9/29/2014
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Diabetes Update: Guidelines, Treatment Options & Trends
Melissa Max, PharmD, BC-ADM, CDE Assistant Professor of Pharmacy Practice Harding University College of Pharmacy
+ Disclosure
Conflicts Of Interest and Financial Relationships Disclosures: Melissa Max, PharmD, BC-ADM, CDE – No COI/Financial Relationships to Disclose.
Learning Objectives
Analyze differences between the recommendations of the ADA/EASD and the AACE regarding the treatment of diabetes.
Interpret recent recommendations regarding interventions for patients with prediabetes/at increased risk for developing diabetes.
Describe the place in therapy for newer pharmacotherapeutic agents.
Apply knowledge of evidence-based recommendations to specific patient cases.
Identify trends in pharmacotherapeutic management of diabetes.
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+ Type 2 Diabetes (T2D) Overview
Hallmarks of T2D Decreased insulin sensitivity Progressive loss of β cell function
Therapeutic goals are not exclusively glucocentric
Optimizing physical activity, weight loss and healthy eating are key
Progressive disease Monotherapy failure Next steps?
+ Inpatient Use
Insulin remains gold standard
Significant concerns regarding the use of metformin, secretagogues and GLP1 RAs in inpatient setting
Imperative that pharmacists be familiar with various diabetes pharmacotherapeutic agents as patients will be admitted and discharged on these therapies
+ Current Guidelines
American Diabetes Association annual clinical practice recommendations, released each January
American Diabetes Association and European Association for the Study of Diabetes 2012 Position Statement for T2D
American Association of Clinical Endocrinologists Comprehensive Diabetes Management Algorithm 2013
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Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596
+ ADA/EASD Summary
Metformin—first line
Consider insulin as initial therapy if significant hyperglycemia or high A1C
If noninsulin monotherapy not effective over 3 months, add a second oral agent, GLP-1 agent , or insulin
Each new class of agent added lowers A1C ~1%
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+ AACE & ADA/EASD Comparison
AACE ADA/EASD A1C target <6.5% A1C target < 7%* Monotherapy if A1C < 7.5% May consider lifestyle alone for 3 months if Dual therapy for A1C A1C < 7.5% 7.6-9% Dual therapy if A1C ≥ Consider use of insulin as initial therapy— 9% A1C > 9% Consider use of insulin Focus on total cost of as initial therapy— therapy A1C ≥ 10%
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+ Multifactorial Interventions
Glucose lowering
Optimal Lifestyle Lipid modification modification CV risk & tobacco reduction cessation
BP lowering
Goals for Glycemic Control
ADA 1 AACE 2 A1C (%) <7 a ≤6.5
Fasting/preprandial 70–130 mg/dL <110 mg/dL glucose Peak postprandial <180 mg/dL <140 mg/dL b glucose
aGoal for most adult patients. Goal for individual patients is A1C as close to normal (<6%) as possible without significant hypoglycemia. b2-hour postprandial.
1. ADA Position Statement 2012. Available at: http://care.diabetesjournals.org/content/35/Supplement_1/S11.full.pdf+html. 2. AACE Guidelines 2011. Available at: https://www.aace.com/sites/default/files/DMGuidelinesCCP.pdf.
