NMQF. Washington DC 2014

Transcription

1 NMQF Washington DC 2014

2 ACE/AACE Treatment Algorithm Jaime A. Davidson, MD, FACP, MACE Prof. of Medicine Division of Endocrinology, Diabetes and Metabolism President WorldWIDE Diabetes Advisor to the AACE BOD

3 Jaime Davidson, MD Disclosure Information Consultant, and/or an Advisory or Speaker s Board member: AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Company, Bayer Pharmaceuticals, Eli Lilly & Co., Janssen, Roche Diagnostic, Johnson & Johnson, Merck-Sharp and Dome, Novo Nordisk and Sanofi. Dr. Davidson intends to reference unlabeled/unapproved uses of SGLT 2 inhibitors in his presentation.

4 Relationship between Glycemia and Complications DCCT and UKPDS Event Rate per 1000 Pt-Y 43% reduction in risk for every 10% decrease in HbA1c 37% reduction in risk for every 1% decrease in HbA1c DCCT UKPDS Current Mean HbA1c (%)

5 Why Does Diabetes Cost Us So Much? 1. Complications due to poor control 2. Litigious societies adding unnecessary cost to doctors visits, hospitals, pharmacies, medications, etc. 3. Access to care 4. Health education 5. Chronic and complex condition

6 Patients NOT receiving recommended care Diabetes: worst treated US illness 60% 55% Percentage NOT receiving recommended care 1 50% 46% 40% 30% 36% 35% 32% 20% 10% 0% Diabetes Colorectal cancer Congestive heart failure High blood pressure Coronary artery disease 1 McGlynn et al. N Engl J Med 2003;348:

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10 Pathogenesis of Type 2 Diabetes An Evolving Concept Islet b-cell Impaired Insulin Secretion Decreased Incretin Effect Increased Lipolysis Islet a-cell Increased Glucagon Secretion Increased HGP Decreased Glucose Uptake Increased Glucose Reabsorption

11 Considerations for Therapy Selection Baseline HbA1c Efficacy profile Risk for hypoglycemia Risk for fractures Weight effects Adverse event profile Edema GI side effects (nausea, vomiting, diarrhea) Comorbidities Cardiovascular disease Renal impairment Costs and formulary availability

12 Properties of the Ideal Drug Robust HbA1c No hypoglycemia No weight gain Complimentary actions Durability Well tolerated Long-term safety Simple administration Added value e.g., BP, lipids, β cell function, CVD protection, etc.

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15 Endocrine Practice. 2009;15(6): AACE / ACE Diabetes Algorithm: Principles Prioritize medication choices according to safety, risk of hypoglycemia, efficacy, simplicity, anticipated degree of patient adherence and cost of medications. Stratify treatment choices based on A1C level. Recommend only combinations of medications approved by the FDA that provide complementary mechanisms of action.

16 Endocrine Practice. 2009;15(6): AACE / ACE Diabetes Algorithm: Principles Monitor therapy with A1C and SMBG. Adjust or advance therapy frequently (every 2 to 3 months) if appropriate goal has not been achieved. Provide a flowchart and table summarizing major considerations.

17 ADA? O High

18 AACE / ACE Diabetes Algorithm: Principles (2) Minimize risk of hypoglycemia and weight gain When other agents fail to achieve goal, advance to insulin therapy ± oral agents. Starting insulin with an A1c in the 7% range, AM prandial insulin may be best choice Endocrine Practice. 2009;15(6):

19 AACE / ACE Diabetes Algorithm: Principles (2) Individualize therapy for each patient Major cost of diabetes is due to complications, including hypoglycemia. Minimize total cost of care, not cost of medications per se Endocrine Practice. 2009;15(6):

20 % mortality Association of severe hypoglycaemia and risk of mortality in ACCORD 1 or more severe episodes No severe episodes 4 HR 1.41 HR Intensive group Standard group Bonds DE et al. Br Med J 2010; Gerstein HC et al. N Engl J Med 2008; Patel A et al. N Engl J Med 2008

21 Proportion reporting at least one severe hypo UK Study Group: Proportion experiencing at least 1 episode of severe hypoglycaemia over 9 12 months ns * * * Type 2 treated Type 2 < 2 yrs Type 2 > 5 yrs Type 1 < 5 yrs Type 1 > 15 yrs with sulfonylureas UK Hypoglycaemia Study Group. Diabetologia 2007

22 AACE / ACE Diabetes Algorithm: Principles (3) Lifestyle modification, diabetes education, and dietary consultation are essential, have major benefits, and should be initiated with medical therapy. Delay of pharmacotherapy is inappropriate because lifestyle interventions are usually not sufficient. Endocrine Practice. 2009;15(6):

23 AACE / ACE Diabetes Algorithm: Principles (3) An A1C of 6.5% is recommended as the primary goal. This level must be customized for each patient considering: co-morbidities, duration of diabetes, history of hypoglycemia, hypoglycemia unawareness, patient education, motivation, adherence, age, life expectancy and other medications Endocrine Practice. 2009;15(6):

