Prediabetes Treatment Algorithm

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5 Prediabetes Treatment Algorithm T2DM = type 2 diabetes mellitus BP = blood pressure CVD = cardiovascular disease TZD = thiazolidinedione GLP-1 RA= glucagon-like peptide-1 receptor agonist Weight-loss agents orlistat, lorcaserin, and phentermine/topiramate can prevent progression to T2DM Improve BP, triglycerides, and insulin sensitivity Metformin and acarbose can reduce progression to T2DM by 25% - 30% Use for prediabetes is off-label Both are safe, confer CVD risk benefit; metformin is well tolerated TZDs prevented progression to T2DM in 60% - 75% of patients in clinical trials Associated with adverse outcomes GLP-1 receptor agonists may be as effective as TZDs Promote weight loss, but inadequate safety data TZDs and GLP-1 RAs reserved for patients not responding to conventional therapies or at highest risk for T2DM AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3):

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7 Risk of Hypoglycemia Plays a significant role in choice of agents in AACE algorithm For patients at highest risk of hypoglycemia, may consider close evaluation of agents chosen as well as therapeutic goal Patients with type 2 diabetes at highest risk of low blood glucose include those with: Diabetes duration >15 years Advanced macrovascular disease Hypoglycemia unawareness Limited life expectancy Severe comorbidities AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3): ; AACE Algorithm for Glycemic Control, Endocr Pract. 2009;15(6):

8 AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3): Sitagliptin [package insert]. Whitehouse Station, NJ; Merck Co. Inc.; Saxagliptin [package insert]. Princeton, NJ; Bristol Meyers Squibb; 2009; Linagliptin [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Clinical Considerations Combining therapeutic agents with different modes of action may be advantageous Use insulin sensitizers such as metformin and/or TZDs as part of the therapeutic regimen in most patients (unless contraindicated or intolerance to these agents has been demonstrated) Insulin and secretagogues are the only medications that cause significant hypoglycemia Therefore, dosage of secretagogues or insulin should be adjusted as blood glucose levels decline, when used in combination with metformin, TZD, DPP-4 inhibitors, and/or incretin mimetics (GLP-1 agonists) TZD = thiazolidinediones; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1

9 Clinical Considerations The weight gain associated with thiazolidinediones in some patients may be partly offset by combination therapy with metformin If A1C is elevated and preprandial blood glucose measurements are at target levels, carefully assess postprandial glucose levels Individualize treatment regimens! AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3): ;

10 Effect of Glucose-lowering Drugs on Patient Weight Therapeutic Options Weight Sulfonylurea 1,2 TZD 3,4 Insulin 5,6 Metformin 7 DPP-4 inhibitor 8 GLP-1 receptor agonist 9 SGLT-2 Inhibitors 10 A1C = glycated hemoglobin; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; SGLT-2 = sodium glucose co-transporter-2; TZD = thiazolidinedione 1. Malone M. Ann Pharmacother. 2005;39: Glipizide [package insert]. New York, NY; Pfizer; Pioglitazone [package insert]. Deerfield, IL: Takeda Pharmaceuticals America; Rosiglitazone [package insert]. Research Triangle Park, NC; GlaxoSmithKline; Nathan DM, et al. Diabetes Care. 2008;31(1): Holman RR. NEJM. 2007;357(17): Metformin[package insert]. Princeton NJ; Bristol Meyers Squibb; Sitagliptin [package insert].

11 AACE Diabetes Algorithm Guide therapy based on A1C level Focus on lifestyle intensification at all levels Important tenets: Target A1C is <6.5% Based on associated lower risk of micro- and macrovascular complications Recommend monitoring A1C quarterly, along with fasting and postprandial blood glucose, with intensification of therapy until goal A1C is achieved Individualize A1C target based on comorbidities Patient should monitor fasting and postprandial blood glucose levels Use agents with maximal efficacy, associated with lowest risk of hypoglycemia Sulfonylureas are therefore much lower in algorithm Earlier use of incretin mimetics and DPP-4 inhibitors to stimulate insulin secretion without hypoglycemia A1C = glycated hemoglobin; DPP-4 = dipeptidyl-peptidase 4 AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3):

