Type 2 Diabetes Prevention and Therapy. Veronica Piziak MD, PhD Scott and White

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3 Type 2 Diabetes Prevention and Therapy Veronica Piziak MD, PhD Scott and White

4 Disclosures: Research support: J&J Objectives: Epidemiology of diabetes Diagnosis of diabetes Treatment goals

5 Every Day in the United States Approximately 66 people lose their eyesight because of diabetes 128 people begin treatment for end-stage renal disease (ESRD) More than 4000 new cases* of diabetes will be diagnosed today 195 lower-limb amputations are performed because of diabetes 640 people die from diabetes and its complications *Patients ages 20 years. Centers for Disease Control. National Diabetes Fact Sheet. Accessed March 5, 2009.

6 Type 2 Diabetes Associated with Serious Complications Diabetic Retinopathy Leading cause of blindness in adults Stroke CV Disease & Stroke account for ~85% of deaths in T2D patients Cardiovascular Disease Diabetic Nephropathy Major cause of kidney failure Diabetic Neuropathy Major cause of lower extremity amputations CV = cardiovascular. National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics fact sheet: general information and national estimates on diabetes in the United States, Bethesda, MD: U.S. Department of Health and Human Services, National Institute of Health, 2005.

7 Type 2 Diabetes Definition A disorder of glucose, lipid, protein metabolism characterized by peripheral insulin resistance, inadequate pancreatic insulin secretory response and disordered glucagon supression. Risk factors: Obesity Heredity Environment

8 Obesity Trends Among U.S. Adults 2010 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% CDC Data 2010

9 State-specific Prevalence of Obesity* Among U.S. Adults, by Race/Ethnicity, White non-hispanic Black non- Hispanic Hispani c (*BMI 30)

10 High fructose corn syrup GLUCOSE HYPERTRIGLYCERIDEMIA HEART DISEASE

11 Can Diabetes be Prevented? Yes Diet High fiber, low sugar, low fat 5% weight loss 150 minutes of exercise / week

12 When to use Metformin for prevention In addition to lifestyle counseling, metformin may be considered in those who are at very high risk for developing diabetes (combined IFG and IGT plus other risk factors such as A1C >6% Pre diabetes Hypertension, low HDL cholesterol, elevated triglycerides, or family history of diabetes in a first-degree relative) and who are obese and under 60 Metabolic syndrome ADA practice guidelines 2011

13 Diagnosis of Diabetes A1c may now be used Prediabetes % Diabetes 6.5% Laboratory determination, venous sample Not point of care testing ADA practice guidelines 2011

14 Fasting Glucose (mmol/l) Diagnostic Criteria for Diabetes, IFG, and IGT (mg/dl) IFG Normal glucose IFG + IGT IGT h Postload Glucose (mmol/l) IFG = impaired fasting glucose. American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S5-S20. Diabetes (mg/dl)

15 ADA Treatment Goals Hyperglycemia Hypertension Dyslipidemia FPG/ 90 PPG A1C Blood pressure LDL HDL Triglycerides American Diabetes Association. Diabetes Care mg/dl <180 mg/dl < 7% lowest possible without hypoglycemia < 130/<80 lower if renal disease <100 mg/dl, patients with diabetes (70( 70-90) <70 mg/dl, very high risk patients with diabetes and CVD >50 mg/dl, women >40 men < 150mg/dl

16 ADA RENAL GUIDELINES MICROALBUMIN/CREATININE SPOT URINE ANNUAL SCREENING ANNUAL CREATININE ESTIMATE GFR TO CHECK FOR DISEASE calculator.cfm NEED AGE,GENDER,CREATININE,RACE

17 ADA RENAL GUIDELINES ESTIMATE GFR ANUALLY STAGE ML/MIN 1.RENAL DAMAGE NORMAL OR INCREASED GFR =/>90 2.RENAL DAMAGE MILDLY DECREASED GFR MODERATELY DECREASED GFR SEVERELY DECREASED GFR RENAL FAILURE <15 DIALYSIS STAGE 3 OR MORE REFER Diabetes Care 2011; 29:S

