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  • Need insulin to get fat in and keep it there. Other (??)
  • Lipid Management in Clinical Practice - Section 1
  • A study investigated whether reduced beta-cell mass could contribute to impaired insulin secretion, a main characteristic of type 2 diabetes. To this aim, pancreatic tissue from 124 autopsies was examined and beta-cell mass measured in 91 obese individuals (41 with type 2 diabetes, 15 with impaired fasting glucose, and 35 nondiabetic) and in 33 lean subjects (16 with type 2 diabetes and 17 nondiabetic). A significant reduction in beta-cell mass was observed in obese individuals with type 2 diabetes (–63%, P <0.05) compared with lean nondiabetic individuals. Thus, beta-cell mass is decreased in patients with type 2 diabetes. Slide provided by Dr. Leahy — for training use only.
  • Slide Index ARC-GL0011 L: A,B,C DISCUSSION POINTS: These data show that postprandial GLP-1 concentrations are reduced in subjects with type 2 diabetes and impaired glucose tolerance (IGT). The top line represents GLP-1 concentrations in subjects with normal glucose tolerance (NGT). GLP-1 concentrations are statistically significantly reduced in patients with type 2 diabetes compared to NGT subjects from t=60 min to 150 min. SLIDE BACKGROUND: Fifty-four subjects with type 2 diabetes (BMI 30.2 kg/m2, age 55.9 y, A1C 8.4%), 15 IGT (BMI 35.0 kg/m2, age 55.3 y, A1C 6.1%), and 33 NGT (BMI 29.6 kg/m2, age 56.2 y, A1C 5.9%). All antidiabetic medications were discontinued 3 days prior to study during which time subjects were fed a mixed meal (t=0) and blood samples taken for 6 subsequent hours. Plasma concentration of GLP-1 were measured by means of RIA specific for C-terminus of GLP-1, which measures the sum of GLP-1 (7-36) amide and its metabolite GLP-1 (9-36) amide.
  • DISCUSSION POINTS: Food elicits dynamic changes in insulin secretion, beginning with the so-called cephalic phase, in which anticipation of a meal releases insulin. This is mediated by the CNS. An early prandial phase, mediated by gut-derived incretin hormones (eg, GLP-1 and GIP) occurs after food intake but before the ingested nutrients appear in the circulation. To identify the contributions of these endogenous substances, 6 young healthy subjects were first given increasing oral glucose loads of 25 g, 50 g, and 100 g. They then received an isoglycemic intravenous glucose infusion that was designed to mimic the plasma profile achieved by the oral load. 1 The intravenous glucose bypassed the gastrointestinal tract and therefore enabled an investigation of the role of incretins. Shown here (left chart) is the response to 50 g oral glucose compared with the matched intravenous infusion, demonstrating essentially identical rises and falls in plasma glucose. Yet the insulin secretory response (β-cell responses), demonstrated here by the connecting peptide (C-peptide) concentrations, were dramatically different (right chart). The oral challenge was followed by a robust increase in C-peptide levels. In contrast, insulin secretion following the isoglycemic intravenous glucose infusion was significantly less. The difference is ascribed to incretins, which are secreted in response to the presence of food in the GI tract and not when glucose is administered parenterally. The incretin effect thus refers to the difference in the magnitude of insulin secretion seen after glucose is ingested compared with that seen after an isoglycemic intravenous infusion. These findings suggest that incretins, and not merely the direct actions of glucose, affect the insulin secretory response. Reference: Nauck MA, Homberger E, Siegel EG, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab . 1986;63:492-498.
  • The Incretin Effect in Subjects Without and With Type 2 Diabetes In 1964, it was demonstrated that the insulin secretory response was greater when glucose was administered orally through the GI tract than when glucose was delivered via intravenous (IV) infusion. The term incretin effect was coined to describe this response involving the stimulatory effect of gut hormones known as incretins on pancreatic secretion. 1,2 The incretin effect implies that nutrient ingestion causes the gut to release substances that enhance insulin secretion beyond the release caused by the rise in glucose secondary to absorption of digested nutrients. 1 Studies in humans and animals have shown that the incretin hormones GLP-1 and GIP account for almost all of the incretin effect, 3 stimulating insulin release when glucose levels are elevated. 4,5 Although the incretin effect is detectable in both healthy subjects and those with diabetes, it is abnormal in those with diabetes, as demonstrated by the study shown on the slide. 6 In this study, patients with type 2 diabetes and weight-matched metabolically healthy control subjects were given glucose either orally or IV to achieve an isoglycemic load. 6 In those without diabetes (shown on the left), the plasma insulin response to an oral glucose load was far greater than the plasma insulin response to an IV glucose load (incretin effect) — that is, the pancreatic beta cells secreted much more insulin when the glucose load was administered through the GI tract. 6 In patients with type 2 diabetes (shown on the right), the same effect was observed but was diminished in magnitude. 6 The diminished incretin effect observed in patients with type 2 diabetes may be due to reduced responsiveness of pancreatic beta cells to GLP-1 and GIP or to impaired secretion of the relevant incretin hormone. 7,8 References: 1. Creutzfeldt W. The incretin concept today. Diabetologia . 1979;16:75–85. 2. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept . 2005;128:87–91. 3. Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology . 2004;145:2653–2659. 4. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology . 2002;122:531–544. 5. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep . 2003;3:365–372. 6. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia . 1986;29:46–52. 7. Creutzfeldt W. The entero-insular axis in type 2 diabetes—incretins as therapeutic agents. Exp Clin Endocrinol Diabetes . 2001;109(suppl 2):S288–S303. 8. Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest . 1993;91:301–307.
