NO DISCLOSURES. Modern Management of Diabetes Mellitus. Case 1. Case 2. What should be done now? What should be done now?

Transcription

1 Modern Management of Diabetes Mellitus UCSF Primary Care Update Hawaii April 7, 2014 Elizabeth J. Murphy, MD, DPhil Professor of Clinical Medicine University of California, San Francisco Chief, Division of Endocrinology San Francisco General Hospital NO DISCLOSURES 2 Case 1 54 yow BMI 28 and family history of diabetes recently diagnosed with DM2 based on an A1C of 6.9%. 60 yom with BMI 32, DM2 for 5 years. On year A1C has increased to 8.2%. What should be done now? What should be done now? 3 4 1

2 Case 3 72 yom BMI 32 with CVD s/p CABG, 10 year history of DM2, CRI (Cr 2) with worsening PDR. On basal insulin, A1C 8.2%. What should be done now? Diabetes in 1940s and 50s Mortality o Newly dx 10 y old, life expectancy 45 y o 1/3 of patients died within 25 y of dx o Newly dx 50 y old, life expectancy 66 y Goals o Prevent hospitalization and death DKA Hyperosmolar Coma Severe hypoglycemia 5 6 The Queen of Pee Urine Dip Stick s President of American Chemical Society, American Society for Clinical Chemistry 1956 with her husband Al Free developed dry reagents for urinalysis (CLINSTIX) Made at home monitoring of glucose control possible for the first time Led to a test strip to measure glucose in the blood 7 8 2

3 First Glucose meter - Ames Reflectance Meter Introduced 1971 For use in doctors office only $500 Used a Dextrostix strip Wash the strip, put a drop of blood on it, wait 60s, wash it off with water, blot it Self Monitoring Blood Glucose 1980s patient friendly models available Originally strong opposition from clinicians/ada 1986 ADA finally recommended use for insulin users Allowed for the first time accurate home determination of blood glucose levels Allowed for a new degree of tight control 9 10 HbA1C 1969 Increase in diabetes was noted Mid 1970s Became available as a clinical test 1976 Showed lowering glucose lowered HbA1c s Began seeing more widespread use in DM 2009 o Assay standardized so that A1C becomes a diagnostic criteria for DM Tight Control Trials Start of UKPDS - DM Start of the DCCT - DM1 1 NEJM 1976; 295:

4 DCCT - Conventional Therapy Young (<40) DM1 patients without complications Conventional therapy o Insulin QD or BID (lente, ultralente, NPH, R) o Daily urine or blood glucose monitoring o Diet and exercise education Goals o Absence of symptoms of glycosuria or hyperglycemia o Absence of ketonuria o Maintenance of normal growth, development and ideal body weight o Avoidance of severe or frequent hypoglycemia UKPDS - Treatment Goals Patients newly diagnosed with T2DM Conventional Therapy o FPG < 270 mg/dl (in lab, no SMBG available) o No symptoms of hyperglycemia o Diet instruction from a dietician Therapeutic Options o Sulphonylureas o Metformin o Insulin New England Journal of Medicine, 329(14), September 30, Lancet, 1998; 352: Number and Percentage of U.S. Population with Diagnosed Diabetes, Estimated lifetime risk of developing diabetes for individuals born in the United States in 2000 Percentage with Diabetes Percentage with Diabetes Number with Diabetes Number with Diabetes (Millions) Year 0 CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at Narayan et al, JAMA,

5 Number of people with diabetes (20-79 years), 2010 and 2030 What is the only safe way to treat DM long-term? Don t develop it in the first place. Economic Costs of Diabetes, 2012 Relative HgA 1c Total cost of diabetes $245 billion excess medical expenditures $176 billion to treat diabetes directly to treat diabetes-related chronic complications attributed to diabetes excess medical costs reduced national productivity: $27 billion $58 billion $31 billion $69 billion American Diabetes Association website. Diabetes Care. 2013; 5

6 Case 1 54 yow BMI 28 and family history of diabetes recently diagnosed with DM2 based on an A1C of 6.9%. 60 yom with BMI 32, DM2 for 5 years. On year A1C has increased to 8.2%. What should be done now? a) Explain to the patient they are at goal but provide DM education (lifestyle modification) as well b) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose c) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose, provide glucose meter teaching with recommended daily BS checks Case 3 72 yom BMI 32 with CVD s/p CABG, 10 year history of DM2, CRI with worsening PDR. On basal insulin but A1C still at 8.2%. What should be done now? a) Explain to the patient the need for aggressive control to reduce complications, add meal time insulin, goal A1C 7%, SMBG QID b) Explain to the patient the need to improve his glucose control, goal A1C 7%, emphasize improved adherence, diet and exercise c) Explain to the patient the need to improve his glucose control, goal A1C 8%, emphasize improved adherence, diet and exercise d) Tell the patient it would be good to improve his glucose but he has lots of other medical problems and he s close to goal. Just don t let it get worse. Tight Control Trials DCCT UKPDS ACCORD ADVANCE VADT

