Advances in Outpatient Diabetes Care: Algorithms for Care and the Role of Injectable Therapies Module D 1
Learning Objectives Apply the principles of the comprehensive diabetes algorithms to patients with type 2 diabetes Design therapeutic options to dual therapy in patients not well-controlled by metformin alone that are associated with a low risk of hypoglycemia and weight gain Identify therapeutic options for prandial control in basal insulin treated patients other than prandial insulin when intensification of therapy is required 2
Case Study: Philip 65-year-old African- American man Retired executive, lives with wife Hospital admission for motor vehicle accident medical history No prior history of DM Polyuria, fatigue BMI = 30 kg/m 2 (overweight) Only modestly active Family history: brother treated for T2DM Hypertension Lisinopril 20 mg daily BMI = body mass index; DM = diabetes mellitus; T2DM = type 2 diabetes mellitus. 3
Admission Orders Consider obtaining an A1C level in patients with Diabetes admitted to the hospital if the result of testing in the previous 2 3 months is not immediately available Risk factors for undiagnosed diabetes who exhibit hyperglycemia in the hospital A1C = glycated hemoglobin. Umpierrez GE et al; Endocrine Society. J Clin Endocrinol Metab. 2012;97(1):16 38. American Diabetes Association. Diabetes Care. 2014;37(suppl 1):S14 80. 4
Diagnosis and Recognition of Hyperglycemia and Diabetes in the Hospital Setting Admission Assess all patients for a history of diabetes Obtain laboratory BG testing on admission No history of diabetes BG <140 mg/dl No history of diabetes but BG >140 mg/dl History of diabetes Initiate POC BG monitoring according to clinical status Start POC BG monitoring x 24-48h Check A1C level Glucose management and monitoring A1C 6.5% POC BG = point-of-care blood glucose testing. Adapted from Umpierrez GE et al; Endocrine Society. J Clin Endocrinol Metab. 2012;97(1):16 38. 5
Percent Hyperglycemia in the Hospital and Status Post-Discharge Sample of a managed care outpatient database (8547 patients) with linkage to inpatient data from June 1, 2003, to June 30, 2006. Nearly 60% of patients either had DM or manifested hyperglycemia (defined here as BG >130 mg/dl). 30.00 28 25.00 20.00 19.50 15.00 10.00 9.6 5.00 0.00 Established diabetes Newly diagnosed diabetes Returned to normoglycemia, but had stress hyperglycemia Waddell M et al. Postgrad Med. 2009;121(3):61 66. 6
Philip Workup and Diagnosis Admission A1C = 9.1% FPG = 195 mg/dl Normal sensory exam BP = 135/80 mm Hg BMI = 30 kg/m 2 Diagnosis: newly diagnosed uncontrolled T2DM Philip is treated with basal-bolus insulin in the hospital to a BG <140 mg/dl BP = blood pressure; FPG = fasting plasma glucose. 7
Discharge Considerations What are your discharge plans for this patient? Will he be discharged on insulin therapy? When and where will follow-up take place? What education does he need prior to discharge?
