TREATMENT OF DIABETES AFTER METFORMIN GREGG GERETY, MD ALBANY MEDICAL COLLEGE, DIVISION OF COMMUNITY ENDOCRINOLOGY JULY 14, 2017
Outline Review treatment algorithms from ADA/ EASD & ACE/AACE. Review positive CVOT results for empagliflozin & liraglutide. Improve awareness of treatment options for T2DM.
Main Pathophysiological Defects in incretin effect gut carbohydrate delivery & absorption T2DM pancreatic glucagon secretion pancreatic insulin secretion HYPERGLYCEMIA? + hepatic glucose production peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 1. Patient-Centered Approach...providing care that is respectful of and responsive to individual patient preferences, needs, and values - ensuring that patient values guide all clinical decisions. 1. Gauge patient s preferred level of involvement. Explore, where possible, therapeutic choices. Utilize decision aids. Shared decision making final decisions re: lifestyle choices ultimately lies with the patient. Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Glycemic targets - HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l]) - Pre-prandial PG <130 mg/dl (7.2 mmol/l) - Post-prandial PG <180 mg/dl (10.0 mmol/l) - Individualization is key: Tighter targets (6.0-6.5%) - younger, healthier Looser targets (7.5-8.0%+ ) - older, comorbidities, hypoglycemia prone, etc. - Avoidance of hypoglycemia PG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Lifestyle - Weight optimization - Healthy diet - Increased activity level Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Oral agents & non-insulin injectables - Metformin - Sulfonylureas - Thiazolidinediones - DPP-4 inhibitors - Meglitinides - α-glucosidase inhibitors - Bile acid sequestrants - Dopamine-2 agonists - GLP-1 receptor agonists - Amylin mimetics Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
Class Mechanism Advantages Disadvantages Cost Biguanides SUs / Meglitinide s TZDs Activates AMPkinase Hepatic glucose production Closes KATP channels Insulin secretion PPAR-γ activator insulin sensitivity Extensive experience No hypoglycemia Weight neutral? CVD Extensive experience Microvasc. risk No hypoglycemia Durability TGs, HDL-C? CVD (pio) Gastrointestinal Lactic acidosis B-12 deficiency Contraindications Hypoglycemia Weight gain Low durability? Ischemic preconditioning Weight gain Edema / heart failure Bone fractures? MI (rosi)? Bladder ca (pio) Low Low High α-gis Inhibits α glucosidase Slows carbohydrate absorption No hypoglycemia Nonsystemic Post-prandial glucose? CVD events print] Table 1. Properties of anti-hyperglycemic agents Gastrointestinal Dosing frequency Modest A1c Mod. Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of
Class Mechanism Advantages Disadvantage s DPP-4 inhibitors GLP-1 receptor agonists Amylin mimetics Bile acid sequestran ts Inhibits DPP-4 Increases GLP-1, GIP Activates GLP-1 R Insulin, glucagon gastric emptying satiety Activates amylin receptor glucagon gastric emptying satiety Bind bile acids Hepatic glucose production No hypoglycemia Well tolerated Weight loss No hypoglycemia? Beta cell mass? CV protection Weight loss PPG No hypoglycemia Nonsystemic Post-prandial glucose CVD events Dopamine- Activates DA No hypoglyemia Table 2 1. Properties receptor of anti-hyperglycemic? CVD events agents Modest A1c? Pancreatitis Urticaria GI? Pancreatitis Medullary ca Injectable GI Modest A1c Injectable Hypo w/ insulin Dosing frequency GI Modest A1c Dosing frequency Modest A1c Dizziness/ Cost High High High High High Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
Class Mechanism Advantages Disadvantages Cost Insulin Activates insulin receptor peripheral glucose uptake Universally effective Unlimited efficacy Microvascular risk Hypoglycemia Weight gain? Mitogenicity Injectable Training requirements Stigma Variable Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin Table 1. Properties of anti-hyperglycemic agents
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulin - Neutral protamine Hagedorn (NPH) - Regular - Basal analogues (glargine, detemir) - Rapid analogues (lispro, aspart, glulisine) - Pre-mixed varieties Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulin Insulin level Rapid (Lispro, Aspart, Glulisine) Short (Regular) Intermediate (NPH) Long (Detemir) Hours Long (Glargine) 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours after injection
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Implementation strategies: - Initial therapy - Advancing to dual combination therapy - Advancing to triple combination therapy - Transitions to & titrations of insulin Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print]
T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print]
