An Update on Guidelines and Evidence of the Treatment of Type 2 Diabetes Mellitus

Transcription

1 Nevada Academy of Family Physicians 29 th Annual Summer CME Meeting August 3 5, 2018 An Update on Guidelines and Evidence of the Treatment of Type 2 Diabetes Mellitus Presented by: James D. Honeycutt, MD, FAAFP Approved for 1.0 Prescribed CME Saturday, August 4, :15 11:15am Nevada Academy of Family Physicians 705 Tahoe St., Ste. A, Reno, NV

2 Nevada Academy of Family Physicians 29 th Annual Summer CME Meeting August 3 5, 2018 NOTES Nevada Academy of Family Physicians 705 Tahoe St., Ste. A, Reno, NV

3 Objectives Update to Guidelines and Evidence Regarding the Clinical Management of Type 2 Diabetes Guidelines Regarding Target Hgb A1C What brought us to this point? Review history of T2DM treatment targets Where are we going? J. David Honeycutt, MD, FAAFP Understand evidence behind the recommendations How do we get there? Select pharmacotherapies with patient oriented outcomes Evaluate Top 15 Practice Influencing Studies T2DM Management A Brief History 1921 Insulin therapy discovered 1923 Commercial production of insulin 1940 ADA founded 1947 Blood sugar control measure with urine 1955 First oral medication (sulfonylureas) 1970 First glucose meter 1976 First insulin pumps 1977 Hemoglobin A1C test developed 1978 Pirart s study links BG and complications 1989 ADA s first Standards of Care guide New Guideline from ACP on Target A1c T2DM Management A Brief History 1993 DCCT (benefit of BG control for T1DM) 1995 Metformin available in U.S Acarbose (AGi) available in U.S Troglitazone (TZD) approved by FDA 1998 Repaglinide developed, UKPDS results 2005 Exenatide approved (GLP-1 RA) 2006 Sitagliptin approved (DPP-4 inhibitor) 2008 ACCORD, ADVANCE, VADT published 2013 Canaglifozin approved (SGLT-2i) How Does this Differ from Others? ADA (2018) <7%, 6.5% or higher AACE (2018) 6.5% optimal, or individualized ICSI (2014) <7% to <8% NICE (2015) 6.5% or 7% SIGN (2018) 6.5% or 7% VA/DoD 6-7% or 7-8.5% or 8-9% Looking at the Evidence from 2008 ACCORD (goal <6.5% vs 7-7.9%) Excess mortality in intensive group (NNTH = 90) ADVANCE (goal 6.5% vs 7.5%) No reduction in CV events Less progression to proteinuria (NNT = 100) VADT (goal <6.0% vs <9.0%) No difference in CV or microvascular complications Underpowered for main hypothesis test UKPDS (Follow-up) % yields macro/microvascular benefit compared to 8% Meta-analysis of 5 studies showed intensive BG control Reduced non-fatal MI and all-cardiac mortality No effect on all-cause mortality AAFP Statement Support for 2016 ACP CPG Hgb A1c level <7% for many but not all patients No endorsement of the 2018 ACP guideline Supports individualized targets Shared decision-making balancing harms/benefits Not one size fits all approach Not all <6.5% should be de-intensified

