diabetes medications update eric l. johnson, m.d. assistant medical director altru diabetes center...
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Diabetes Medications Update
Eric L. Johnson, M.D.
Assistant Medical DirectorAltru Diabetes CenterAltru Health System
Associate ProfessorDepartment of Community and Family Medicine
University of North DakotaSchool of Medicine and Health Sciences
Grand Forks, ND
Disclosures
• Off label use of some medications will be discussed
Objectives
• Assess knowledge of usual diabetes medications
• Implement proper medication use per guideline management
• Improve knowledge of side effects and contraindications of diabetes medications
Diabetes Mellitus
• Type 1: Usually younger, insulin at diagnosis
• Type 2: Usually older, often oral agents at diagnosis
• Type “1.5” (Latent Autoimmune), mixed features
• Gestational: Diabetes of Pregnancy
U.S. Prevalence of Diabetes 2010
• Diagnosed: 26 million people—8.3% of population (90%+ have Type 2)
• Undiagnosed: 7 million people
• 79 million people have pre-diabetes
CDC 2011
Diabetes DiagnosisCategory FPG (mg/dL) 2h 75gOGTT A1C
Normal <100 <140 <5.7
Prediabetes 100-125 140-199 5.7-6.4
Diabetes >126** >200 >6.5Or patients with classic hyperglycemic symptoms with plasma glucose >200
** On 2 separate occasionsDiabetes Care 35:Supplement 1, 2012Diabetes Care 35:Supplement 1, 2012
*IFG=impaired fasting glucose.Copyright® 2000 International Diabetes Center, Minneapolis, USA. All rights reserved. Adapted with permission.
Natural History of Type 2 Diabetes
Years of Diabetes
Glu
cose
(mg/
dL)
50 –
100 –
150 –
200 –
250 –
300 –
350 –
0 –
50 –
100 –
150 –
200 –
250 –
-10 -5 0 5 10 15 20 25 30
Rel
ativ
e Fu
nctio
n (%
)
Fasting Glucose
Postmeal Glucose
Obesity IFG* Diabetes UncontrolledHyperglycemia
Insulin Resistance
-cell Function-Cell Failure
The Ominous OctetIslet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
NeurotransmitterNeurotransmitterDysfunctionDysfunction
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
Islet -cell
IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion
IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis
Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
DecreasedDecreasedIncretin EffectIncretin Effect
DecreasedDecreasedIncretin EffectIncretin Effect
DeFronzo Diabetes 2008
Targets for glycemic (blood sugar) control in
most non-pregnant adultsADA AACE
A1c (%) <7* ≤6.5Fasting (preprandial) plasma glucose 70-130 mg/dL <110 mg/dL
Postprandial (after meal) plasma glucose <180 mg/dL <140 mg/dL
• American Diabetes Association. Diabetes Care. 2012;35(suppl 1) • https://www.aace.com/sites/default/files/DMGuidelinesCCP.pdf 2011
*<6 for certain individuals
Goals of Glucose Management
Goals of Glucose Management
• More stringent (<6.5) appropriate:
-No significant CVD
-Short duration
-Long life expectancy
American Diabetes Association. Diabetes Care. 2012;35(suppl 1)
Goals of Glucose Management
Less stringent (<8) appropriate:
• History of severe hypoglycemia
• Limited life expectancy
• Advanced complications or comorbid conditions
• Longstanding difficult to control diabetesAmerican Diabetes Association. Diabetes Care. 2012;35(suppl 1)
Goals of Glucose Management
• Hypoglycemia must be considered
• “Many factors, including patient preferences, should be taken into account when developing a patient's individualized goals”
American Diabetes Association. Diabetes Care. 2012;35(suppl 1)
A1C ~ “Average Glucose”
American Diabetes Association
A1C eAG
% mg/dL mmol/L
6 126 7.0
6.5 140 7.8
7 154 8.6
7.5 169 9.4
8 183 10.1
8.5 197 10.9
9 212 11.8
9.5 226 12.6
10 240 13.4
Formula: 28.7 x A1C - 46.7 - eAG
Diabetes Medications
Diabetes Medications
• Many new medications in last decade
• Three main categories– Oral agents (pills)- many different kinds old and new
– Insulin- newer, more modern insulins
– Newer, non-insulin injectable medications
• Choices allow individualization of treatment plan
• Different medications, different indications, different situations
Glucose-lowering Potential of Diabetes Therapies*
Treatment FPG HbA1C
Sulfonylureas 50-60 mg/dl 1-2%
Metformin 50-60 mg/dl 1-2%
-Glucosidase Inhibitors (Precose) 15-30 mg/dl 0.5-1% Repaglinade (Prandin) 60mg/dl 1.7%
Thiazolidinediones 40-60 mg/dl 1-2%
Gliptins (Januvia,Onglyza) targets ppd 0.5 - 0.8%
*based on package insert data as monotherapy
Glucose-lowering Potential of Injection Diabetes Therapies*
Treatment FPG HbA1C
Exenatide (Byetta) targets ppd 1-1.5%
Liraglutide (Victoza) targets ppd 1-1.5%
Pramlintide (Symlin) targets ppd 1-2%
Insulin Limited by 1.5-3.5%
hypoglycemia
*based on package insert data as monotherapy
ADA/EASD consensus algorithmType 2
MET: metformin; SU: sulfonylurea. Nathan et al. Diabetes Care 2009;32(1): 193-203
aSU other than glyburide or chlorpropamide. bInsufficient clinical use to be confident regarding safety.
