Antihyperglycemic Agents: Which One to Use · 8/2/19 1 Antihyperglycemic Agents: Which One to Use Nicole Temofonte, D.O. August 2019 Objectives • List the glycemic goals for nonpregnant

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Antihyperglycemic Agents: Which One to UseNicole Temofonte, D.O.

August 2019

Objectives• List the glycemic goals for nonpregnant adults with DM Type 2.

• Discuss the approach to treatment of DM Type 2.

• Identify resources for algorithms for management of DM Type 2.

• Review the classes of medications used for treatment of diabetes mellitus.

• Differentiate the different types of insulin based on onset, peak and duration of action.

• Describe approaches to selection of antihyperglycemic agents in adult patients with DM Type 2.

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Glucose-lowering medication in type 2 diabetes: overall approach.

American Diabetes Association Clin Diabetes 2019;37:11-34

©2019 by American Diabetes Association

Intensifying to injectable therapies.

American Diabetes Association Clin Diabetes 2019;37:11-34©2019 by American Diabetes Association

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What is the ultimate goal?• Achieve glycemic control with minimal side effects.

� Achieving this goal for each individual patient is of more importance than establishing a universally accepted algorithm.

Common Themes of Algorithms• Individualize glycemic targets for each patient

• Intensify treatment to achieve and maintain individual targets� Avoid clinical inertia� Combination therapy� Insulin

� Likely eventually for many patients

� Not a threat� Should not be delayed

Garber AJ, et al. Endocr Pract. 2018;24:91-120. ADA. Diabetes Care. 2018;41:S73-S85.

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What are the glycemic goals for nonpregnant adults with diabetes?

A1C <7.0%

Preprandial capillary plasma glucose

80-130 mg/dl

Peak postprandialcapillary plasma glucose

<180 mg/dl

TAILOR THERAPY FOR INDIVIDUAL PATIENTS!!!!Age/life expectancy

Comorbid conditionsDiabetes duration

Hypoglycemia statusIndividual patient

concernsKnown CVD/advanced

microvascular complications

American Diabetes Association. 6. Glycemic targets: Standards of Medical Care in Diabetes—2019. Diabetes Care 2019;42(Suppl. 1):S61–S70

Depicted are patient and disease factors used to determine optimal A1C targets.

American Diabetes Association Clin Diabetes 2019;37:11-34©2019 by American Diabetes Association

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What is the approach to DM management?

• Lifestyle management� Diabetes Self Management Education (DSME)� Medical Nutrition Therapy (MNT)� Physical activity� Smoking cessation counseling� Psychosocial assessment and care

American Diabetes Association. 5. Lifestyle management: Standards of Medical Care in Diabetes—2019. Diabetes Care 2019;42(Suppl. 1):S46–S60.

What is the approach to DM management?

• Lifestyle management

• Pharmacologic therapy� DM Type 1

� Insulin treatment is essential for Type 1 Diabetes� Pramlintide

� Pancreas and islet cell transplantation

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DM Type 2 Pharmacotherapy• Many agents

� Oral� Injectable

� Not all injectable agents are insulin!

Need to stay current• Ever changing

• New agents

• Learn more about existing agents

• New combination formulations

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Pathogenesis of type 2 diabetes: the triumvirate.

Ralph A. DeFronzo Diabetes 2009;58:773-795

©2009 by American Diabetes Association

Ominous Octet Pathway and Agents that Target Them

Cavaiola TS, Pettus JH. Management Of Type 2 Diabetes: Selecting Amongst Available Pharmacological Agents. [Updated 2017 Mar 31]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Figure 6, The Ominous Octet Pathways and Agents That Target Them. Available from: https://www.ncbi.nlm.nih.gov/books/NBK425702/figure/type2-diab-mgmt-pharm_f_type2-diab-mgmt-pharm_etx-dm-ch17-fig6/

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Insulin

Sulfonylureas

Biguanides

Glycosidase inhibitors

TZDs

Meglitinides

GLPanalogues

Amylinanalogues

DPP-4 Inhibitors

1921

1946

1957

1995

1997

1997

2005

2006

Pharmacologic Therapy for Diabetes mellitus Timeline

Bile Acid Sequestrants

2008

Bromocriptine

2009

SGLT2inhibitors

2013

Where are we now?

