Best Practice Diabetes Drug Management Secrets-2014

Foot Amputation

Loss of EyesightDiet/Exercise/

Lows/Kidneys/Nerve/ED/Depression

By Sharon A. Watts DNP, RN-BC, CDE

Disclaimers

• I have no affiliations with drug companies

• I have no affiliations with any industry

• I do believe decisions about drugs should be based on evidence, cost to society and individual patient lifestyle & benefit vs. risk

Objectives

• Identify common prescribing rules for diabetes drugs.

• Select diabetes therapies for several case study presentations based on best practice prescribing knowledge.

4

Fact or Fiction?

New Patient -65 year old DM x 12 years, LDL-145, A1c 11%, B/P 162/85, microalbumin/creatinine ratio 200

The Most Important Thing I can do for my patient with diabetes today

if I only have time for one change today it should be to lower his high A1c?

Strategy Complication Reduction of Complication

Blood glucose control ▪ Heart attack 37%1

Blood pressure control

▪ Cardiovascular disease▪ Heart failure▪ Stroke▪ Diabetes-related deaths

51%2

56%3

44%3

32%3

Lipid control

▪ Coronary heart disease mortality▪ Major coronary heart disease event▪ Any atherosclerotic event▪ Cerebrovascular disease event

35%4

55%5

37%5

53%4

Treating the ABCs Reduces Diabetic Complications

1 UKPDS Study Group (UKPDS 33). Lancet. 1998;352:837-853.2 Hansson L, et al. Lancet. 1998;351:1755-1762. 3 UKPDS Study Group (UKPDS 38). BMJ. 1998;317:703-713.4 Grover SA, et al. Circulation. 2000;102:722-727.5 Pyŏrälä K, et al. Diabetes Care. 1997;20:614-620.

Estimated time to benefit

While glucose and lipid management remain important, blood pressure lowering has the greatest and most immediate impact on morbidity and mortality (52 [EL 1; RCT], 326 [EL 1; RCT,

Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group [Erratum in: BMJ. 1999;318:29]. BMJ. 1998;317:703-713. [EL 1; RCT] Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med. 2008;359:1565-1576. [EL 1; RCT, questionnaires and other variables may have confounded]

AACE Guidelines-2011

Glucose control 8 yearsBlood pressure control 2-3 years Lipid control 2-3 years

Progressive Decline in Beta Cell Function

UKPDS 16. Diabetes 1995; 44: 1249-58

20

40

60

80

100

Conventional Sulphonylurea Metformin

Non overweight Overweight

Beta cell loss ~4% per year

HOM

A %

B

00 1 2 3 4 5 6 0 1 2 3 4 5 6

Years from randomisation

Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes

5.Gut CHOAbsorption:

Incretin,Pramlintide,Glucosidase inh.

Peripheralglucose uptake

--

-

1.Pancreatic insulin

Secretion:Incretin, ranolazine

2.Pancreatic glucagon

Secretion- Incretin

HYPERGLYCEMIA

6.Fat- TZD, metformin

7.Brain-TZD,INCRETIN,bromocryptine

8.Kidney-SGLT2

3.Muscle- TZD, Incretin

4.Liver

Hepatic glucose production

:Metformin, incretin

De

Metformin-The Pinnacle of Sweet Success

BIGuanides

Metformin• Cardiovascular benefit• Decrease A1c by 1.0 – 2.0• No hypoglycemia• Cannot be used in renal failure

(Cr Cl < 30 ml/min, s. creat > 1.5 in males, > 1.4 in females)

• Adverse effects: nausea, vomiting, diarrhea, lactic acidosis, B12 deficiency

• Generic available• Use Metformin SA!!!!

https://www.aace.com/files/algorithm-07-11-2013.pdf p. 12 accessed 12.16.13

AACE Metformin Recommendations

This limitation has been challenged, however, and lower doses have been proposed for patients with moderate renal insufficiency (126).

The AACE agrees with the Kidney Disease: Improving Global Outcomes 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease recommendations, which state that metformin should be continued in patients

with an eGFR ≥45 mL/min/1.73 m2 (GFR categories G1-G3a), that its use should be reviewed in those with an eGFR of 30 to 44 mL/min/1.73

m2 (GFR category G3b), and that it should be discontinued in patients with an eGFR <30 mL/min/1.73 m2

(GFR categories G4-G5) (127).

