Multiple Facts Should Be Considered When Setting a Glycemic Goal Patient attitude and expected treatment effts Risks potentially associated with hypoglycemia, other adverse events Disease duration Me stringent Highly motivated, adherent, excellent self-care capacities Low Newly diagnosed Less stringent Less motivated, nonadherent, po self-care capacities High Long-standing Life expectancy Long Sht Imptant combidities Absent Few/mild Severe Established vascular complications Absent Few/mild Severe Resources, suppt system Readily available Limited 1 Republished with permission of American Diabetes Association, from Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379; permission conveyed through Copyright Clearance Center, Inc.
Typical A1C Reductions by Treatment Regimen Monotherapy Route of Administration A1C (%) Reduction Sulfonylurea Oral 1.5-2.0 Metfmin Oral 1.5 TZDs Oral 1.0-1.5 Meglitinides Oral 0.5-2.0 Alpha-glucosidase inhibits Oral 0.5-1.0 DPP-4 inhibits Oral 0.7 GLP-1 recept agonists Injectable 0.8-1.8 Amylin analogs Injectable 0.6 Insulin Injectable Open to target 2 A1C = glycated hemoglobin; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; TZDs = thiazolidinediones. Unger J, et al. Postgrad Med. 2010;122:145-157; Nauck MA, et al. Diabetes Care. 2009;32:S223- S231.
A1C Reductions With GLP-1 Recept Agonists: Summary of Clinical Trial Data Exenatide 10 mcg Twice Daily Change in A1C a Liraglutide 1.8 mg Once Daily 1 Change in A1C a Exenatide 2 mg Once Weekly 1 Change in A1C a + None 2b -0.5 + None a -1.1 + None a -1.6 + SU 3-0.9 + SU -1.1 + SU -1.9 + MET 4-0.8 + MET -1.0 + MET -1.5 + MET +SU 5-0.8 + (MET + SU) -1.3 + (MET + SU) -1.5 + TZD ± MET 1-0.9 + (MET + TZD) -1.5 + MET ± SU -1.1 3 a Placebo-subtracted; b Background al antihyperglycemic agent(s). A1C = glycated hemoglobin; GLP-1 = glucagon-like peptide-1; MET = metfmin; SU = sulfonylurea; TZD = thiazolidinedione. 1. Mundil D, et al. Diab Vasc Dis Res. 2012;9:95-108; 2. Poon T, et al. Diabetes Technol Ther. 2005;7:467-477; 3. Buse JB, et al. Diabetes Care. 2004;27:2628-2635; 4. DeFronzo RA, et al. Diabetes Care. 2005;28: 1092-1100; 5. Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.
Change in Weight (lb) Weight Reduction With GLP-1 Recept Agonists: Summary of Clinical Trial Data 0.0-1.0-2.0-3.0-4.0-5.0-6.0-7.0-8.0-9.0 + None a,1,2 + SU 1 + MET 1 + SU/MET 1 + TZD ± MET 1 + MET ± SU 1-4.0-5.1-5.5-3.5-0.4-8.1-6.2-6.2-3.5-4.0-3.9-4.4 a Background al antihyperglycemic agent(s). GLP-1 = glucagon-like peptide-1; MET = metfmin; SU = sulfonylurea; TZD = thiazolidinedione. -5.1-5.7-7.0 Exenatide 10 mcg twice daily Liraglutide 1.8 mg once daily Exenatide 2 mg once weekly 4 1. Mundil D. Diab Vasc Dis Res. 2012;9:95-108; 2. Poon T, et al. Diabetes Technol Ther. 2005;7:467-477.
Risk f Nausea: Long-Acting vs Sht-Acting GLP-1 Recept Agonists 50 Liraglutide once daily Exenatide twice daily Exenatide once weekly Participants Repting Nausea (%) 40 30 20 10 28 26 26 35 35 14 9 21 0 1 2 3 4 LEAD-6 DURATION-1 DURATION-5 DURATION-6 DURATION = Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Facts Through Intervention With Exenatide Once Weekly; GLP-1 = glucagon-like peptide-1; LEAD = Liraglutide Effect and Action in Diabetes. 5 1. Buse JB, et al. Lancet. 2009;374:39-47; 2. Drucker D, et al. Lancet. 2008;372:1240-1250; 3. Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310; 4. Buse JB, et al. Lancet. 2013;381:117-124.
6 Predisposing and Precipitating Risk Facts f Hypoglycemia Predisposing Facts (Predicts) Precipitating Facts (Potentiating) Age Body weight Duration of disease Histy of severe hypoglycemia Use of sulfonylureas Insulin intake Chronic kidney disease Chronic liver disease Hypoglycemic unawareness/diminished counterregulaty response Cognitive impairment Antidiabetic agents (eg, sulfonylureas, meglitinides, insulin) Potentiats of sulfonylureas Potentiats of hypoglycemia (eg, angiotensin-converting enzyme inhibits) Overmedication Missed, delayed, reduced meals Alcohol intake Acute illness (po intake) Addison s disease Increased exercise Gastroparesis 6 Alagiakrishnan K, et al. Postgrad Med. 2010;122:129-137.