18 STATIN IN DIABETES CONTROL OF: LIPIDS LDL < 100 (<70) > Age 40 Statins recommended regardless of LDL Reduce the LDL by 30-40% ADA Practice Guidelines Jan 2011 Diabetes Care Statins are contraindicated in pregnancy Aspirin in any diabetic who has had a CV event and men> 50, women >60 with a risk factor

19 The Goals of Glucose Control Depend on the patient and the duration of disease

20 How Low should we go? Early aggressive therapy <7.0 if possible without hypoglycemia ADA Guidelines Goals of therapy: Control glucose individual level for patient HbA1c 7-7.5% 7 7.5% for patients with multiple comorbidities?? Avoid hypoglycemia! Prevent microvascular complications Prevent macrovascular complications Montori VM, Fernandez-Balsells ann Int Med 2009;150:

21 How low should you go? Community based study of patients between age with Type 2 diabetes A1c and death >10 highest death rate > 8 to < 6 next highest death rate Lowest death rate between 6 8 < 7 goal is from UKPDS Excluded patients age >60 Newly diagnosed diabetes Huang et al Diabetes Care June 2011

22 INVEST Blood pressure control Diabetic patients with SBP not controlled (>( 140 mm Hg) had the worst outcomes. Tight Control < 130 mm Hg) of SBP was not associated with improved CV outcomes compared with Usual Control ( mm Hg) There was increased risk for mortality in the Tight Control group which persisted during extended follow-up SBP < 115 mm Hg was associated with an increase in risk for mortality

23 INVEST Results: Outcomes Tight Control Group All Cause Mortality (n=2255) Adjusted Hazard Ratios Reference 0.5 <110 Other Significant Variables in Cox Regression Model < < < <130 Systolic Blood Pressure (mmhg) Age, Race, PAD, MI, CHF, US Residency, Renal Impairment, LVH, TIA/Stroke Cooper-Dehoff R. ACC Late-Breaking Clinical Trials. Atlanta, GA

24 Intensive vs Conventional Glucose Control in Critically Ill Patients The NICE-SUGAR Investigators 3000 patients completed in each arm, groups well matched Methods Within 24 hours after admission to an intensive care unit (ICU), adults were randomly assigned to undergo either intensive glucose control, target blood glucose range of 81 to 108 mg% conventional glucose control, with a target of 180 mg% or less The primary end point as death from any cause within 90 days after randomization NEJM;360:1283

25 Results: A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control control group died (odds ratio for intensive control, 1.14, 95% confidence interval, 1.02 to 1.28; P=0.02). Operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). NS Severe hypoglycemia (blood glucose level, 40 mg per deciliter was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control control group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0.84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement replacement therapy (P=0.39). Conclusion: Blood glucose target of less than 180 mg% resulted in lower mortality than a target of 81 to 108 mg%. On the basis of our results, we do not recommend use of the lower target in critically ill adults. Check Mayo Clinic Proceedings May 2009;84:400 Question 40, 89 NICE-SUGAR Study

26 Diabetes Education The basis for adequate diabetes control

27 New 2009 AACE/ACE Algorithm Lifestyle Modification A1c %* A1c % A1c > 9.0% MET TZD DPP 2 AGI MET + TZD MET Monotherapy 2 3 months Dual Therapy + MET + GLP-1 + or DPP4 1 GLP-1 or DPP4 1 TZD 2 Glinide or SU 5 GLP-1 or DPP4 1 + Colesevelam 2 3 AGI 3 months Triple Therapy TZD 2 INSULIN ± Other Agent(s) 6 Glinide or SU 4,7 2 3 months MET + MET + Dual Therapy 8 GLP-1 or DPP4 1,10 or TZD 2 SU or Glinide 4,5 Triple Therapy 9 GLP-1 or DPP4 1 GLP-1 or DPP4 1 TZD 2 INSULIN ± Other Agent(s) months +TZ D 2 +SU months Symptoms INSULIN ± Other Agent(s) 6 Drug Naive No Symptoms MET + Under Treatment GLP-1 or DPP4 1 ±SU 7 TZD 2 GLP-1 ±TZD or D DPP4 1 2 INSULIN ± Other Agent(s) 6 Rodbard HW, et al. Endocrine Practice. 2009;15(6):

