Diabetes: The Treatment

Diabetes: The Treatment

© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.

Reproduction in whole or in part without permission is prohibited.

3/23/2012 1 This activity is supported by an educational grant from Merck & Co.

Scott Stolte, PharmD Associate Dean of Academic Affairs

Bernard J. Dunn School of Pharmacy, Shenandoah University

The Basics

The Patient

The Pearls

The Treatment

3/23/2012 2 This activity is supported by an educational grant from Merck & Co.


Accreditation Pharmacists: 0798-0000-12-014-L01-P Pharmacy Technicians: 0798-0000-14-010-L01-T Nurses: N-738

Faculty

Scott Stolte PharmD Associate Dean for Academic Affairs, Shenandoah University

CE Credit(s) 1.0 contact hour(s)

Faculty Disclosure Dr. Stolte has no actual or potential conflicts of interest in relation to this program.

Learning Objectives • Characterize lifestyle modifications and their role in the management of diabetes • Outline the pharmacotherapy options for managing diabetes • Discuss the role of new medication options for the treatment of diabetes

Legal Disclaimer The material presented here does not necessarily reflect the views of Pharmaceutical Education Consultants (PharmCon) or the companies that support educational programming. A qualified healthcare professional should always be consulted before using any therapeutic product discussed. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity.

PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing education.

• Characterize lifestyle modifications and their

role in the management of diabetes.

• Outline the pharmacotherapy options for

managing diabetes.

• Discuss the role of newer medication options

for the treatment of diabetes.


• Results in:

– Beneficial impact on health and psychosocial outcomes

– Improved patient knowledge and self-care behavior

– Improved glycemic control and quality of life

• Goals of education:

– Motivate patients

– Improve personal attitudes towards DM

– Increase diabetes-related knowledge

– Develop skills and behaviors needed to optimize diabetes

care





• Overview of diabetes

• Goals of therapy

• Monitoring of diabetes control

• Non-pharmacologic options

– Nutrition

– Physical activity

• Pharmacologic options

• Management of hyperglycemia/hypoglycemia

• Sick day management / Ketone testing

• Diabetes complications and prevention

• Miscellaneous – psychosocial aspects, individual considerations


• Self-monitoring blood glucose

– Meter education – Do not assume anyone else is doing this!

• Proper use and care of monitor

• Proper technique

• Interpretation and use of data

• Appropriate times to test blood glucose

• Lifestyle modifications – EVERY PATIENT!

– Nutrition and physical activity – Again, do not assume coverage!

• Minimum – Know where to send patients for planning and care

(Dietician, Physical Therapy, etc.)

• Can also develop expertise as pharmacists

– Can lower HbA1C – 1-2%, improve CV health, promote weight

loss


• For most, it is going to be hard. – It will require changes, and the patient is not likely to favor those

changes.

• How does a patient lose weight? – Calories expended must exceed calories consumed! – SIMPLE, yet

difficult.

• Nearly impossible to succeed without social support.

• Success begets success!

• May include: – CHO monitoring

– Portion control

– Food labels

– Meal spacing

– Meal planning


• Meals

– Use smaller plates – 9 inch dinner plate

– Lunch and dinner

• Fill half (2 quadrants) of plate with vegetables

• ¼ of plate with 3 oz. of fish, chicken, or lean meat

• ¼ of plate with low glycemic index (GI) CHO

– Barley, beans, legumes, pasta, dark bread, apple, orange, yogurt

• Add 1 serving of raw fruit daily

– Breakfast – use only 2 quadrants

• Nutrition labels – pay very close attention to serving size





• Patient should receive pre-exercise evaluation prior to

beginning physical activity regimen

• If Type 1 or Type 2 on hypoglycemics

– Monitor glucose before and after exercise

– CHO source should be easily available

– Keep BG >110 mg/dL

– Do not exercise if ketones present

• Resistance training also improves glycemic control

• At least 150 minutes/week of activity at 50-70% of max heart

rate – 90-120 bpm for 50 year old.