T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print]
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
equential Insulin Strategies in T2DM Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Age Weight Sex / racial / ethnic / genetic differences Comorbidities - Coronary artery disease - Heart Failure - Chronic kidney disease - Liver dysfunction - Hypoglycemia Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Age: Older adults - Reduced life expectancy - Higher CVD burden - Reduced GFR - At risk for adverse events from polypharmacy - More likely to be compromised from hypoglycemia Less ambitious targets HbA1c <7.5 8.0% if tighter targets not easily achieved Focus on drug safety
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Weight - Majority of T2DM patients overweight / obese - Intensive lifestyle program - Metformin - GLP-1 receptor agonists -? Bariatric surgery - Consider LADA in lean patients Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
Diabetes Care, Diabetologia. 19 April Adapted Recommendations: When Goal is to Avoid Weight 2012 [Epub Gain ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities - Coronary Disease - Heart Failure - Renal disease - Liver dysfunction - Hypoglycemia Metformin: CVD benefit (UKPDS) Avoid hypoglycemia? SUs & ischemic preconditioning? Pioglitazone & CVD events? Effects of incretin-based therapies Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities - Coronary Disease - Heart Failure - Renal disease - Liver dysfunction - Hypoglycemia Metformin: May use unless condition is unstable or severe Avoid TZDs? Effects of incretin-based therapies Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
Original Article Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes Bernard Zinman, M.D., Christoph Wanner, M.D., John M. Lachin, Sc.D., David Fitchett, M.D., Erich Bluhmki, Ph.D., Stefan Hantel, Ph.D., Michaela Mattheus, Dipl. Biomath., Theresa Devins, Dr.P.H., Odd Erik Johansen, M.D., Ph.D., Hans J. Woerle, M.D., Uli C. Broedl, M.D., Silvio E. Inzucchi, M.D., for the EMPA-REG OUTCOME Investigators N Engl J Med Volume 373(22):2117-2128 November 26, 2015
Study Overview In this study, the addition of empagliflozin, an inhibitor of sodium glucose cotransporter 2, to standard care reduced cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk.
Cardiovascular Outcomes and Death from Any Cause. Zinman B et al. N Engl J Med 2015;373:2117-2128
Zinman B et al. N Engl J Med 2015;373:2117-2128 Glycated Hemoglobin Levels.
Conclusions Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.
Original Article Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes Steven P. Marso, M.D., Gilbert H. Daniels, M.D., Kirstine Brown-Frandsen, M.D., Peter Kristensen, M.D., E.M.B.A., Johannes F.E. Mann, M.D., Michael A. Nauck, M.D., Steven E. Nissen, M.D., Stuart Pocock, Ph.D., Neil R. Poulter, F.Med.Sci., Lasse S. Ravn, M.D., Ph.D., William M. Steinberg, M.D., Mette Stockner, M.D., Bernard Zinman, M.D., Richard M. Bergenstal, M.D., John B. Buse, M.D., Ph.D., for the LEADER Steering Committee on behalf of the LEADER Trial Investigators N Engl J Med Volume 375(4):311-322 July 28, 2016
Study Overview Patients with type 2 diabetes and high cardiovascular risk were assigned to receive either the glucagon-like peptide 1 analogue liraglutide or placebo. The rate of first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke was lower with liraglutide.
Primary and Exploratory Outcomes. Marso SP et al. N Engl J Med 2016;375:311-322
Conclusions In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo.
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities - Coronary Disease - Heart Failure - Renal disease - Liver dysfunction - Hypoglycemia Increased risk of hypoglycemia Metformin & lactic acidosis US: stop @SCr 1.5 (1.4 women) UK: dose @GFR <45 & stop @GFR <30 Caution with SUs (esp. glyburide) DPP-4-i s dose adjust for Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities - Coronary Disease - Heart Failure - Renal disease - Liver dysfunction - Hypoglycemia Most drugs not tested in advanced liver disease Pioglitazone may help steatosis Insulin best option if disease severe Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities - Coronary Disease - Heart Failure - Renal disease - Liver dysfunction - Hypoglycemia Emerging concerns regarding association with increased mortality Proper drug selection in the hypoglycemia prone Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
Adapted Recommendations: When Goal is to Avoid Hypoglycemia Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print]
Adapted Recommendations: When Goal is to Minimize Costs Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print]
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