METFORMIN-Lactic acidosis

• Conditions that cause a hypoxemic state:– Renal insufficiency– Concurrent liver disease or alcohol abuse

(sgot/sgpt 2x ULN)– Heart failure (stage III & IV)– History of lactic acidosis – Decreased tissue perfusion or hemodynamic

instability – Hypoxic or acute illness

Sulfonylureas• Increase insulin secretion• Decrease A1c by 1.0 – 2.0• Risk of hypoglycemia(5x

that of metformin only)• Can be used in mild renal

failure, however risk of hypoglycemia more

• Skip a meal, skip a dose• Adverse effects: minimal• Generics available

Sulfonylureas

• Glipizide– Short acting-need to take ½ hr. prior to meal– Lesser risk of hypoglycemia– Safer than other sulfonylureas in older

subjects– Can be used in mild renal failure(CrCl <10)– Change to other medications if renal failure

worsens or if hypoglycemia with renal failure

Sulfonylureas

• Glyburide– Longer acting-can take right w/meal– Stronger potency than glipizide– Increase risk of hypoglycemia– Not recommended if Cr Cl < 50 ml/min

• Glimepiride (generic now)

– Can given once daily dose with meal– Can be used in mild renal failure(CrCl <10)

Use of sulfonylurea as second-line therapy for type 2 diabetes generated glycemiccontrol and QALYs comparable with those associated with other agents but atlower cost.Diabetes Care February 26, 2014 http://care.diabetesjournals.org/content/early/2014/02/18/dc13-1901.long

• Repaglinide (Prandin), Nateglinide (Starlix) • MOA

o Stimulate glucose-dependent release of insulin by closing the ATP-dependent K+ channels of the pancreatic beta-cells

o Shorter half life than SU• A1c lowering

o 0.5-1%• If the meal is skipped, then omit dose• Take medication just prior to eating a carbohydrate meal.

Nonsulfonylurea Secretagogue

Cont’d…

• Indicationso Monotherapy with dieto Combination with metformin & TZD

• Benefitso Decrease in post-prandial glucoseo Short half-lifeo May demonstrate less hypoglycemia than SUo Use Caution: co-administration of repaglinide with gemfibrozil

is contraindicated. (Gemfibrozil is a hepatic enzyme inducer, therefore repaglinide level could be increased).

Nonsulfonylurea Secretagogue

…cont’d

Cont’d…

• Patient Typeo Pt with more predominant post-prandial

hyperglycemiao Pt with hypoglycemia episodes on SUo Pt with less consistent food plano Not for the pt with SU failure &

persistently above glycemic goals

…cont’d

Nonsulfonylurea Secretagogue

Thiazolidinediones (TZDs) Pioglitazone (Actos) & Rosiglitazone (Avandia)

o Alters transcription of genes that regulate carb and lipid metabolism

o Increase insulin stimulated glucose uptake by muscle cellso Decrease insulin resistance in peripheral tissues

Cont’d…

Thiazolidinediones(TZDs)…cont’d

Contraindicated - NYHA Class III and IV Heart Failure Precautions

o Concurrent use of insulin or nitrates (rosiglitazone)o Hepatic dysfunction o Cardiovascular Dx

Side Effectso Weight gaino Edemao Exacerbate or lead to HFo Risk of bone fracture

o Pioglitazone is associated with a small risk of bladder cancer.

o Restricted access to rosiglitazone due to concerns about cardiovascular safety.

o A1c lowering (1-1.5%)

Case Study BreakNew Patient -65 year old DM x 12 years, LDL-105, A1c 11%, B/P 122/85, BMI-44 microalbumin/creatinine ratio 200 Meds-Glipizide 10 mg BID, Metformin 1 gm BID

Blood Glucose:AM Lunch Dinner HS291 220 301195 247267 299178 288 351

251 333 356No lows

GLP-1 Agonists (liraglutide and exenatide)MOA

BloodGlucose Body Cell

Pancreas

LiverStomach

InsulinReceptorInsulin

Oral glucose stimulates GLP-1 & GIP Incretin HormonesDPP-4 Inhibitors rapidly degrade the incretin hormonesGLP-1 agonist bind to GLP-1 receptorsGLP-1 agonists are not susceptible to DPP-4

Decrease Gastric Emptying Increase Insulin

Decrease Appetite

Decrease Glucagon

GLP-1 Agonists• A1c lowering- Adding a GLP-1 agonist to metformin or SU resulted

in mean decrease in A1c ranging from 0.8-1.0% o Not susceptible to DPP-4 degradationo Increases Insulin secretion only in response to glucose load or

elevated glucose concentrationo Given as a subcutaneous injection

• Side effects: nausea/hypoglycemia/wt. losso Avoid use in patients with history of pancreatitiso Liraglutide is associated with thyroid C cell tumors in rodents,

but unknown in humans

VA/DoD Guidelines http://www.healthquality.va.gov/diabetes/DM2010_FUL-v4e.pdf

Reference - GLP-1 AgonistsAgent A1c reduction Initial dose Max Renal Considerations

Exenatide ~0.5-1.0% 5 mcg BID________________0-60 min before meals

10 mcg BID

Do not use if CrCl<30 or ESRD

Liraglutide ~1.0-1.5% 0.6 mg daily x 1 week, then 1.2 mg daily________________Independent of meal

1.8 mg daily

Use with caution in patients with renal impairment. No dose adjustment recommended.