28 Treating Diabetes: Insulin resistance Beta and Alpha Cell Dysfunction

29 Antidiabetic agents: Mechanism of Action 4 Liver: hepatic glucose output Metformin HGO 1 Intestine: glucose/fat absorption decreased digestion of carbohydrate/fat Acarbose/ bile acid binding resin bromocriptine Insulin resistance Blood glucose 2 Muscle and adipose tissue: glucose uptake/ glucose utilization Metformin, TZDs TZD s careful preserve Beta cell function #43 decrease dose with insulin Insulin resistance 3 Pancreas: insulin secretion Sulfonylureas, nateglinide DeFronzo RA. Diabetes. 1988;37: Lebovitz HE. In Joslin's Diabetes Mellitus. 1994: ; Amatruda JM. In: Diabetes Mellitus DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73: Whitcomb RW et al. In: Diabetes Mellitus. 1996;Cavaghan MK et al. J Clin Invest. 1997;100: Ehrmann DA et al. J Clin Endocrinol Metab. 1997;82: ; Wolffenbuttel BHR. Eur J Clin Pharmacol. 1993;45:

30 GLP-1 1 Modes of Action in Humans Upon ingestion of food Stimulates glucose-dependent insulin secretion Suppress glucagon secretion Slows gastric emptying GLP-1 is secreted from the L-cells in the intestine This in turn Reduces food intake Improves insulin sensitivity Long term effects demonstrated in animals Increases beta-cell mass and maintains beta-cell efficiency Drucker DJ. Curr Pharm Des 2001; 7: Drucker DJ. Mol Endocrinol 2003; 17:

31 Improvement in Cardiovascular Risk Factors with 3.5 Years of Exenatide Treatment (n = 151) Change from Baseline LDL-C C (mg/dl) ± Systolic Blood Pressure (mmhg) -3.5 ± 1.2-2% Diastolic Blood Pressure (mmhg) -3.3 ± 0.8-4% HDL-C C (mg/dl) 8.5 ± % Triglycerides (mg/dl) ± % Total Cholesterol (mg/dl) ± 3.1-5% Weight loss avg 5.3 kg Klonoff DC, et al. Curr Med Res Opin 2008;24: Nausea main side effect (use 20 minutes before meals), pancreatitis possible. Do not use Cr Cl <30 Caution CrCl <50

32 Liraglutide (Victoza) 0.6 mg / day starting dose Titrate mg / day Multidose pens Reduces postmeal glucose (A1c 1% lower) Nausea most common side effect Associated with pancreatitis in rare instances Use with metformin, sulfonylureas, TZD Weight loss 2 kg/26 weeks Medullary carcinoma in animals

33 GLP-1 1 Secretion and Inactivation meal Intestinal GLP-1 release T 1/2 = 1 to 2 min Active GLP-1 DPP-4 GLP-1 inactive (>80% of pool) DPP-4 = dipeptidyl peptidase 4; GLP-1 = glucagon-like peptide 1. Deacon CF, et al. Diabetes. 1995;44:

34 Mean Change in FPG, mg/dl Sitagliptin Monotherapy (Januvia) Significantly Lowers FPG and PPG Levels 24-week placebo-adjusted results FPG Mean Baseline: 170 mg/dl P<0.001* n = 234 (95% CI: 24, 10) Mean Change in 2-Hour PPG, mg/dl Hour PPG Mean Baseline: 257 mg/dl P<0.001* (95% CI: 59, 34) n = 201 *Compared with placebo. Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value. Difference from placebo. CI=confidence interval; FPG=fasting plasma glucose; PPG=postprandial plasma glucose (meal challenge test). Aschner P et al. Diabetes Care. 2006;29:

