET +GLP1 or DPP4+TZDGlinides or SUAdapted from AACE December 2009 update with permissionInsulin + other agents
81 AACE/ACE Diabetes Algorithm ADA/ EASD CriteriaEvidence basedRecognize that beta cell failure is progressive, and eventually insulin will be required, so recommends this transition earlyGreater emphasis on direct medication costs and efficacyEmphasis on one or two drug regimens, minimizes use of multiple drugsAACE/ ACE CriteriaAttempts to provide a place and recommendation for all FDA approved drugsGreater emphasis on hypoglycemia avoidanceRecognizes that people may want choices, so allows a wide variety of choices and combinations for individual situations
82 National Trends in Use of Different Therapeutic Drug Classes to Treat Diabetes, 1994-2007 Alexander, G. C. et al. Arch Intern Med 2008;168:
83 Leading Diabetes Medications by Treatment ClassAlexander, G. C. et al. Arch Intern Med 2008;168:
85 Factors to Consider when Choosing Pharmacological Agent(s) for Diabetes Current A1CDuration of diabetesBody weight (BMI, abdominal obesity)Age of patientCo-morbiditiesCost of medicationConvenience
86 Considerations when Choosing a Drug Within a Class Adverse effects are not “class-specific”Phenformin vs. MetforminTroglitazone vs. Rosiglitazone vs. PioglitazoneDrugs within a class may not be equally effective
87 LIFESTYLE MODIFICATION MonotherapyMETDPP4GLP1TZDAGIMET+GLP-1 or DPP4TZDGlinide or SUColesevelamAGIDual TherapyMET+GLP1 or DPP4+SUTZD+TZDsymptomatic orsevere hyperglycemiaTriple TherapyInsulin + other agents
88 The Role of Incretin Mimetics in Treating Type 2 Diabetes Investigations • Innovation • Clinical ApplicationThe Role of Incretin Mimetics in Treating Type 2 DiabetesProgram ChairmanCharles Faiman, MD, FRCPC,MACEPast ChairmanConsultant StaffDepartment of Endocrinology, Diabetes and MetabolismCleveland Clinic Foundation
89 Case Presentation50-year-old patient with type 2 diabetes on glyburide 5 mg/d and metformin 1000 bid presents with a random blood sugar of 240 mg/dL and HbA1c 8.0%Weight 250 lb Ht 5’9” BMI 36.9
90 What would be the best therapeutic option to treat this patient’s diabetes? 1. Add pioglitazone 30 mg/d 2. Add insulin glargine 10 units qhs 3. Start nateglinide 120 mg tid 4. Start sitagliptin 100 mg/d 5. Start exenatide 5 mcg bid
91 What would be the best therapeutic option to treat this patient’s diabetes? 1. Add pioglitazone 30 mg/d 2. Add insulin glargine 10 units qhs 3. Start nateglinide 120 mg tid 4. Start sitagliptin 100 mg/d 5. Start exenatide 5 mcg bid
92 David M. Nathan, MD The New England Journal of Medicine Perspectives February 1, 2007“A host of medications that are already available are effective as monotherapy or in combination with metformin or one of the TZDs (the approved uses of sitagliptin). The fact that these medications achieve better glycemic control than sitagliptin suggests the need for caution in approving a new medication that has received limited testing.”
93 A Consensus Statement From the American Diabetes Association and the European Association for the Study of DiabetesNathan DM et al. Diabetes Care. 2006;29:
94 Management of Hyperglycemia in T2DM DiagnosisLifestyle intervention + MetforminA1C≥7%NoYes*Add basal insulin*- most effectiveAdd sulfonylurea- least effectiveAdd glitazone- no hypoglycemiaNoA1C≥7%Yes*NoA1C≥7%Yes*NoA1C≥7%Yes*Intensify insulin*Add glitazone*Add basal insulin*Add sulfonylurea*NoA1C≥7%Yes*NoA1C≥7%Yes*Add basal or intensify insulin*Intensive insulin + metformin ± glitazoneAdapted from Nathan DM et al. Diabetes Care. 2006;29:
95 Algorithm OverviewThe algorithm takes into account the characteristics of the individual interventions, their synergies, and expenseThe goal is to achieve and maintain glycemic levels as close to the nondiabetic range as possible and to change interventions at as rapid a pace as titration of medications allowsPramlintide, exenatide, α-glucosidase inhibitors, and the glinides are not included in this algorithm, owing to their generally lower overall glucose-lowering effectiveness, limited clinical data, and/or relative expense.These may, however, be appropriate choices in selected patients
96 ADOPT: A Diabetes Outcome Progression Trial—Safety Profile Incidence of Selected Adverse EventsSelected EventsRSG(N=1456)n (%)MET(N=1454)SU(N=1441)Gastrointestinal335 (23.0)557 (38.3)*316 (21.9)Edema205 (14.1)104 (7.2)*123 (8.5)*Hypoglycemia142 (9.8)168 (11.6)557 (38.7)*MI, fatal2 (0.1)3 (0.2)MI, non-fatal25 (1.7)21 (1.4)15 (1.0)CHF22 (1.5)19 (1.3)9 (0.6)†Stroke16 (1.1)17 (1.2)Change in weight observed in study: RSG +0.7 kg/year; MET -0.3 kg/year; SU 0.2 kg/year* P≤0.01 vs RSG† P≤0.05 vs RSGData from Kahn SE et al. N Engl J Med. 2006;355:
97 ADOPT—ImplicationsCurrent oral agent therapy is associated with significant adverse eventsWeight gain, edema, lactic acidosis, GI side effects, and hypoglycemia are significant problemsGLP-1 agonists cause significant weight lossDPP-4 inhibitors have no associated weight gain or complications
98 Relationship Between Weight Gain in Adulthood and Risk of T2DM MenWomenRelative Risk-10-55101520Weight Change (kg)Data from Willett WC et al. N Engl J Med. 1999;341:427.
99 Weight Gain and Glycemic Control Weight gain seems to be inseparable from glycemic control with many antidiabetic treatments, including sulfonylureas, insulin, and thiazolidinediones, which have an estimated 2 kg weight gain for every 1% decrease in HbA1CBuse J et al. Clin Ther. 2007;29:
100 Clinical Role of GLP-1—Mimetics Overweight patients with type 2 diabetes requiring initial treatmentOverweight patients with type 2 diabetes on metformin, sulfonylurea, or combinationAddition to thiazolidinediones to avoid weight gain
101 Reduced Incretin Effect in Patients With T2DM Control subjectsT2DM patients8060402080604020Intravenous glucoseOral glucoseInsulin (mU/L)Insulin (mU/L)**********Time (min)Time (min)*P≤0.05Data from Nauck M et al. Diabetologia. 1986;29:46-52.