+ Individualization of A1C Goal
Tighter targets (6.0 - 6.5 %) – younger, healthier
Looser targets (7.5 – 8.0 % or more) – older, comorbidities, risk of hypoglycemia
Avoidance of hypoglycemia
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Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596 (Adapted with permission from: Ismail-Beigi et al. Ann Intern Med 2011;154:554)
+ Antihyperglycemic Therapy
Nonpharmacologic Weight optimization Healthy diet Increased physical activity
Pharmacotherapeutic options Oral agents Parenterals Non-insulin GLP-1 RA Amylin mimetic Insulin
+ 12 Drug Classes
Biguanides Bile Acid Sequestrants
Sulfonylureas DPP-4 Inhibitors
Meglitinides GLP-1 Receptor Agonists* Amylin Mimetic* Thiazolidinediones Insulin* Alpha Glucosidase Inhibitors Sodium Glucose Co- Transporter-2 (SGLT2) Dopamine-2 Agonists Inhibitors
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+ Drug Selection Considerations
Duration of disease
Which blood glucose level is not at target
Patient preference for route of administration
The degree of A1C-lowering effect required to achieve goal
Adverse effect profile and the patient’s tolerability
Comorbidities
+ Primary Glucose Lowering Effect
Fasting Post-prandial Metformin GLP-1 Agonists* DPP-4 Inhibitors TZD SU SU Rapid-acting insulin Long-acting insulin
Alpha-glucosidase inhibitors
Meglitinides
+ Weight
Weight Loss/Neutral Weight Gain GLP-1 Agonists* Insulin
DPP4 Inhibitors SU (neutral) TZD SGLT2 Inhibitors
Metformin (neutral)
Pramlintide
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+ Pharmacotherapy Pearls
+ SU Cautions
Risk of hypoglycemia is substantially increased in the elderly
Even a mild episode of hypoglycemia may lead to adverse outcomes in frail elderly patients.
Avoidance of hypoglycemia is an important consideration in choosing therapeutic agents and establishing glycemic goals in elderly adults.
Effective dose generally about ½ maximum dose
+ Sulfonylureas (SU)
Avoid glyburide in older adults
Assess patients for hypoglycemia regularly More likely to occur: After exercise/missed meals Eat poorly or abuse alcohol Impaired renal or cardiac function Following hospitalization
In patients with T2D, hypoglycemia risk is linked more to treatment strategies than A1C
If recurrent/severe hypoglycemia occurs, strongly consider changing therapy and/or targets
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+ Metformin Cautions
Use in renal dysfunction CI: Scr> 1.5 mg/dL male, > 1.4 mg/dL female Decrease dose if GFR < 45, d/c if < 30
Other cautions Heart failure History of alcoholism/binge drinking Age > 80 years Active liver disease GI intolerance & weight loss Hypoxic conditions—lactic acidosis Iodinated contrast material
+ Metformin Pearls
Effective treatment dose generally 1500-2000 mg daily
Patient counseling GI distress in ~30%, transient Administer with meals, consider XR formulation
B12
+ TZD Pearls
May be used in renal impairment
Do not cause hypoglycemia
Should not be used in patients with class III or IV HF
AE: edema, fractures, bladder CA
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+ Recent Approvals
SGLT2 Inhibitors DPP4 Inhibitor/Combo Canagliflozin Alogliptin
Dapagliflozin Alogliptin + metformin
Empagliflozin Alogliptin + pioglitazone
+ Recent Approvals
GLP1 Agonist New Indication Albiglutide Liraglutide Once weekly; SQ 3 mg daily 30 mg once weekly; FDA committee may increase to 50 mg recommendation 9/12/14 once weekly if inadequate glycemic response
+ SGLT2 Inhibitors
Sodium-glucose co-transporter type 2 (SGLT2) Inhibitors MOA: inhibition of SGLT2 receptors in kidney responsible for glucose reabsorption in proximal tubule Action—reduce reabsorption of filtered glucose, lower the renal threshold for glucose, and increase urinary glucose excretion
Insulin independent MOA; decreases fasting and post-prandial glucose concentrations
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+ SGLT2 Pearls
Benefit AE/Risk Weight loss Genital mycotic infections
Blood pressure UTI
Low incidence of Hypotension hypoglycemia Lipid effects Pleiotropic benefit Renal effects Similar to DPP4 inhibitors in A1C Bladder cancer lowering efficacy
+ SGLT2 Dosing & Administration
Canagliflozin 100-300 mg daily dose; before the first meal of the day Moderate renal impairment [eGFR] 45 to 59 mL/min— max dose 100 mg daily Not indicated in patients with GFR <45 mL/min or in patients with severe hepatic impairment
Dapagliflozin 10 mg once daily, with or without food Not recommended for use in patients with eGFR < 60 mL/min or in patients with active bladder cancer For patients with severely reduced liver function, starting dose of 5 mg is recommended
+ SGLT2 Dosing & Administration
Empagliflozin 10 mg and 25 mg tablet CI Severe renal impairment (eGFR <30 mL/minute/1.73 m2) ESRD or dialysis Anticipated availability currently undetermined
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+ SGLT2 Place in Therapy
Add-on to metformin, after trying usual second-line therapies
Not mentioned in the ADA guidelines, as these guidelines were published before the approval of SGLT2 inhibitors
The AACE consider these agents to use with caution: as monotherapy in patients with an A1C less than 7.5%; as part of a dual or triple regimen in those with an A1C of 7.5% to 9.0%.