No No hypoglycemiaWeight loss
Nausea/vomiting
Lifestyle and MET + intensive insulin
Lifestyle and MET+ basal insulin
Lifestyle and MET+ SUa
At diagnosis:
Lifestyle +
MET
Step 1 Step 2 Step 3
Lifestyle and MET + pioglitazone
No No hypgglycemiaedema/CHF
Bone loss
Lifestyle and MET + GLP-1 agonistb
Lifestyle and MET + pioglitazone
+ SUa
Lifestyle and MET+ basal insulin
Tier 2: Less well-validated therapies/studies
Tier 1: Well-validated core therapies
Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is <7% and then at least every 6 months. The interventions should be changed if A1C is ≥7%.
Key Points of Medication Selection in Type
2• Metformin at diagnosis unless a
contraindication
• Second line agents- basal insulin or many other meds
• Advance therapy as disease progresses
• ADA/EASD will have a new guideline in 2012
Oral Diabetes Medications
Sulfonylureas• Oldest oral medications
• Stimulate pancreas to secret more insulin
• Effective, inexpensive
• Glyburide, Glipizide, Glimiperide
Caveats with Sulfonylureas
• Hypoglycemia (particularly in elderly)
• Premature B-cell exhaustion?
• Caution in liver disease, renal disease
• Weight gain
• Rash
• Avoid if anaphylactic to sulfa
Metformin
• Improves insulin resistance• Reduced Hepatic Glucose production• Effective, inexpensive• Extremely low incidence of hypoglycemia• Weight neutral or weight loss• Positive effects on lipid profiles• Long term use may result in better CVD
outcomes• Can be combined with virtually all other DM
meds
Caveats with Metformin• Liver Disease• Renal Disease• GI upset• Heavy Alcohol Use• Intravascular Dye Studies (IVP, Angio,etc)• CHF• Not for persons over 80• Can result in B12 deficiency
Thiazolidinediones (TZD’s)
• Pioglitazone (Actos)
• Rosiglitazone (Avandia)
• Improves insulin resistance
• Extremely low incidence of hypoglycemia
• The role of TZD’s is rapidly diminishing
Caveats with TZD’s
• CHF (or if hx/risk?)• Patients already dealing with edema• Potential weight gain• Renal disease-fluid overload• Current TZD’s rare liver disease, not
recommended in active liver disease• Heart disease risk? (Rosiglitazone-restrictions)
• Bladder cancer? Pioglitazone (Actos)
Gliptins(DPP-IV)
• DPP-IV inhibitors• Sitagliptin (Januvia) • Saxagliptin (Onglyza)• Linagliptin (Tradjenta)
• Oral agents
• Weight neutral or weight loss
• Can use with Metformin, Sulfonylurea, TZD, or insulin (sitagliptin)
Gliptins’ Caveats, Benefits
Caveats:• Hypoglycemia if used with sulfonyurea or
insulin• Nausea, rash
Benefits:
Few drug interactions; can be renally dosed
“Niche” Drugs• Colesevelam (Welchol)
- adjunct to lower A1c and LDL
• Repaglinide (Prandin), Nateglinide (Starlix)- may replace SU if sulfa allergy
- Prandin may be useful in CKD• Acarbose (Precose), Miglitol (Glyset)
- limited efficacy, GI intolerance, cost• Bromocriptine (Cycloset)
- limited efficacy? Mechanism uncertain• Salsalate-older NSAID, may lower blood sugar,
no indication yet
Non-Insulin Injectable Medications
Glucagon-like Peptide-1 (GLP-1)
• Gut hormone
• Stimulates pancreas to secret insulin
• Suppresses glucagon action
• Many target organs
• Weight regulation
GLP-1 Medications
• Exenatide (Byetta) GLP-1 mimetic• Liraglutide (Victoza) GLP-1 analog• Both available in pen injectors (easy)• Modest weight loss• Combined with other agents except DPP-