  • Key Points: An example of the insulin deficiency associated with type 2 diabetes is shown in this study using a hyperglycemic clamp to demonstrate the difference between individuals with normoglycemia and type 2 diabetes. The Beta Cell dysfunction that follows is characterized by the loss of first phase insulin secretion followed by reduction in second phase insulin secretion characterized by a reduction in beta cell mass. First phase insulin secretion provides a burst of insulin secreted in response to the initial rise in blood glucose after eating a meal. With time second phase insulin secretion is further diminished by beta cell mass decline, resulting in progressive loss of insulin response. This process reinforces the concept of the natural history of type 2 DM
  • Brown et al estimated glycemic burden that accumulates from treatment failure in a prospective, population-based study in patients with type 2 diabetes completing courses of treatment with nondrug therapy diet and exercise, sulfonyluria monotherapy, metformin monotherapy, and combination oral antihyperglycemic therapy. The average patient accumulated nearly 5 A1C years of excess glycemic burden >8.0% from diagnosis until starting insulin and about 10 A1C years of burden <7.0%. These data support the concept that glucose-lowering treatments in type 2 diabetes should be changed much sooner or that treatments less likely to fail should be used. An action point at 7.0% or lower is more likely to prevent additional deterioration than the traditional action point of 8.0%. Reference 1. Brown JB, Nichols GA, Perry A. The burden of treatment therapy in type 2 diabetes. Diabetes Care . 2004;27:1535-1540. Base A1C 7.0% D/E SU Metformin SU + Metformin Total glycemic burden (mo) 22.5±32.0 41.5±43.4 33.5±34.7 58.3+46.2 Avoidable burden (mo) 15.8±24.6 36.6±39.6 25.9+30.1 51.1+41.6 [Brown/1537/B] [Brown/1538/B] [Brown/1537/E] [Brown/1537/D] [Brown/1537/B] [Brown/1537/B] [Brown/1537/C] [Brown/1538/B] [Brown/1537/C] [Brown/1538/A]
  • Key Points: Elevated fasting glucose indicates need for basal insulin to suppress gluconeogenesis overnight. With basal insulin, patient needs to be on at least one oral agent to address mealtime glucose excursions Elevated post-meal glucose indicates need for bolus insulin to cover meal related carbohydrate intake. Most common starting points are Basal Insulin and Mixed Insulin but both point to Basal/Bolus regimen of increased flexibility. Note page reference (3-5) to 4 th edition Quick Guide to get people into the SDM materials. Insulin detemir is a new basal insulin that is expected to be approved by FDA by the end of 2005.