Guideline Approach to Therapy in Patients With Newly Diagnosed Type 2 Diabetes Applying It to Philip Lifestyle intervention ± metformin Will we implement with this patient? Yes or No Lifestyle intervention is cornerstone therapy for all patients and most patients will receive metformin unless they have contraindications or can t tolerate it Depending on his A1C level, consider combination therapy or insulin If A1C level not at target (3 6 months), we ll add more therapy eg, If A1C 7.5%: consider combination therapy. If A1C 9: consider insulin This will depend on his BMI Let s come back and talk about where Philip is For example, if his BMI <30, DPP-4 inhibitor (consider GLP-1 RA, SGLT-2 inhibitor); if it is 35> BMI >30, GLP-1 RA, SGLT-2 inhibitors DPP-4 inhibitor and if BMI >35, GLP-1 RA, SGLT-2 inhibitors Consider bariatric surgery in nonresponders Raz I. Diabetes Care. 2013;36(suppl 2):S139 S144. 9
Setting Glycemic Goals for Philip Age 64 years BMI 28.6 kg/m 2 (overweight) A1C level Elevated on admission at 9.1% Lifestyle Only moderately active Cardiovascular Well-controlled hypertension (135/80 mm Hg) History of myocardial infarction Lipid profile not optimal (LDL <70 mg/dl but HDL not at goal) What glycemic goal would you set for Philip? What other treatment goals should he have? 10
Reducing the Risk of T2DM Complications: Comprehensive Diabetes Management American Diabetes Association. Diabetes Care. 2014;37(suppl 1):S14 S80. 11
Setting Individualized Glycemic Goals in T2DM 2012 ADA/EASD Position Statement ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes. Inzucchi S et al. Diabetes Care. 2012;35(6):1364 1379. Ismail-Beigi F et al. Ann Intern Med. 2011;154(8):554 559. 12
Philip Target A1C level: 7.0% Physician begins discussing pharmacotherapy for Philip Diabetes educator consult Patient education Detailed dietary and exercise recommendations Weight-loss strategies 13
Weight Reduction in T2DM Calorie restriction Key factor for weight loss Moderate calorie restriction recommended 500 1000 kcal/day fewer than baseline intake Dietary changes Reduce saturated and trans fatty acids, cholesterol, and sodium Behavioral modification Self-monitoring of food intake with daily log Stimulus control Cognitive restructuring Stress management Physical activity At least 150 minutes/week of moderate activity Aerobic, resistance, flexibility training In patients with T2DM, weight loss and exercise can reduce insulin resistance and hepatic glucose production. Bantle JP et al. Diabetes Care. 2008;31(suppl 1):S61 S78; Brown A et al. Postgrad Med. 2010;122(1):163 171; Inzucchi SE et al. Diabetologia. 2012;55(6):1577 1596; Ismail-Beigi F. N Engl J Med. 2012;366(14):1319 1327; National Institutes of Health. Obes Res. 1998;6(suppl 2):51S 209S. 14
LOOK AHEAD Study Intensive Lifestyle Intervention and Risk Reduction Primary objective To examine, in overweight volunteers with T2DM, the longterm effects of an intensive lifestyle intervention program designed to achieve and maintain weight loss by decreased caloric intake and increased physical activity Comparison Control condition involving a program of diabetes support and education Look AHEAD Research Group. Arch Intern Med. 2010;170(17):1566 1575. 15
LOOK AHEAD Study Intensive Lifestyle Intervention and Risk Reduction Diet modification, exercise, behavioral training Group support with in-person and telephone follow-ups Parameter Lifestyle Intervention (n = 2570) Support and Education (n = 2575) Weight loss, % 6.5 0.88 a Treadmill fitness, % METS 12.74 1.96 a A1C level 0.36 0.09 a Systolic BP, mm Hg 5.33 2.97 a Diastolic BP, mm Hg 2.92 2.48 b HDL-C, mg/dl 3.67 1.97 a Triglycerides, mg/dl 25.56 19.75 b a P <0.001; b P = 0.01. HDL-C = high-density lipoprotein cholesterol; MET = metabolic equivalent. Look AHEAD Research Group. Arch Intern Med. 2010;170(17):1566 1575. 16
