Diabetes management: Non-insulin medications

Kristi Kulasa, MD

Assistant Clinical Professor of Medicine

Director, Inpatient Glycemic Control

Department of Endocrinology, Diabetes and Metabolism

November 10, 2015

Learning Objectives

1. Describe the role of diet, exercise, and patient education in the treatment of diabetes

2. Know the mechanism of action, dosing schedule, indications, percent A1c reduction, and side effects for common medications to treat type 2 diabetes including biguanides, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, incretins, and SGLT-2 inhibitors

3. Explain the clinical rationale for choosing a particular medication to treat type 2 diabetes in terms of A1c reduction, adverse effects, and co-morbidities

4. Differentiate key points in the treatment of type 1 and type 2 diabetes

Outline

• Mechanisms of Hyperglycemia

• Available Treatment Options

• Published algorithms for treatment of type 2 diabetes

• Case Discussions

COLESEVELAM

ACARBOSE

GLP-1R AGONISTS

DPP-4 INHIBITORS

INSULIN SU

DPP-4 INH MEGLITINIDES

GLP-1R AGONISTS

GLP-1 R

AGONISTS

MET

TZD

TZD

SGLT-2

RECEPTOR

BLOCKERS

HYPERGLYCEMIAReabsorb

Filtered

Glucose

Derangements at the Level of the

Hypothalamus Lead to Appetite

Dysregulation and Obesity

Increased Lipolytic Activity

Leading to Deleterious

Effects in Both Insulin

Secretion and Action

Inappropriate

Hepatic

Glucose

Production

Impaired Insulin – Mediated

Glucose Disposal

β

Reduced

Insulin

Secretion

α

Increased Post-

Prandial Secretion

of Glucagon

Decreased Incretin Action

Leads to Glucose

Stimulated Insulin ReleaseGut

Glucose

Absorption

Lifestyle

• Diet and Exercise

– A1C reduction 1-2%

– Weight loss

– Improved utilization of insulin

– Compliance difficult

• Patient Education

– Survival skills- meds, meter, hypoglycemia

– Who to call

Biguanide

• Generic: Metformin

• US Brand: Fortamet®, Glucophage®, Glucophage® XR, Glumetza®, Riomet®

• MOA: decreases hepatic gluconeogenesis and improves insulin sensitivity in peripheral tissues

• A1C lowering: 1.0-2.0%

• Advantages: weight neutral, no hypoglycemia

• Disadvantages: GI s/e (diarrhea, nausea, vomiting). Contraindicated with serum creatinine ≥1.5 mg/dL in males or ≥1.4 mg/dL in females. More recent studies OK w/ Clcr down to 30 mL/minute w/ dose reduction < 45 mL/minute. Avoid use in patients with impaired liver function due to potential for lactic acidosis.

Sulfonylurea

• 1st generation:

– Acetohexamide

– Chlorpropamide (Diabinese)

– Tolbutamide (Orinase)

• 2nd generation:

– Glipizide (Glucotrol) (Glucotrol XL)

– Gliclazide (Diamicron R) (Diamicron MR)

– Glyburide (Glibenclamide) (Diabeta) (Micronase) (Glynase)

– Glimepiride (Amaryl)

Sulfonylurea

• MOA: stimulates insulin secretion

• A1C lowering: 1-2%

• Advantages: rapid acting, low cost

• Disadvantages: weight gain, hypoglycemia, effectiveness

decreases over time. Use with caution in elderly patients,

malnourished patients and in patients with impaired renal

or hepatic function

Thiazolidinediones

• Pioglitazone - Actos®

• Rosiglitazone - Avandia®

• MOA: improves insulin sensitivity in

adipose tissue, skeletal muscle and liver

• A1C lowering: 0.5-1.4%

• Advantages: improved lipid profile (Pioglitazone), potential decrease MI (Pioglitazone), no hypoglycemia

• Disadvantages: fluid retention, CHF, weight gain, bone fractures, bladder CA, potential to increase MI (rosiglitazone)

SGLT-2 Inhibitors

• Canagliflozin - Invokana®

• Dapagliflozin – Farxiga®

• Empagliflozin – Jardiance®

• MOA: blocks reabsorption of glucose by the kidney

• A1C lowering: 0.7-1.0%

• Advantages: weight loss and no hypoglycemia

• Disadvantages: UTI, genital infections, increased urination, intravascular volume contraction/symptomatic hypotension, hyperkalemia, cannot use in renal impairment (contraindicated GFR < 30 ml/min, not rec GFR <45-60 ml/min), euglycemicDKA.