– Every day preferred, resistance training added at least 3x weekly


• Symptoms – hunger, shaky, sweaty, headache, dizziness,

palpitations, anxious, irritable, tingling, faintness, difficulty

thinking and concentrating

• Hypoglycemia unawareness is a problem:

– Loss of physical and emotional symptoms

– Have to rely on mental symptoms

• Difficulty concentrating, slowed speech, slowed thinking, lack of

coordination, confusion, disorientation

– Most common in children < 7 yo and long-standing DM

• Don’t forget about glucagon

– All diabetes patients at risk for severe hypoglycemia should have


• Importance of routine medical care – Seen every 6 months

– Routine labs.

– Foot care and examination

– Dental care and examination

• Immunizations – Yearly influenza vaccine

– Pneumococcal vaccine

• Alcohol – Alcohol ingested with food – little effect on BG

– ≥ 3 drinks/day can contribute to hyperglycemia

– Type 1 – increased risk of fasting or nocturnal hypoglycemia with evening alcohol ingestion


• Categorized by onset and duration of action

• Concentrations

– U-100

• 100 u/mL, 10 mL vial, 1000 units/vial

– U-500

• 500 u/mL, 20 mL vial, 10,000 units/vial

• Used mainly in Type 2 DM with severe insulin resistance




PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing education. PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing education.

Detemir may require BID dosing in 33-50%

If evidence of detemir or glargine ‘wearing-off’ – consider BID…

Evidence = controlled mid-injection pre-prandial BG and elevated

pre-injection pre-prandial BG

*Doses > 90 u/d should be split into 2 injections

Future Alternatives - Insulin degludec


• Hypoglycemia

• Injection Site Reactions – Lipoatrophy – caused by insulin antibodies

– Lipohypertrophy – caused by injections into same site

– Weight gain – primarily abdominal • Related to daily dose and insulin levels

• Less with long-acting insulins

– Cancer?? • Reports with glargine

• Not substantiated in clinical trials

• Diabetes increases cancer risk

– Obesity

– Insulin resistance





• Amylin mimetic - SYMLIN®

• Mechanism of action – Slows gastric emptying

– Suppresses glucagon secretion

– Reduces appetite

• Role in therapy – Uncontrollable/Erratic postprandial BG values with

insulin therapy

• Efficacy – Reduces HbA1C by 0.4-0.5%

– Weight reductions of 2.6 – 6 lbs.


• Dosing – Type 1

– Starting dose – 15 mcg SQ 15 minutes prior to major meals

• May titrate in 15 mcg increments when minimal/no nausea x 3 days

• Max dose – 60 mcg prior to meals

– 0.6 mg/mL, 5 mL vial; Prefilled syringes (Symlin Pen 60, 120)

• Once in use, room temp for 28 days (≤ 77°F)

• Not in use = refrigerate

– Reduce dose of premeal insulin by 50% - BLACK BOX WARNING

– Do not mix with insulin, administer separately


• PK – Peak = 20 minutes, Duration of action = 3-4 hours

– Renal excretion

• Adverse effects – Hypoglycemia

– GI – nausea (28-48%), anorexia (9-17%), vomiting (7-11%)

– Headache (5-13%)

• Warnings – Watch use with gastroparesis, hypoglycemia unawareness

• Drug Interactions – Do not use with other agents that can alter GI motility or slow GI

absorption of nutrients

– May delay absorption of other oral medications – give 1 hour prior or 3 hours after injection


• Biguanide

• Mechanism of action

– Improve insulin sensitivity at the liver (inhibits gluconeogenesis)

– Improves insulin sensitivity in the periphery (skeletal muscles) and

adipose cells

• Dosing

Max EFFECTIVE

Dose=

2000 mg/day





• Metformin/Glyburide - GLUCOVANCE®

• Metformin/Glipizide – MetaGlip®

• Metformin/Rosiglitazone – AVANDAMET®

• Metformin/Pioglitazone – ACTOplus MET™

• Metformin/Pioglitazone XR – ACTOplus MET XR™

• Metformin/Sitagliptin – JANUMET®

• Metformin/Saxagliptin – KOMBIGLYZE® XR

• Metformin/Repaglinide - PrandiMet®


Should be used for all Type 2 DM patients, unless

contraindication

UK-PDS

Reduced macrovascular complications in obese patients

Reduced all-cause mortality and stroke risk compared to intensive insulin

therapy or sulfonylurea

Reduced diabetes-related death and MI compared to conventional therapy

Monotherapy

Decrease fasting BG 60-80 mg/dL, HbA1C by 1.5-2%

Increase HDL-C (2%), decrease TG (16%) and LDL-C (8%)