Effect of Antihyperglycemic Drugs on A1C Level, Hypoglycemia, Weight (Injectable Therapies Are Highlighted) Drug A1C Reduction (%) Hypoglycemia Incidence (%) a Weight Effects (kg) Sulfonylureas 1 2 18 30 +2 Pioglitazone 0.5 1.4 0 3.7 a +0.9 to +2.6 Linagliptin 0.4 0.3 a No change Saxagliptin 0.4 0.5 3 5 a 0.1 to 1.2 Sitagliptin 0.6 0.8 <3-5 a 0.2 to 0.8 Exenatide twice daily 0.5 1 4 5 2.8 to 3.1 Liraglutide 0.84 1.14 8 12 1 to 2.26 Exenatide once weekly 1.5 5-2 2 SGLT-2 inhibitors 0.5 0.7 1.4 1.1 to 2.2 Basal insulin b 1.5 3.5 c 29.9 61.2 +2 to +4 a Similar to placebo. b Includes NPH, insulin glargine, and insulin detemir. c No dose or A1C-lowering limit. Exenatide once weekly not approved for use with basal insulin. Adapted from Boland CL et al. Ann Pharmacother. 2013;47(4):490 505; and Monami M et al. Diabetes Obes Metab. 2014;16(5):457 466. 17
Philip Discharge Planning Discuss with the patient the need for basal insulin in addition to oral agents Educator to provide hands-on instruction on administration techniques Provide education to caregiver/family if possible Comprehensive outpatient education should be scheduled Philip is discharged on oral metformin 1000 mg bid and a basal insulin pen device, 0.2 u/kg in the evening with instructions to self-titrate to an FPG level of 70 130 mg/dl Some might suggest lower boundary of 80 mg/dl as in 3 0 3 algorithm, given that Philip is new to insulin and has a prior history of myocardial infarction 18
Predischarge Checklist Diet information Monitor/strips & Rx Rx for/supplies of medications, insulin, needles Treatment goals Contact phone numbers Medi-Alert bracelet Survival Skills training Meal planning Sick day planning Involve nursing, dietitian, diabetes educator 19
Survival Skills to Be Taught Before Discharge Basic understanding of what diabetes is How and when to take diabetes medications Basic knowledge of effect of carbohydrates on glucose levels Recognition, treatment, and prevention of hypoglycemia Self-monitoring of BG and implication of results What to do during illness How to dispose of lancets and insulin syringes Moghissi ES et al; American Association of Clinical Endocrinologists; American Diabetes Association. Endocr Pract. 2009;15(4):353 369. 20
Transition to Discharge Does patient have a glucose monitor for home use? Is patient clear about the diabetes therapy after discharge? Does patient have appropriate outpatient follow-up appointment with primary care, specialist, diabetes specialist clinic? Additional attention to difficulties with insurance, transportation, etc Divide material up throughout course of hospital stay; support and reinforce with written material; ensure that follow-up connection is made with outpatient provider 21
Specific Advantages of Main Drug Classes Metformin First-line therapy in most consensus algorithms Large safety margin Can be used by most patients Decreases hepatic glucose production, has a mild effect on peripheral resistance, and increases both total and active endogenous GLP-1 in response to food Might also be cardioprotective in obese T2DM patients Reduction in mortality in UKPDS Lowers risk of cancer in T2DM patients Insulin Most powerful agent to lower glucose; no dose limit to efficacy; indicated when A1C levels above 9% Garber AJ et al. Endocr Pract. 2013;19(3):536 557. Inzucchi SE et al. Diabetes Care. 2012;35(6):1364 1379. Raz I. Diabetes Care. 2013;36(suppl 2):S139 S144. 22
Guideline Approach to Therapy in Patients With Newly Diagnosed Type 2 Diabetes Philip Set A1C goal 7% Lifestyle intervention ± metformin If A1C 7.5%: consider combination therapy Diet, exercise program set up Metformin 1 g bid prescribed Yes, metformin + insulin If A1C 9%: consider insulin Yes, Basal insulin started, titrated against FPG Raz I. Diabetes Care. 2013;36(suppl 2):S139 S144. 23