Incretins

Lipidsonline.org

• Gut hormones that are secreted from enteroendocrine

cells into the blood within minutes of eating

DPP-IV inhibitors

• Sitagliptin – Januvia®

• Saxagliptin – Onglyza®

• Linagliptin - Tradjenta®

• Alogliptin – Nesina®

• MOA: glucose mediated insulin release, decreases glucagon, slows gastric emptying

• A1C lowering: 0.6-0.9%

• Advantages: weight neutral, can use with renal impairment, glucose dependent action, no hypoglycemia

• Disadvantages: expensive (now covered on most plans)

Glucagon-like peptide 1 agonists

• Exenatide - Byetta®

• Liraglutide - Victoza®

• Exenatide Once Weekly - Bydureon®

• Albiglutide – Tanzeum®

• Dulaglutide – Trulicity®

• MOA: glucose mediated insulin release, suppresses glucagon secretion, slows gastric emptying, reduces food intake

• A1C lowering: 0.9-1.9%

• Advantages: weight loss, glucose dependent action, no hypoglycemia

• Disadvantages: injections, GI s/e (nausea, vomiting), expensive

Insulin

http://www.medicalcriteria.com/criteria/dbt_insulin.ht

m

Insulin

Category/Name of Insulin Brand Name

(manufacturer)

Onset, Peak, Duration Appearance

Rapid-Acting

Insulin Lispro

Insulin Aspart

Insulin Glulisine

Humalog (Lilly)

Novolog (Novo Nordisk)

Apidra (Sanofi-Aventis)

w/in 15 min, 1-3h, 3-5h

w/in 15 min, 1-3h, 3-5h

15-30 m, 30-60 m, 4h

Clear

Clear

Clear

Short-Acting

Regular Humulin R (Lilly)

Novolin R (Novo Nordisk)

30-60 min, 2-4h, 5-8h Clear

Intermediate-Acting

NPH Humulin N (Lilly)

Novolin N (Novo Nordisk)

1-2h, 4-10h, 14+ hrs Cloudy

Long-Acting

Insulin Detemir

Insulin Glargine

Levemir (Novo Nordisk)

Lantus (Sanofi-Aventis)

3-4h, 6-8h, 20-24h

1.5h, flat, 24h

Clear

Clear

Insulin Mixtures

NPH/Reg (70%/30%)

LisproProtamine/Lispro (50%/50%)

LisproProtamine/Lispro (75%/25%)

AspartProtamine/Aspart (70%/30%)

Humulin 70/30 (Lilly)

Novolin 70/30 (Novo)

Humalog Mix 50/50 (Lilly)

Humalog Mix 75/25 (Lilly)

Novolog Mix 70/30 (Novo)

15-30m, 30m-3h, 14-24h

5-10m, 1-4h, 18-24h

Cloudy

Cloudy

Cloudy

Cloudy

Cloudy

Insulin

• A1C lowering: unlimited

• Advantages: no dose limit, rapidly effective, improved lipid

profile

• Disadvantages: weight gain, hypoglycemia, injections

(Qday-QID), monitoring

Type 1 vs Type 2

Type 1 Diabetes

• 5-10% of patients with DM

• Autoimmune destruction of pancreatic islets destroying ability to make insulin

• Absolute insulin deficiency

• Treatment MUST include insulin

Type 2 Diabetes

• 90-95% of patients with DM

• Metabolic disorder characterized by insulin resistance

• Relative insulin deficiency

• Treatment CAN include insulin, esp late in disease process

ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Case 1

• 45 y/o male with newly diagnosed type 2 diabetes. He Has been symptomatic with 2 months of polyuria, polydipsia and unintentional weight loss of 20 lbs.