Weight loss (2-5 kg)

Combination therapy

Studied with every other available medication

Best combo effects with sulfonylurea

Further reduction of 25-30% in FBG, 2.2% in HbA1C


• GI (30%)

– Low doses to start

– Titrate slowly

– Take after meals

– Transient over several weeks

– XR formulation may reduced GI effects

• Malabsorption of B12 and folate

• Metallic taste

• Lactic acidosis (<1 case/100,000 treated patients)

– More common if patient has:

• Disease of hypoperfusion – Ex: intermittent clauidication

• Liver disease


• Renal impairment – BASED ON SrCr! – Men – SrCr > 1.5 mg/dL, Women – SrCr > 1.4 mg/dL

– GFR < 60 mL/min

• Unstable CHF

• Asthma/COPD ??

• Severe infection

• Hypoxic conditions

• Hepatic impairment

• Alcohol abuse

• IV radiocontrast agents – hold day of procedure, next 2-3 days

• Pregnancy

• History of lactic acidosis





• Monitoring

– Baseline and yearly hepatic and renal function

– Periodic vitamin B12 and folate

• Deficiencies related to duration of metformin treatment

• Drug-drug interactions

– Cimetidine

• Increases metformin concentration

– Cationic medications – procainamide, digoxin, quinidine,

trimethoprim, vancomycin

• May lead to increased metformin concentration



– Enhances insulin secretion from βcells – short-term efficacy

• Bind to SU-1 receptor

– Also leads to suppression of hepatic glucose production – long-term

– Increases sensitivity of pancreatic βcells to glucose – long-term

• Dosing – not including 1st generation agents


• Dosing

– Lower doses for:

• Elderly – avoid glyburide and chlorpropamide

• Compromised renal and hepatic function – avoid glyburide and

chlorpropamide

– Titrate every 1-2 weeks until desired dose is reached

• Efficacy

– Equipotent doses of all agents produce similar responses

– Decrease FBG by 60-70 mg/dL, HbA1C by 1.5-2%

– Primary failure – 15-25%

– Secondary failure – 5-7%/year


Positive predictors of response Newly diagnosed Type 2 with no indicators of Type 1 High fasting C-peptide Moderate fasting hyperglycemia (<250 mg/dL)

Precautions Pregnancy Severe infection Conditions prone to severe hypoglycemia Renal or liver disease

Malnutrition

Monitoring Baseline liver and kidney function





• Adverse effects

– Hypoglycemia

– Weight gain

– GI (5%) – dose related

– Dermatologic reactions (2%)

– Hematologic effects (<0.1%)