4 Choosing a Target for My Patient Hgb A1c level <7% for many but not all patients Hgb A1c level 6.5% can be considered Not all 6.5% should be de-intensified Individualize targets based on risks There is no one size fits all approach Remember who the Expert really is Remember that target A1C is just part of the guideline ADA Standards of Medical Care in Diabetes Top 15 Practice Influencing Studies Focus on evaluation and management of T2DM Studies from June 2017 July 2018 Not reflected in current guidelines Quality of evidence varies Studies given in chronological order Cardiovascular Outcomes with the Diabetes Drug Canagliflozin Two industry sponsored RCT s each with 10k pts Mean age 63, A1C 8.2% On metformin, SU, or drug combinations Canaglifozin vs placebo over average 3.6 years Benefits Decrease non-fatal MI/CVA, CV-related death (NNT = 224) Decrease composite renal endpoint (NNT = 288) Harms Lower-extremity amputation (NNTH = 347) Fractures (NNTH = 290) Male genital infections (NNTH = 43) Yeast vagnitis (NNTH = 20) Glycemic Control in Diabetic Patients with Chronic Kidney Disease Cohort study of 6,165 diabetic adults with CKD Mean age 70, egfr <60mL/min/1.73m 2 On insulin or oral drugs Followed for 2.3 years 3% progressed to ESRD 16% died U-shaped relation between HbA1c and mortality HbA1c 6-6.9% reference standard HbA1c <6.0% and >9% had higher mortality HbA1c 7-8.9% no difference Liraglutide and Renal Outcomes in Patients with Longstanding T2DM Renal outcomes for industry-sponsored LEADER trial Mean age 64, A1c 8.7%, egfr 80mL/min/1.73m 2 Liraglutide vs placebo over 4 years decreased Combined renal endpoint (NNT = 60) Size of egfr decline for baseline 30-60mL/min/1.73m 2 Caveats Decreased new-onset macroalbuminuria carried data No effect on ESRD Cost of liraglutide appox $10k/yr Effects of Once-Weekly Exenatide on Cardiovascular Outcomes Industry-sponsored RCT to establish CV safety 15k patients, mean age 62, mean A1C 8% At baseline 70% had prior CV events Exenatide vs placebo over 3 years A1c decrease (0.5% vs no change) Primary CV outcome (11.4% vs 12.2%) Found to be non-inferior Not found to be superior Pioglitazone vs. Sulfonylurea as Add- On Treatment for Type 2 Diabetes RCT 3k metformin-treated T2DM patients Mean age 62, mean duration of T2DM 8yrs Mean HbA1c 7.7% and 11% had known CVD Excluded those with Cr > 1.5mg/dL Pioglitazone vs Glimepiride/Gliclazide for 5 yrs Composite primary CV outcomes identical (7%) HbA1c similar (approx 7.3%) New HF in 1% of both groups Unspecified adverse events > with pioglitazone Hypoglycemia more likely with SU

5 Canagliflozin as Primary & Secondary Prevention in Patients with T2DM Reanalysis of industry funded CANVAS Program Previously demonstrated decreased CV/renal events in patients with T2DM and elevated CV risk RCT 10k patients treated with Canaglifozin for 3.6yrs Divided into primary/secondary prevention groups Secondary prevention had higher rate of CV composite outcome Rate of CV composite outcome still lower with Canaglifozin (NNT = 206) Also reduced renal complications No evidence of heterogeneity between groups Intensive vs. Individualized Type 2 Diabetes Control Economic analysis of diabetes management Individualized glycemic control led to Lifetime cost-savings of $13k per person Decreased life-years (36 days) Increased QALY (36 days) Increased lifetime risk for diabetes complications 1% Decreased risk for severe hypoglycemia 1% Refining the Use of Ezetimibe: Results of an IMPROVE-IT Reanalysis Re-analysis of IMPROVE-IT results for T2DM 4,933 study participants had diabetes (27%) Were more likely to be Older, female, have prior MI or CABG Also less likely to meet lab targets LDL goal <70mg/dL, and hs-crp <2mg/L Ezetimibe reduced primary composite CV endpoint in Patients with T2DM (NNT = 18) Patients w/o T2DM with highest CV risk (NNT = 13) CV Outcomes with Canagliflozin vs. Non-SGLT2i Antidiabetes Drugs Retrospective cohort study comparing CV outcomes with SGLT-2i vs other medications Canagliflozin had lower risk for HF admission over 30 month period than DPP-4 (HR, 0.7) GLP-1 RA (HR, 0.6) SU (HR, 0.5) No difference in composite CV endpoint AMI, ischemic stroke, hemorrhagic stroke How Broad Are the Benefits of SGLT- 2 Inhibitors? Industry-funded, multinational, retrospective observational CVD-REAL 2 study 400k patients from 6 nations 27% had established CVD 45% were women Treatment with SGLT-2i reduced risk for Death (HR, 0.51) HF hospitalization (HR, 0.64) MI (HR, 0.81) Stroke (HR, 0.68) Monotherapy with Metformin vs. SU s for T2DM w/ Impaired Renal Function Cohort study of 175k veterans with T2DM & CKD Pts initiated metformin or SU as monotherapy k deaths occurred during follow-up Metformin compared to SU had 36% lower mortality risk Associated with fewer deaths per 1000 person-years by following egfr rates as well (ml/min/1.73m 2 ) >90: : : : 12.1 SGLT-2i and GLP-1 RA Confer Survival Benefit in Patients with T2DM Meta-analysis of 236 RCT s (176k patients) Evaluated survival benefits of 3 medications Lower absolute mortality risk with SGLT-2 inhibitors 1.0% (NNT = 100) GLP-1 agonists - 0.6% (NNT = 166) No significant difference between these two No mortality benefit with DPP-4 inhibitors Annual cost to prevent one event > $1 million Metformin Isn't Associated with Acidosis in Diabetic Patients with Moderate Kidney Disease Cohort study comparing risks for acidosisrelated hospitalization with metformin use 75k patients with T2DM, mean age 60 No increased risk if egfr 30mL/min Risk doubled if egfr <30mL/min (NNTH = 85)