2014

Inhaled insulin

DM Type 2 Pharmacotherapy• Oral agents

� Biguanides� Metformin (Glucophage)� Metformin liquid (Riomet)� Metformin extended release (Glucophage XR, Fortamet, Glumetza)

� Sulfonylureas� Glimepiride (Amaryl)� Glyburide (Diabeta, Micronase)� Glipizide (Glucotrol, Glucotrol XL)� Micronized glyburide (Glynase)

� Meglitinides� Repaglinide (Prandin)� Nateglinide (Starlix)

� Thiazolidinediones� Pioglitazone (Actos)� Rosiglitazone (Avandia)

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• Oral agents� DPP-IV inhibitors

� Sitagliptin (Januvia)� Saxagliptin (Onglyza)� Linagliptin (Tradjenta)� Alogliptin (Nesina)

� Alpha-glucosidase inhibitors� Acarbose (Precose)� Miglitol (Glyset)

� Bile acid sequestrants� Colesevelam (Welchol)

� Sodium glucose co-transporter 2 (SGLT2) inhibitors� Canagliflozin (Invokana)� Dapagliflozin (Farxiga)� Empagliflozin (Jardiance)� Ertugliflozin (Steglatro)

� Dopamine agonist� Bromocriptine (Cycloset)

DM Type 2 Pharmacotherapy

• Injectable agents� GLP-1 Agonists

� Exenatide (Byetta)� Exenatide extended release (Bydureon)� Liraglutide (Victoza)� Dulaglutide (Trulicity)� Lixisenatide (Adlyxin)� Semaglutide (Ozempic)

� Amylin analog� Pramlintide (Symlin)

� Insulin (see next two slides)


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• Insulin� Rapid acting� Lispro (Humalog)� Aspart (Novolog)� Glulisine (Apidra)

� Inhaled (Afrezza)� Short acting� Regular (Humulin R 100U)� Regular (Novolin R)

� Intermediate acting� NPH (Humulin N)� NPH (Novolin N)


• Insulin� Long acting

� Glargine 100 units/ml (Lantus)� Detemir (Levemir)

� Ultra-long acting� Degludec (Tresiba)

� Mix insulin � 70% NPH and 30% regular (Humulin 70/30)� 70% NPH and 30% regular (Novolin 70/30)� 50% insulin lispro protamine and 50% insulin lispro (Humalog

50/50)� 75% insulin lispro protamine and 25% insulin lispro (Humalog

75/25)� 70% insulin aspart protamine and 30% insulin aspart (Novolog

70/30)� Concentrated

� Glargine 300 units/mL (Toujeo)


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DM Type 2 Pharmacotherapy• Metformin monotherapy should be started at diagnosis of DM Type 2 unless

a patient has a contraindication� Should be continued as long as tolerated and not contraindicated� Other agents including insulin should be added� Periodic measurement of vitamin B12 should be considered in patient’s with long

term use especially those with anemia and/or peripheral neuropathy

American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care 2019;42(Suppl. 1):S90–S102

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Biguanides• Metformin

� Mechanism of action-� Suppresses hepatic glucose production (hepatic gluconeogenesis)

� Increases insulin sensitivity (increase peripheral glucose uptake and utilization)

Golan, D.E. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 3rd edition. Wolters Kluwer|Lippincott Williams & Wilkins. Philadelphia 2012.

Advantages Disadvantages• Generally well tolerated

• Usually not accompanied by hypoglycemia when used as monotherapy

• Weight stability or modest weight loss

• Cost-generic available

• Adverse gastrointestinal side effects- abdominal pain, nausea, diarrhea but generally resolve over time� Slow titration may increase tolerability

• Reduces intestinal absorption of B12

• Most serious adverse effect is lactic acidosis although low risk (incidence 9 per 100,000 person years)

• May be safely used in patients with eGFR ≥ 30 mL/min/1.73m2*� REVIEW NEW LABELING GUIDELINES!

• Should be held in patients receiving intravenous contrast medium and/or undergoing a surgical procedure until stable renal function can be established

• C/I in patients with factors predisposing to lactic acidosis� Impaired renal function eGFR<30� Concurrent liver disease or alcohol abuse� Unstable or acute heart failure� Past history of lactic acidosis� Decreased tissue perfusion or hemodynamically unstable

Biguanides-Metformin

McCulloch, D.K., Nathan, D. M., Mulder, J.E. (2016) Metformin in the treatment of adults with type 2 diabetes mellitus. Accessed online 2/2106.

