Type 2 Diabetes: Disease Overview and Pharmacologic Management
Jerry Meece, RPh, CDE, FACA, FAADE
Director of Clinical Services
Plaza Pharmacy and Wellness Center
Gainesville, Texas
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Agenda
• Overview of type 2 diabetes (T2D)
• Pathophysiology
• Symptoms and diagnosis
• ADA treatment algorithm
• Glycemic targets
• Challenges and barriers in treatment
• Implications of micro- and macrovascular
complications
• Medication class review
• ADA treatment algorithm
• Diabetes management software
• Conclusion
What proportion of people with diabetes have …
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• Controlled BP (<130/80 mmHg)*
• LDL at the goal level (<100 mg/dl)
• A1C at the goal level (<7%)
• What proportion have met all three?
56.2%
51.1%
52.5%
18.8%
*ADA BP goal changed in 2015 to 140/90 mmHg
Stark Casagrande S, Fradkin JE. The Prevalence of Meeting A1C, Blood Pressure, and LDL Goals Among People With Diabetes, 1988-2010. Diabetes Care.
2013;36 (8) 271-2279
Natural History of Type 2 Diabetes
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Pathophysiology of Type 2 Diabetes
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Common Symptoms of T2D
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• Hyperglycemia
• Polydipsia (abnormal thirst)
• Polyphagia (excessive hunger)
• Polyuria (excessive urination)
• Blurred vision
• Cuts/bruises that are slow to heal.
• Weight loss
Standards of Medical Care in Diabetes—2016 January 2016 Volume 39, Supplement 1-American Diabetes Association
ADA Treatment Algorithm for T2D
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*Inzucchi SE, et al. Diabetes Care. 2015;38:140-149
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Glucose Criteria to Diagnose Prediabetes and Diabetes
Test Normal Prediabetes Diabetes
Fasting Glucose <100 mg/dL 100 - 125 mg/dL ≥ 126 mg/dL
2-hr OGTT <140 mg/dL 140 - 199 mg/dL ≥ 200 mg/dL
A1C <5.7% 5.7 - 6.4% ≥ 6.5%
Standards of Medical Care in Diabetes—2016 January 2016 Volume 39, Supplement 1-American Diabetes Association
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General Glycemic Targets
Measure ADA AACE
A1C <7.0% ≤6.5%
Preprandial capillary plasma glucose 90-130 mg/dL <110 mg/dL
Postprandial capillary plasma glucose <180 mg/dL <140 mg/dL
Standards of Medical Care in Diabetes—2016 January 2016 Volume 39, Supplement 1-American Diabetes Association
Garber, AJ, et al.Endocrine Practice, 2013;19(Suppl 2):1-38.
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Pediatric Glycemic Targets
Standards of Medical Care in Diabetes—2016 January 2016 Volume 39, Supplement 1-American Diabetes Association
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Older Adult Glycemic Targets
Similar goals as younger adults IF:
• Functional and cognitively intact
• Have significant life expectancy
• Not frail or in weakened condition
• Hypoglycemia should be avoided
• Hyperglycemia leading to symptoms or risk
of acute hyperglycemic complications
should be avoided
American Diabetes Association Diabetes Care 2016 Jan; 39(Supplement 1): S81-S85
Glycemic Targets Should be Individualized
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Inzucchi SE, et al. Diabetes Care 2012;35:1364-1379.
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Challenges • Progressive cardiovascular disease
• Staying motivated
• Clinical inertia
• Obesogenic culture
• Self-management support
Barriers • Adherence
• Health illiteracy
• Costs
• Social and family support
Challenges and Barriers in Treatment
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Two Studies You Need to Know
DCCT
Diabetes Control And Complications Trial
UKPDS
United Kingdom Prospective Diabetes Study
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With an A1c of 7.2%
• 54% reduction in development of nephropathy
• 60% reduction in development of neuropathy
• 76% reduction in development of retinopathy
Diabetes Control and Complications Trial (DCCT)
DCCT Research Group. N Engl J Med. 1993; 329:977-986; Ohkubo Y, Kishikawa H, Araki E, et al. Diabetes Res Clin Pract. 1995;28:103-117
Good Glycemic Control Lowers the Risk of Complications
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DCCT Research Group. N Engl J Med. 1993; 329:977-986; Ohkubo Y, Kishikawa H, Araki E, et al. Diabetes Res Clin Pract. 1995;28:103-117
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. DCCT/EDIC Research Group. JAMA. 2003;290:2159-2167.
Each 1% fall in A1c results in a
20%–30% relative
risk reduction in
microvascular complications
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“You can't manage what you can't measure.” -- Peter Drucker
Type 2 Diabetes Therapy: Sites of Action
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Noninsulin Agents Available for T2D
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Class Primary Mechanism of Action Agent(s)
Biguanide Decrease HGP
Increase glucose uptake in muscle Metformin
Sulfonylureas Increase insulin secretion
Glimepiride
Glipizide
Glyburide
Thiazolidinediones Increase glucose uptake in muscle and fat
Decrease HGP
Pioglitazone
Rosiglitazone
DPP-4 inhibitors Increase glucose-dependent insulin secretion
Decrease glucagon secretion
Alogliptin Linagliptin Saxagliptin Sitagliptin
SGLT2 inhibitors Increase urinary excretion of glucose
Canagliflozin
Dapagliflozin
Empagliflozin
GLP-1 receptor agonists
Increase glucose-dependent insulin secretion
Decrease glucagon secretion
Slow gastric emptying
Increase satiety
Albiglutide
Dulaglutide
Exenatide
Exenatide XR
Liraglutide
DPP-4 = dipeptidyl peptidase; HGP = hepatic glucose production
Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
Noninsulin Agents Available for T2D
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HGP = hepatic glucose production
Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
Class Primary Mechanism of Action Agent(s)
-Glucosidase inhibitors Delay carbohydrate absorption from intestine Acarbose Miglitol
Bile acid sequestrant Decrease HGP?