7 DCCT - Outcomes, 6.5 y f/u Median HbA1c concentrations during DCCT, the training period between DCCT and EDIC, and EDIC 76% reduction in risk for development of retinopathy 54% reduction in risk of progression of retinopathy 39% reduction in risk of new microalbuminuria 54% reduction in risk of albuminuria 60% reduction in neuropathy No significant reduction in macrovascular disease (41% reduction, NS) New England Journal of Medicine, 329(14), September 30, Nathan D M, and for the DCCT/EDIC Research Group Diabetes Care 2014;37: DCCT/EDIC - Prevalence and Incidence of Albuminuria DCCT/EDIC - Cumulative Incidence CVD Outcomes 42% reduction in CVD risk 57% reduction in risk of nonfatal MI, stroke or CVD death JAMA 2003;290: N Engl J Med 2005;353:

8 Tight Glucose vs Tight Blood Pressure Control in the UKPDS UKPDS 10 y follow-up Intensive Glucose Control 0 % Reduction In Relative Risk Stroke 5% Any Diabetic Endpoint DM Deaths % 10% % +* % +* % +* Tight Glucose Control P < 0.05 compared to conventional rx *P <0.05 compared to glucose control Microvascular Complications 32% + 37% +* Tight BP Control 0.85* 0.87* 0.67* 0.73* Turner RC, et al. BMJ. 1998;317: NEJM, 2008; 359: Tight Control Trials ACCORD - Primary and Secondary Outcomes DCCT UKPDS ACCORD ADVANCE VADT 31 The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:

9 ACCORD: Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups T2DM Trial Subject Comparison UKPDS ADVANCE ACCORD VADT # 4,209 11,140 10,251 1,791 subjects Age (y) BMI Dx (y) New A1C % The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358: T2DM Trial Complication Comparison UKPDS ADVANCE ACCORD VADT Any 36% % retinopathy Severe eye - 7% - 6% dz Macroalb 2% 3.5% - 19% Microalb 12% 27% - 29% CVD 7.5% 32% 35% 40% T2DM Trial A1C Lowering Comparison UKPDS ADVANCE ACCORD VADT Starting A1C% Goal A1C% < Int. A1C% Ctrl A1C% Duration of Follow-up 10+10=

10 Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS DCCT / EDIC* ACCORD ADVANCE What I know About Glucose Lowering 1. Lowering A1C prevents microvascular complications. The lower the better. The earlier in the disease the better. 2. Lowering A1C early in the disease prevents macrovascular complications. VADT Kendall DM, Bergenstal RM. International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024) Initial Trial Long Term Follow up * in T1DM Case 1 54 yow BMI 28 and family history of diabetes recently diagnosed with DM2 based on an A1C of 6.9%. Five things Physicians and Patients Should Question What should be done now? a) Explain to the patient they are at goal but provide DM education (lifestyle modification) as well b) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose c) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose, provide glucose meter teaching with recommended daily BS checks

11 Self-Monitoring of Blood Glucose In patients not treated with insulin, self-monitory was associated with higher A1C and increased psychological burden. 1 Other studies show a modest benefit SMBG can have an important role in improving metabolic control if part of a wider educational strategy Selected monitoring may be more effective than daily monitoring Metformin Advantages: o Lowers A1C 1.5-2% o Weight loss (0-2 kg) o Lowers TG, LDLc; Increases HDLc o No hypoglycemia when used alone o Inexpensive Disadvantages o Majority of patients with GI SE o Risk of lactic acidosis o Impairs B12 absorption 1 Franciosi et al, Diabetes Care 24:1870, Metformin and B12 True B12 deficiency is associated with megaloblastic anemia, peripheral neuropathy (which could be misdiagnosed as diabetic neuropathy), depression and cognitive impairment. Metformin consistently decreases B12 levels in a dose and duration dependent manner Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomized placebo controlled trial BMJ 2010;340:c

12 Metformin and B 12 Classic symptoms often absent with biochemical B12 deficiency Some feel to make the diagnosis one needs to show a defect in a functional biomarker as well (e.g. MMA or total homocysteine) Could consider checking for megaloblastic anemia yearly, checking B12 levels every 2-3 years Case 1 54 yow BMI 28 and family history of diabetes recently diagnosed with DM2 based on an A1C of 6.9%. What should be done now? a) Explain to the patient they are at goal but provide DM education (lifestyle modification) as well b) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose c) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose, provide glucose meter teaching with recommended daily BS checks yom with BMI 32, DM2 for 5 years. On year A1C has increased to 8.2%. 60 yom with BMI 32, DM2 for 5 years. On year A1C has increased to 9.2%