102 Summary of GLP-1— Effects in Humans Central nervous systemPromotes satiety and reduction of appetiteLiver Glucagon reduces hepatic glucose outputβ cellEnhances secretion of glucose-dependent insulinStomach Regulates gastric emptyingPotential increase in β-cell massα cell Glucagon secretion post-mealFlint A et al. J Clin Invest. 1998;101: Larsson H et al. Acta Physiol Scand. 1997;160: Nauck MA et al. Diabetologia. 1996;39: Drucker DJ. Diabetes. 1998;47:
103 Glucose-dependent Effects of GLP-1 Infusion on Insulin and Glucagon Levels in T2DM Patients 15.025012.5PlaceboGlucosemmol/L*20010.0mg/dLGLP-17.51505.0100*P<0.05Patients with T2DM (N=10)2.550250When glucose levelsapproach normal values,insulin levels decrease.*40Insulin200pmol/L30150mU/L1002050*10*2020When glucose levels approach normal values, glucagon levels rebound.*Glucagonpmol/L1515pmol/L101055Infusion–3060120180240MinutesAdapted from Nauck MA et al. Diabetologia. 1993;36:
104 Exenatide: HbA1C and Body Weight Reductions Preliminary Analysis for Subjects Treated for 2 YearsTwo-year data for 82-wk cohort (N=146)Mean ± SEΔ A1C (%)Δ Body Weight (kg)Placebo-controlledPlacebo-controlledOpen-label ExtensionsOpen-label Extensions0.0Baseline A1C: 8.2%Baseline weight: 100 kg-2-0.5-5.5±0.5 kg-1.2±0.1%-1.0-4-1.5-60.00.51.01.52.00.00.51.01.52.0Duration of Treatment (Years)Duration of Treatment (Years)Kendall D. ADA
105 Insulin glargine, mean dose at endpoint = 25.0 U/day Effect of Exenatide vs Insulin Glargine in Pts with Suboptimally Controlled T2DM on HbA1C0.06.57.07.58.08.5A1C (%)Exenatide, 10 mg BID8.2%Insulin glargine, mean dose at endpoint = 25.0 U/dayDISCUSSION:HbA1c was measured at screening (Week -4), baseline (Week 0), Week 12, Week 26 (endpoint) and, if possible, at the time of discontinuation for those who dropped out of the study before completion of Week 26.Eight patients in each group discontinued without a post-baseline measurement of HbA1c. Thus, the intent-to-treat sample is made up of 275 exenatide and 260 insulin glargine patients.HbA1c was significantly reduced from baseline at Week 26 in both treatment arms (change from baseline to endpoint, exenatide: ± 0.059%, insulin glargine: ± 0.058%).The 95% CI for the difference between treatments (exenatide–insulin glargine) was % to 0.157%. This is within the non-inferiority criteria of the upper limit <0.4%.STUDY BACKGROUND:At endpoint, the average dose of insulin glargine was 25.0 IU/day (n = 244). 21.6% of insulin glargine patients, compared with 8.6% of exenatide patients, achieved a fasting glucose of <5.6 mmol/L (100 mg/dL).The daily insulin dose achieved in the present study is lower when compared to other published large-scale randomized clinical trials of insulin glargine (Riddle et al, Diabetes Care. 2003; Benedetti et al, Horm Metab Res 2003; Fritsche et al, Ann Intern Med 2003; Rosenstock et al, Diabetes Care 2001; Yki-Jarvinen et al, Diabetes Care 2000). However, in the present study, the baseline HbA1c was lower than each of those previous trials, possibly resulting in less insulin required to attain a certain glycemic improvement, and all patients entered this trial already taking two oral agents. The mean reduction in HbA1c in the present trial was within the range of reductions observed in previous insulin glargine trials with comparable study designs (ranging from -0.4 to -1.0% for weeks), except the Treat-to-Target trial (-1.65% at 24 weeks) (Riddle et al, Diabetes Care. 2003).In the Treat-to-Target trial, Riddle et al described a number of factors to explain the magnitude of the HbA1c decrease observed, including an ambitious titration target combined with a protocol for encouraging patient adherence. Although problematic to compare across trials, the Treat-to-Target trial also reported a higher incidence of symptomatic (13.9 events per year) and nocturnal hypoglycemia (4.0 events per year) and slightly greater weight gain (+3.0 kg) than observed in the present trial. Moreover, the mean HbA1c achieved at study endpoint in the Treat-to-Target trial (6.96%) was not greatly different from the mean value achieved in the current study (7.12%), and the proportion of patients achieving HbA1c 7% was 58% (Treat-to-Target) versus 48% (present study).Two recently published trials have demonstrated very favorable results adding insulin glargine to patients receiving metformin and/or combination oral therapy (Janka et al, Diabetes Care, 2005 and Raskin et al, Diabetes Care 2005). However the study designs of these trials included the addition of new sulfonylurea therapy (Janka) or the discontinuation of some oral therapies during a run-in period (Raskin), making a direct comparison of these trial results somewhat difficult to interpret.The insulin glargine titration schedule and approach to encouraging patient adherence in the present trial may have been more reflective of real-world usage; as a result, the data (~1% lowering) may better indicate the broader clinical experience with insulin glargine.Intent-to-treat sample was defined as any randomized patient who had at least one post-baseline measurement of the dependent variable.7.1%Week1226ITT population; Mean ± SE shownAdapted from Heine R et al. Ann Intern Med. 2005;143:
106 Change in Body Weight—Time Course Exenatide+1.8 kg2Insulin glargine1Difference of 4.1 kgbetween groupsDISCUSSION:Insulin glargine patients gained weight throughout the trial period, while exenatide was associated with progressive reductions in weight.Mean body weight was significantly different between the two treatments as early as 2 weeks, and this difference persisted throughout the study.Adjusted mean change in body weight at endpoint was -5.1 ± 0.4 lbs for exenatide, +4.0 ± 0.4 lbs for insulin glargine.Mean difference (exenatide - insulin glargine) was -9.0 lbs, 95% CI for the difference -10.1, -7.7 lbs.Baseline body weights were exenatide: 87.5 ± 16.9 kg and insulin glargine: 88.3 ± 17.9 kg.Enhancing insulin secretion in the absence of weight gain is an important aspect of the incretin mimetics, and may represent an important therapeutic advance in the treatment of type 2 diabetes.STUDY BACKGROUND:Intent-to-treat sample was defined as any randomized patient who had at least one post-baseline measurement of the dependent variable.Change in Body Weight (kg)*-1***-2*-2.3 kg*-3248121826WeekITT population; Mean ± SE shown;*P<0.0001, exenatide vs insulin glargine at same time point*P<0.0001Adapted from Heine R et al. Ann Intern Med. 2005;143:
107 Effects of Exenatide and Placebo on Body Weight Patients With T2DM Treated With a TZD with or Without MetforminExenatide1.0Placebo0.50.0Change in Body Weight (kg)-0.5*-1.0†††-1.5-2.0-2.54881216Weeks*P <0.01: †P <0.001Adapted from Zinman B et al. Ann Intern Med. 2007;146:
108 Liraglutide Is a Long-acting Human GLP-1 IncretinKnudsen LB et al. J Med Chem. 2000;43: ; Degn KB et al. Diabetes. 2004;53:108
109 Changes in HbA1c From Baseline for Liraglutide 1 Changes in HbA1c From Baseline for Liraglutide 1.8 mg vs Comparator and PlaceboData originally presented as Marre M et al. Diabetes. 2008;57(suppl 1):A4 (LEAD 1); Nauck MA et al. Diabetes. 2008;57(suppl 1):A15 (LEAD 2); Garber A et al. Lancet. 2009;373: (LEAD 3); Zinman B et al. Diabetologia. 2008;51(suppl 1): A898 (LEAD 4); Russell-Jones D et al. Diabetes. 2008;57(suppl 1):A159 (LEAD 5).109
110 Body Weight Change: Liraglutide 1.8 mg vs Comparator and Placebo Data originally presented as Marre M et al. Diabetes. 2008;57(suppl 1):A4 (LEAD 1); Nauck MA et al. Diabetes. 2008;57(suppl 1):A15 (LEAD 2); Garber A et al. Lancet. 2009;373: (LEAD 3); Zinman B et al. Diabetologia. 2008;51(suppl 1): A898 (LEAD 4); Russell-Jones D et al. Diabetes. 2008;57(suppl 1):A159 (LEAD 5).110
111 Liraglutide Consistently Reduces Systolic Blood Pressure Data originally presented as Marre M et al. Diabetes. 2008;57(suppl 1):A4 (LEAD 1); Nauck MA et al. Diabetes. 2008;57(suppl 1):A15 (LEAD 2); Garber A et al. Lancet. 2009;373: (LEAD 3); Zinman B et al. Diabetologia. 2008;51(suppl 1): A898 (LEAD 4); Russell-Jones D et al. Diabetes. 2008;57(suppl 1):A159 (LEAD 5).111
112 Outline of LEAD 6 Study Design Buse JB et al. Diabetes Care Mar 23.112
113 LEAD 6 14-week Extension: Shifting Patients to Liraglutide Improves HbA1c Control Buse JB et al. Diabetes Care Mar 23.113
114 LEAD 6 14-week Extension: Shifting Patients to Liraglutide Improves FPG Control Buse JB et al. Diabetes Care Mar 23.114
115 Potential Roles of GLP-1 Mimetics Once-weekly injection of exenatide-LAR in overweight patients with T2DM who require initial therapy or combination with other oral agentsPotential treatment for overweight nondiabetic patientsPotential treatment of overweight, insulin- treated patients with T2DM
116 Exenatide LAR 15-Week Study in T2DM: Results Baseline HbA1C (mean ± SD) 8.5 ± 1.2%Baseline fasting BG 9.9 ± 2.3 mmol/L*Blood glucoseKim D. Diabetes Care. 2007;30:
117 Exenatide LAR 15-Week Study in T2DM: Results—Safety and Tolerability ReactionPlaceboExenatide 0.8 mg/wkExenatide 2 mg/wkNausea (mild–moderate) *15%19%27%Injection site bruising0%13%7%Injection-site pruritus6%% patients with exenatide antibodies67% of all exenatide LAR-treated patientsWeight change-0.04 kg-0.03 kg-3.8 kg*No vomiting notedNo severe hypoglycemia or withdrawal due to adverse events observedKim D. Diabetes Care. 2007;30:
118 Will the DPP-4 Inhibitors Replace GLP-1 Mimetics? DPP-4 inhibitors have similar action to GLP-1 agonists but do not result in weight loss; therefore, for patients in whom weight loss is needed, GLP-1 agonists are indicated.Lack of weight loss with DPP-4 inhibition is thought to be due to lesser increase in GLP-1 levels (3x) compared with that of GLP-1 mimetic (10x) or due to lack of PYY* activation by DPP-4*PPY = peptide YY (intestinal satiety hormone)
119 Sitagliptin: Mechanism of Action Glucose- dependent Insulin(GLP-1and GIP) Glucose uptake by peripheral tissueIngestion of foodPancreasRelease ofactive incretinsGLP-1 and GIPBeta cellsAlpha cellsGI tract Blood glucose in fasting and postprandial statesDPP-4 enzymeGlucose-dependentMechanism of Action of SitagliptinThis illustration describes the mechanism of action of JANUVIA™ (sitagliptin phosphate).The incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis.When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. With higher insulin levels, tissue glucose uptake is enhanced.In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells.Decreased glucagon levels, along with higher insulin levels, lead to reduced hepatic glucose production and are associated with a decrease in blood glucose levels in the fasting and postprandial states.The effects of GLP-1 and GIP are glucose dependent.The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly inactivates incretin hormones.Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones. Hepatic glucose production Glucagon(GLP-1)InactiveGLP-1InactiveGIPIncretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels in response to a mealGLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
120 Sitagliptin: Mechanism of Action (cont) Glucose dependent Insulin(GLP-1and GIP) Glucose uptake by peripheral tissueIngestion of foodPancreasRelease ofactive incretinsGLP-1 and GIPBeta cellsAlpha cellsGI tract Blood glucose in fasting and postprandial statesSitagliptin(DPP-4 inhibitor)XDPP-4 enzymeGlucose-dependentMechanism of Action of SitagliptinThis illustration describes the mechanism of action of JANUVIA™ (sitagliptin phosphate).The incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis.When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. With higher insulin levels, tissue glucose uptake is enhanced.In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells.Decreased glucagon levels, along with higher insulin levels, lead to reduced hepatic glucose production and are associated with a decrease in blood glucose levels in the fasting and postprandial states.The effects of GLP-1 and GIP are glucose dependent.The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly inactivates incretin hormones.Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones. Hepatic glucose production Glucagon(GLP-1)InactiveGLP-1InactiveGIPIncretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels in response to a mealConcentrations of the active intact hormones are increased by sitagliptin,thereby increasing and prolonging the actions of these hormonesGLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
121 Role of DPP-4 Inhibitors Approved as single agents or in combination with a glitazone, sulfonylurea, or metforminSitagliptin approved to be used in combination with insulin
122 Saxagliptin: Difference from Placebo in Adjusted Mean Change from Baseline in HbA1cRosenstock J et al. Curr Med Res Opin. 2009;25: ; Hollander P et al. J Clin Endocrinol Metab. 2009;94: ; DeFronzo RA et al. Diabetes Care. 2009;32:
123 Inclusion Criteria: 7%–10% Sitagliptin Provides Significant and Progressively Greater Reductions in A1CWith Progressively Higher Baseline A1CInclusion Criteria: 7%–10%18-Week StudyBaseline A1C (%)Mean (%)<8% 8<9% >9%<8% 8<9% >9%n=96n=130n=70Reduction in A1c (%)Reduction in A1C (%)n=62n=27n=37Reductions are placebo-subtractedAdapted from Raz I et al. and Aschner P et al. ADA 2006.