Exenatide ER

~1.5% 2 mg weekly________________Independent of meal

2 mg weekly

Do not use if CrCl<30 or ESRD

Byetta PI. 12/2011Victoza PI. 4/2012.Bydureon PI. 1/2012

DPP-4 Inhibitors• Prevent the degradation of GLP-1• Do not affect:

o Satietyo GLP-1 effects on gastric emptyingo A1c lowering an average of 0.5-0.7% as monotherapy-efficacy

of DPP-4 inhibitors appears to decline after 1 year of treatment.

• Once daily dosing• Dose adjustment in renal dysfunction• Sitagliptin:

o Possible association pancreatitiso Evaluated with insulin

VA/DoD Guidelines http://www.healthquality.va.gov/diabetes/DM2010_FUL-v4e.pdf

Reference DPP-4 InhibitorsSitaglipton Saxaglipton

Usual Adult Dose 100 mg once daily 2.5-5 mg once daily

Dosage Adjustment 50 mg once daily in patients with moderate kidney dysfunction (CrCL> 30mL/min but £ 50 mL/min)*25mg once daily in patients with sever renal impairment and ESRD

2.5 mg once daily in patients with moderate-severe kidney dysfunction (CrCL> 50mL/min) or ESRD2.5mg once daily if patient is on concomitant strong CYP3A4/5 inhibitor

medication interactions Insulin and insulin secretagogues (increased hypoglycemia risk)

Strong CYP3A4/5 inhibitors (increased saxagliptin concentrations), insulin, and insulin secretagogues (increased hypoglycemia risk)

Adverse Events Acute pancreatitisHeadache, hypersensitivity reactions, hypoglycemia infection

Edema, headache, hypersensitivity reactions, hypoglycemia, infection

• Linagliptin is administered 5mg orally once daily either as monotherapy or in combination with metformin, sulfonylureas, or TZDs. o It may be taken with or without food. o No dosage adjustment is needed for renal or hepatic insufficiency. o Monitoring- AIC, Renal Function

National PBM medication VHA Pharmacy Benefits Management Services and Medical Advisory Panel http://www.pbm.va.gov/medicationMonograph.aspxAdapted from:Wigle PR et al. PSAP VII, verified from Thomson Micromedex Accessed 3/25/11.

Discontinuation Criteria• These agents are not to be used in patients with history of pancreatitis. • Pancreatitis has been reported with the DPP-4 inhibitors. Monitor

patients carefully for the development of pancreatitis after initiation or dose increases of agent. Discontinue agent if pancreatitis is suspected while using these products.

• Serious allergic and hypersensitivity reactions (e.g. anaphylaxis, angioedema, exfoliative skin conditions including Stevens-Johnson syndrome) have been reported with the DPP-4 inhibitors. If these reactions occur, discontinue agent and initiate alternative treatment for diabetes.

• Consider lowering insulin or Sulfonylurea dose if DPP4 inhibitor is initiated.

Dipeptidyl-peptidase-4 (DPP-4) Inhibitors: Sitagliptin, Saxagliptin, and Linagliptin Criteria for Use http://www.pbm.va.gov/CriteriaForUse.aspx Dipeptidyl-peptidase-4 (DPP-4) Inhibitors: Sitagliptin, Saxagliptin, and Linagliptin Criteria for Use http://www.pbm.va.gov/CriteriaForUse.aspx National PBM medication VHA Pharmacy Benefits Management Services and Medical Advisory Panel http://www.pbm.va.gov/medicationMonograph.aspx

SGLT2 Inhibitor Drug ClassSGLT2 Protein that absorbs glucose for energy for body

• This can cause the expulsion of 100 to 300 calories of excess glucose each day.

• Clinical trials for SGLT2 candidates have all shown weight loss.

SGLT2 inhibitors work by preventing the reabsorption of glucose in the kidneys

• canagliflozin and dapagliflozin FDA Approved

• side effects include genital and urinary tract infections and decreases in bone density

Insulin Stepwise Logic

Step 1• Make sure not Type 1• Thin, erratic BG, 911 hx, orals < 2 yrs, Neg C-Peptide

Step 2• How Long Diabetes? BMI, Current Blood Glucose, ADHERENCE?• Start Basal around 6-10 yrs 0.1 u/Kg

Step 3

• Bolus start 1 unit/serving carbohydrate at meal pre/post prandial , nutrition consultation

• Titrate insulin safely by 10-20% increments• If on insulin only may need more of a 50-50 mix Basal/Prandial (Type 1)

Multiple injections of insulin: Basal bolus plan

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Plas

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Insu

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33

Kinetics of Long-Acting Insulin

NPHDetemir

Glargine

“Basal” insulin; NOT meal coverage. Can/should give even when NOT eating!