24 AACE / ACE Diabetes Algorithm: Principles (4) Rapid-acting insulin analogues are superior to regular human insulin and provide a better, safer alternative. yield better reproducibility and consistency between patients and within patients reduce risk of hypoglycemia Insulin regimens such as basal, basal-bolus, prandial, pre-mixed and CSII can be combined with a variety of oral agents. Basal analogues preferred Endocrine Practice. 2009;15(6):

25 Insulin Level (mu/ml) Glucose Insulin Rate (mg/min) Rapid Acting Analogues vs Regular Human Insulin Regular human insulin Insulin Lispro Time (hours) Time (hours) 0.05 U/kg (n = 6) 0.1 U/kg (n = 9) 0.2 U/kg (n = 9) 0.3 U/kg (n = 3) Woodworth, et al. Diabetes. 1993;42(suppl 1):54A.

26 Rapid Analogues vs Regular Human Insulin Analogues T max (hours)* Regular human * 0.2 U/kg SC. Diabetes Care. 1996;19:1437.

27 GIR (mg/kg/min) Basal Insulin Variability Same Patient NPH Glargine Detemir Time (hrs) Heise T et al. Diabetes 2004;53:

28 Major Advantages of the AACE Algorithm 1. Includes all major classes of medications 2. Does not relegate important agents to a second tier 3. Incretin analogs and DPP-4 inhibitors are not relegated to a category of too new. SGLT-2 inhibitors are also included 4. Suggested agents based on A1C level and targeted agent activity 5. Attempts to reduce total costs of care including costs related to hypoglycemia and complications 6. Simple graphical layout with emphasis on early intervention and A1c at presentation 7. Simplified table of Benefits and Risks of each medication

29 Early vs Late Intervention in Type 2 Diabetes Trial Intensive Arm HbA 1c Reduction No. Patients/ Trial Duration Disease Severity Goal: <6.0% CVD or 2 risk N=10,251 factors ACCORD Endpoint: 6.4% Early diagnosis and intensive 3.4 yr glucose 10 yr from T2DM 1.4% from BL in 4 months diagnosis control therapy from the start are the key to Goal: <6.5% Vascular disease N=11,140 or 1 risk factor ADVANCE long-term Endpoint: risk 6.5% reduction in diabetes 5.0 yr 8 yr from T2DM 0.6% from BL in 12 months diagnosis VADT UKPDS 80 Goal: 1.5% vs standard Endpoint: 6.9% 2.5% from BL in 3 months Goal: FPG <108 mg/dl Intervention endpoint: 7.0% Follow-up: 7.7% N= yr N= yr 12 yr from T2DM diagnosis Newly diagnosed with T2DM Macrovascular Benefit No Yes BL=baseline; T2DM=type 2 diabetes mellitus. Holman RR, et al. N Engl J Med. 2008;359: ; ACCORD Study Group. N Engl J Med. 2008;358: ; ADVANCE Collaborative Group. N En Med. 2008;358: ; Duckworth W, et al. N Engl J Med. 2009;360:

30 Elevated Mealtime Glucose Is a Concern at All Levels of HbA 1c HbA 1c Mean FPG % Patients With FPG >140 mg/dl Mean 2-h Glucose % Patients With 2-h Glucose >200 mg/dl < > In diagnosed and undiagnosed diabetes only from NHANES III ( ). FPG=fasting plasma glucose.

31 Mean HbA 1c at Last Visit Clinical Inertia: Standard Therapeutic Approaches Lead to Prolonged Hyperglycemia 10% Insulin Combination 9.6% Diet/Exercise Monotherapy Therapy 9% 8.6% 9.0% 8% 7% ACE Goal 6.5% 6% Diagnosis Years At insulin initiation, the average patient had 5 years with HbA 1c >8% 10 years with HbA 1c >7% Brown JB, et al. Diabetes Care. 2004;27:

32 A1C (%) Glucose control : 4 years of data in managed care (N 9376) SU TZD MET (n=2,373) (n=1,590) (n=5,453) Time (months) Riedel AA, et al. Diabetes. 2006;55(suppl 1):A132.

33 First Step- Metformin + Lifestyle Recognizes failure of life-style alone Inhibits hepatic glucose outputpredominantly lowers fasting glycemia Lowers HbA1c by ~1.5% No hypoglycemia Effective in obese and non-obese patients and in preventing diabetes in pre-diabetics (DPP) Glucophage off-patent, very inexpensive

34 Daily glycemic variation (mmol/l) by A1c levels in Breakfast type 2 diabetes 14 Fasting (nocturnal period) Postprandial (daytime period) Morning Period < Diabetes Duration (yrs) L Monnier,C Colette, G Dunseath and D Owens. Diabetes Care. 2007;30:

35 HbA1c (%) Initial Treatment : Insulin plus Metformin in Type 2 Diabetes HbA1c Results Baseline 3-month 5.9 Lingvay et al, J. Investigative Medicine 55: 62, 2007

36 Percent with First Adverse Event Phase 2b/3 Pooled Population Time to Onset of First Primary MACE HR 0.45 (95%CI ) Control n= BL Weeks Patients at Risk Control All SAXA All SAXA (n=3356) (Frederich R, et al. Postgraduate Medicine 2010;122(3). doi: /pgm )