Module i type 2 dm Module i type 2 dm Presentation Transcript

  • Changing Technology: Redefining the Natural History of Type 2 DiabetesProfessor Roger Mazze
  • What characterizes the natural history of type 2 diabetes? Normal Pre-diabetes  By HbA1c  By Diurnal Glucose Pattern Impaired Glucose Tolerance Overt Type 2 Diabetes  Insulin Resistance  Insulin Deficiency  Impaired Incretin Function
  • The Natural History of Type 2 Diabetes Pre-diabetes Deterioration of Glucose ControlNormal •Insulin Resistance •Insulin Deficiency •Incretin DysfunctionNormal View slide
  • SDM: Applications to Type 2Diabetes Management View slide
  • Classifying Diabetes: Underlying DefectsType 1 GDM Type 2  Genetic predisposition: Genetic predisposition:  Genetic predisposition: 80-90% concordance in identical twins 50% concordance in high  Environmental factor: identical twins obesity, inactivity  Environmental factor:  Excessive hepatic glucose Environmental factor: obesity output  insulin resistance/Insulin virus  Prior exposure to deficiency/Impaired incretin effect Auto-immune hyperglycemia in destruction of the pregnancy pancreatic beta cells  Human Placental Lactogen Insulin deficiency  Insulin resistance/Insulin deficiency
  • Priorities of Care for Adults with Diabetes Diagnosis–Prevention Dx Fasting Glucose > 126 Casual > 200 + Symptoms Prevent Pre-diabetes (IFG-IGT) & Metabolic Syndrome Self-Management Knowledge and Skill Monitoring Medication Problem solving Food plan & nutrition Risk reduction Living & coping Physical activity Microvascular Other essentials Glucose Lipids Hypertension complications of care CVD Risk ASA, tobacco, ACEI/ARB, statinHemoglobin A1C Annual Lipid Profile Blood Pressure Annual Screening Target < 7.0% LDL < 100 (every visit) Nephropathy HDL > 40 Dx and Rx < 130/80 Microalbumin screening Hospital care SMBG Calculated GFR Pre 70-120 mg/dL Trigs < 150 Foot care Retinopathy2 hr. post < 160 mg/dL Dilated retinal exam Dental care (~ 50% of readings) DM + CVD Neuropathy Immunizations Neuro and foot exam LDL < 70 Sexual health International Diabetes Center.
  • SDM: Focusing on Type 2Diabetes Management
  • Diagnosis of Type 2 Diabetes Blood Glucose and HbA1c Levels New Fasting OGTT HbA1c Diabetes Diabetes Diabetes >126 mg/dL >200 mg/dL >6.5% Impaired fasting Impaired glucose High risk for glucose Pre-diabetes tolerance diabetes (54 million) 100-125 mg/dL 140-199 mg/dL 6.0-6.4% Normal Normal Normal 70-99 <140 mg/dL <6.0% mg/dLADA Standards of Care. Diabetes Care, Suppl.1, 2010; ADA , EASD, IDF InternationalExpert Committee Report on HbA1c for Diagnosis of Diabetes.
  • ADA Clinical Practice Recommendations Diagnosis of Diabetes A1C ≥ 6.5% – Test performed NGSP certified and standardized to DCCT* FPG ≥ 126 mg/dl – No caloric intake for at least 8 hours 2 hour glucose ≥ 200 mg/dl during an OGTT – Test performed as per WHO (75 g glucose) If classic symptoms of hyperglycemia = random glucose ≥ 200 mg/dl NORMAL PREDIABETES IFG or IGT DIABETES FPG < 100 FPG > 100 – 125 (IFG) FPG > 126 2-h PG < 140 2-h PG 140 – 199 (IGT) 2-h PG > 200 A1c < 5.7% A1c 5.7 – 6.4% A1c > 6.5% American Diabetes Association. Diabetes Care 323(Suppl 1), 2009
  • Confirming the Diagnosis with Repeat Testing
  • Risk Factors for Type 2 Diabetes (screening forasymptomatic patients) Age > 45 years Family history of type 2 diabetes in parents or siblings Overweight or Obesity (BMI >25 kg/m²) Habitual physical inactivity Race/ethnicity e.g. Native American, African American, Hispanic, Asian American and Pacific Islanders Previously identified pre-diabetes (IFG or IGT) Hypertension >140/90 mmHg in adults HDL <35 mg/dL and triglycerides >250 mg/dL History of GDM or delivery of baby weighing >9 lbs. Polycystic Ovary Syndrome/Acanthosis Nigricans History of vascular disease Source: American Diabetes Association, 2010
  • Treat to TargetHbA1c < 7%Fasting and Pre meal glucose 70-120 mg/dL(50% of the time)Postprandial glucose <160 mg/dL(Two hours after the start of a meal the BG shouldbe no more than 20 to 40 mg/dL above the pre-meal BG)Bedtime glucose 100-160 mg/dL International Diabetes Center
  • Blood Glucose Monitoring To improve clinical decision-making To adjust therapy To evaluate efficacy of the therapy To pin point problems To support adherence to regimen Feedback for the patient Use glucose meter with verified data (memory with date/time)
  • Redefining Pathophysiology of Type 2Diabetes? Impaired Incretin Action Insulin Relative Insulin Resistance Deficiency Pre-diabetes and Type 2 Diabetes
  • Natural History of Type 2 Diabetes 350 (mg/dL) Post-meal glucose 300 250 Fasting glucose Glucose 200 150 100 50 Relative Function 250 200 Insulin resistance 150 100 Insulin level 50 β cell function Incretin action 0 -15 -10 -5 0 5 10 15 20 25 30 Pre-diabetes Onset Years metabolic syndrome DiabetesAdapted from: UKPDS 33: Lancet 1998; 352, 837-853 ; DeFronzo RA. Diabetes. 37:667, 1988; Saltiel J. Diabetes. 45:1661-1669, 1996.Robertson RP. Diabetes. 43:1085, 1994; Tokuyama Y. Diabetes 44:1447, 1995. Polonsky KS. N Engl J Med 1996;334:777.