Initiation and Adjustment of Insulin Regimens Start once-a-day long-acting insulin analog or NPH bedtime or morning Starting dose 10 units or 0.2 units/kg Titrate against FPG until in target range (70 130 mg/dl) Increase dose typically by 2 units q 3 days Can increase dose by 4 units q 3 days if BG >180 mg/dl If hypoglycemia occurs or if BG <70 mg/dl Reduce dose by 4 U, or by 10% if dose is >60 U Adapted from Nathan DM et al. Diabetes Care. 2009;32(1):193 203. 24
Philip Sees Primary Care Physician at 6 Months Basal insulin dose is 30 units, FPG is between 80 and 110 mg/dl most days PPG is between 180 and 220 mg/dl BMI = 30 kg/m 2 He denies any symptoms of hypoglycemia How would you modify his injectable therapy? Continue to titrate basal insulin therapy? Add prandial insulin? Add a GLP-1 RA? PPG = postprandial glucose. 25
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Guideline Approach to Therapy in Patients With Newly Diagnosed Type 2 Diabetes Step Action in Philip Set A1C goal 7% Lifestyle intervention ± metformin If A1C 7.5%: consider combination therapy If A1C 9%: consider insulin Metformin 1 mg bid Set up with dietitian, exercise trainer Yes, metformin + basal insulin Basal insulin started, titrated against FPG (conservative dosing discontinuation of nutritional and correction dosing used in hospital) With SMBG 1 4 times/day orders for test strips, lancets, syringes, needles (unless a pen ordered), and a glucagon kit If A1C not at target (3 6 months), add an agent, depending on BMI BMI <30 kg/m 2 35> BMI >30 kg/m 2 BMI >35 kg/m 2 DPP-4 inhibitor (Consider GLP-1 RA, SGLT-2 inhibitor) GLP-1 RA, SGLT-2 inhibitors DPP-4 inhibitors GLP-1 RA, SGLT-2 inhibitors Consider bariatric surgery in nonresponders Raz I. Diabetes Care. 2013;36(suppl 2):S139 S144. 27
Role of Incretin-based Therapies in Reducing Hyperglycemia Ussher JR, Drucker DJ. Endocr Rev. 2012;33(2):187 215. 28
GLP-1 Receptor Agonists Place in Therapy: ADA/EASD Recommendations Second-line in addition to metformin In 3-drug combinations With basal insulin Among preferred agents in specific situations When goal is to avoid hypoglycemia When goal is to avoid weight gain Actions complement those of commonly used antihyperglycemic agents Class Effectiveness Cellular Mechanism Primary Physiologic Actions Insulin Highest Activate insulin receptors GLP-1 RA High Activate GLP-1 receptors Inzucchi SE et al. Diabetes Care. 2012;35(6):1364 1379. Glucose disposal Hepatic glucose production Insulin secretion (glucose dependent) Glucagon secretion (glucose dependent) Satiety 29
GLP-1 Receptor Agonists Place in Therapy in the AACE 2013 Algorithm Recommended for treatment-naïve patients at every A1C level as Monotherapy or Part of combination-therapy regimens Both oral or with insulin Based on multifactorial mechanism of action, glucose-dependent mechanism of action (low risk of hypoglycemia), and potential for weigh loss/no risk of weight gain Garber AJ et al. Endocr Pract. 2013;19(3):536 557. 30
Marketed GLP-1 Receptor Agonists Characteristic Exenatide bid Liraglutide Exenatide ER Albiglutide Dulaglutide Initial US approval 2005 2010 2012 2014 2014 Trade name Byetta Victoza Bydureon Tanzeum Trulicity Description Synthetic exendin-4, a peptide identified in H. suspectum; activates GLP-1 receptors and is resistant to DPP-4 degradation GLP-1 modified to be resistant to DPP-4 degradation Exenatide contained in hydrolyzable polymer microspheres for extended release GLP-1 modified to be resistant to DPP-4 degradation GLP-1 modified to be resistant to DPP-4 degradation Administration Subcutaneous injection Half-life 2.4 hours 13 hours >1 week 5 days 5 days Dosing 2 daily, before meals 1 daily, anytime 1 weekly 1 weekly 1 weekly 1. Byetta (exenatide) [prescribing information]. 2. Victoza (liraglutide) [prescribing information]. 3. Bydureon (exenatide extendedrelease for injectable suspension) [prescribing information]. 4. Tanzeum (albiglutide) [prescribing information]. 5. Trulicity (dulaglutide) [prescribing information].