• Drug-drug interactions

– CYP2C9 inhibitors/inducers affect concentration

• Inhibitors – fluconazole, trimethoprim, amiodarone

• Inducers – rifampin, phenobarbital



– Enhance insulin secretion similar to sulfonylureas

• Increased absorption and shorter half-life than SFUs

– Require the presence of glucose to stimulate insulin

• Restore first-phase insulin response

• Dosing


• Dosing

– Up to 30 minutes prior to each meal • Do not take if meal is skipped

– Titrate weekly

– Good alternative to SFUs for elderly and renal impairment

• Efficacy

– Reduce FBG 9-31 mg/dL, PPBG 47 mg/dL, HbA1C 0.8-1%

– Repaglinide greater efficacy than nateglinide

• Adverse effects

– Hypoglycemia – less than SFUs

– Weight gain – repaglinide > nateglinide

• Precautions

– Hepatic impairment

– Do not use with SFUs – also not recommended for patients with SFU failure

• Drug-Drug Interactions

– Repaglinide only • Gemfibrozil – increased risk of hypoglycemia

• Inhibitors or inducers of CYP2C8 and CYP3A4


• Mechanism of Action

– Agonize PPAR (peroxisome proliferator activator

receptor)γ on fat and vascular cells

– Increases non-VAT fat, decreases lipolysis

– Enhances insulin action at the receptor and post-

receptor level in skeletal muscle and adipose tissue

– Lowers plasma insulin concentrations

– Dosing





• Dosing

– Slow onset of action – 2-3 months

– Maximum effect – 3-4 months

– Wait at least 12 weeks to titrate

• Efficacy

– Reduce FBG 60-70mg/dL, HbA1C by 0.5-1.4%

– Other effects

• Pioglitazone – decrease TGs 10-20%, increase HDL-C

• Rosiglitazone – increase LDL-C 5-15%, increase HDL-C

• Convert small, dense LDL-C to larger, less dense LDL-C


• Weight gain – can be > 10 kg

– Dose-related

– Correlated with better response

• Edema

– Dose-related

– Worse when combined with insulin

• Anemia

• GI

• Liver toxicity

• Fracture risk/Osteoporosis

• Bladder cancer – pioglitazone

– 4.3X increased risk than other DM therapies

– Risk when used for >12 months

• Macular edema?


• Rosiglitazone

– Meta-analyses

• 2007 – 43% higher rate of MI, no effect on CV death

• 2010 – 28% higher rate of MI, no effect on CV death

– REMS – Risk Evaluation and Mitigation Strategy

• Limits use to those with treatment success or no other options

• Physician and patient - enroll in Avandia-Rosiglitazone Medication

Access Program

• Pioglitazone

– Studies – no CV effect or small CV disease benefit


• Monitoring

– Liver function – baseline and periodically

• Contraindications

– Heart failure

– Active hepatic disease

– AST or ALT 2.5x ULN • AST normal – 5-40 U/L, reference ranges provided by lab

• ALT normal – 7-56 U/L, reference ranges provided by lab

– Pioglitazone • Active bladder cancer

• Precautions

– CV disease

– FRAX – 10 year risk of fracture >10%

– Pioglitazone • History of bladder cancer

• Drug Interactions – pioglitazone>rosiglitazone

– Concentration altered by CYP2C8/9 inhibitors/inducers

– CYP2C8/9 inhibitor • Increase amiodarone, fluoxetine, glimeperide, glipizide, nateglinide, phenytoin,

sertraline, warfarin






– Competitively inhibit α-glucosidases in the small intestine

• α-glucosidases break down more complex into more simple sugars

• Inhibit breakdown of oligo- and disaccharides into monosaccharides

– Results in delay in CHO absorption and reduced PPBG

• Dosing

– Take with first bite of meal

– Patient tolerance usually limits titration to max dose

– Rarely used as monotherapy


• Efficacy

– Reduce FBG 0-15 mg/dL, PPBG 40-50 mg/dL, HbA1C 0.3-

0.8%

• Adverse effects

– GI (up to 80%)

• Bloating, abdominal discomfort, diarrhea, flatulence

• Low doses or slow titration

• Usually self-limiting and transient

– Dose-related increase in LFTs

• Hypoglycemia management

– Opportunity for pharmacist intervention!


• Contraindications – Inflammatory bowel disease

– Renal dysfunction (SrCr > 2 mg/dL)

– Elevated LFTs

– Complete/partial GI obstruction

• Precautions – Irritable bowel syndrome

– Conditions aggravated by increased gas formation

– Ketoacidosis

• Drug-drug interactions – May decrease digoxin absorption

– May increase warfarin effect

– Separate administration of medications with NTI’s


• Mechanism of action – hypothesized: – May reduce hepatic insulin resistance

– May reduce intestinal glucose absorption

– May affect glucose metabolism

• Dosing – 625 mg tablets: 6 tablets daily or 3 tablets twice daily with meal or

liquid

• PK – not metabolized systemically

• Efficacy – Reduces FBG 13-15 mg/dL, HbA1C 0.3-0.5%

– Reduces LDL-C 12-16%

– Not used as monotherapy – combo with SFUs, metformin, or insulin





Adverse effects Constipation (11%) Dyspepsia (8%) Nausea Flatulence

Contraindications TG > 500 mg/dL Pancreatitis due to high TGs History of bowel obstruction

Drug-drug interactions Give other medications at least 4 hrs prior


• Mechanism of action – hypothesized – Increases early morning dopaminergic activity – “Resets” abnormally elevated hypothalamic drive that

leads to increased BG, TGs, and FFAs with insulin resistance

• Dosing – Starting – 0.8 mg daily, increase by 0.8 mg weekly until

1.6 – 4.8 mg/day is reached or side effects prevent further titration

– Should be taken within 2 hrs of waking with food

• PK – Bioavailability = 7%, 90-96% protein bound, t1/2 = 6 hrs. – Metabolized by CYP3A4, excreted in bile