  • What is the relationship betweengaining weight and developinginsulin resistance?
  • Role of Obesity in Development of Insulin Resistance  Central obesity is critical factor: Waist to hip ratio >1 Waist >40 inches in men Waist >35 inches in women  Abdominal adipose tissue is more metabolically active than subcutaneous fat.  Increased release of FFA, TNF-α leading to insulin resistance.FFA TNF-α Resistin
  • Elevated FFAs Play Key Role in Insulin Resistance Impaired Glucose-Stimulated Insulin Secretion↓Gluconeogenesis ↓ Glucose Uptake FFA ↓ Glucose Uptake
  • Relative Insulin Deficiency Decline In β -Cell Function 100 Loss of first-phase insulin secretion 75 β-Cell Function* 50 (%) IGT Postprandial Type 2 Type 2 diabetes 25 hyperglycemia diabetes phase III phase I Type 2 diabetes phase II 0 -12 -10 -6 -2 0 2 6 10 14 Years from Diagnosis*HOMA = homeostasis model assessment; IGT = impaired glucose tolerance. Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS. Lebovitz. Diabetes Rev. 1999, 7:139-53. UKPDS Group. UKPDS 16 Diabetes 1995, 44:1249-58.
  • Insulin Deficiency: Impaired β-Cell Function Normal versus Type 2 Diabetes 200 mg/dL Glucose Secreted Insulin (ng/ 2.5 Normal 2.0 1.5 Diabetes ml/islet) 1.0 0.5 0 2 4 6 8 10 12 14 16 18 Time (hours)Diabetes 1989; 38:673; DeFronzo et al. Diabetes Care. 1992;15:318-368
  • β cell Volume in HumansImpact of Obesity and Glucose Intolerance 4 3 ß-cell volume (%) -40% 2 -41%* -63% 1 0 Body weight: Lean Obese Glycemic status: Normal Diabetes Normal Impaired Diabetes * % Difference between Normal and DiabetesButler AE et al. Diabetes. 2003;52:102–110.
  • Glucotoxicity Hypothesis. β-cells exposed to even mild chronic hyperglycemia develop changes characterized by dysfunctional insulin secretion associated with altered gene and protein expression.
  • What is the role of incretins?  A substance released by the gut in response to food that stimulates insulin secretion  Intestine Secretion Insulin = Incretin  Possible candidates: amino acids, lipids, hormones, peptides (proteins)  Currently two well-described incretins – Glucagon-like peptide-1 (GLP-1) – Glucose-dependent insulinotropic peptide (GIP)
  • Early Slowed gastric Satiety emptyingglucagon Insulin GLP-1 GLP-1 GLP-1 L L L ©2008 International Diabetes Center. All rights reserved
  • GLP-1 Levels in Impaired Glucose Tolerance (IGT) and Type 2 Diabetes Meal 20 * * * * NGT subjects * IGT subjects 15 * T2DM patients * Mean 10 GLP-1 (pmol/L) * 5 0 0 60 120 180 240 Time (min) * P <0.05 between T2DM and NGT group.Toft-Nielsen M, et al., J Clin Endocrinol Metab 2001; 86:3717–3723.
  • Incretin Effect Beta-cell response to isoglycemic glucose challenge Oral glucose (50 g) or isoglycemic infusion 2.0 Plasma glucose (mg/dL) IV glucose * Oral glucose C-peptide (nmol/L) 200 * 1.5 * Incretin effect * * 1.0 * 100 * 0.5 0 0.0 0 60 120 180 0 60 120 180 Time (min) Time (min)Nauck MA, et al., J Clin Endocrinol Metab 1986; 63:492–498.
  • Incretin Effect in Subjects without and with Type 2 Diabetes Given Glucose by IV and Orally Control Subjects Patients with Type 2 Diabetes (n=8) (n=14) 0.6 0.6 80 80 Incretin Effect 0.5 0.5 60 60IR Insulin, mU/L IR Insulin, mU/L 0.4 0.4 nmol/L nmol / L 40 0.3 40 0.3 0.2 0.2 20 20 0.1 0.1 0 0 0 0 0 60 120 180 0 60 120 180 Time, min Time, min Oral glucose load Intravenous (IV) glucose infusion Nauck M et al., Diabetologia 1986; 29:46–52.