Increase incretin levels? Colesevelam
Dopamine-2 agonist Activates dopaminergic receptors Bromocriptine
Glinides Increase insulin secretion Nateglinide
Repaglinide
Amylin analogue
Decrease glucagon secretion
Slow gastric emptying
Increase satiety
Pramlintide
Metformin
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Insulin Secretagogues
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Thiazolidinediones (Glitazones)
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DPP-4 Inhibitors
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SGLT2 Inhibitors
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Vasilakou, D, et. al. Sodium–Glucose Cotransporter 2 Inhibitors for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann Intern Med. 2013;159:262-274.
Normal Kidney: Glucose Reabsorption
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(Plasma Glucose ≤180 mg/dL)
Adapted with permission from Rothenberg PL et al.
SGLT = sodium-glucose co-transporter.
1. Kanai Y et al. J Clin Invest. 1994;93(1):397-404. 2. You G et al. J Biol Chem. 1995;270(49):29365-29371. 3. Rothenberg PL et al. Poster
presented at: 46th European Association for the Study of Diabetes Annual Meeting; September 20-24, 2010; Stockholm, Sweden.
Glomerulus Proximal Convoluted Tubule
Early Distal
Glucose reabsorption into systemic circulation
Glucose SGLT1 SGLT2
Glucoregulatory Effects of GLP-1
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Comparison of GLP-1 RAs
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SBP = systolic blood pressure.
Lund A et al. Eur J Intern Med. 2014;25(5):407–414.
Parameter Short-acting GLP-1 RAs Long-acting GLP-1 RAs
Exenatide
Lixisenatide
Albiglutide
Dulaglutide
Exenatide LAR
Liraglutide
A1C reduction ~0.5%–1.2% ~0.8%–1.9%
Body weight reduction ~1–4 kg ~1–4 kg
SBP reduction ~3–4 mm Hg Up to 6 mm Hg
Heart rate increase No effect or small increase
(0–2 bpm) 2–4 bpm
Lipids Small improvements
in some studies
Small improvements
in some studies
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• Patient not achieving target A1C levels on one or two orals
• High fasting plasma glucose level
• Adherence issues
• When avoidance of hypoglycemia is particularly important
(occupation, lifestyle etc.)
• When weight loss is a consideration
Considerations for Use of a Long-acting GLP-1 RA
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Insulin and Insulin Delivery Devices
Insulin Delivery Devices
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Insulin Mimics Normal Physiologic Profile
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Principle of insulin use - to create as normal a glycemic profile as possible without causing unacceptable
weight gain or hypoglycemia
Supplement to The Journal of the American Osteopathic Association April 2013;113(4): Supplement 2: S6–S16
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1. Insulin Therapy for Type 2 Diabetes: Making It Work. JFPONLINE.com Vol 59, Apr 2010
2. Insulin Regimens for Type 2 Diabetes Mellitus. JFPONLINE.com (December 2006-Supplement)
Actions/Uses of Insulin
Bolus insulin (carb insulin, mealtime insulin) (Regular, lispro,
aspart, glulisine)
• Short-acting insulin or rapid-acting insulin (RAI) – Controls postprandial glucose (PPG) proactively
• Correction insulin (same insulins as above) – Corrects hyperglycemia reactively
Basal insulin (NPH, glargine [U-100 and U-300], detemir, degludec)
• Controls fasting and preprandial glucose
• Released at nearly constant levels throughout the day
Common mistake: Using basal insulin to try and control PPG
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www.dlife.com/diabetes/insulin/about/insulin/insulin/chart accessed 5/1/2011
Insulin Pharmacokinetics Summary
Insulin Onset Peak Duration
Rapid Acting
Aspart 10-20 min. 1-3 hours 3-5 hours
Lispro < 15 min. 30-90 minutes < 5 hours
Glulisine ~20 min 1 hour 5.5 hours
Regular
Humulin R 30-60 min. 2-3 hours 4-6 hours
Novolin R 30 min. 2.5-5 hours 8 hours
NPH
Humilin N 2-4 hours 4-10 hours 14-18 hours
Peakless Basal
Glargine 100 u/ml 1-4 hours Minimal 24 hours
Detemir 1-4 hours Minimal Up to 24 hours
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Becker, RH, Dahmen, R, et.al. Diab Care, 2015;38(4):637-643
Rodbard, HW, Cariou, B, Zinman, B, et al. Diabet Med 2013;30(11)1298-1304
Insulin Pharmacokinetics Summary Cont’d
Insulin Onset Peak Duration
Increased Duration Basal Insulins
Glargine 300 units/ml Develops over 6 hrs None > 30 hours (median)
Degludec 1-4 hours None Approx 42 hrs
Complimentary Features of Basal Insulin and Incretin-based Therapy
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ADA Treatment Algorithm for T2D
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*Inzucchi SE, et al. Diabetes Care. 2015;38:140-149
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Key Takeaways
• Glycemic targets and glucose-lowering
therapies should be individualized
• Diet, exercise and education are the foundations
of therapy
• Unless contraindicated, metformin is optimal
1st-line drug
• After metformin, combination therapy with 1-2
other oral and/or injectable agents; minimize
side effects
• Ultimately, many patients will require insulin
therapy alone or in combination with other
agents to maintain glycemic control
• All treatment decisions should be made in
conjunction with the patient (focus on
preferences, needs and values)
• Comprehensive CV risk reduction is a major
focus of therapy
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