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FDA LABEL CHANGES FOR METFORMIN*• Before starting metformin, obtain the patient's eGFR.• Metformin is contraindicated in patients with an eGFR <30mL/min/1.73m2.• Starting metformin in patients with an eGFR between 30–45mL/min/1.73m2 is

not recommended.• Obtain an eGFR at least annually in all patients taking metformin. In patients

at increased risk for the development of renal impairment such as the elderly, renal function should be assessed more frequently.

• In patients taking metformin whose eGFR later falls <45mL/min/1.73m2, assess the benefits and risks of continuing treatment. Discontinue metformin if the patient's eGFR later falls <30mL/min/1.73m2.

• Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30–60mL/min/1.73m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin if renal function is stable.Metformin-containing Drugs: Drug Safety Communication-Revised Warnings for Certain Patients with Reduced Kidney Function Posted online 4/8/2016 www.fda.gov

Sulfonylureas (SFU)• First generation: Tolbutamide, Chlorpropamide

• Second generation: Glyburide, Glipizide, Glimepiride

• Mechanism of action-� Known as a secretagogue-Enhance insulin secretion by inhibiting ATP-dependent

potassium channels in the islet cells

• Stimulates release of endogenous insulin

• Glycemic benefits are nearly fully realized at half maximal doses and higher doses should generally be avoided

• Should not be used in settings of advanced hepatic or renal impairment given metabolism and clearance pathways

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Advantages Disadvantages• Onset of glucose lowering effect is

relatively rapid

• Cost-generic available

• Hypoglycemia which can be prolonged and life threatening. Severe episodes are more likely to occur in the elderly. Glyburide is associated with a substantially greater risk of hypoglycemia than other second generation sulfonylureas (glipizide and glimepiride and their extended formulations).

• Increased risk of cardiovascular mortality (based on studies with first generation)

• Weight gain of ~2kg following initiation of therapy

• Maintenance of glycemic targets over time is not as good as monotherapy with TZD or Metformin

Sulfonylureas-Glyburide, Glipizide, Glimepiride

Meglitinides• Repaglinide, Nateglinide

• Mechanism of action-� Also a secretagogue. Stimulate insulin secretion although bind to a different site

within the sulfonylurea receptor

• Shorter half life than the sulfonylureas and must be administered more frequently

• Repaglinide has little renal clearance (principally metabolized in the liver)

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Advantages Disadvantages• Possible less frequent hypoglycemia

vs. SFU• Multiple daily doses

• Hypoglycemia

• Weight gain

• Cost

Glinides-Repaglinide, Nateglinide

α-Glucosidase Inhibitors• Acarbose, Miglitol

• Mechanism of action-� Delay the absorption of dietary carbohydrates by inhibiting intestinal brush border α-glucosidase enzymes� Reduce the postprandial peak in blood glucose


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Advantages Disadvantages• Lower postprandial glucose levels

without causing hypoglycemia• Increased delivery of carbohydrate to

the colon commonly results in increased gas production and gastrointestinal symptoms

• Increase aminotransferase and triglycerides

• Be aware of contraindications� IBD� Cirrhosis� DKA� Bowel obstruction� Severe digestive problems

α-Glucosidase Inhibitors


Thiazolidinediones (TZD)• Pioglitazone, Rosiglitazone

• Mechanism of action-� Peroxisome proliferator-activated receptor gamma (PPAR γ) modulators� Increase the sensitivity of muscle, fat, and liver to endogenous and exogenous

insulin

• Other agents typically preferred

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Advantages Disadvantages• More durable effect on glycemic

control especially when compared to sulfonylureas

• FDA Black Box-Congestive heart failure

• Weight gain and fluid retention with peripheral edema and increased risk for CHF

• Hepatotoxicity

• Several meta analyses have suggested a 30-40% relative increase in risk for MI with rosiglitazone??