124 regimen of glimepiride Placebo-controlled Sitagliptin Add-on to Glimepiride or Glimepiride/MetforminStudy—Design and PatientsRANDOMIZT441 Randomized patients with T2DM age 18–78 yrsPlaceboPlaceboSitagliptin 100 mg qdSitagliptin 100 mg qdStratum 1 Glim (≥4 mg/day) aloneStratum 2 Glim + MF (≥1500 mg/day)ScreeningPeriodSingle-blindPlaceboDouble-blindPhase BWeek 0Week 24Week 80Continue/startregimen of glimepiride± metforminWeek-2 eligible ifA1C 7.5%–10%Hermansen K et al. Diabetes Obes Metab. 2007;9:
125 Summary of Conclusions (24 weeks) Sitagliptin significantly improved A1C when added to:Overall cohort: Sitagliptin reduced A1C by 0.7% (P<0.001)Stratum 1: Glimepiride = -0.6%Stratum 2: Glimepiride + Metformin = -0.9%Hypoglycemia rates were similar to those observed for other AHA when added to SFUSitagliptin + glimepiride = 7.5%Sitagliptin + glimepiride + metformin = 16.4%Hermansen K et al. Diabetes Obes Metab. 2007;9:
126 Saxagliptin: Drug Interactions and Use in Specific Populations Drug interactions: Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin exposure, the dose should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin)Patients with renal impairment: Saxagliptin dose is 2.5 mg/d for patients with moderate or severe renal impairment, or with ESRD requiring hemodialysis (CrCl ≤50 mL/min). Saxagliptin should be administered following hemodialysis. Saxagliptin has not been studied in patients undergoing peritoneal dialysis. Assessment of renal function is recommended prior to initiation of saxagliptin and periodically thereafterPregnant and nursing women: There are no adequate and well-controlled studies in pregnant women. Saxagliptin, like other antidiabetic medications, should be used during pregnancy only if clearly needed. It is not known whether saxagliptin is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when saxagliptin is administered to a nursing woman.Pediatric patients: Safety and effectiveness of saxagliptin have not been established.Onglyza ® (saxagliptin) [package insert]. Princeton, NJ; Bristol-Myers Squibb; 2009.
127 Addition of Sitagliptin to Insulin— Effect on HbA1c at 24 Weeks Sitagliptin change from baseline in A1C at Week (P<0.001)Placebo change from baseline
128 Why DPP-4 Inhibitors?Excellent in patients with mild hyperglycemia requiring insulin secretagogueNo contraindication in heart failure and no risk of edema or lactic acidosisCan be used in renal insufficiency without risk of hypoglycemia or lactic acidosisNo weight gainImmediate activity without causing hypoglycemia
129 Should DPP-4 Inhibitors Be First-line Agents? If β-cell-sparing effect shown in rats proves to be true in humans, DPP-4 inhibitors could become the preferred first-line agentsAppropriate for patients with mild elevation of glucose with contraindications to other agents that cause hypoglycemiaShould be considered early in overweight patientsShould be considered in patients with heart failureStrongly considered in patients with renal failure
130 Ratio (pmol/L/pmol/L) Sitagliptin Improved Markers of β-Cell Function — 24-week Monotherapy Study0.5580Proinsulin/insulin ratioHOMA-β750.570P<0.001*650.4560P<0.001*Ratio (pmol/L/pmol/L)550.450450.3540350.330PlaceboSitagliptin 100 mgPlaceboSitagliptin 100 mg∆ from baseline vs pbo=13.2(95% CI 3.9, 21.9)∆ from baseline vs pbo=0.078(95% CI , )Hatched = BaselineSolid = Week 24*P value for change from baseline compared to placeboAschner P et al. ADA
131 GLP-1 Improves β-cell Mass in Fatty Zucker Diabetic Rats β-cell Mass (mg)β-cell Proliferation (%)β-cell Apoptosis (%)1612842.52.01.50.51.0302010P<0.05P<0.01P<0.001Beta-Cell Mass (mg)Proliferating Beta Cells (%)Apoptotic Beta Cells (%)ControlGLP-1- treatedControlGLP-1- treatedControlGLP-1- treatedWeeksAdapted from Farilla L et al. Endocrinology. 2002;143:
132 Conclusions—GLP-1 Mimetics GLP-1 mimetics are important new therapeutic options that have important roles in current therapy and major potential future rolesGLP-1 mimetics have excellent glucose-lowering efficacy and are associated with significant weight lossCombination with glitazones prevents glitazone-induced weight gainLong-acting GLP-1 mimetics will increase their acceptanceβ-cell preservation, if proven in humans, may make these mimetics early treatment options in the futureUse in patients with glucose intolerance or simple obesity for weight reduction needs further evaluation
133 Conclusions—DPP-4 Inhibitors DPP-4 inhibitors have a major role in diabetes managementAbility to use in renal insufficiency, heart failure, and hepatic disease markedly increases therapeutic options for our patientsQuick onset of action and lack of hypoglycemia may make these first-line agents in hospitalized patientsExcellent agents for the growing population of patients requiring modest glucose loweringEfficacy is enhanced with increased baseline HbA1CNew data support efficacy with sulfonylureas, which will greatly enhance the usefulness of DPP-4 inhibitorsMay be used as single agents or in combination with metformin, glitazones, sulfonylurea, or insulin
134 Future Management Directions in DM2 Longer – acting incretin mimeticsOther DPP-IV inhibitorsOther agents - e.g., SGLT-2 inhibitorsNewer insulin formulations (oral / inhaled)Weight (“girth”) control - medical / surgicalDM2 prevention - action in the pre-diabetes (impaired tolerance) phase
135 SGLT-2 Inhibitors – Useful Adjuncts? Mechanism of action - sodium-glucose transporter inhibition – prevents glucose reabsorption in the proximal tubal resulting in glucose loss (analogous to the apparently benign condition of renal glycosuria) Not insulin dependent. Effective in DM2 and DM1.Studies to date - monotherapy and as add on to metformin, SU’s, TZD’s, DPP-IV inhibitors & insulin – most studies preliminaryRoute - oral, daily (contraindicated with severe CKD)Efficacy - HbA1c reduction ~ % : weight loss – 1-2 kgSide effects - small(?) increase in U.T.I.’s & genital moniliasis. No hypoglycemia with monotherapy.See Lancet 2010;375: &