Initiating Basal Insulin

• Generally start 0.1-0.2 Units/kg• Titrate 10-20% at a time (every 2-7days) until

target range, or any low blood sugar • Rotate injection sites• Do not shake N too hard• Check fasting and before meal Blood Sugars to

identify if basal dose correct

Teach Mobility of Injection Sites!

Administration

Prandial Insulin

• No set rules for initiation but safe practice is 1 unit per CHO consumed

• May be able to start daily or twice daily

• Titrate based on 2 hour pre/ post-prandial level

0 1 2 3 4 5 6 7 8 9

Plas

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Kinetics of Short-Acting Insulin

Aspart, lispro, glulisine

Regular

SAI Use • Meal Coverage• Regular may be useful for pt who “grazes”

Hypoglycemia• Some dangerous sequelae of hypoglycemia:

– tachycardia– bradyarrhythmias– frequent ventricular ectopic beats– ST depression– T-wave flattening – QT prolongation

Kodl C.T. & Seaquist E. R. (2008) Practical strategies to normalize hyperglycemia without undue hypoglycemia in Type 2 diabetes mellitus. Current Diabetes Reports 8, 375- 382.

Hypoglycemia (cont.)• Studies have also shown the effects of diminished

subsequent hypoglycemia response after a first episode (even in those without diabetes).

• The compensatory increase in cortisol production during a first hypoglycemic episode may play a central role in minimizing the protective hormonal responses during a subsequent episode

Davis S.N. Mann S. Briscoe V.J. Ertl A.C. & Tate D. B. (2009) The effects of intensive therapy and antecedent hypoglycemia on counter regulatory responses to hypoglycemia in type 2 diabetes. Diabetes 58 701-705.

Hypoglycemia (cont.)• If the blood glucose falls to 50 mg/dL (2.8

mmol/L), transient cognitive deficits may also ensue, which can result in falls or aspiration.

• If the blood glucose falls <40 mg/dL (2.2 mmol/L), seizure or coma may ensue.

Ben-Ami, H., Nagachandran, P., Mendelson, A.,and Edoute, Y. 1999. Drug-induced hypoglycemic coma in 102 diabetic patients. Arch. Intern. Med. 159:281–284.

Cryer, P.E. 2001. The prevention and correction of hypoglycemia. In Handbook of physiology. Section 7,The endocrine system. Volume 2, The endocrine pancreas and regulation of metabolism. L.S. Jefferson and A.D.Cherrington, editors. Oxford University Press. New York, New York, USA. 1057–1092.

Key Take Home Points• View BS’s in a daily pattern• Use ½ dose of SU-Clinically effective dose• Use Metformin or Metformin SA-think compelling reason NOT

to be on it• Start basal insulin early (UKPDS-6 yrs-50%) 0.1 U/kg• 9-9-9 Rule of starting basal insulin• Start bolus insulin early if needed 12~15 yrs-1 unit per CHO-

check 2 hr PP levels• Titrate insulin 10~20% at a time• If not on orals 50-50% mix basal/bolus to control blood glucose• Avoid Hypoglycemia

Resources

http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/Diabetes-2pager-March2009.pdf accessed 1.3.14

Onset Peak Duration CommentRapid Acting

Novolog 10-20 min 1-3 hours 3-5 hrsBoth types are used in insulin pumps, inject 10 min prior to meals

Humalog 15-30 min 30 min to 2 ½ hours 3-5 hrs

Covers insulin needs for meals eaten within 10-30mins, or as advised by physician

Short Acting

Regular (R) 30 min-1 hr 2-5 hours 5-8 hrs Increased risk of nocturnal hypo-glycemia compared to Novolog

Intermediate Acting

NPH (N)

1-2 hrs 4-12 hours 18-24 hrs Usually given twice daily; Increasedrisk of nocturnal hypoglycemia compared to Novolog

Long Acting Lantus- pen or vial Levemir-pen or vial

1-1 ½ hrs None 20-24 hrs Lantus-usually given once a dayLevemir-Once or twice a day

Pre-mixed Novolog Mix70/30 10-20 min 1-4 hrs Up to 24 hrs May be given up to three times per

day.

Types of Insulin

http://diabeteshealth.com/media/pdfs/PRG0113/Insulin.pdf