  • Incretin Action: Role of Glucagon Like Peptide -1 (GLP-1) CNS Effects: Promotes satiety and reduction of appetite LIVER Less glucagon = lesshepatic glucose output BETA CELL Increases insulin secretion ALPHA CELL STOMACH Decreases post-meal Slows gastric glucagon secretion emptyingAhren B Curr Diab Rep 2003; 3:365-372.Baggio LL and Drucker DJ. Gastroenterology 2007; 132:2131-2157.
  • How GLP-1 is Rapidly Degraded by DPP-4 Active GLP-1 His Ala Glu Gly Thr Phe Thr SerAsp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala DPP-4 Arg Gly Lys Val Leu Trp DPP-4 Cleaves Here (Half-life = 60-90 seconds) Inactive GLP-1 (can’t bind to GLP-1 receptor) Glu Gly Thr Phe Thr SerAsp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile + Ala Arg Gly Lys Val Leu Trp His AlaMeier et al., Diabetes Metab Res Rev 2005; 21:91–117.
  • What is the role of Dipeptidyl-Peptidase 4(DPP-4)? DPP-4 is a ubiquitous(present everywhere) serine protease  High levels in lumen of intestine, liver, lung, kidney  Membrane-bound and free-circulating form Multiple Substrates  Incretins (GLP-1, GIP)  Hormones (prolactin, IGF-1, luteinizing hormone)  Neuropeptides (substance P, neuropeptide Y)  Chemokines (CCL22) Expressed on surface of T-cells  T-cell activation and other immunological responsesIdris and Donnelly, Diabetes,Obesity and Metab. 2007; 9:153–165.
  • Are type 2 diabetesand pre-diabetespart of a larger syndromethat contains a constellation ofadditional metabolicabnormalities?
  • National Cholesterol Education Program Definition of Metabolic Syndrome Any three of the following: Risk Factor Defining Level Abdominal obesity Waist circumference Men: > 40 in (>102 cm) Women: > 35 in (>88 cm) Triglycerides > 150 mg/dL HDL-C Men: < 40 mg/dL Women: < 50 mg/dL Blood pressure > 135/85 mm/Hg Fasting glucose > 100 mg/dLNCEP ATP III. JAMA 2001, 285:2486.
  • Treatment Options for Type 2Diabetes: Matching therapy todefect
  • Targeting Therapies to the Natural History of Type 2 Diabetes Exercise Thiazolidinediones (TZD) Medical Metformin Insulin Nutrition Therapy Secretagogues GLP-1 Agonist DPP-4 Inhibitors α Glucosidase Inhibitors Insulin Resistance Insulin Level Pre Diabetes Metabolic Syndrome Impaired Incretin Action -15 -10 -5 0 5 10 15 20 25 30 Onset Diabetes Clinical Diagnosis Years ©2010 International Diabetes Center. All rights reserved
  • From Staged Diabetes Management Quick Guide 5th Edition, 2009
  • Insulin Sensitizer: Metformin Action  Precautions and – Decreases liver glucose contraindications production • Kidney disease: serum creatinine >1.4 F, >1.5 M Clinical indicators (eGFR <60 ?)(<30???????) – Effective at any BMI • Liver disease: if present or if – A1C <9% as monotherapy excessive alcohol intake, – High fasting blood glucose metabolic acidosis (160-250 mg/dL) • Heart disease: Active cardiac – Dyslipidemia or pulmonary disease • Surgical procedures: Hold Side effects metformin at time of, or prior to, – GI distress (affecting weight iodinated contrast dye loss?) – Metallic taste Blonde et al. The Endocrinologist 1996:6:431-438. Ong et al. Diabetes Care 29:2361-2364, 2006
  • Metformin is 1st line therapyUKPDS 35: Lancet. 1998;352:837-853UKPDS 38: BMJ 317, 703-713, 1998UKPDS 32: BMJ 316:823-8, 1998
  • Dose Effect: Metformin Metformin Dose 500 mg 1000 mg 1500 mg 2000 mg 2500 mg Change in FPG (mg/dL) 0 -20 -19 - 31 -40 - 41 -60 - 62 -80 - 78Garber et al., Am J Med, 1997.