13 82 yom with BMI 32, DM2 for 5 years. On year A1C has increased to 9.2%. 60 or 82 yom with BMI 32, DM2 for 5 years. On year A1C has increased to 8.2% or 9.2% or 82 yom with BMI 32, DM2 for 5 years. On year A1C has increased to 8.2% or 9.2%. HYPOGLYCEMIA adverse drug reporting and a national household survey of insulin use 97,648 ED visits annually for insulin-related hypoglycemia and errors 29% hospitalized Over 80 years old c/w Double the rate of ED visits 5 fold increase in hospitalization Most common causes were decreased food intake and using the wrong insulin 51 Geller et al., JAMA Intern Med. Published online March 10,

14 Food Insecurity & Diabetes (US Low Income Population, NHANES ) 21 million adults 8.3 million kids 12 million adults 977,000 kids % 10.2% Food secure Food insecure p=0.03 after adjusting for age, gender, race/ethnicity; p=0.09 after adjusting for above + education + income as continuous Seligman, Jl Nutr, variable + income as ordinal variable 60 or 82 yom with BMI 32, DM2 for 5 years. On year A1C has increased to 8.2% or 9.2%. TZDs Lower A1C % no hypoglycemia when used alone November, 2013 FDA lifted its earlier restrictions on rosiglitazone prescribing CVD risk?, if so more likely in folks with CHF at baseline More concerning risks o Osteoporosis and increased fracture (dose and duration dependent) o Bladder cancer with pioglitazone? (dose and duration dependent) o Weight gain, edema Good for significant A1C lowering when there is a major concern for hypoglycemia Should be stopped when insulin is started Preference for pioglitazone

15 60 or 82 yom with BMI 32, DM2 for 5 years. On year A1C has increased to 8.2% or 9.2%. 57 Plasma Insulin Responses to Oral and Intravenous Glucose Non-Diabetic Insulin ( U/mL) Oral Intravenous Insulin ( U/mL) Diabetic Oral Intravenous Minutes GIP, GLP-1, CCK T 1/2 2-5 minutes Minutes J Clin Invest 1967; 46: GLP-1 as a Therapeutic Target Long Acting GLP-1 Analogues Longer Acting GLP-1 Heloderma suspectum Gila Monster Prevent GLP-1 Breakdown DPPIV- Inhibition (also increases GIP) Exenatide (Byetta) o BID SC injection o Qweek SC Injection (LAR) Liraglutide (Victoza) o QD SC injection Albiglutide (Syncria) Taspoglutide Semaglutide Lixsenatide

16 DPPIV Inhibitors Sitagliptin (Januvia) Vidagliptin (Galvus) Saxagliptin (Onglyza) Alogliptin Linagliptin (Ondera) Dutogliptin Metogliptin GLP-1 Analogue Actions Lower A1C % Advantages: o Weight loss (2-3 kg), less hypo Disadvantages: o Injectable o GI Side Effects (nausea, vomiting) o Expensive o Pancreatitis? o Pancreatic cancer? o Medullary thyroid cancer? Improvements in HbA 1C With Initial Coadministration of Sitagliptin and Metformin DPPIV Inhibitors HbA 1C (%)* Mean Baseline HbA 1C = 8.8% N= Sita 100 mg QD Met 500 mg BID Met 1000 mg BID Sita 50 mg BID + Met 500 mg BID Sita 50 mg BID + Met 1000 mg BID Lowers A1C % (mean diff from baseline) Advantages: o Oral, weight neutral, less hypo Disadvantages: o Expensive o Nausea Potential AE o Pancreatitis? o Cancer? o Immune modulating effects (T cell effects)? * Placebo-subtracted LS mean change form baseline at Week 24. Sita=sitagliptin; Met=metformin. Aschner P, et al. Oral presentation at the EASD 42 nd Annual Meeting; September 2006; Copenhagen