Incretin Hormones
+ DPP- 4 Inhibitors
MOA: prolong the t½ of GLP-1 and stimulate glucose- dependent insulin secretion, reducing postprandial glucose elevations
Efficacy: decrease A1C 0.7-1%
Adverse effects: Upper respiratory infections, UTI, HA Pancreatitis
Low incidence of hypoglycemia
Weight neutral
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+ DPP-4 Inhibitors
Sitagliptin Dose: 25-100 mg daily CrCl ≥50 ml/min, dose is 100 mg daily CrCl <50 but ≥ 30 ml/min, dose is 50 mg daily CrCl <30 ml/min, dose is 25 mg daily
Linagliptin Dose: 5 mg daily
+ DPP-4 Inhibitors
Saxagliptin Dose: 2.5-5 mg daily 2.5 mg dose for patients with CrCl ≤ 50 ml/min
Alogliptin Dose 12.5-25 mg daily Reduce by half for patients with CrCl 30-50 ml/min
+ DPP- 4 Inhibitors: Place in Therapy
ADA considers these as second-line therapies to be added on to metformin.
AACE recommends these as one of several preferred agents, after metformin, as monotherapy.
They can be used as part of a dual therapy regimen.
They can be considered as part of a multi-drug regimen with metformin, in drug-naïve, asymptomatic patients with A1C > 9%.
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+ GLP-1 Receptor Agonists
MOA: similar to human GLP-1 Enhance insulin secretion Suppress postprandial glucagon when blood glucose elevated; reduce hepatic glucose production
Exenatide, exenatide extended-release
Liraglutide
Albiglutide
+ GLP-1 Agonists
Benefit Risk/Disadvantage Weight loss Expensive Injectable dosage form Low risk of hypoglycemia Pancreatitis
Renal insufficiency Efficacy Thyroid cell cancer in Blood pressure/lipid rodents—long-acting improvement formulations
N&V β-cell preservation Gastroparesis
+ GLP-1 Agonists: Place in Therapy
ADA considers these as second-line therapies to be added on to metformin, if target A1C not met.
AACE recommend these as the preferred agent, after metformin, as monotherapy or as first choice of agents for add-on therapy to metformin in patients with A1C values 6.5% to 7.5%, or as metformin add- on therapy for A1C of 7.6% to 9%.
Additionally, these agents can be considered as part of a multi-drug regimen with metformin, in drug- naïve, asymptomatic patients with A1C > 9%.
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+ New GLP-1 RA formulation
FDA has approved extended-release exenatide in a pen form.
Indication—adjunctive therapy, T2D
Dose—2 mg SQ once weekly
Advantage—Ease the self-injection process by eliminating the need for the patient to transfer the medication between vial and syringe.