137 Investigations • Innovation • Clinical Application Sequencing Oral Therapy in Type 2 Diabetes: DPP-4 Inhibitors as Monotherapy or Combination Therapy with Metformin, Sulfonylureas, and TZDs—Constructing Outcome-Optimizing Oral RegimensAligning Oral Therapy with Appropriate Patient Subgroups and Clinical SituationsAlexander Turchin, MD, MSAssistant Professor, Harvard Medical SchoolBrigham and Women's HospitalBoston, MA
138 TopicsDPP-4 inhibitors as monotherapy or combination therapy with metformin, sulfonylureas, and TZDs - constructing outcome-optimizing oral regimensAligning oral therapy with appropriate patient subgroups: how to choose and what to choose - a systematic, guideline-consistent approach based on clinical evidence
139 DPP-IV Inhibitors Sitagliptin (Januvia) Saxagliptin (Onglyza) [Vildagliptin][Alogliptin]Glucose-dependent stimulation of insulin secretionReduction of gastric emptyingReduction of inappropriate glucagon secretionBeta-cell proliferation / regenerationAdapted from: Nauck MA et al. (2009). Diabetes Care 32(S2):S223
140 SIDE EFFECTS (putative) Risks & BenefitsEFFICACY↓A1c 0.7%(up to 1.5% if starting A1c higher)COST$200 / month*DPP-IVinhibitorsSIDE EFFECTS (common)- noneSIDE EFFECTS (putative)PancreatitisPharyngitisCONTRAINDICATIONSh/o pancreatitis* Source – drugstore.com
141 Risks: Immunodeficiency DPP-4 is found on the surface of lymphocytesIt inhibits breakdown of multiple cytokines and hormones including many involved in immune cell regulationBUTMeta-analysis of 12 Phase IIb / III trials involving 3,415 patients on sitagliptin vs. 2,724 patients on placebo showed incidence of infections 34.5% vs. 32.9% (NS)Incidence of nasopharyngitis was 7.1% vs. 5.9% (NS)From: Williams-Herman, D et al. (2008). BMC End Dis 8(14)
142 Risks: Pancreatitis88 cases of pancreatitis in patients on sitagliptin have been reported to the FDA by 09/2009BUTRetrospective study of 786,656 patients including patients with h/o chronic pancreatitis and other pancreatitis risk factors15,826 patients on sitagliptinIncidence of pancreatitis increased in patients with diabetes; no difference for sitagliptinFrom: Garg R et al. (2010). Diabetes Care online 08/03/10
143 The Rest - Daily Efficacy (A1c) Cost* (1 month) Side effects -1.5% Thiazolidinediones(TZD)MetforminSulfonylureasEfficacy(A1c)-1.5%-1.0%-1.5%$250$4§Cost*(1 month)$4§HypoglycemiaWeight gainCHFWeight gainBone lossSide effectsGIAll are approved as monotherapy or in combination with each other* Source – drugstore.com if not specified otherwise§ Wal-Mart
144 α-glucosidase inhibitors The Rest – with Mealsα-glucosidase inhibitorsGlinidesEfficacy(A1c)-1.5%-0.7%$200Cost*(1 month)$100HypoglycemiaWeight gainGISide effectsAll are approved as monotherapy or in combination with each other* Source – drugstore.com if not specified otherwise
145 ADA Consensus Algorithm lifestyle + metformin + basal insulinlifestyle + metformin + intensive insulinAt diagnosis: lifestyle + metforminlifestyle + metformin + sulfonylureaDPP-IV inhibitors not recommendeddue to lack of long-term safety recordlifestyle + metformin + pioglitazonelifestyle + metformin + sulfonylurea + basal insulinLess well validated therapieslifestyle + metformin + GLP-1 agonistAdapted from: Nathan DM et al. (2009). Diabetes Care 32(1):193
151 Questions? Alexander Turchin, MD, MS email@example.com Investigations • Innovation • Clinical ApplicationQuestions?Alexander Turchin, MD, MS
152 Investigations • Innovation • Clinical Application Cardiovascular, Metabolic, and Renal Considerations: Optimizing Efficacy and Safety of DPP-4 Inhibitor Therapy in High Risk PatientsEvidence-Based Therapy for T2D in Patients with CV and/or Renal Risk Factors or DysfunctionDerek LeRoith, MD, PhD, FACPChief, Division of Endocrinology, Diabetes and Bone DiseaseDirector, Metabolism Institute,Mount Sinai School of MedicineNew York, NY
153 No A1C threshold is apparent Slide 4The risk of CHD is significantly increased in patients with Type 2 diabetes. Cardiovascular disease causes 80% of all diabetic mortality, and in 75% of those cases, it is a result of coronary atherosclerosis.Cardiovascular disease causes greater than 75% of all hospitalizations for diabetic complications.Greater than 50% of patients with newly diagnosed Type 2 diabetes have pre-existing cardiovascular disease. This means that the risk factors for macrovascular disease are already at work before the diagnosis of diabetes.These points provide a rationale for early and aggressive management of cardiovascular risk in patients with diabetes.No A1C threshold is apparentFinnish study by Kuusisto et al;UKPDS epidemiologic analysis; EPIC-Norfolk StudyImpaired glucose tolerance (IGT) and postprandial hyperglycemia are CV risk factorsFunagata Diabetes Study,;Honolulu Heart Program; DECODE Study; Rancho Bernardo Study
154 Mortality in Multiple Risk Factor Intervention Trial (MRFIT) Diabetes(n = 5163)No Diabetes(n = 342,815)Relative Risk*CVD85.1322.883.0CHD65.9117.033.2Stroke6.721.752.8Other CVD12.994.082.3Other160.1353.202.5*Age-adjusted rate per 10,000 person-years. Relative risk adjusted for age, race, income, systolic BP, and smoking.Savage PJ. Ann Intern Med. 1996;124:154
155 “Ticking clock” hypothesis: Glucose abnormalities increase CV risk “Ticking Clock” Hypothesis: Glucose Abnormalities Increase CV Risk, Even Before Dx DMNurses’ Health Study, N = 117,629 women, aged 30–55 years; follow-up 20 years (1976–1996)Relative risk of MI or stroke*“Ticking clock” hypothesis: Glucose abnormalities increase CV riskAfter diabetes diagnosisBefore diabetes diagnosisDiabetes atbaselineResults from the Nurses’ Health Study indicated that women who eventually developed diabetes were at a significantly elevated risk of myocardial infarction (MI) and stroke prior to the diagnosis of diabetes, relative to women who did not develop diabetes.Hu et al found that of 117,629 female nurses free of cardiovascular (CV) disease at baseline, 1508 had diabetes at baseline, and 5894 developed diabetes during the 20 years of follow-up.For women who developed type 2 diabetes during follow-up, the adjusted relative risk of MI or stroke was 2.8 prior to the diagnosis of diabetes, and 3.7 after the diagnosis of diabetes (adjusted for age, BMI, smoking status, menopausal status, family history, and hormone replacement status).Elevated risk of CV disease began at least 15 years before the diagnosis of diabetes. This has been referred to as the “ticking clock” hypothesis.No diabetes*Adjustedn = 1508 diabetes at baselinen = 5894 new-onset diabetesHu FB et al. Diabetes Care. 2002;25:155
