sign in sign up
<<
Home , Diabetes management, Insulin (medication), Liraglutide, Meglitinide, Metformin, Pioglitazone

DIABETES MANAGEMENT

Annette Hess, PhD, FNP-BC, CNS University of Alabama at Birmingham School of Nursing

• 25.8 million children and adults (8.3% of the population) have diabetes in the U.S.

• Disproportionately affects older people – prevalence is higher among racial and ethnic minority populations

• Annual economic burden of diabetes is estimated to be $174 billion – $116 billion for direct medical costs – $58 billion for indirect costs (disability, work loss, premature mortality) Associated with Serious Complications

Diabetic Retinopathy CV Disease & Stroke account for ~65% of Leading cause deaths in T2D patients of blindness in adults

Diabetic Nephropathy Diabetic Major cause of failure Neuropathy Major cause of lower extremity amputations

CV = cardiovascular. National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics fact sheet: general information and national estimates on diabetes in the United States, 2005. Bethesda, MD: U.S. Department of Health and Human Services, National Institute of Health, 2005. Background: Management

• Management of – Crucial – Improved macrovascular & microvascular outcomes • Controlling levels – Nutritional therapy – MODERATION!! – , if needed – Increased physical activity – Antidiabetes medications

Source: 2007–2009 National Health Interview Survey.

Targets for Diabetes Control

Biochemical Index ADA Goal ACE Goal A1C < 7% < 6.5%

Preprandial Glucose 90-130 mg/dl <110 mg/dl

Peak Postprandial <180 mg/dl ----- Glucose

2 Hour Postprandial --- <140 mg/dl Glucose

Breakdown of Treatments for Diabetes in the United States Background: Treatment

• Treatment regimens include monotherapy and combinations of two or three drugs from different classes. – Twelve (12) classes of diabetes medications are available: • () • (Actos, Avandia) • (, Glucotrol, Diabeta, Amaryl) • Dipeptidyl peptidase-4 (DPP-4) inhibitors (Januvia, Onglyza, Tradjenta) • (Novolog, Humalog, Apidra, Lantus, 70/30) • (Starlix, Prandin) • -like -1 (GLP-1) receptor (Byetta, Victoza, Bydureon) • (synthetic ) Symlin • Alpha-glucosidase inhibitors (Precose, Glyset) • Bile-acid sequestrant (Colesevalam) • Dopamine () • Sodium-glucose cotransporters 2 (SGLT2) Inhibitor (Invokana) • Choosing among the available medications requires consideration of their benefits, mode of action/class, adverse effects, and cost. Preparations Principles of Insulin Therapy

Strive for Ideal Replicate body’s normal insulin secretion

Start with practical Replicate body’s normal insulin secretion as closely as possible from the start

Individualized therapy Match insulin to patient’s lifestyle and eating patterns Insulin Analogs

• Analogs are more predictable and more reliable and consistent in action. There is less chance of • Rapid Acting: -Humalog (Lispro) -Novolog (Aspart) -Apidra (Glulisine) • Long Acting (Basal): - Lantus (Glargine) - Levemir (Detemir)  Mixes: Novolog 70/30  Humalog 75/25 & 50/50

Advanced Basal/ Insulin Therapy

Multiple Daily Injections (MDI) Basal/Bolus Insulin Multiple Daily Injections (MDI) • Simple: – 2 injections, once daily basal (long acting) insulin, once daily bolus (rapid acting) insulin with largest meal (90/10 rule)

• Advanced: – 4 injections, once daily basal (long acting) insulin, bolus insulin (rapid acting) with each meal (MDI)

Basal/Bolus Insulin Multiple Daily Injections (MDI)

• Many patients will accept a 2 injections program as first step in advancing to MDI (90/10 rule)

• Many patients will resist going from a 1 injection daily regimen to a 4 injections daily regimen (Basal + mealtime insulin)

• Eventually work toward 4 injections daily Basal/Bolus Insulin Multiple Daily Injections (MDI)

• Basal insulin daily + bolus insulin with each meal • 2 strategies: 1)“Bergenstal” formula* (if not carb counting) 2)Insulin/carb ratio (if carb counting)

*Diabetes Care July 2008 31:1305-1310 Basal/Bolus Insulin Multiple Daily Injections (MDI)