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13 The Ticking Clock Increased risk for both microvascular and macrovascular disease begins early in the prediabetic state Insulin resistance is already present in patients with NGT who later develop T2DM Patients with prediabetes already have high insulin resistance and significantly decreased beta-cell function Both diabetic retinopathy, peripheral neuropathy, and nephropathy occur in patients with prediabetes Patients with prediabetes have a 2 to 3-fold increase in CHD risk, similar to patients with diabetes CHD = coronary heart disease; NGT = normal glucose tolerance; T2DM = type 2 diabetes mellitus AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3): ; DeFronzo RA et al. Am J Cardiol. 2011;108(3 Suppl):3B-24B

14 Landmark Glycemia Trials Action to Control Cardiovascular Risk in Diabetes (ACCORD) Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation (ADVANCE) Veterans Affairs Diabetes Trial (VADT) All conducted in: Older patients ( 60 years of age) Patients with cardiovascular disease (CVD; 1/3 to 1/2 of cohorts) or 1 CVD risk factors Ray et al. Lancet. 2009;373:

15 UKPDS: Benefits of Glycemic Control Every 1% decrease in A1C led to significant reductions in diabetes-related complications 14% 21% 37% 43% Risk of myocardial infarction Risk of diabetesrelated death Risk of microvascular complications Risk of amputation or PVD Death Decrease was statistically significant for all comparisons shown Stratton IM et al. BMJ. 2000;321:

16 UKPDS: United Kingdom Prospective Diabetes Study Follow-Up A1C Mean A1C levels for patients originally assigned to receive either sulfonylurea insulin or conventional therapy are shown Clinical data were not available in years 6 through 10 (when questionnaires were used) Holman R et al NEJM, 2008;359:

17 UKPDS: United Kingdom Prospective Diabetes Study Follow-Up Any diabetes-related endpoint Study follow-up revealed a sustained decrease in the number of diabetesrelated endpoint events for patients who received initial intensive treatment Holman R et al NEJM, 2008;359:

18 UKPDS: United Kingdom Prospective Diabetes Study Follow-Up All-cause mortality A similar long-term benefit in terms of reduced mortality risk was observed for patients who received initial intensive treatment Holman R et al NEJM, 2008;359:

19 Myocardial Infarction Hazard Ratio (fatal or non-fatal myocardial infarction or sudden death) Intensive (SU/Ins) vs. Conventional Glucose Control HR (95%CI) Conventional Intensive Δ Ins = insulin; HR = hazard ratio; SU = sulfonylurea Holman R et al NEJM, 2008;359:

20 Myocardial Infarction Hazard Ratio UKPDS 10-year follow-up (fatal or non-fatal myocardial infarction or sudden death) Intensive (metformin) vs. conventional glucose control Conventional Intensive Δ Holman R et al NEJM, 2008;359:

21 A1C Targets in ADVANCE, VADT, and ACCORD ADVANCE ACCORD VADT A1C (%) A1C = glycated hemoglobin; ACCORD = The Action to Control Cardiovascular Risk in Diabetes study; ADVANCE = The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trial; VADT = Veterans Affairs Diabetes Trial The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008;358: Abraira, C, et al. J Diab Comp, 2003; Patel, A. et al. N Engl J Med, 2008;358:

22 Severe Hypoglycemia In ACCORD, ADVANCE and VADT ACCORD ADVANCE VADT Intensive Standard Intensive Standard Intensive Standard (% / year) 3.1% 1.1% 0.7% 0.4% 12.0% 4.0% ACCORD = The Action to Control Cardiovascular Risk in Diabetes study; ADVANCE = The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trial; VADT = Veterans Affairs Diabetes Trial The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008; 358: Abraira, C, et al. J Diab Comp, 2003; Patel, A. et al. N Engl J Med, 2008;358:

23 CVD Outcomes In ACCORD, ADVANCE, and VADT ACCORD ADVANCE VADT Intensive Standard Intensive Standard Intensive Standard Baseline 8.1% 8.1% 7.5% 7.5% 9.4% 9.4% Final 6.4% 7.5% 6.4% 7.0% 6.9% 8.4% CVD/year 2.1% 2.3% 2.0% 2.1% 3.8% 4.9% ACCORD = The Action to Control Cardiovascular Risk in Diabetes study; ADVANCE = The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trial; CVD = cardiovascular disease; VADT = Veterans Affairs Diabetes Trial The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008; 358: Abraira, C, et al. J Diab Comp, 2003; Patel, A. et al. N Engl J Med, 2008;358:

24 Recent ACCORD Data 10,251 T2D age 40 to 79, A1c goal vs. <6.0 Active therapy mean 3.7 years, follow-up 1-2 years 5-year outcomes comparing intensive vs standard: MI, revascularization & ACS: 11% Coronary revascularization: 16% MI: 16% (20% during active therapy period) Unstable angina 19% With lowest achieved HbA1C concentrations included as a time-dependent covariate, all hazards became non-significant. INTERPRETATION: Raised glucose concentration is a modifiable risk factor for ischaemic heart disease. CVD = cardiovascular disease Gerstein et al. Lancet. 2014; 384:

25 Effect of Intensive Control of Glucose on Cardiovascular Outcomes and Deaths in Patients with Diabetes Mellitus A Meta-analysis of Randomized Controlled Trials UKPDS PROactive ADVANCE VADT ACCORD Total N Years Patientyears 46,237 15,059 55,700 10,030 35, ,905 Control A1c 7.9% 7.6% 7.3% 8.4% 7.5% 7.5% Intensive A1c 7.0% 7.0% 6.8% 6.9% 6.4% 6.6% Ray et al. Lancet 2009; 373:

26 Probability of Non-fatal Myocardial Infarction Events with Intensive Glucose-lowering vs. Standard Treatment Non-fatal myocardial infarction Ray et al. Lancet. 2009;373:

27 Probability of Coronary Heart Disease Events with Intensive Glucose-lowering vs. Standard Treatment Coronary heart disease events Ray et al. Lancet. 2009;373:

28 Probability Stroke with Intensive Glucose-lowering vs. Standard Treatment Stroke Ray et al. Lancet. 2009;373:

29 Probability of All-cause Mortality with Intensive Glucose-lowering vs. Standard Treatment All-cause mortality Ray et al. Lancet. 2009;373:

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31 Algorithm To Achieve Glycemic Goals Baseline A1C 6.5% - 7.5% Monotherapy may be effective in this range Metformin first choice for monotherapy if no contraindications Consider DPP-4 if PP and FPG, GLP-1 if PP, TZD if metabolic syndrome or NAFLD, AGI if PP Do not recommend secretagogue (SU or glinide) in this range due to risk of hypoglycemia; short-lived effect If monotherapy is unsuccessful, move on to dual oral rx; often need to augment reduction in PP BG to get to goal in this A1C range DPP-4=dipeptidyl peptidase-4; PP=post-prandial; FPG=fasting plasma glucose; GLP-1 = glucagon-like peptide-1; TZD=thiazolidinedione; NAFLD=non-alcoholic fatty liver disease; AGI=alpha-glucosidase inhibitor; SU=sulfonylurea; A1C=glycated hemoglobin; SGLT-2=sodium glucose transport-2 AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3):

32 Algorithm to Achieve Glycemic Goals Baseline A1C 7.6%-9.0% Dual therapy with metformin provides superior glycemic control over metformin alone. If dual oral rx is unsuccessful, consider triple therapy If triple oral rx fails to achieve A1C goal, initiate insulin GLP-1 RA = glucagon-like peptide-1 receptor agonist DPP4-i=dipeptidyl peptidase 4 inhibitor TZD=thiazolidinedione SGLT-2=sodium glucose cotransporter 2 inhibitor QR=quick-release AG-i=alpha-glucosidase inhibitor SU=sulfonylurea GLN=glinide AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3):

33 Algorithm to Achieve Glycemic Goals Baseline A1C > 9.0% If patient is asymptomatic with recent onset of disease and drug naïve, may consider starting with dual or triple oral regimens If symptomatic, start insulin Once A1C has improved to <7.5%, consider initiation of dual oral therapy with tapering and possible discontinuation of insulin rx AACE Comprehensive Diabetes Management Algorithm Endocr Pract. 2013;19(3):

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37 AACE/ACE ALGORITHM SUMMARY COMPLICATION-CENTRIC OBESITY TREATMENT PREDIABETES ALGORITHM AACE T2D ALGORITHM PRINCIPLES MINIMIZE RISK OF HYPOGLYCEMIA AVOID TREATMENTS CAUSING WEIGHT-GAIN OPTIMIZING GLYCEMIA: RATIONALE BASE TREATMENT APPROACH ON LEVEL OF GLYCEMIA INSULIN TREATMENT CONCEPTS CVD RISK FACTOR TREATMENT DYSLIPIDEMIA, BP