Best Practice Diabetes Drug
Management Secrets-2014
Loss of
Eyesight
Diet/Exercise/Lows
/Kidneys/Nerve/ED
/Depression
Foot
Amputation
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.
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?
4
Treating the ABCs Reduces
Diabetic Complications
Strategy
Complication
Blood glucose control ▪ Heart attack
Blood pressure
control
Lipid control
1 UKPDS
 37%1
▪ Cardiovascular disease
 51%2
▪ Heart failure
 56%3
▪ Stroke
 44%3
▪ Diabetes-related deaths
 32%3
▪ Coronary heart disease mortality
35%4
▪ Major coronary heart disease event
55%5
▪ Any atherosclerotic event
37%5
▪ Cerebrovascular disease event
53%4
Study Group (UKPDS 33). Lancet. 1998;352:837-853.
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.
2 Hansson
Reduction of
Complication
Estimated time to benefit
Glucose control
Blood pressure control
Lipid control
8 years
2-3 years
2-3 years
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,
AACE Guidelines-2011
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]
Progressive Decline in Beta Cell Function
HOMA %B
100
Non overweight
Overweight
80
60
40
20
0
Beta cell loss ~4% per year
0
1
2
3
4
5
6
0
1
2
3
4
5
Years from randomisation
Conventional
UKPDS 16. Diabetes 1995; 44: 1249-58
Sulphonylurea
Metformin
6
Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes
5.Gut CHO
Absorption:
8.Kidney
-
-
Incretin,
Pramlintide,
Glucosidase inh.
1.Pancreatic
insulin
Secretion:
Incretin, ranolazine
2.Pancreatic
glucagon
Secretion- Incretin
7.BrainTZD,INCRETIN,
bromocryptine
HYPERGLYCEMIA
SGLT2
De
-
-
3.MuscleTZD, Incretin
4.Liver
Hepatic glucose
production
:
Metformin, incretin
Peripheral
glucose
uptake
6.Fat- TZD, metformin
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 glycemic
control and QALYs comparable with those associated with other agents but at
lower cost.
Diabetes Care February 26, 2014
http://care.diabetesjournals.org/content/early/2014/02/18/dc13-1901.long
Nonsulfonylurea Secretagogue
•
•
•
•
•
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.
Cont’d…
Nonsulfonylurea Secretagogue
…cont’d
• Indications
o Monotherapy with diet
o Combination with metformin & TZD
• Benefits
o
o
o
o
Decrease in post-prandial glucose
Short half-life
May demonstrate less hypoglycemia than SU
Use Caution: co-administration of repaglinide with
gemfibrozil is contraindicated. (Gemfibrozil is a hepatic
enzyme inducer, therefore repaglinide level could be
increased).
Cont’d…
Nonsulfonylurea Secretagogue
…cont’d
• Patient Type
o Pt with more predominant post-prandial
hyperglycemia
o Pt with hypoglycemia episodes on SU
o Pt with less consistent food plan
o Not for the pt with SU failure &
persistently above glycemic goals
Thiazolidinediones (TZDs)
 Pioglitazone (Actos) & Rosiglitazone (Avandia)
o
o
o
Alters transcription of genes that regulate carb and lipid
metabolism
Increase insulin stimulated glucose uptake by muscle cells
Decrease insulin resistance in peripheral tissues
Cont’d…
Thiazolidinediones(TZDs)…cont’d
 Contraindicated -
NYHA Class III and IV Heart Failure
Precautions
o
o
o
Concurrent use of insulin or nitrates (rosiglitazone)
Hepatic dysfunction
Cardiovascular Dx
 Side Effects
o
o
o
o
Weight gain
Edema
Exacerbate or lead to HF
Risk of bone fracture
o
o
o
Pioglitazone is associated with a
small risk of bladder cancer.
Restricted access to rosiglitazone
due to concerns about
cardiovascular safety.