• Decrease bone density and increased fracture risk particularly in women

• ?Bladder cancer? Should not be used in patients with active bladder cancer

Thiazolidinediones-Pioglitazone, Rosiglitazone

GLP-1 Agonists• Drugs in class:

� Exenatide � Liraglutide

� Once daily� Dulaglutide

� Once weekly� Lixisenatide

� Once daily� Semglutide

� Once weekly

• Subcutaneous injection• Mechanism of action-

� Secretion of insulin by pancreatic βcells in a glucose dependent manner� Suppresses secretion of glucagon by pancreatic αcells� Slows gastric emptying� Decreases appetite

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• Mechanism of action-� ↑ Incretins (GLP-1 and GIP) by inhibiting DPP-4 à ↑ glucose mediated insulin

secretion and suppresses glucagon secretion� DPP-4 is the enzyme which inactivates incretins

• Weight neutral

• Low risk of hypoglycemia (if not on additional agents that can cause hypoglycemia)

• Oral


Dipeptidyl Peptidase-4 InhibitorsSitagliptan, Saxagliptan, Linagliptan, Alogliptan

Advantages Disadvantages• Weight neutral

• Low risk of hypoglycemia (if not on additional agents that can cause hypoglycemia)

• Oral

• Newer agents

• Cost

• Potential risk of acute pancreatitis and pancreatic cancer-insufficient evidence to establish causal relationship

• Mild urinary or respiratory infections

• Joint pain

• ?Heart failure? Research ongoing� Discontinue Saxagliptan and Alogliptan in

patients who develop heart failure

• Dose adjustment in renal disease (except linagliptan)

• Monitor LFTs with alogliptin

Dipeptidyl Peptidase-4 Inhibitors

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Amylin Analogs• Pramlintide

� Stable analog of human amylin� Amylin

� Β-cell hormone co-secreted with insulin and helps regulate postprandial glucose levels

� Type 1 DM-lack endogenous amylin� Type 2 DM-relative deficiency of endogenous amylin

• Mechanism of action-� Slows gastric emptying, reduces postprandial glucagon and glucose release and

promotes satiety� Administered as subcutaneous injection before meals


Advantages Disadvantages• Not associated with hypoglycemia

unless used in conjunction with agents that can cause hypoglycemia

• Weight loss

• Subcutaneous injection before all meals

• Most common adverse effect is nausea

Amylin Analogs

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Sodium glucose co-transporter 2 (SGLT2) inhibitorsCanagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin

• Mechanism of action-� Inhibits SGLT2 in the proximal nephron� Blocks glucose reabsorption by the kidney increasing glycosuria.

American Diabetes Association. Diabetes Care. 2016;39(suppl 1):S1-S112.

When is insulin used?• Type 1 DM

� Multiple daily injections or continuous subcutaneous insulin infusion� Match prandial insulin to mealtime carbohydrate intake taking into account

premeal blood sugar and planned physical activity

• Type 2 DM

American Diabetes Association. Diabetes Care. 2016;39(suppl 1):S1-S112.

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Types of Insulin

• Rapid acting (analogs)� Lispro (Humalog)� Aspart (Novolog)� Glulisine (Apidra)

• Short acting (human)� Regular (Humulin R, Novolin R)

• Intermediate acting (human)� NPH (Humulin NPH, Novolin NPH)

• Long acting (analogs)� Glargine (Lantus)� Detemir (Levemir)

PrandialBolus

Basal

Types of Insulin

• Rapid acting (analogs)� Human insulin inhalation powder

(Afrezza)

https://afrezza.com/uploads/hcp/holding-the-afrezza-inhaler.png

• Ultra-long acting (analogs)� Degludec (Tresiba)

PrandialBolus

Basal

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INSULIN Onset Peak Duration Prandial/Bolus Insulin

Rapid actingLispro (Humalog), Aspart (Novolog),Glulisine (Apidra)

5-15 min 1-1.5 hrs 3-4 hrs

Short actingRegular 30-60 min 2 hrs 6-8 hrs

BasalIntermediate acting

NPH 2-4 hrs 6-7 hrs 10-20 hrsLong acting

Glargine (Lantus) 1.5 hrs Flat ~24 hrsDetemir (Levemir) 1 hr Flat 17 hrs

Greenspan, Francis S. and Gardner, David G. (2011) Greenspans’ Basic and Clinical Endocrinology (9th ed.). Lange/McGraw Hill.

https://dtc.ucsf.edu/images/charts/4.f.i.jpg

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Degludec• Ultralong acting basal insulin

� ½ life ~25 hours� Duration of action >42 hours� Glucose lowering effect is evenly distributed over 24 hour dosing interval

Vora, Jiten et al. (2015) Clinical use of insulin degludec. Diabetes Research and Clinical Practice. 109(1)19-31.

Concentrated insulins

Lamos, E. M., Younk, L. M., & Davis, S. N. (2016). Concentrated insulins: the new basal insulins. Therapeutics and Clinical Risk Management, 12, 389–400.