  • Targeting Therapies to the Natural History of Type 2 Diabetes Metformin Insulin Thiazolidinediones (TZD) GLP-1 Agonist Secretagogues DPP-4 Inhibitors Alphaglucosidase inhibitors Medical Nutrition Therapy Insulin Resistance Insulin Level Pre Diabetes Metabolic Syndrome Impaired Incretin Action -15 -10 -5 0 5 10 15 20 25 30 Onset Diabetes Clinical Diagnosis Years
  • Insulin Sensitizer: ThiazolidinedionePioglitazone (Actos®) and Rosiglitazone (Avandia®) Action  Precautions and Contraindications Improves insulin sensitivity Kidney Disease: monitor Clinical indicators volume status Insulin resistance Liver Disease: don’t Overweight/obese initiate therapy if ALT>2.5X upper limit of normal, more High fasting blood glucose monitoring for mildly Metabolic syndrome elevated ALTs Side effects Heart Disease: Evidence of NYHA class III or IV Edema (concern with CHF) cardiac status Weight gain Pregnancy
  • Thiazolidinediones (TZDs) Adverse Effects and Safety  Black box warning for CHF Observe patient for rapid weight gain, edema, dyspnea  Peripheral edema 2-7% of subjects in clinical trials  Increased risk of bone fracture in women and men Hand, wrist, and hip  Hepatic safety Pio/rosiglitazone - no increased risk of abnormal liver function studies; interval monitoring of ALT still advisedGrey et al. J Clin Endocrinol Metab 2007; 92:1305–1310;Meier et al. Arch Intern Med 2008; 168:820-825.
  • Effect of Thiazolidinediones Peroxisome Proliferator-Activated Receptor (PPAR) Agonists Muscle Adipose Tissue  Increase glucose uptake &  Shift from visceral to disposal subcutaneous fat  Lower FFA levels (reducing insulin resistance) TZD Liver PPARγ  Decrease glucose production Activate Gene Blood Vessel Expression  Lower BP Cell Signaling Pancreas  Reduce inflammation  Improve Beta-cell function Nucleus Inside Cell Lipid Profile  Pioglitazone: Triglyceride, HDL  Rosiglitazone: LDL, HDLSimonson and Kendall Curr Opin Endocrinol Diabetes 2006; 13:162–170.
  • Targeting Therapies to the Natural History of Type 2 Diabetes Insulin Thiazolidinediones (TZD) GLP-1 Agonist Secretagogues DPP-4 Inhibitors Alphaglucosidase inhibitors Medical Nutrition Metformin Therapy Insulin Resistance Insulin Level Pre Diabetes Metabolic Syndrome Impaired Incretin Action -15 -10 -5 0 5 10 15 20 25 30 Onset Diabetes Clinical Diagnosis Years
  • Insulin Secretion: Normal vs. Type 2 Diabetes 200 mg/dL Glucose 2.5 Secreted Insulin Normal (ng/ml/islet) 2.0 1.5 Diabetes 1.0 0.5 0 2 4 6 8 10 12 14 16 18 Time (hours)Diabetes 1989; 38:673.
  • Insulin SecretagoguesGlipizide (Glucotrol®), Glyburide (Diabeta®), Glimepiride(Amaryl®), Repaglinide (Prandin®), and Nateglinide (Starlix®) Action  Side effects • Releases insulin from • Weight gain pancreas in response to a Hypoglycemia glucose challenge  Precautions and • Repaglinide and Nateglinide have a short contraindications half-life • Kidney disease: use with caution Clinical Indicators • Liver disease • Insulin deficiency • Pregnancy • Leaner patients • High postprandial BG 200-300 mg/dL
  • Monotherapy Failure at 5 Years ADOPT Study; FPG >180 mg/dLKahn et al., NEJM 2006; 355:2427-2443.
  • Dipeptidyl Peptidase-4 InhibitorSitagliptin (Januvia) and Saxagliptin (Onglyza)  Action DPP-4 Inh. Selective inhibitor of dipeptidyl peptidase -4 (DPP-4) Increases GLP-1 levels 2-3 fold Enhances insulin secretion, reduces glucagon levelsDPP-4 X His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Gly Lys Val Leu  Side effects Arg Very well tolerated; very low risk of hypoglycemia Weight neutral  Precautions and contraindications Kidney disease; adjust dosage Pregnancy (Category B)
  • Sitagliptin and Metformin Monotherapy and Combination Duration 24 weeks; Baseline A1C = 8.8% n=175 n=178 n=177 n=183 n=178 0 Mean A1C Reduction (%) -0.5 (-0.8) (-1.0) -1 Sita 100 mg Met (-1.3) qd 500 mg -1.5 bid Met (-1.6) 1000 mg bid Sita 50 mg -2 + Met (-2.1) 500 mg bid Sita 50 mg -2.5 + Met 1000 mg bidGoldstein et al. Diab Care 2007; 30:1979-1987.