• “Bergenstal” formula: (if not carb counting) Of total daily dose, ~50% basal insulin ~50% bolus insulin

First, reduce basal (glargine or detemir)by 50% at initiation of bolus insulin Basal/Bolus Insulin Multiple Daily Injections (MDI)

• “Bergenstal” formula (cont’d) • Then, add mealtime rapid acting insulin (bolus)(aspart): 50% of total daily dose Split total rapid acting(aspart,lispro,glulisine) as: 50% with largest meal 33% with next largest meal 17% with smallest meal

Basal/Bolus Insulin Multiple Daily Injections (MDI)

• “Bergenstal” formula for MDI • Example: – Patient currently on 50 units of glargine or detemir once daily – Cut glargine by 50% (25 units daily) (this will now be 50% of total daily insulin) Basal/Bolus Insulin Multiple Daily Injections (MDI) • “Bergenstal” formula (cont’d) • Add mealtime rapid acting insulin (bolus) – 25 total units daily – (this will be 50% of total daily insulin dose) Given as: ~50% of this with largest meal 13 units ~33% of this with next largest meal 8 units ~17% of this with smallest meal 4 units

Basal/Bolus Insulin Multiple Daily Injections (MDI)

So, our patient finishes this consult with: • Basal (~50% of daily total) 25 units once daily

• Rapid acting 13 units largest meal (~50% of daily total) 8 units next largest 4 units smallest meal Doses are titrated per SBGM Modified Bergenstal Formula

• 50% basal long acting – in this case 25 units of Lantus or Levemir

• 50% bolus rapid acting – 25 total units aspart/lispro/glulisine – split 3 ways ~ 8 units with each meal

Basal/Bolus Insulin Multiple Daily Injections (MDI)

• In carb counting MDI, reduce basal 30-40% when starting bolus (mealtime) insulin in type 2 diabetes

• Bolus (mealtime insulin) ~2u/15 gram carb – Based on patient’s history /

• Correction (sensitivity factor) ~1 u to drop blood 30 points

• Need to know pre-meal blood sugar Insulin Errors

• For many years, insulin errors have been associated with the highest risk of injury to patients and are identified as one of the top high-alert medications by the Institute for Safe Medication Practices (ISMP).

• Approximately 40 percent of 888,000 identified adverse drug events (ADEs) reported to the Medicare Patient Safety Monitoring System (MPSMS) and 25 percent of the reviewed 100,000 emergency hospitalizations of patients over age 64 for ADEs involved insulin or other diabetes agents.

Insulin Medication Errors

Untreated hyperglycemia can also result in ketoacidosis and other serious adverse clinical outcomes, prolonged length of stay in the hospital, and poor patient experience of their hospital treatment.

From the 2,685 medication error event reports submitted to the Pennsylvania Patient Safety Authority, the predominant types of medication error events associated with insulin were drug omission (24.7 percent), wrong drug (13.9 percent), wrong dose, or overdosage (13 percent).

Diabetes Medications Glycemic Control • Type 1: Always insulin, maybe Symlin in combo

• Type 2: Many oral med choices, insulin, non- insulin injectable

Glucose-lowering Potential of Injection Diabetes Therapies*

Treatment Frequency Postprandial↓ HbA1C 

Exenatide (Byetta) BID targets ppd 0.9%

Liraglutide (Victoza) QD targets ppd 1.1%

Pramlintide (Symlin) With meals targets ppd 0.57%

Insulin Varies Limited by 0.17% hypoglycemia

*based on package insert data as monotherapy 90/10 Rule

• Because type 2 patients take larger doses of basal insulin, it is tempting to split the basal dose and give BID.

• If going to 2 injection program, it is better to keep basal once daily and add a rapid acting insulin injection prior to the largest meal (90/10 rule). Basal Insulin in Type 2 Diabetes • Metformin, – maybe TZD - Avandia and Actos , maybe SU - Glucotrol, Glucotrol XL, Glyburide, maybe gliptin ()-Januvia, Onglyza

• Glargine (Lantus) or Detemir (Levemir) started at 10 units at HS

• Increase 3 units every 3 to 5 days until blood <110 (or <140)

• Most with type 2 diabetes have a total daily dose (TDD) of on 50- 80+ units OR take 50-80+ units of basal insulin day/day Rationale for Update

• In 2007, AHRQ published its first systematic review on the comparative effectiveness of oral medications for type 2 diabetes.