6 Diagnosing Diabetes Using a Single Blood Sample Prospective cohort study 13k patients over 20yrs Among 978 patients with elevated FBG or HbA1c Combined elevation noted in same sample in 40% 98% specific for T2DM dx in 5 years (LR+, 29) Poor sensitivity at 55% (LR-, 0.5) Combined elevation also predicted over 25 years PAD (HR, 2.5) CVD (HR, 1.5) CKD (HR, 1.5) All-cause mortality (HR, 1.5) How Do Glargine and Detemir Compare with NPH Insulin in a Real- World Setting? Retrospective study of patients taking insulin analogs (glargine or detemir) vs NPH insulin 25k pts, mean age 60, started basal insulin % of patients on NPH insulin; 8% on analogs Over average follow-up of 1.7 years no significant difference between Hypoglycemia-related admissions and ED visits Mean HbA1c levels Review of Objectives Guidelines Regarding Target Hgb A1C What brought us to this point? Reviewed history of T2DM treatment targets Where are we going? Understand evidence behind the recommendations How do we get there? Selected pharmacotherapies with patient oriented outcomes Evaluated Top 15 Practice Influencing Studies Bibliography Lipska KJ et al. Association of initiation of basal insulin analogs vs neutral protamine Hagedorn insulin with hypoglycemia-related emergency department visits or hospital admissions and with glycemic control in patients with type 2 diabetes. JAMA 2018 Jul 3; 320:53. Selvin E et al. Prognostic implications of single-sample confirmatory testing for undiagnosed diabetes: A prospective cohort study. Ann Intern Med 2018 Jun 19; [e-pub]. Lazarus B et al. Association of metformin use with risk of lactic acidosis across the range of kidney function: A community-based cohort study. JAMA Intern Med 2018 Jun 4; [e-pub]. Zheng SL et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagonlike peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: A systematic review and meta-analysis. JAMA 2018 Apr 17; 319:1580. Marcum ZA et al. Mortality associated with metformin versus sulfonylurea initiation: A cohort study of veterans with diabetes and chronic kidney disease. J Gen Intern Med 2018 Feb; 33:155. Kosiborod M et al. Lower cardiovascular risk associated with SGLT-2i in >400,000 patients: The CVD-REAL 2 study. J Am Coll Cardiol 2018 Mar 11; [e-pub]. Qaseem A et al. Hemoglobin A 1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: A guidance statement update from the American College of Physicians. Ann Intern Med 2018 Mar 6; [e-pub]. Patorno E et al. Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: Population based cohort study. BMJ 2018 Feb 6; 360:k119. Giugliano RP et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with vs. without diabetes: Results from IMPROVE-IT. Circulation 2017 Dec 20; [e-pub]. Bibliography Laiteerapong N et al. Individualized glycemic control for U.S. adults with type 2 diabetes: A cost-effectiveness analysis. Ann Intern Med 2017 Dec 12; [e-pub]. Mahaffey KW et al. Canagliflozin for primary and secondary prevention of cardiovascular events: Results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 2017 Nov 13; [e-pub]. Vaccaro O et al. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): A randomised, multicentre trial. Lancet Diabetes Endocrinol 2017 Nov; 5:887. Holman RR et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017 Sep 28; 377:1228. Mann JFE et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017 Aug 31; 377:839. Navaneethan SD et al. Diabetes control and the risks of ESRD and mortality in patients with CKD. Am J Kidney Dis 2017 Aug; 70:191. Neal B et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017 Jun 12. Duckworth W et al for the VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009 Jan 8; 360:129. Gerstein HC et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med2008Jun6 Patel A et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med2008Jun6 Holman RR et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008 Oct 9; 359:1577. Ray KK et al. Effects of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: A meta-analysis of randomised controlled trials. Lancet 2009 May 23; 373:1765. Questions?