  • DPP-4 Inhibitor vs. SulfonylureaChange in A1CDepending on baseline A1C Change in Weight S U DPP- 4
  • New Summary of Available DPP-4 Inhibitors Medication Indications Dose HbA1c ↓ Sitagliptin (Januvia®) Monotherapy, metformin, 100 mg 0.6-0.9% TZD, sulfonylurea daily* Vildagliptin (Galvus®)** Metformin, TZD 50 mg 2x/ 0.6-1.0% (not available in US) day Sulfonylurea 50 mg daily Saxagliptin (Onglyza®) Monotherapy, metformin, 2.5 or 5 mg 0.6-0.9% TZD, sulfonylurea daily*** *Dose adjustment for renal disease: CrCl ≥30-49 mL/min: 50 mg daily; CrCl <30 mL/min: 25 mg daily** Contraindicated for patients with liver impairment***Dose adjustment for renal disease: CrCl<50 mL/min: 2.5 mg daily
  • Targeting Therapies to the Natural History of Type 2 Diabetes Insulin GLP-1 Agonist DPP-4 Inhibitors Alphaglucosidase inhibitors Medical Nutrition Metformin Thiazolidinediones (TZD) Therapy Insulin Resistance Secretagogues Insulin Level Pre Diabetes Metabolic Syndrome Impaired Incretin Action -15 -10 -5 0 5 10 15 20 25 30 Onset Diabetes Clinical Diagnosis Years
  • Alpha-Glucosidase InhibitorAcarbose (Precose®) and Miglitol (Glyset®) Action  Precautions and – Delays carbohydrates contraindications absorption by interfering Kidney disease: Serum with their breakdown creatinine >2.0 mg/dL Clinical indicators Liver disease: Evidence of – Insulin deficiency/ severe disease insulin resistance Heart disease: none – A1C<8% as monotherapy Inflammatory bowel – High post-prandial disease blood glucose Pregnancy Side effects – Flatulence, abdominal pain, and diarrhea – Generally poorly tolerated
  • Targeting Therapies to the Natural History of Type 2 Diabetes Insulin GLP-1 Agonist Alphaglucosidase inhibitors Medical Nutrition Metformin Thiazolidinediones (TZD) Therapy Insulin Resistance Secretagogues DPP-4 Inhibitors Insulin Level Pre Diabetes Metabolic Syndrome Impaired Incretin Action -15 -10 -5 0 5 10 15 20 25 30 Onset Diabetes Clinical Diagnosis Years
  • Incretin Mimetic (GLP-1 Analog)Exenatide (Byetta®)  Action – Enhances glucose-dependent insulin secretion – Slows gastric emptying – Reduce food intake  Clinical Indicators – Elevated postmeal BG – In combination with metformin, sulfonylurea, thiazolidinedione or metformin/sulfonylurea  Side effects – Nausea (~40% patients) vomiting (13%) and diarrhea (13%) – Hypoglycemia with sulfonylurea  Precautions and Contraindications – Kidney Disease: Creatine Clearance <30 ml/min – Gastrointestinal disease – Pregnancy (Category C)
  • Effect of Exenatide in Combination with Oral Therapies Baseline vs. 30 weeks 5 µg BID 10 µg BID Placebo 0.4 Change in A1C (%) from Baseline Baseline Baseline Baseline A1C 8.7% A1C 8.5% A1C 8.6% 0.2 0 -0.2 -0.4 P<0.001 -0.6 P<0.0001 P<0.0001 -0.8 P<0.001 P<0.0001 P<0.0001 -1 Exenatide Exenatide + Exenatide + + Metformin Sulfonylurea Met and SUBuse JB, Diabetes Care 2004; 27:2628–2635.Defronzo RA, Diabetes Care 2005; 28:1092–1100.Kendall DM, Diabetes Care 2005; 28:1083–1091.
  • When to Inject Exenatide Placebo -60 minutes Plasma glucose (mg/dL) Meal -15 minutes 250 0 minutes +30 minutes 200 +60 minutes 150 100 50 -60 0 60 120 180 240 300 360 Time after meal (minutes) N=18, randomized, six way crossover study, with fixed breakfastLinnebjerg et al., Diab Med 2006; 23:240–245.