156 High Risk of Cardiovascular Events in Type 2 Diabetes 5101520253035404550No diabetesType 2 diabetes7-year incidence of cardiovascular events (%)Slide 67.High Risk of Cardiovascular Events in Type 2 DiabetesBecause of the aging of the population and an increasing prevalence of obesity and sedentary life habits, the prevalence of type 2 diabetes (90% of all cases of diabetes) is increasing [Grundy et al, 1999]. Type 2 diabetes is associated with a marked increase in the risk of cardiovascular disease. In a Finnish population-based cohort, the 7-year incidences of fatal or nonfatal MI, fatal or nonfatal stroke, and death from cardiovascular causes among 1373 nondiabetic subjects were compared with the incidences among 1059 patients with type 2 diabetes. Both the presence of diabetes and the history of a previous MI at baseline were associated with an increased incidence of cardiovascular events. In both diabetic patients and nondiabetic subjects, a history of prior MI at baseline was significantly associated with an increased incidence of MI, stroke, and cardiovascular death. Diabetic patients without prior MI had as high a cardiovascular risk as nondiabetic subjects with previous MI. The authors concluded that cardiovascular risk factors must be as aggressively treated in patients with diabetes as in nondiabetic patients with prior MI [Haffner et al, 1998].Once patients with diabetes develop clinical coronary heart disease, they have a particularly poor prognosis. The course of acute MI in 85 patients with diabetes was compared with that in 415 nondiabetic patients. Mean follow-up was 35 months. The patients with diabetes experienced a more complicated in-hospital and post-discharge course than did the nondiabetic patients, including higher incidences of post-infarction angina, infarct extension, heart failure, and death [Stone et al, 1989].Prior myocardial infarctionMyocardial infarctionStrokeCardiovascular deathsHaffner, NEJM 1998,156
157 DCCT/EDIC: Incidence of Any CVD Event EDIC observation0.12Conventional treatmentEDIC A1C mean 8.2%0.10¯42% Risk reduction P=0.020.08Cumulative incidence0.060.040.02DCCT/EDIC: Incidence of Any Cardiovascular Disease OutcomeThe Epidemiology of Diabetes Interventions and Complications (EDIC) study is a long-term observational follow-up (mean 17 years) to the Diabetes Control and Complications Trial (DCCT), which studied whether the use of intensive therapy as compared with conventional therapy affected the incidence of cardiovascular disease (CVD) in patients with type 1 diabetes. Ninety-seven percent of the original DCCT cohort joined the EDIC follow-up (N=1,394).A total of 144 cardiovascular events occurred in 83 patients during mean 17 years of follow-up, 46 among 31 patients assigned to intensive treatment and 98 among 52 patients assigned to conventional treatment.As compared with conventional treatment, intensive treatment reduced the risk of any CVD outcome by 42% (95% confidence interval, 9% to 63%; P=0.02).The authors conclude that the large reduction in the risk of cardiovascular events will improve the projected long-term health and economic benefits of intensive therapy for diabetes.DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:Intensive treatmentEDIC A1C mean 8.0%0.0012345678910111213141516171819202120 yearsYears since entry into studiesDCCT=Diabetes Control and Complications Trial.EDIC=Epidemiology of Diabetes Interventions and Complications.DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:
158 Legacy Effect of Earlier Glucose Control After median 8.5 years post-trial follow-upAggregate EndpointAny diabetes related endpoint RRR: 12% 9%P:Microvascular disease RRR: 25% 24%P:Myocardial infarction RRR: 16% 15%P:All-cause mortality RRR: 6% 13%P:RRR = Relative Risk Reduction, P = Log Rank10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359
159 Cardiovascular Safety: Exenatide BID Meta-analysis of clinical trials for exenatide twice dailyNo increased risk of CV eventsRelative risk (95% CI) = 0.69 ( ) versus pooled comparatorsRetrospective, comparative analysis of large health insurance databaseExenatide-treated (n = 21754) versus non-exenatide-treated (n = )Significantly lower risk of CV event for exenatide-treated patientsHazard ratio (95% CI) = 0.81 ( ); P = .011Lower risk despite greater inherent CV risk due to higher rates of hyperlipidemia, hypertension, obesity, and prior CADExenatide meta-analysis: Shen, last sentence (no increased risk) and lines (relative risk)Liraglutide: first bullet of “update” press releaseShen L, et al. Diabetes. 2009;58(suppl 1):366-OR.Best JH, et al. Presented at the ADA 70th Scientific Sesions; 712-P.159
160 Cardiovascular Safety: Liraglutide US FDA analyses of clinical trial data identified no excess risk of CV events versus comparators (active or placebo)Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trialDesigned to assess CV safety and satisfy FDA guidelines for T2DM treatmentsScheduled to begin Autumn 2010Exenatide meta-analysis: Shen, last sentence (no increased risk) and lines (relative risk)Liraglutide: first bullet of “update” press releaseFDA briefing materials – liraglutide.b2-01-FDA.pdf; Update on FDA Advisory Committee meeting onliraglutide for the treatment of type 2 diabetes.AttachmentGUID=1c87137d-806f-41bc-832a-e5a74aa86164;LEADER trial press release.160
161 CV Safety With DPP-4 Inhibitors: Sitagliptin Over 10,000 patients with T2DM, treated with sitagliptin 100 mg/day or placebo (non-exposed), up to 2 years.The patients were from trials using sitagliptin as monotherapy, or in combination with metformin, sulfonylurea, pioglitazone or insulin.Incidence rates of adverse events in the Cardiac Disorders Systems Order Class was ~4% per 100 Patient years, in both the sitagliptin and non-exposed patients.Williams-Herman D, et al.BMC Endocr Disord Apr 22;10:7.
