Best Practice Diabetes Drug Management Secrets-2014 Foot Amputatio n Loss of Eyesight Diet/ Exercise/ Lows/ Kidneys/ Nerve/ED/ Depression By Sharon A. Watts DNP, RN-BC, CDE
Feb 25, 2016
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
ma
Insu
lin L
evel
s
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
ma
Insu
lin L
evel
s
37
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