Human Regular U500

DegludecU200

GlargineU300

Duration of action

6-10 hours 42 hours >30 hours

Half-life 4 hours 25 hours 18-19 hours

Steady State 2-3 days 5 days

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ADA Guidelines: Pharmacologic Approach to Glycemic Treatment• Focus on using an available agent that fits with patient’s preference and

accessibility.

• The practitioner decides the best class for an individual.

American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care 2019;42(Suppl. 1):S90–S102

ADA Guidelines: Pharmacologic Approach to Glycemic Treatment

DiagnosisNeed to initiate

pharmacotherapy

Need to initiate additional therapy

Lifestyle management

Metformin

Lifestyle management

Metformin

Best option for the patient

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What factors should you consider?• Efficacy• Presence or absence of symptoms of hyperglycemia• HbA1C• Side effect profile• Hypoglycemia risk• Effect on weight• Cost/availability• Durability• Patient preference/adherence• Patient comorbidities • Frequency/ease of administration• Oral vs. subcutaneous

Choice of number of agents for antihyperglycemic therapy in Type 2 DM

• Monotherapy

• Dual Therapy

• Triple Therapy

• Combination Injectable Therapy

At diagnosis During treatment

Most patients require more

than one agent

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Choice of number of agents for antihyperglycemic therapy in Type 2 DM

• Established ASCVD or CKD

• Compelling need to minimize hypoglycemia

• Compelling need to minimize weight gain or promote weight loss

• Cost is a major issue

American Diabetes Association. (2019) 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care. 42(Suppl. 1):S90–S102

Writing Committee et al. JACC 2018;j.jacc.2018.09.020

©2018 by American College of Cardiology

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When to initiate insulin?• Insulin

� Can be effective when other agents are not� Can be used safely when other agents cannot� Early initiation

� Hyperglycemia severe� Blood glucose is ≥300 mg/dL or A1C is ≥10%

� Symptoms of hyperglycemia� Hypertriglyceridemia� Ketosis� Glucose toxicity

American Diabetes Association. (2019) 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care. 42(Suppl. 1):S90–S102

Goals of Insulin Therapy• Achieve optimal glycemic control but avoid:

� Hypoglycemia� Weight gain� Negative impact on patient’s lifestyle

• Understand the appropriate glycemic target for the individual patient

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References• American Association of Clinical Endocrinologists AACE Diabetes Resource Center. Outpatient Slide Library. Glycemic

Management in Type 2 Diabetes. Accessed July 2019 www.outpatient.aace.com/slide-library.

• American Association of Clinical Endocrinologists AACE Diabetes Resource Center. Outpatient Slide Library. Glycemic Management in Type 2 Diabetes: Efficacy and Safety of Modern Antihyperglycemic Therapies. Accessed July 2019 www.outpatient.aace.com/slide-library.

• American Diabetes Association. (2019) 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care. 42(Suppl. 1):S90–S102

• Cavaiola TS, Pettus JH. Management Of Type 2 Diabetes: Selecting Amongst Available Pharmacological Agents. [Updated 2017 Mar 31]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK425702/

• Davies, M.J., D’Alessio, D.A., Fradkin, J., Kernan, W.N., Mathieu, C., Mingrone, G., Rossing, P., Tsapas, A., Wexler, D.J., Buse, J.B. (2018). Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report By the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 41(12):2669-2701.

• Garber, A.J., Abrahamson, M.J., Barzilay, J.I., Blonde, L., Bloomgarden, Z. T., Bush, M.A., Dagogo-Jack, S., , DeFronzo, R.A., Einhorn, D., Fonseca, V.A., Garber, J.R., Garvey, W.T., Grunberger, G., Handelsman, Y., Hirsch, I.B., Jellinger, P.S., McGill, J.B., Mechanick, J.I., Rosenblit, P.D. & Umpierrez, G.E. (2019). CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM – 2019 EXECUTIVE SUMMARY. Endocrine Practice. 25(1):69-100.

• Steinberg, J. Carlson, L. (2019). Type 2 Diabetes Therapies: A STEPS Approach. American Family Physician. 99(4):237-243.

Antihyperglycemic Agents: Which One to Use · 8/2/19 1 Antihyperglycemic Agents: Which One to Use Nicole Temofonte, D.O. August 2019 Objectives • List the glycemic goals for nonpregnant

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