162 Cardiovascular Safety in Saxagliptin Clinical Trials Data from 8 randomized, double-blind, phase 2b/3 trialsaMajor adverse cardiovascular events (MACE)bAcute cardiovascular events (ACE)cEvent typeSaxagliptinn (%)ComparatorACE38 (1.1)23 (1.8)MACE23 (0.7)18 (1.4)All deaths10 (0.3)12 (1.0)CV deaths7 (0.2)10 (0.8)0.44(0.24, 0.82)MACEACE0.59(0.35, 1.00)In December 2008, the US FDA issued Guidance for Industry recommending that therapy sponsors should demonstrate that a new therapy, “…will not result in unacceptable increase in cardiovascular risk.” .Because saxagliptin trials were completed prior to the Guidance was issued, post-hoc analyses of cardiovascular safety were performed. Data were presented at the 2009 ADA Scientific Sessions. [2,3]The FDA Advisor Committed determined that, based on clinical trial results, saxagliptin does not increase the risk for cardiovascular events. However, given the low rate of cardiovascular events in the studies, the FDA Advisory Committee has recommended postmarketing studies to confirm the CV safety results from the clinical trials.[2,4]Cox Proportional Hazard Ratio(95% confidence interval)a Saxagliptin exposure: n = 3356 (3758 patient-years);comparator exposure: n = 1251 (1293 patient-years).b Stroke, myocardial infarction, cardiovascular death.c Includes revascularization.Wolf R, et al. ADA 69th Scientific Sessions. Late Breaking Abstract Handout. 2009;8-LB:LB3.Guidance for Industry: Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Available at: Saxagliptin gets favorable FDA panel review, but cancer concerns raised about Liraglutide. Available at: Wolf R, et al. ADA 69th Scientific Sessions. Late Breaking Abstract Handout. 2009;8-LB:LB3. ONGLYZA (Saxagliptin) Cardiovascular Profile Acceptable According to FDA Advisory Committee. Available at:
163 Summary of Incretin Actions on Different Target Tissues Insulin secretionGlucagon secretionGastric emptyingAppetiteCardioprotectionCardiac outputInsulin biosynthesisb cell proliferationb cell apoptosisNeuroprotectionGlucose productionInsulin sensitivityBrainHeartGI tractLiverMuscleStomachGLP-1The two principal incretins, GIP and GLP-1, both act on the b-cell to stimulate glucose-dependent insulin secretion and in preclinical studies, both incretins stimulate b-cell proliferation and reduce b-cell apoptosis. GLP-1 also has multiple actions on other cell types, including reduction of glucagon secretion from the islet a-cell, inhibition of food intake and gastric emptying, and regulation of cardiovascular function and contractility. Although GLP-1 action on the liver and muscle is thought to be indirect, possibly via other hormones or through the nervous system, treatment of diabetic subjects with GLP-1R agonists has also been associated with increased insulin sensitivity in peripheral tissues such as muscle and liver.Drucker D. J. Cell Metabolism 2006
164 Position Statementa Regarding ACCORD, ADVANCE, and VADT Results Clinical implication = individualized goals and careGeneral A1C goal of < 7%For microvascular disease preventionReasonable for macrovascular risk reduction, pending more evidenceA1C goals closer to normal for some patientsShort diabetes duration, long life expectancy, no significant CVDLevels reached without significant adverse treatment effectsLess stringent goals for some patientsHistory of severe hypoglycemia, limited life expectancy, advanced micro- or macrovascular complications, extensive comorbid conditions, long-standing diabetes with difficulty achieving glycemic goalsFXCX:Refer to – PriMed C&EAdditional lines added under “General A1C goal of < 7%”: p191/c2/bullet 2aAuthored by the American Diabetes Association, American College of Cardiology Foundation, and American Heart Association.Skyler JS, et al. Diabetes Care. 2009;32:
165 Risk of Hypoglycemia in Type 2 DM Hypoglycemia associated with use of sulfonylureas and insulin.Severe hypoglycemia is clinically evident, however, mild to moderate hypoglycemia maybe asymptomatic and remain unreported.When unreported, asymptomatic hypoglycemia maybe detrimental to patients.Asymptomatic hypoglycemia maybe more prevalent in older patients.Chico A et al Diabetes Care 26:Matyka K et al Diabetes Care 20:aHypoglycemia requiring third-party assistance.Monami M, et al. Eur J Endocrinol. 2009;160:Buse JB, et al. Lancet. 2009;374:39-47.
166 Risk Factors and Consequences of Hypoglycemia in Type 2 Diabetes Use of insulin secretagogues and insulin therapyMissed or irregular mealsAdvanced ageDuration of diabetesImpaired awareness of hypoglycemiaConsequences2,3Suboptimal glycemic controlOther health effects1. Amiel SA et al. Diabet Med. 2008;25:245–254.2. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.3. Cryer PE. J Clin Invest. 2007;117:868–870.
167 Fear of hypoglycemia is an additional barrier to control Hypoglycemia May Be a Barrier to Glycemic Control in Patients With Type 2 DiabetesHypoglycemia is an important limiting factor in glycemic management and may be a significant barrier to treatment adherenceFear of hypoglycemia is an additional barrier to controlA study in patients with type 2 diabetes showed increased fear of hypoglycemia as the number of mild/moderate and severe hypoglycemic events increasedAmiel SA et al. Diabet Med. 2008;25:245–254.
168 Current Treatments Increase Risk of Hypoglycemia p<0.05 glibenclamide vs. rosiglitazonePatients with hypoglycaemia** (%)1039515202530354045RosiglitazoneMetforminGlibenclamide1251020GlargineNPH15Hypoglycaemia, events/patient/year*Current treatments increase risk of hypoglycaemiaMany drugs currently used for the treatment of type 2 diabetes cause hypoglycaemiaRosiglitazone 10% of patientsMetformin 12%Glibenclamide 39%ReferencesRiddle et al. Diabetes Care 2003;26:3080Kahn et al (ADOPT). NEJM 2006;355:2427–43*All symptomatic hypoglycaemic events** Patients self-reporting (unconfirmed) hypoglycaemiaRiddle et al. Diabetes Care 2003;26:3080; Kahn et al (ADOPT). NEJM 2006;355:2427–43
169 Hypoglycemia Risk With GLP-1 Receptor Agonists Meta-analysis15 trials with exenatide BID or liraglutide versus active comparators or placeboLow risk of hypoglycemia except in combination with SUsSignificantly less minor hypoglycemia with liraglutide than with exenatide in head-to-head comparisonLiraglutide or exenatide + MET and/or SUMajor hypoglycemiaa: 2 events in patients treated with exenatide + SUaHypoglycemia requiring third-party assistance.Monami M, et al. Eur J Endocrinol. 2009;160:Buse JB, et al. Lancet. 2009;374:39-47.