Considerations in Type 2 Diabetes Mellitus Pharmacotherapy Efficacy a Metfmin High Low Hypoglycemia Risk b Weight Maj Adverse Event(s) Cost Neutral/ loss GI, lactic acidosis SUs High Moderate Gain Hypoglycemia Low TZDs High Low Gain DPP-4 inhibits Edema, heart failure, fracture Low Intermediate Low Neutral Rash, rhinitis High GLP-1 RAs High Low Loss GI High Moderate Insulin Highest High Gain Hypoglycemia Variable SGLT-2 inhibits Intermediate Low Neutral Urinary tract/genital infections, BP, Hct High a Efficacy varies depending on duration of disease; b As monotherapy. 7 BP = blood pressure; DPP-4 = dipeptidyl peptidase-4; GI = gastrointestinal; GLP-1 RAs = glucagon-like peptide-1 recept agonists; Hct = hematocrit; SGLT-2 = sodium-glucose cotranspter-2; SUs = sulfonylureas; TZDs = thiazolidinediones. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379; Kim Y, Babu AR. Diabetes Metab Syndr Obes. 2012;5:313-327.
Proposed Recommendations f Use of Metfmin Based on egfr egfr (ml/min/1.73 m 2 ) 60 Action a No renal contraindications to metfmin Monit renal function annually <60 and 45 Continue use <45 and 30 Prescribe metfmin with caution Use lower dose (eg, 50%, half-maximal dose) Closely monit renal function (every 3 months) Do not start new patients on metfmin <30 Stop metfmin 8 a Additional caution is required in patients at risk f acute kidney injury with anticipated significant fluctuations in renal status, based on previous histy, other combidities, potentially interacting medications. egfr = estimated glomerular filtration rate. Republished with permission of American Diabetes Association, from Lipska KJ, et al. Diabetes Care. 2011;34:1431-1437; permission conveyed through Copyright Clearance Center, Inc.
DPP-4 Inhibits and GLP-1 Recept Agonists: Different Agents With Different Clinical Effects Effects/Parameters DPP-4 Inhibit GLP-1 Recept Agonist Route of administration Oral Subcutaneous injection Effect on incretin hmones GLP-1 in physiologic range Limited by endogenous GLP-1 secretion Pharmacologic levels of GLP-1 No limitations due to endogenous GLP-1 secretion Dosing/timing of administration Once daily A1C reduction 0.5%-1.1% 0.6%-1.9% Body weight Neutral Reduced Once twice daily once weekly Hypoglycemia Low incidence Low incidence Appetite No effect Suppressed Gastric emptying No effect Slowed (shter-acting agents) Gastrointestinal None Nausea, diarrhea, vomiting 9 A1C = glycated hemoglobin; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1. Davidson JA. Mayo Clin Proc. 2010;85:S27-S37.
Management of Hyperglycemia: A Patient-Centered Approach From the ADA/EASD Healthy eating, weight control, increased physical activity Initial drug monotherapy Efficacy ( A1C) Hypoglycemia Weight Side effects Costs Metfmin high low risk neutral/loss GI/lactic acidosis low Metfmin + Metfmin + Metfmin + Metfmin + Metfmin + Three-drug combinations Sulfonylurea + TZD DPP-4 i GLP-1 RA Insulin + TZD SU DPP-4 i GLP-1 RA Insulin DPP-4 Inhibit + SU TZD Insulin GLP-1 recept agonist + SU TZD Insulin Insulin (usually basal) + TZD DPP-4 i GLP-1 RA If combination therapy that includes basal insulin has failed to achieve A1C target after 3-6 months, proceed to a me complex insulin strategy, usually in combination with one two non-insulin agents. Insulin (multiple daily doses) 10 A1C = glycated hemoglobin; ADA = American Diabetes Association; DPP-4 = dipeptidyl peptidase-4; EASD = European Association f the Study of Diabetes; GI = gastrointestinal; GLP-1 = glucagon-like peptide-1; i = inhibit; RA = recept agonist; SU = sulfonylurea; TZD = thiazolidinedione. Republished with permission of American Diabetes Association, from Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379; permission conveyed through Copyright Clearance Center, Inc.
Lipid and Blood Pressure Changes From Baseline (%) Long-Term Effects on Cardiovascular Risk Facts With GLP-1 Recept Agonists a 10 TG, mg/dl TC, mg/dl HDL-C, mg/dl +8.5 * LDL-C, mg/dl SBP, mm Hg DBP, mm Hg 0-10 -20 * -10.8 * -11.8-3.5 * -3.3-30 -40 *P <.001 P <.01-50 * -44.4 11 a 217 patients with type 2 diabetes mellitus treated with GLP-1 recept agonist daily f at least 3 years. DBP = diastolic blood pressure; GLP-1 = glucagon-like peptide-1; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; SBP = systolic blood pressure; TC = total cholesterol; TG = triglyceride. Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.