GLP-1 Receptor Agonists FDA-Approved Agents Liraglutide Albiglutide Dulaglutide Exenatide Exenatide ER Key Features Injectable administration Mimic action of native GLP-1 Increase glucose-dependent insulin secretion Suppress glucagon production in glucosedependent manner Slow gastric emptying Increase satiety (reducing appetite/food intake) ER = extended release; GLP-1 = glucagon-like peptide 1. Garber AJ et al. Endocr Pract. 2013;19(suppl 2):1 48. 32
Placebo-adjusted A1C (%) Glucose Control With GLP-1 Receptor Agonists Placebo-adjusted Change From Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alb 1 Dul 2 Exe 3 Exe ER 4 Lir 5 Alb 6 Dul 7 Exe 8 Exe ER 9 Lir 10 Alb 11, * Exe 12 Exe ER 13, Lir 14 Baseline A1C (%) 8.1 7.6 7.8 8.5 8.3 8.1 8.1 8.2 8.6 8.4 8.2 8.6 8.3 8.5 0-0.5-1 -1.5-1.0-0.8-0.7-0.9-0.9-1.1-1.4-1.5-1.5-1.5-0.8-1.0-1.5-1.4-2 *Metformin with or without SU or TZD. Metformin with or without SU. Absolute change from baseline (active-controlled trial). 1. Tanzeum (albiglutide) injection [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Umpierrez G et al. Diabetes Care. 2014;37:2168 2176. 3. Moretto TJ et al. Clin Ther. 2008;30:1448 1460. 4. Russell-Jones D et al. Diabetes Care. 2012;35:252 258. 5. Garber A et al. Lancet. 2009;373:473 481. 6. Ahrén B et al. Diabetes Care. 2014;37:2141 2148. 7. Dungan KM et al. Lancet. 2014;384:1349 1357. 8. DeFronzo RA et al. Diabetes Care. 2005;28:1092 1100. 9. Bergenstal RM et al. Lancet. 2010;376:431 439. 10. Pratley RE et al. Lancet. 2010;375:1447 1456. 11. Pratley RE et al. Lancet Diabetes Endocrinol. 2014;2:289 297. 12. Buse JB et al. Diabetes Care. 2004;27:2628-2635. 13. Diamant M et al. Lancet. 2010;375:2234 2243. 14. Marre M et al. Diabet Med. 2009;26:268 278. 33
Weight (kg) Weight Change With GLP-1 Receptor Agonists Absolute Change From Baseline (Not Head-to-Head Trials) 0-1 -2-3 -4 Monotherapy Add-on to Metformin Add-on to SU Alb 1 Dul 2 Exe 3 Exe ER 4 Lir 5 Alb 6 Dul 7 Exe 8 Exe ER 9 Lir 10 Alb 11, * Exe 12 Exe ER 13, Lir 14-0.9-2.3-3.1-2 -2.5-1.2-2.6-2.8-2.3-3.4-0.6-1.6-2.6-0.2 *Metformin with or without SU or TZD. Metformin with or without SU. 1. Tanzeum (albiglutide) injection [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Umpierrez G et al. Diabetes Care. 2014;37:2168 2176. 3. Moretto TJ et al. Clin Ther. 2008;30:1448 1460. 4. Russell-Jones D et al. Diabetes Care. 2012;35:252 258. 5. Garber A et al. Lancet. 2009;373:473 481. 6. Ahrén B et al. Diabetes Care. 2014;37:2141 2148. 7. Dungan KM et al. Lancet. 2014;384:1349 1357. 8. DeFronzo RA et al. Diabetes Care. 2005;28:1092 1100. 9. Bergenstal RM et al. Lancet. 2010;376:431 439. 10. Pratley RE et al. Lancet. 2010;375:1447 1456. 11. Pratley RE et al. Lancet Diabetes Endocrinol. 2014;2:289 297. 12. Buse JB et al. Diabetes Care. 2004;27:2628 2635. 13. Diamant M et al. Lancet. 2010;375:2234 2243. 14. Marre M et al. Diabet Med. 2009;26:268 278. 34
Patients (%) Hypoglycemia With GLP-1 Receptor Agonists Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials) 40 35 30 25 20 15 10 5 0 Monotherapy Add-on to Metformin Add-on to SU Alb 1 Dul 2 Exe 3 Exe ER 4 Lir 5 Alb 6 Dul 7 Exe 8 Exe ER 9 Lir 10 Alb 11, * Exe 12 Exe ER 13, Lir 14 0 12.3 8 9 4.0 5.2 5.0 3 1 3 10.4 36 13.0 8.1 *Metformin with or without SU or TZD. Metformin with or without SU. 1. Nauck M et al. Diabetes. 2013;62(suppl 2): Abstr. 55-LB. 2. Umpierrez G et al. Diabetes Care. 2014;37:2168 2176. 3. Moretto TJ et al. Clin Ther. 2008;30:1448 1460. 4. Russell-Jones D et al. Diabetes Care. 2012;35:252 258. 