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

jmeece@cooke.net

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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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