• In 2011, this review was updated to include newer medications and two-drug combination therapies: – Noninsulin injectables: GLP-1 receptor agonists, , and (FDA-approved in 2005 and 2010, respectively). – DPP-4 inhibitors: sitagliptin and (FDA-approved in 2006 and 2009, respectively). – Evidence about combinations of medications, including combinations of medications with insulin therapy. Priority Medication Comparisons

Monotherapy Main Intervention Comparisons as main Metformin • , , DPP-4 inhibitor, , or a GLP-1 agonist intervention • Combination of metformin plus thiazolidinedione • Combination of metformin plus sulfonylurea • Combination of metformin plus DPP-4 inhibitor • Combination of metformin plus meglitinide

Thiazolidinedione • Different thiazolidinedione, Sulfonylurea, DPP-4 inhibitor, Meglitinide, or a GLP-1 agonist Sulfonylurea • DPP-4 inhibitor, Meglitinide, or a GLP-1 agonist DPP-4 inhibitor • DPP-4 inhibitor, Meglitinide, or a GLP-1 agonist Meglitinides • GLP-1 agonist Combination of metformin plus (a Combination of metformin plus (a thiazolidinedione or Combination thiazolidinedione or a sulfonylurea or one of a sulfonylurea or a meglitinides or DPP-4 inhibitor or therapy as the meglitinides or a DPP-4 inhibitor or a GLP- GLP-1 agonist or a basal insulin or a premixed insulin) 1 agonist or a basal insulin or a premixed main insulin) intervention Combination of metformin plus (a Combination of a thiazolidinedione plus (a sulfonylurea thiazolidinedione or a sulfonylurea or a or a meglitinides or DPP-4 inhibitor or GLP-1 agonist) meglitinides or DPP-4 inhibitor or GLP-1 agonist or a basal insulin or a premixed insulin) Intermediate Outcomes: Overview of Weight Results • MET is associated with less weight gain when compared to other monotherapies or combinations (moderate to high strength of evidence)

• When compared to SUs, GLP-1 receptor agonists are associated with less weight gain (moderate to high strength of evidence)

• MET + SUs are associated with less weight gain than are combinations with TZDs (moderate strength of evidence)

• Some newer agents, in combination show promise for lower levels of weight gain (low strength of evidence).

DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GLP-1 receptor agonists = glucagon-like peptide-1 receptor agonists; MET = metformin; SU = second-generation sulfonylureas; TZD = thiazolidinediones. Details of HbA1c and Weight Intermediate Outcomes: Comparisons of Monotherapies

Outcomes Drug Comparisons Strength of Evidence HbA1c MET, SU, TZD, and Rep reduce HbA1c by about 1%. Specific comparisons include: • MET versus SU High • SU versus TZD; Pio versus RSG; MET versus TZD; SU versus Rep Moderate • MET lowers HbA1c 0.4% better than do DPP-4 inhibitors. Moderate

Weight From the 2007 report, TZD, SU, and Rep increase weight by 1-5 kg, but MET did not increase weight in placebo-controlled trials.

MET maintained or decreased weight when compared to other monotherapies as shown below: • MET versus TZD, -2.6 kg; MET versus SU, -2.7 kg High • MET versus DPP-4 inhibitors, -1.4 kg Moderate GLP-1 receptor agonists were associated with less weight gain, by -2.5 kg, when compared to SUs. Moderate SU and MEG had similar effects on body weight. High DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors; GLP-1 receptor agonists = glucagon-like peptide-1 receptor agonists; HbA1c = A1c; MEG = meglitinides; MET = metformin; Pio = ; Rep = ; RSG = ; SU = second- generation sulfonylureas; TZD = thiazolidinediones. Overview of Adverse Events and Side Effects • SUs and MEGs cause more hypoglycemia than MET, TZDs, or DPP-4 inhibitors (moderate to high strength of evidence)

• Most MET combinations increased the risk of hypoglycemia often combined with SUs (moderate strength of evidence)

• MET is associated with more GI adverse events (mainly ) when compared to other agents (moderate to high strength of evidence)

• TZDs are associated with a higher risk of CHF compared to SUs (moderate strength of evidence)*

• TZDs alone or in combination are associated with a higher risk of fractures compared to other agents (high strength of evidence)

• TZDs are low for injury (range, 0% to 0.9%) compared to SUs (range 0% to 1%) & MET (range 0.8% to 2.2%)

In 2007, the FDA issued an alert and changed labeling to state that TZDs cause or exacerbate CHF in some patients. In 2010, the FDA placed additional prescribing restrictions on rosiglitazone use for type 2 diabetes in response to data that suggest an elevated risk of cardiovascular events including and stroke.