17 CD26/DPPIV Expressed on the surface of most cell types T-cell activation marker 62 known substrates Tumor suppressor role Inhibitors inhibit T-cell proliferation Good or evil: CD26 and HIV infection. J Derm Sci. 2000; 22: Role of CD26/dipeptidyl peptidase IV in human T cell activation and function. Front Biosci. 2008;13: Dipeptidyl peptidase IV (DPPIV), a candidate tumor suppressor gene in melanomas is silenced by promoter methylation. Front Biosci : yom with BMI 32, DM for 5 years. On year has increased to 8.2% or 9.2% Renal Handling of Glucose SLGT2 Inhibitors (180 L/day) (900 mg/l)=162 g/day Glucose SGLT2 S1 SGLT1 90% S3 10% No Glucose Lowers A1C about 1% at max dose No hypoglycemia when used alone or with MF Advantages Weight loss kg Decrease in SBP 5 mmhg Disadvantages Increased mycotic genital infections in men and women (10% of women get yeast infections) Increased UTIs and fracture Polyuria, presyncope, sycope Increases Cr, decreases egfr, can cause hyperkalemia Expensive 17

18 SGL2 Inhibitors Canagliflozin (Invokana) Dapagliflozin (Fraxiga) rejected by FDA for safety concerns, resubmission approved 1/2014 Ipragliflozin Tofogliflozin Empagliflozin Remogliflozin etabonate Mean difference from placebo PRANDIN vs. Placebo Treatment After 3 months of Treatment The between-group change in HbA1c, which reflects long-term glycemic control, was 1.7% units. HbA1c (%) PL R Baseline Change from Baseline * PL = placebo (N=33) R = repaglinide (N=66) *: p< 0.05 for between group difference Source: Package insert Prandin 70 What I know About Glucose Lowering 1. Lowering A1C prevents microvascular complications. The lower the better. The earlier in the disease the better. 2. Lowering A1C early in the disease prevents macrovascular complications. 3. Hypoglycemia, especially in the elderly, is bad. 18

19 Drugs with Poor A1C Effect DPPIV Inhibitors α- glucosidase inhibitors (acarbose,miglitol) Colesevolam (Welchol) Bromocriptine (cycloset) ADA-EASD Position Statement: Management of Hyperglycemia in T2DM ANTI HYPERGLYCEMIC THERAPY Glycemic targets - HbA1c < 7.0% - Individualization is key: Tighter targets ( %) younger, healthier Looser targets ( %+ ) older, comorbidities, hypoglycemia prone, etc. - Avoidance of hypoglycemia 73 Diabetes Care, Diabetologia. 19 April 2012 Good Rx.com A1C Cost/mth Sulfonylurea 1-2% $3-10 Metformin 1-2% $4 Pioglitazone % $69 15 Exenatide % $422 Canagliflozin 0.5-1% $310 Sitigliptin % $ Acarbose % $60 40 Colesevelam % $ Bromocriptine 0.4%? $ Test strips 0.4%? $ ADA Type 2 Consensus Statement Diabetes Treatment Algorithm An American Diabetes Association consensus statement represents the authors collective analysis, evaluation, and opinion at the time of publication and does not represent official association opinion. Diabetes Care. Published online Oct 22,

20 Revised Consensus Algorithm - ADA and EASD Diabetes Care 31:173, Diabetes Care, Diabetologia. 19 April 2012 Trends in Noninsulin antidiabetic drug prescriptions Diabetes Care Publish Ahead of Print, published online March 12, 2014 Trends in new Noninsulin antidiabetic drug prescription Diabetes Care Publish Ahead of Print, published online March 12,

21 Use of Diabetes Medications yom with BMI 32, DM2 for 5 years. On year A1C has increased to 8.2% GOAL A1C < 7% or lower if tolerated without hypoglycemia 0 Biguanides Sulfonylureas Insulins DPP-4 Inhibitors Fixed Dose Combo US UK Germany France Glitazones GLP-agonist Meglitinide IMS Midas Prescribing Insights yom with BMI 32, DM2 for 5 years. On year A1C has increased to 8.2%. 60 yom with BMI 32, DM2 for 5 years. On year A1C has increased to 9.2%

22 80 yom with BMI 32, DM2 for 5 years. On year A1C has increased to 8.2%. GOAL: - Prevent hospitalization and symptomatic hyperglycemia - A1C < 8% or lower if tolerated without hypoglycemia 82 yom with BMI 32, DM2 for 5 years. On metformin for several years but A1C in past year A1C has increased to 8.2% yom with BMI 32, DM2 for 5 years. On year A1C has increased to 9.2%. The Prevalence of Meeting A1C, Blood Pressure, and LDL Goals Among People With Diabetes, Casagrande et al Diabetes Care, 36: ,

23 Crude and Age-Adjusted Incidence of End-Stage Renal Disease Related to Diabetes Mellitus (ESRD-DM) per 100,000 Diabetic Population, United States, Crude and Age-Adjusted Percentage of Adults Aged 18 Years or Older with Diagnosed Diabetes Reporting Visual Impairment, United States,