35 Sitagliptin: Once-Daily Dosing Proven 24-Hour Glycemic Control Patients With Renal Insufficiency*, A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with end-stage renal disease requiring hemodialysis or peritoneal dialysis. 50 mg once daily 25 mg once daily Moderate CrCl 30 to <50 ml/min (~Serum Cr levels [mg/dl] Men: > ; Women: > ) Severe and ESRD CrCl <30 ml/min (~Serum Cr levels [mg/dl] Men: >3.0; Women: >2.5) Assessment of renal function is recommended prior to initiation and periodically thereafter. * can be taken with or without food. Patients with mild renal insufficiency 100 mg once daily. ESRD=end-stage renal disease requiring hemodialysis or peritoneal dialysis. Answer to question #50

36 Saxagliptin (Onglyza) 2.5, 5 mg Lowers A1c about 0.5-1% May be used with dose adjustment in renal insufficiency No weight loss

37 Linaglipitin (Tradjenta) Approved for type 2 diabetes DPP-4 4 inhibitor Monotherapy, combination with Metformin,Sulfonylurea, pioglitazone A1c decreased 0.7% Only 1 dose 5mg/day

38 Bile Acid Binding Resin Colesevelam (Welchol) Approved for use in Type 2 diabetes Lowers A1c by 0.8% 625 mg x 6/day Add on to metformin May increase triglycerides when used with sulfonylurea or insulin. Don t t use when triglycerides are >500 May have GI side effects May cause malabsorption of medications

39 Cycloset - bromocriptine Quick-release formulation of bromocriptine that increases CNS dopaminergic activity. Lowers the A1c by about 0.8 % Weigh neutral, no hypoglycemia Nausea is the major side effect Initial dose is one 0.8 mg tablet daily, titrated weekly by 1 tablet until therapeutic dose (1.6 to 4.8 mg, or between 2 and 6 tablets per day) is achieved.

40 Plasma Insulin Levels Action Profiles of Insulins Aspart, glulisine, lispro 4 5 hours Regular 6 8 hours NPH hours More nocturnal hypoglycemia #73 Detemir ~14 hours Glargine ~24 hours Hours Burge MR, Schade DS. Endocrinol Metab Clin North Am. 1997;26: ; Barlocco D. Curr Opin Invest Drugs. 2003;4: ; Danne T et al. Diabetes Care. 2003;26:

41 What does basal insulin cover? Excessive gluconeogenesis Does this occur in the hospital? Does stress occur in the hospital? Protein and fat intake to some extent Calculate the starting dose: Type 2: units / kg/day Teach the patient to titrate

42 Action Profiles of short acting Insulins Aspart, glulisine, lispro 4 5 hours Regular 6 8 hours Plasma Insulin Levels Hours Burge MR, Schade DS. Endocrinol Metab Clin North Am. 1997;26: ; Barlocco D. Curr Opin Invest Drugs. 2003;4: ; Danne T et al. Diabetes Care. 2003;26:

43 RATE AT WHICH NUTRIENTS CHANGE BLOOD GLUCOSE % C H A N G E Carbohydrate Protein FAT Rate of Change in hours

44 Bolus insulin Meal supplement Mainly covers carbohydrate Helps with protein and fat coverage Correction factor Compensates for insufficient basal insulin or insufficient meal supplement If NPO use regular insulin q 6 hours

45 BOLUS COVERAGE Correction factor Supplemental scale May use anytime Meal times are convenient x units/ y mg%> z mg% Insulin resistance Type units/50 mg%>150 mg%

46 BOLUS INSULINGO FIGURE: Type 2 Diabetes Meal coverage Counting carbohydrates 1 unit / 5-10 gm CHO Can t count carbs? MD count them and estimate the meal supplement

47 Summary Type 2 is increasing at a rate that parallels obesity Prevention is vitally important Consider A1c for diagnosis Treatment goals vary with the duration and of the disease