Glucose-lowering Potential of Diabetes Therapies*

Treatment FPG  HbA1C 

Sulfonylureas 50-60 mg/dl 1-2%

Metformin 50-60 mg/dl 1-2% a-Glucosidase Inhibitors (Precose) 15-30 mg/dl 0.5-1%

Repaglinade (Prandin) 60mg/dl 1.7%

Thiazolidinediones 40-60 mg/dl 1-2%

DPP-4 Inhibitors targets ppd 0.5 - 0.8% (Gliptins - Januvia,Onglyza)

*based on package insert data as monotherapy Key Points of Medication Selection in Type 2 Diabetes • Metformin at diagnosis unless a contraindication – Diabetes Prevention Program study (2002)

• Second line agents- many other meds, in addition to Metformin

• A1C >9 at diagnosis- Insulin often prescribed

Glucagon-like Peptide-1 (GLP-1)

• Gut which slows the digestive process • Stimulates to secrete insulin after meals • Suppresses glucagon action during sleep & other times when glycogenolysis not needed • Decreases • Promotes satiety and weight loss • Caution in renal or hepatic impairment – Risk of & Thyroid GLP-1

• Exenatide (Byetta) GLP-1 mimetic • Liraglutide (Victoza) GLP-1 analog • Bydureon GLP-1 mimetic extended release • Available in pen injectors (easy) • Modest weight loss • Combined with other agents except DPP-IV inhibitors or insulin (exenatide has basal insulin data)

GLP-1 Caveats

• , vomiting • Pancreatitis • Medullary thyroid carcinoma in rodents (liraglutide) • Hypoglycemia when combined with sulfonyurea Pramlintide-Synthetic Amylin (Symlin) • Amylin secreted by normal pancreas along with insulin, to regulate blood glucose

• Decreases Postprandial hyperglycemia. Used in Type 1 and Type 2 patients

• Used only as an adjunct to insulin

• Available in pen injector

• Possible significant hypoglycemia New Diabetes Medications

• Bydureon – Helps pancreas produce insulin more efficiently in an extended-release formula of exenatide ( Byetta ) – GLP-1 – Administer 2 mg by once every seven days (weekly), at any time of day

• INVOKANA – SGLT2 inhibitor – Helps lower blood sugar in adults with type 2 diabetes via increased of glucose in the urine – 100 mg daily – Decreases weight and – Adverse reactions • Female genital mycotic • UTI • Increased urination

Criteria for Drug Selection

/Dyslipidemia Byetta/Victoza Byetta/Victoza Glucophage Glucophage Januvia Welchol Prandin/Starlix Cycloset – increases dopamine  Renal Insufficiency  Inexpensive Amaryl Januvia (dose adjusted) metformin Onglyza (dose adjusted) glipizide/glyburide Tradjenta  Prandin/Starlix  Actos/Avandia  pioglitazone (2011)

ADA Medication Algorithm

• Metformin at diagnosis for most patients – Any GI discomforts: Change Metformin to Metformin XR (slow releasing) – Easier tolerated

• Insulin may be considered as second line therapy

Nathan et al Diabetes Care 2009 AACE Medication Algorithm

• Metfomin (possibly others) are first line therapy in type 2 diabetes

• Insulin may be a first line therapy if A1C >9

www.aace.com/pub Basal Insulin in Type 2 Diabetes

• Glargine (Lantus), Detemir (Levemir) • Good, potent add-on to oral diabetes medications for improved A1C • Second line agent for many patients • A1C >9, diabetes longer than 5 to 7 years • AACE: ? Weight benefit with Detemir • Pen injectors easy

Summary

• Most patients with type 2 diabetes will eventually require insulin

• Basal insulin once daily is an easy and effective therapy for most patients with type 2 diabetes

• Behavioral / Lifestyle Intervention is CRITICAL!! QUESTIONS & ANSWERS

Sources of Additional Information for Healthcare Providers and Patients

– American Association of Clinical Endocrinologists (AACE) http://www.aace.com/

– American Association of Diabetes Educators (AADE) http://www.diabeteseducator.org