  • Liraglutide (Victoza®) GLP-1 analog Half-life 13 hours, resistant to DPP-4 degradation Daily injection (weekly titration 0.6 mg to 1.2 mg to 1.8 mg) G.I. Side effects common (~15-30% report nausea; 10-15% report diarrhea) and transient in nature Approved January, 2010, not recommended as first-line therapy, rather in combination with Met, SU, TZDs His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Gly Ile Ala Trp eu Albumin A rg V al L Gly Arg Gly
  • Liraglutide (Victoza®) Precautions andContraindications  Not for treatment of type 1 DM  Has not been studied in combination with insulin  Not studied in patients with history of pancreatitis  7 cases pancreatitis vs. 1 in comparator (2.2 vs. 0.6 cases /1000 pts years)
  • Liraglutide vs. Sulfonylurea (LEAD-3)Effects on A1C and Weight at 52 Weeks Change in A1C (%) from Baseline Baseline A1C 8.3% Baseline Weight ~205 lbs 0 6 Change in Weight (lbs) from Baseline -0.2 4 -0.4 2 -0.6 0 -0.8 -2 -1 -4 -1.2 -6 1.2 mg 1.8 mg Glimepiride 1.2 mg 1.8 mg Glimepiride n=251 n=247 n=248 n=251 n=247 n=248 Garber et al. Lancet 2009; 373:438-449
  • Targeting Therapies to the Natural History of Type 2 Diabetes Insulin GLP-1 Agonist Medical Nutrition Metformin Thiazolidinediones (TZD) Therapy Insulin Resistance Secretagogues Alphaglucosidase inhibitors DPP-4 Inhibitors Insulin Level Pre Diabetes Metabolic Syndrome Impaired Incretin Action -15 -10 -5 0 5 10 15 20 25 30 Onset Diabetes Clinical Diagnosis Years
  • The Burden of Type 2 DiabetesTreatment FailureMean A1C at Last Visit* 10 9.6% 8.9% Combination (%) 9 8.6% oral agents SU or Diet and metformin 8 Exercise 7 ADA Goal 2.5 Years 2.9 Years 2.8 Years Initiation 8.2 Years of insulin therapy Years Elapsed Since Initial Diagnosis *Adapted from: Brown JB et al. Diabetes Care. 2004;27:1535-1540.
  • The Role of Insulin TherapyCritical role in both Type 1 and Type 2 diabetes  Greatest potency of available therapies  Demonstrated benefit – multiple clinical trials Impaired Insulin Incretin Action Deficiency Insulin Relative Insulin Resistance DeficiencyType 1 Diabetes Pre-diabetes and Type 2 Diabetes
  • Clinical Indicators for Insulin in Type 2 DiabetesInitiate if: A1C >7% for 3 months and on maximum effective dose of 2 or more glucose-lowering agents Symptomatic and glucose >300 mg/dL If clinically stable and high intake of sweetened Beverages (>36 oz or 3 cans/day), eliminate sweetened Beverages and re-evaluate need for insulin in 1-2 weeks Staged Diabetes Management Quick Guide 5th Edition, 2009
  • Normal Insulin SecretionMealtime (bolus)insulin needs ~ 50%
  • Insulin Time Action Curves Rapid-Acting: Lispro, Aspart, GlulisineRelative Insulin Effect Short-Acting: Regular Intermediate: NPH Long-Acting: Glargine, Detemir 0 2 4 6 8 10 12 14 16 18 20 Time (Hours) Bergenstal, Effective insulin therapy. International Textbook of Diabetes Mellitus Vol 1. 3rd Ed Chichester NY, John Wiley and Sons, Inc. 2004:995-1015.
  • Selecting an Insulin Regimen Background Background and Premixed Insulin (Basal) Insulin Mealtime Insulin ± Sensitizer(s) + Oral Agent(s) ± Sensitizer(s)Glycemic •Elevated fasting • Elevated PPG •Elevated FPGFactors and/or post-meal • Increasing daytime BG •Stable daytime BG •Intensive controlPatient •More flexibility •Decreased dexterity •OverwhelmedFactors •Erratic schedule or visual acuity •Desire single injection •Regular schedule Type 2 Insulin Guidelines © 2007 International Diabetes Center, Park Nicollet Institute
  • Basal (Background) Insulin in Type 2 Diabetes TZD or Metformin SU (LA 0.1 – 0.2 U/kg)
  • Basal (Background) andBolus (Mealtime) Insulin Regimen Metformin
  • Premixed withRapid Acting Insulin Regimen Humalog Mix 75/25 or NovoLog Mix 70/30 Metformin
  • Targeting Therapies to the Natural History of Type 2 Diabetes Insulin Medical Nutrition Metformin Thiazolidinediones (TZD) Therapy Insulin Resistance Secretagogues Alphaglucosidase inhibitors DPP-4 Inhibitors GLP-1 Agonist Pre Diabetes Metabolic Syndrome Impaired Incretin Action -15 -10 -5 0 5 10 15 20 25 30 Onset Diabetes Clinical Diagnosis Years
  • From Staged Diabetes Management Quick Guide 5th Edition, 2009