Efficacy—Up to 1.6% reduction in A1C
+ Emerging therapies
+ Insulins Ultra rapid-acting
Afrezza® Insulin human (rDNA origin); ultra rapid-acting mealtime inhalable powder Approved July 2014 Lung function testing Less hypoglycemia
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+ Ultra rapid-acting Conversion
+ Ultra Long-Acting Insulins
Insulin degludec Approved EU; FDA rejected Feb 2013; requested additional safety data Consistency, efficacy, safety, flexibility
Peg-lispro Phase III trials complete; NDA expected first quarter 2015 Improved glycemic control; IMAGINE-1 & IMAGINE-3
U300 EDITION II—less nocturnal hypoglycemia compared to glargine Flatter and longer PK/PD profile; DOA 40 hours
+ Insulin Combination
Insulin degludec + insulin aspart
Fixed combination basal with bolus
Once-daily for T1 and T2 (remaining meals with aspart)
Rejected Feb 2013 by FDA; requested additional CV data
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+ Trends
Increasing use of basal insulin and GLP1 RA More effective at lowering A1C Not associated with increased hypoglycemia Weight loss
Insulin and SGLT2 inhibition
Prevention of disease progression in patients at increased risk for developing diabetes
+ GLP1/Insulin Combinations
Insulin degludec and liraglutide Once-daily basal insulin and once-daily GLP-1 analogue T2DM
Lixisenatide and insulin glargine GLP-1 agonist and basal insulin analog T2DM
+ Pipeline Incretins
GLP-1 RA DPP4 inhibitor Lixisenatide Omarigliptin Once daily for T2D Once-weekly, adults, T2 NDA expected 2015 Phase III trials
Dulaglutide Once weekly T2D Trelagliptin succinate AWARD; REWIND Once-weekly for T2D Phase III trials Semaglutide Once-weekly T2D SUSTAIN
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+ Case 1
A 47-year-old woman, newly diagnosed with T2D, presents with an A1C of 11.6% and a fasting glucose concentration of 350 mg/dL. In addition to improvements in physical activity and food choices, which one of the following is the best initial treatment option for this patient?
A. Metformin
B. Extended release exenatide
C. Insulin glargine and insulin aspart
D. Canagliflozin
+ Case 2
Which one of the following drugs, if coadministered with exenatide, would be most likely to increase hypoglycemia risk?
A. Metformin
B. Glyburide
C. Saxagliptin
D. Pioglitazone
+ Case 3
A 52-year-old woman with a 10-year history of T2D has an A1C of 7.6%. She has a history of metformin intolerance. Current antihyperglycemic therapy is pioglitazone 45 mg/day. Her SCr is 2.1 mg/dL, and her estimated CrCl is 26 mL/minute. Which one of the following would be most appropriate to add to this patient’s drug regimen?
A. Sitagliptin 100 mg/day
B. Liraglutide 0.6 mg/day
C. Extended-release exenatide 2 mg/week
D. Linagliptin 5 mg/day
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+ Case 4
HW is a 45-year-old obese white male with T2D, currently receiving metformin 1 g twice daily, whose postprandial BG is higher than desired. His most recent A1C is 7.5%. Which of the following is the best option for HW?
A. increase metformin to 850 mg three times daily
B. substitute metformin with a SU
C. add a bedtime dose of insulin detemir
D. add sitagliptin 100 mg daily
+ Questions?
+ References
American Diabetes Association
American Association of Clinical Endocrinologists
Standards of Medical Care in Diabetes—2014. Diabetes Care. January 2014; 35: S11-S63
Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach: Position Statement of the American Diabetes Association (ADA) and the European ssociation for the Study of Diabetes (EASD); Diabets Care June 2012 35:1364-1379.
DeFranzo, R.A., Davidson, J.A., & del Prato, S. (2012). The role of the kidneys in glucose homeostasis: A new path towards normalizing glycaemia. Diabetes, Obesity & Metabolism, 14 (1), 5-14.
Inzucchi, S. Oral Antihyperglycemic Therapy for Type 2 Diabetes: Scientific Review. JAMA. 2002; 287:360-372.
DeWitt, D. Outpatient Insulin Therapy in Type 1 and Type 2 Diabetes Mellitus: Scientific Review. JAMA. 2003;289:2254-2264.
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