170 Hypoglycemia Risk With DPP-4 Inhibitors ComparatorsActivePlacebo-ControlledTrialsVildagliptinMonotherapyAdd-on to SU/InsulinSitagliptinDPP-4 InhibitorsSulfonylureasThiazolidinediones0.010.101.010.0Any Hypoglycemia (Mantel-Haenzel Odds Ratio With 95% CI)aHypoglycemia risk similar to placeboa Logarithmic scale.Monami M, et al. Nutr Metab Cardiovasc Dis.Published online June 8, 2009; doi: /j.numecd
171 Age-related Decline in Renal Function in Patients with Type 2 diabetes
172 Dosing GLP-1 Receptor Agonists in Renal Insufficiency Degree of Renal InsufficiencyExenatide BIDLiraglutideMild(GFR > 50 mL/min)No changeUse with caution due to limited clinical experience in this population. No dose adjustment recommended.Moderate(GFR ≥ mL/min)Use caution during initiation or dose escalationSevere(GFR < 30 mL/min)Should not be used in patients with severe renal impairment or end-stage renal diseaseUse with caution in patients with renal transplantationFXCX notes:Exenatide: Byetta pi, sections 5.3 and 8.6Liraglutide: Victoza pi, section 8.6Hypovolemia statement (section 5.3): Nausea and vomiting with transient hypovolemia may worsen renal functionByetta (exenatide) [prescribing information].Victoza (liraglutide) [prescribing information].172172172
173 Dosing DPP-4 Inhibitors in Renal Insufficiency Degree of Renal InsufficiencySitagliptinSaxagliptinMild(GFR > 50 mL/min)100 mg per day5mg per dayModerate(GFR ≥ mL/min)50 mg per dayNo adjustmentSevere(GFR < 30 mL/min)25 mg per day2.5 mg per dayFXCX notes:Exenatide: Byetta pi, sections 5.3 and 8.6Liraglutide: Victoza pi, section 8.6Hypovolemia statement (section 5.3): Nausea and vomiting with transient hypovolemia may worsen renal function173173173
174 Saxagliptin and Sitagliptin in Elderly Patients 5 mg/day vs placeboSitagliptin100 mg/day vs placeboaParticipantsPatients ≥ 65 yearsbMonotherapy and combination therapyN = 274Patients ≥ 65 yearsMonotherapyN = 206A1C change(relative to placebo)- 0.55%- 0.7%AEsSimilar to placeboHypoglycemiaNone reporteda Except in cases of dose adjustment for renal insufficiency.b Pooled analysis of clinical trial data.Barzilai N, et al. Diabetes. 2009;58(suppl 1):587-P.Maheux P, et al. Presented at the 2009 European Association for the Study of Diabetes Meeting. Present No. 766.
175 Investigations • Innovation • Clinical Application Case Studies in Oral Therapeutics for Type 2 Diabetes—Clinical Decisions and Real World OutcomesProgram ChairmanCharles Faiman, MD, FRCPC,MACEPast ChairmanConsultant StaffDepartment of Endocrinology, Diabetes and MetabolismCleveland Clinic Foundation
176 Case Study #147-year-old male with type 2 diabetes mellitus diagnosed 5 years ago, returns for a follow-up visit.He reports feeling well. For exercise, he walks his dog daily for about a mile. He feels he could “do better with his diet”; he has seen a nutritionist and diabetes educator, but says he lacks motivation.
177 Case Study #1On exam he has a BMI of 36, Pulse 74, BP 130/80. Rest of the exam is normalHis current meds are metformin 1000 mg bid, glyburide 10 mg bid, lisinopril 10 mg daily, simvastatin 40 mg daily, and ASA 81 mg daily.Downloaded meter reveals BG testing about once daily; BG range , average 162 mg/dl.A1C 7.8 %, serum creatinine 1.1 mg/dl , LDL-C 66 mg/dl
178 Case Study #1 What is your recommendation for him? Add basal insulin Stop glyburide and start basal bolus insulin treatmentAdd pioglitazone (Actos) 45 mg dailyAdd sitagliptin (Januvia) 100 mg dailyDo not change drug therapy and refer back to the diabetes educatorAdd exenatide (Byetta) bid
179 Case Study #267-year-old woman with DM-2, hypertension, obesity, rheumatoid arthritis and COPD presents with A1c of 7.6%. Her BMI is 34.2 and she is looking to lose weight. She tried metformin previously but did not tolerate due to side effects.Candidate for DPP-IV monotherapyAlternatives: α-glucosidase inhibitorOther options
180 Case Study #382-year-old man with hypertension, hypercholesterolemia, ischemic cardiomyopathy and NYHA class III heart failure presents with a newly diagnosed DM-2 and A1c of 7.4%.Candidate for DPP-IV monotherapyAlternatives: α-glucosidase inhibitorOther options
181 Case Study #459-year-old man with DM-2 treated with metformin, hypertension, dyslipidemia, prostate cancer and osteoporosis presents with A1c of 7.9%. He was previously taking glyburide but had several episodes of severe hypoglycemia (had to be assisted in treatment) and discontinued it 3 months ago. He has a hectic work schedule (marketing executive) and is not always able to have meals at regular times.Candidate for DPP-IV as 2nd line agent (after metformin)Alternatives: α-glucosidase inhibitorOther options
182 Case Study #552-year-old man with no past medical history presents with newly diagnosed DM-2. His A1c is 9.1%. He is adamant in refusing to consider injectable medications.Candidate for DPP-IV as 3d line agent (after metformin + sulfonylurea and / or TZD)Alternatives: α-glucosidase inhibitorOther options
183 Case Study #673-year-old African-American female - T2DM for the past 5 years PM History: GI intolerance with metformin Longstanding hypertension MI at age 65, ejection fraction 40% Meds: Glimepiride 4 mg, Aspirin 325 mg, Metoprolol 50 mg Rosuvastatin 10mg, Furosemide 20mg, Lisinopril 10mg daily Vitals: BMI 29, BP 130/80 Bloods: TCHOL 193, LDL 70, HDL 58, TG 81 FPG 127 mg/dl, A1C 7.5% Creatinine 1.4 mg/dl, GFR 49 ml/min What’s the next step in managing her diabetes?
184 Case Study #6What’s the next step in managing her diabetes? The following should not be used in this patient, except one class: A. Metformin B. Sulfonylureas C. Thiazolidinediones D. Incretin mimetics/ DPP-IV inhibitors E. Insulin
185 Case Study #6What are some of the major risk factors in treating Type 2 diabetic patients? 1. Cardiovascular disease 2. Renal Failure 3. Aging 4. Hypoglycemia