A1c lowering (1-1.5%)
Case Study Break
New Patient -65 year old DM x 12 years, LDL105, 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
291
220
195
267
299
178
251
No lows
Dinner
HS
301
247
288
333
351
356
GLP-1 Agonists (liraglutide and exenatide)MOA
Oral glucose stimulates GLP-1 & GIP Incretin Hormones
DPP-4 Inhibitors rapidly degrade the incretin hormones
GLP-1 agonist bind to GLP-1 receptors
GLP-1 agonists are not susceptible to DPP-4
Decrease
Appetite
Blood
Glucose
Body Cell
Stomach
Liver
Insulin
Insulin
Receptor
Decrease Glucagon
Pancreas
Decrease Gastric Emptying
Increase Insulin
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 degradation
o Increases Insulin secretion only in response to glucose load or
elevated glucose concentration
o Given as a subcutaneous injection
• Side effects: nausea/hypoglycemia/wt. loss
o Avoid use in patients with history of pancreatitis
o 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 Agonists
Agent
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. 12/2011
Victoza PI. 4/2012.
Bydureon PI. 1/2012
DPP-4 Inhibitors
• Prevent the degradation of GLP-1
• Do not affect:
o Satiety
o GLP-1 effects on gastric emptying
o A1c lowering an average of 0.5-0.7% as monotherapyefficacy of DPP-4 inhibitors appears to decline after 1
year of treatment.
• Once daily dosing
• Dose adjustment in renal dysfunction
• Sitagliptin:
o Possible association pancreatitis
o Evaluated with insulin
VA/DoD Guidelines http://www.healthquality.va.gov/diabetes/DM2010_FUL-v4e.pdf
Reference DPP-4 Inhibitors
Sitaglipton
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 ESRD
2.5mg 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 pancreatitis
Headache, 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
o
o
It may be taken with or without food.
No dosage adjustment is needed for renal or hepatic insufficiency.
Monitoring- AIC, Renal Function
National PBM medication VHA Pharmacy Benefits Management Services and Medical Advisory Panel
http://www.pbm.va.gov/medicationMonograph.aspx
Adapted 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
inhibitor is initiated.
or Sulfonylurea dose if DPP4
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 Class
SGLT2 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
Step 2
Step 3
• Make sure not Type 1
• Thin, erratic BG, 911 hx, orals < 2 yrs, Neg C-Peptide
• How Long Diabetes? BMI, Current Blood Glucose, ADHERENCE?
• Start Basal around 6-10 yrs 0.1 u/Kg
• 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
Kinetics of Long-Acting Insulin
Detemir
Plasma Insulin Levels
NPH
Glargine
0 1 2 3 4 5 6 7 8 9 10
11 12 13 14 15 16 17 18
19 20 21 22
“Basal” insulin; NOT meal coverage.
Can/should give even when NOT eating!
33
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!
A d m inistration
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
Kinetics of Short-Acting Insulin
Plasma Insulin Levels
Aspart, lispro, glulisine
Regular
0
1
2
3
4
5
6
7
8
SAI Use
• Meal Coverage
• Regular may be
useful for pt who
“grazes”
9
37
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
Types of Insulin
Onset
Peak
Duration
Comment
10-20 min
1-3 hours
3-5 hrs
Both types are used in insulin
pumps, inject 10 min prior to meals
15-30 min
30 min to 2 ½
hours
3-5 hrs
30 min-1 hr
2-5 hours
5-8 hrs
Increased risk of nocturnal hypoglycemia compared to Novolog
1-2 hrs
4-12 hours
18-24 hrs
Usually given twice daily; Increased
risk of nocturnal hypoglycemia
compared to Novolog
1-1 ½ hrs
None
20-24 hrs
Lantus-usually given once a day
Levemir-Once or twice a day
10-20 min
1-4 hrs
Up to 24 hrs
May be given up to three times per
day.
Rapid Acting
Novolog
Humalog
Covers insulin needs for meals
eaten within 10-30mins, or as
advised by physician
Short Acting
Regular (R)
Intermediate Acting
NPH (N)
Long Acting
Lantus- pen or vial
Levemir-pen or vial
Pre-mixed
Novolog Mix70/30
http://diabeteshealth.com/media/pdfs/PRG0113/Insulin.pdf