• Efficacy – Reduces CV events by 42% – Reduces FBG 28 mg/dL, PPBG 22 mg/dL, HbA1C 0.6-0.8%

• Adverse effects – Nausea (32%), fatigue (4.3%), vomiting, headache, dizziness

• Incidence higher in first 2 weeks • Nearly 50% stopped therapy in recent trial

– Orthostatic hypotension – monitor when on other BP meds

• Drug-drug interactions – Highly protein bound medications – Strong CYP3A4 inhibitors inducers – Reduced efficacy if given with:

• Metoclopramide • Dopamine receptor antagonists (neuroleptics)


• Dipeptidyl peptidase-4 breaks down GLP-1

– Endogenous GLP-1inactivated in < 2 mins

• These medications block this enzyme and GLP-1 breakdown

• Potentiate endogenous GLP-1 activity

– Increase glucose-dependent insulin secretion by βcells

– Suppress glucagon secretion

– Marginal slowing of gastric emptying

• Animal studies – Improve islet survival, maintain βcell mass

and function






• Efficacy

– Reduce FBG 9-17 mg/dL, PPBG 43-62 mg/dL, HbA1C 0.7-

1%

• Adverse Effects

– Nasopharygitis (5-6%), URI (6%), headache (5%), UTI (3%)

– Hypersensitivity reactions

– Hypoglycemia

• With SFUs – 12-15%

• Without SFUs – 2%

– No weight gain

– Case reports of pancreatitis - sitagliptin


• Precautions – Renal impairment

• Drug interactions – Sitagliptin & linagliptin – none significant

– Saxagliptin • Dose reduction with STRONG CYP3A4/5 inhibitors

– Itraconazole, protease inhibitors, clarithromycin, telithromycin, nefazodone

• No dose reduction with moderate inhibitors – Erythromycin, grapefruit juice, fluconazole, verapamil

• Future – additional medications in development – Vildagliptin, alogliptin, etc.



– Biosynthetic forms of incretin, GLP-1

– Potentiates glucose dependent insulin secretion by

pancreatic βcells

– Suppresses inappropriately elevated glucagon secretion

– Reduces food intake/Improves satiety

– Restores first-phase response

– Animal studies – islet neogenesis,βcell proliferation, and

increased βcell mass





* - Can remain at room temp (NTE 77° F) for 30 days, refrigerate pens not in use


• Efficacy – Exenatide – “short-acting”

• Reduces FBG 10-25 mg/dL, PPBG 71 mg/dL, HbA1c 0.8-1.1% • Weight reduction – 3.5-8 lbs at 1 year, 11 lbs. at 2.5 years at

max dose – Weight loss continues with duration of use

– Liraglutide – “long-acting” • Reduces FBG 5-44 mg/dL, PPBG 49 mg/dL, HbA1c 0.8-1.5% • Weight reduction – 0.5-7 lbs

– Exenatide LAR - BYDUREON™ • Approved January 2012 • Dosed once weekly • Greater FBG and HbA1C reductions than exenatide


• Adverse effects

– GI – dose dependent

• Nausea - E: 45-51%, L: 7.5-34.6%

• Vomiting – 12%

• Diarrhea – E: 13%, L: 7.2-17.1%

• Dyspepsia – 6%

– Hypoglycemia – especially with SFUs

– Dizziness – 9%

– Headache – 9%

– Pancreatitis


• Contraindications – Severe GI disease

– Gastroparesis

– Do not take with DPP-4 inhibitor

• Precautions – History of pancreatitis

– Renal impairment or ESRD (CrCl < 30mL/min) – exenatide

– Personal or family history of medullary thyroid carcinoma or with multiple endocrine neoplasia syndrome,type 2 – liraglutide

• Drug-drug interactions – May reduce/slow rate of oral medications

– Medications dependent on threshold concentrations should be taken 1 hour before injection • Pain medications, antibiotics, oral contraceptives

– Exenatide (post-marketing) – warfarin, increased INR





The Basics

The Patient

The Pearls

The Treatment


Diabetes: The Treatment

Documents

Transcript of Diabetes: The Treatment