– American Diabetes Association (ADA) http://www.diabetes.org

– Centers for Disease Control and Prevention (CDC) http://www.cdc.gov

– National Center for Chronic Disease Prevention and Health Promotion

– Diabetes Public Health Resource http://www.cdc.gov/diabetes/

– International Diabetes Federation (IDF) http://www.idf.org/

– Medline Plus – Diabetes Topic Additional Resources

– American Association of Clinical Endocrinologists https://www.aace.com/files/aace_algorithm.pdf

– http://www.ndep.nih.gov/diabetes/diabetes.htm

– National Diabetes Information Clearinghouse (NDIC) http://diabetes.niddk.nih.gov/index.htm

– National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) http://www2.niddk.nih.gov/

– National Institutes of Health (NIH) – Diabetes Health Topic http://health.nih.gov/result.asp/187

– U.S. Food and Drug Administration (FDA) Diabetes Information http://www.fda.gov/diabetes/

– Weight-control Information Network (WIN) http://win.niddk.nih.gov/

References for Insulin Errors

Centers for Medicare & Medicaid Services. FY 2013 Final HAC List. http://www.cms.gov/Medicare/Medicare-Fee-for-Service- Payment/HospitalAcqCond/Downloads/FY_2013_Final_HACsCodeList.pdf (accessed October 31, 2012) Classen DC, Jaser L, Budnitz D. Adverse drug events among hospitalized Medicare patients: Epidemiology and national estimates from a new approach to surveillance. Joint Commission Journal on Quality and Patient Safety. 2010 January;36(1):12-21 Budnitz DS, et al. Emergency hospitalizations for adverse drug events in older Americans. The New England Journal of Medicine. 2011 November 24;365(21):2002- 2012 Sims J, Richardson T, Kerr D. Insulin errors in hospital: Time for a radical re-think on risk? Clinical Risk. 2010 May;16(3):89-92 Cohen MR. Pharmacists’ role in ensuring safe and effective hospital use of insulin. American Journal of Health-System Pharmacy, 2010 August 15;67 (16 Suppl 8):S17-21.

• http://carbchallenge.joslinresearch.org/

• http://www.joslin.org/bin_from_cms/Pharma _Guideline_-rev-emb-_10-_28_2011.pdf Web Addresses

• https://www.aace.com/files/aace_algorithm.pdf

• www.lantus.com or 866-452-6887

• www.lillydiabetes.com or 800-545-5979

• www.novonordisk-us.com or 800-727-6500

• www.minimed.com or 800-843-6687 Case #1

• 52 y/o white female • Diagnosed Type 2 DM in 1998 • PMH: HTN, Dyslipidemia, post-menopausal • FH: Positive for MI in father and uncle • Non-smoker, 1-2 alcohol drinks per week • “Walks a lot at work”

Case #1

• Medications: Metformin 1000 mg BID Glyburide 10 mg BID Pioglitazone 45 mg daily 40 mg daily ASA 81 mg Lisinopril 10 mg daily

Case #1

• Physical Exam: Height: 5’2” Weight: 210 lbs BMI: 38.4 Otherwise normal except trace ankle

BMI calculator: http://www.nhlbisupport.com/bmi/ Case #1 • A1C 8.6 • Fasting glucose 205 • Blood Glucose at home “about 150” checked “regularly”

• What should be next for this patient? Case #1 • Glargine or Detemir now at 55 units q hs • A1C is now 7.6 • SMBG consistently fasting <140 • 2 hour post-prandial 190’s-220’s

• Now what? Case #1 • Next step would be to add rapid acting insulin bolus to largest meal daily (usually evening meal) to address post-prandial glucose

• 90/10 rule: Decrease basal by 10%, give that 10% as rapid acting insulin (bolus)

Case #1 • Metformin was continued • Glargine or detemir(recall already using) decreased 10% to 50 units q hs • Add Rapid acting – (Aspart, glulisine,or lispro) – 5 units with largest meal – (10%of daily total) Case #1

So, this patient is using 90/10 rule for advancement from once daily basal insulin to a 2 injection daily program

50 units glargine or detemir= 90% of daily total 5 units rapid acting= 10% of daily total