5. Garber A et al. Lancet. 2009;373:473 481. 6. Ahrén B et al. Diabetes Care. 2014;37:2141 2148. 7. Dungan KM et al. Lancet. 2014;384:1349 1357. 8. DeFronzo RA et al. Diabetes Care. 2005;28:1092 1100. 9. Bergenstal RM et al. Lancet. 2010;376:431 439. 10. Pratley RE et al. Lancet. 2010;375:1447 1456. 11. Pratley RE et al. Lancet Diabetes Endocrinol. 2014;2:289 297. 12. Buse JB et al. Diabetes Care. 2004;27:2628 2635. 13. Diamant M et al. Lancet. 2010;375:2234 2243. 14. Marre M et al. Diabet Med. 2009;26:268 278. 35
Weight* (kg) GLP-1 Receptor Agonist Weight Effects in Patients With T2DM Meta-analysis of Published Studies 0.0-0.5-1.0-1.5-2.0-2.5 Exenatide -2.03 Liraglutide -2.29 Exenatide ER -2.41 75% of patients lost weight With exenatide bid or exenatide ER: ~10% lost >10 kg ~20% lost 5 10 kg ~48% lost 0 5 kg ~20% 23% gained 0 5 kg ~1% 2% gained 5 10 kg -3.0 * Weight changes in patients treated for 12 weeks. Aroda VR et al. Clin Ther. 2012;34:1247 1258; Buse JB et al. Lancet. 2009;374:39 47; Drucker DJ et al. Lancet. 2008;372:1240 1250; Blevins T et al. J Clin Endocrinol Metab. 2011;96:1301 1310; Rosenstock J et al. Presented at: 47 th EASD Annual Meeting. 2011; Abstract 786; Buse J et al. Lancet. 2013;381:117 124; Pratley RE et al. Presented at: 72 nd ADA Scientific Sessions. 2012; Abstract 945-P. 36
Safety Considerations With GLP-1 Receptor Agonists GI adverse events Pancreatitis Renal impairment CV Common Usually dose-dependent and transient Usually reduced with dose titration Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal relationship has been established Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs. other agents Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected Labeling for GLP-1 receptor agonists suggests consideration of other therapies for patients with a history of pancreatitis Renal Impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration. Use caution when initiating or escalating doses in patients with renal impairment. Exenatide is contraindicated in patients with severe renal insufficiency or ESRD Small increase in pulse rate with these agents, although the clinical significance is not known ER = extended release; MTC = medullary thyroid carcinoma. Garber AJ et al. Endocr Pract. 2013;19(suppl 2):1 48. ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA: American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28, 2013. http://www.diabetes.org/newsroom/press-releases/2013/recommendations-for.html. 37
Safety Considerations With GLP-1 Receptor Agonists Pancreatic cancer Medullary thyroid cancer Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs. other agents Further assessments required from long-duration controlled studies or epidemiologic databases Animal data showed an increased incidence of C-cell tumors with liraglutide and exenatide ER treatment, but confirmatory population studies are lacking Labeling for albiglutide, dulaglutide, exenatide ER, and liraglutide: Patients should be counseled regarding MTC and the signs/symptoms of thyroid tumors Contraindicated in patients with personal/family history of MTC or multiple endocrine neoplasia syndrome type 2 ER = extended release; MTC = medullary thyroid carcinoma. Garber AJ et al. Endocr Pract. 2013;19(suppl 2):1 48. ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA: American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28, 2013. http://www.diabetes.org/newsroom/pressreleases/2013/recommendations-for.html. 38