• A1C 10.7%

• Cr 0.8

• Weight 85 kg (BMI 30)

• What is the most appropriate initial treatment regimen?A. Lifestyle change only, patient is very motivated

B. Lifestyle + metformin

C. Lifestyle + metformin + acarbose

D. Lifestyle + metformin + glipizide + basal insulin

ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Case 2

• 56 y/o male with long-standing uncontrolled type 2 diabetes

x15yrs, CAD s/p MI 2003, class IV CHF and sleep apnea.

• Home regimen: metformin 1000mg bid, glipizide 5mg bid

• A1C 10%

• Cr 0.6

• Weight 95 kg (BMI 35)

• Which of the following medication should be added next?

A. Lifestyle change only, patient is very motivated

B. Pioglitazone (Actos®, TZD)

C. Liraglutide (Victoza®, GLP-1 R agonist)

D. Sitagliptin (Januvia®, DPP-IV inhibitor)

ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Case 3

• 75 y/o female with long-standing type 2 diabetes and osteoporosis recently admitted to the hospital with a hip fracture s/p fall at home in the setting of hypoglycemia.

• Home regimen: metformin 1000mg bid and glipizide 2.5mg bid

• A1C 6.5%

• Cr 0.4

• Weight 40 kg (BMI 19)

• Which of the following medication adjustment is most appropriate?A. No change necessary, A1C at goal

B. Stop glipizide and start sitagliptin (Januvia®, DPP-IV inhibitor)

C. Stop metformin and start canagliflozin (Invokana®, SGLT-2 inhibitor)

D. Stop glipizide and start pioglitazone (Actos®, TZD)

ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Case 4

• 45 y/o male with newly diagnosed DM2 w/ A1C 8.3%. Denies polyuria, polydipsia or blurry vision.

• Home regimen - none

• A1C 8.3%

• Cr 0.85

• Weight 95 kg (BMI 30)

• What is the most appropriate initial treatment regimen?A. Lifestyle change only, patient is very motivated

B. Lifestyle + metformin (Glucophage®, biguanide)

C. Lifestyle + sitagliptin (Januvia®, DPP-IV inhibitor)

D. Lifestyle + canagliflozin (Invokana®, SGLT-2 inhibitor)

ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Case 5• 45 y/o female with uncontrolled DM2 w/ A1C 10.2% as well as

heartburn, HTN and hyperlipidemia needs medication escalation for DM, but is very concerned about weight gain and will not take any medication that will cause weight gain.

• Home regimen – metformin 1000mg bid

• A1C 10.2%

• Cr 0.6

• Weight 90 kg (BMI 34)

• Which of the following medication(s) should be added next?A. Lifestyle change only, patient is very motivated

B. Liraglutide (Victoza®, GLP-1 R agonist) + glipizide (SU)

C. Sitagliptin (Januvia®, DPP-IV inhibitor) + canagliflozin (Invokana®, SGLT-2 inhibitor)

D. Canagliflozin (Invokana®, SGLT-2 inhibitor) + Liraglutide (Victoza®, GLP-1 R agonist)

ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Case 6• 65 y/o female with longstanding DM2 c/b retinopathy, neuropathy and

nephropathy w/ chronic kidney disease (Cr 1.7) as well as coronary artery disease and congestive heart failure admitted to the hospital with CHF exacerbation and acute kidney injury, noted to have hypoglycemia at home 3x/week.

• Home regimen: glipizide 5mg bid

• A1C 7.2%

• Cr 2.2 (GFR 24)

• Weight 80 kg (BMI 28)

• Which of the following medication adjustment is most appropriate?A. No change necessary, A1C at goal given age and co-morbidities

B. Stop glipizide and start pioglitazone (Actos®, TZD)

C. Stop glipizide and start sitagliptin (Januvia®, DPP-IV inhibitor)

D. Stop glipizide and start canagliflozin (Invokana®, SGLT-2 inhibitor)

E. Stop glipizide and start metformin (Glucophage®, biguanide)

ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes

Inzucchi et al, Diabetes Care, 2015

Questions?