37 Hypoglycemic Events & Change in Weight from Baseline Number (%) of subjects with a hypoglycemic event SAXA + MET (N=428) 13 (3.0%) GLIP + MET (N=430) 156 (36.3%) Difference in proportions vs. glipizide + metformin [95%CI] -33.2% [-38.1%,-28.5%] <0.0001* Adjusted change in weight from baseline, mean (%) Mean difference vs. glipizide + metformin [95%CI] -1.1 kg (0.17%) -2.2 kg [-2.7,-1.7] <0.0001* +1.1 kg (0.17%) * Between group comparison significant after controlling overall alpha of the study B. Goke. Int J Clin Pract Nov;64(12):

38 Liraglutide resulted in weight loss SU resulted in weight gain Japanese study Liraglutide 0.9 mg Glibenclamide 2.5 mg p< to Weeks Liraglutide 0.9 mg Glibenclamide 2.5 mg Analysis population: all subjects with baseline and week 24 measurements (LOCF) Statistical analysis: ANOVA model with treatment group and pre-trial treatment as fixed effects and baseline value as a covariate Trial ID: NN

39 GLP and DPP4 Inhibitors GLP and its Analogues Stimulate insulin secretion Suppress glucagon Slow motility Lower A1c by ~1.0%/1.5% 1-2 injections per day or once weekly Weight loss of ~ 5 lb Associated with nausea, vomiting, diarrhea in ~40% Expensive DPP 4 Inhibitors Inhibit breakdown of endogenous GLP, raising levels by ~2- fold Decrease A1c by ~0.6% Oral medication No weight loss No GI side-effects Expensive

40 Rationale for SGLT2 Inhibitors Inhibit glucose reabsorption in the renal proximal tubule Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity This therapy is simple and nonspecific Even patients with refractory type 2 diabetes are likely to respond SGLT2=sodium-glucose cotransporter 2.

41 Normal Kidney Glomerulus Proximal Convoluted Tubule Early Distal Glucose reabsorption into systemic circulation Glucose SGLT2 SGLT1 Adapted with permission from Rothenberg PL et al. SGLT = sodium-glucose co-transporter. 1. Kanai Y et al. J Clin Invest. 1994;93(1): You G et al. J Biol Chem. 1995;270(49): Rothenberg PL et al. Presented at: 46th European Association for the Study of Diabetes Annual Meeting; September 20-24, 2010; Stockholm, Sweden. 41

42 Urinary Glucose Excretion (g/d) Type 2 diabetes + SGLT-2 Inhibitor (70-90 mg/dl) RT G Non-diabetic (180 mg/dl) RT G Type 2 diabetes (240 mg/dl) RT G Plasma Glucose (mg/dl) Adapted with permission from Abdul-Ghani MA, DeFronzo RA. RT G = renal threshold for glucose excretion. 1. Cowart SL, Stachura ME. In: Walker HK et al, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, MA: Butterworths; 1990: Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14(6): Nair S, Wilding JP. J Clin Endocrinol Metab. 2010;95(1): INVOKANA [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; Rave K et al. Nephrol Dial Transplant. 2006;21(8): Oku A et al. Diabetes. 1999;48(9):

43 Treatment with SGLT-2 Inhibitor Glomerulus Proximal Convoluted Tubule Early Distal Glucose in urine Decreased glucose reabsorption into systemic circulation Glucose SGLT2 SGLT2 inhibitor SGLT1 Adapted with permission from Rothenberg PL et al. SGLT = sodium-glucose co-transporter. 1. Rothenberg PL et al. Poster presented at: 46th European Association for the Study of Diabetes Annual Meeting; September 20-24, 2010; Stockholm, Sweden. 3. Cowart SL, Stachura ME. In: Walker HK et al, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, MA: Butterworths; 1990: Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14(6): Oku A et al. Diabetes. 1999;48(9):

44 50 mg qd 100 mg qd 200 mg qd 300 mg qd 300 mg bid Sitagliptin 1 mg qd 5 mg qd 10 mg qd 25 mg qd 50 mg qd Sitagliptin Change in HbA1c in 12-Week Add-on to Metformin Studies of SGLT2 Inhibitors Canagliflozin (placebo adjusted values) 12 wk study (N=451) Empagliflozin (placebo adjusted values) 12 wk study (N=495) Mean change in HbA1c (%) from baseline Mean Baseline HbA1c, % Statistical significance not reported Rosenstock J, et al. Diabetologia 2010;53(Suppl 1):S349; Seman L, et al. Presented at EASD Annual Meeting, Lisbon, September 2011 (abstract #147). Canagliflozin & Empagliflozin not FDA approved

45 Caveats Although the algorithm should apply to most people with type 2 diabetes, it does not apply to all Individualize therapy is a must May select different glycemic goals - Elderly - Persons with projected life span too short to benefit - Persons in whom side-effects outweigh benefits May select different medications based on - Patient acceptance, tolerance - Specific risk factors Don t forget other interventions- lipids, blood pressure, CVD prevention