IV inhibitors• Exenatide approved for combo use with insulin
GLP-1 Caveats
• Nausea, vomiting
• Pancreatitis
• Medullary thyroid carcinoma in rodents (liraglutide)
• Hypoglycemia combined with sulfonylurea
• Caution in renal or hepatic impairment
Pramlintide-Synthetic Amylin(Symlin)
• Amylin secreted by normal pancreas along with insulin to regulate blood glucose
• Enhances Postprandial control. Used in Type 1 and Type 2 patients
• Used as adjunct to insulin• Available in pen injector• Possible significant hypoglycemia
Combination Drug Therapy
• Consider early if failing monotherapy
• Generally additive or synergistic effects
• Triple or quadruple non-insulin drug therapy
-limited benefit in many
-safe for many
• Insulin is often a better,more potent choice
Prediabetes• Lifestyle measures are treatment of choice to
prevent progression to type 2 diabetes• Many meds have some prediabetes data• Metformin may be considered in those with
prediabetes especially for:
BMI >35 kg/m
Age <60 years
Women with prior GDM or PCOS
ADA Diabetes Care. 2012;35(suppl 1)
Insulin Therapies
Intensifying Treatment
Beta-cell function (%)
Beta-cell decline exceeds 50% by time of diagnosis
4 4 12 8 0 8 12
0
50
100
75
25 Type 2 Diabetes
IGT
Years from diagnosis
Postprandial
Hyperglycemia
Diagnosis
Insulininitiation
Lebovitz H. Diabetes Rev 1999;7:139-153.
Beta-cell function declines as Type 2 diabetes progresses
Insulin Therapy
• All Type 1 patients at diagnosis• All type 2 patients will require insulin if they
live long enough
-7 to 10 years post diagnosis
-A1C >9%
-Function of many non-insulin meds based on presence of native insulin
Insulin Therapy
• Modern insulins safer and more predictable
• Most insulin types come in pen injectors
• Pen injectors easy to use, to teach, less cumbersome than vials/syringes
Long-Acting Insulin
• Detemir (Levemir)
• Glargine (Lantus)
• (Human NPH (N) )
• Taken 1 or 2 times daily
• “Basal” insulin
Rapid Acting Insulin
• Aspart (Novolog) • Lispro (Humalog)
• Glulisine (Apidra)
• (Human Regular)
• Taken with meals and snacks
• “Bolus” insulin
Insulin Time Action Curves
0
20
40
60
80
100
120
140
0 2 4 6 8 10 12 14 16
Insu
lin
Eff
ect
Hours
18 20
Intermediate (NPH)
Long(Detemir,Glargine)
Short (Regular)
Rapid (Lispro,Glulisine, Aspart)
adapted from R. Bergenstal, IDC
Basal Insulin in Type 2 Diabetes
• Glargine (Lantus), Detemir (Levemir)
• Good, potent add-on 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
Basal Insulin in Type 2 Diabetes
• Some oral meds may be continued
-metformin, maybe TZD, maybe SU, maybe gliptin (sitagliptin)
• Glargine (Lantus) or Detemir (Levemir) started at 10 units at HS
• Increase 3 units every 3 to 5 days until fasting blood sugars <110 (or <140)
• Most type 2 on 50-80+ units/day
Adding Bolus Insulin in Type 2 Diabetes
• Lispro (Humalog)
• Aspart (Novolog)
• Glulisine (Apidra)
• Pen injectors
• Why is bolus insulin important in Type 2?
Fasting and Postprandial Glycemic Excursions as a Function of A1C
Monnier L et al. Diabetes Care. 2003;26:881-885.
0
20
60
80
2(7.3–8.4)
3(8.5–9.2)
4(9.3–10.2)
5(>10.2)
1(<7.3)
40
Co
ntr
ibu
tio
n (
%)
A1C (%) Quintiles
Postprandial hyperglycemia
Fasting hyperglycemia
Adding Bolus Insulin in Type 2 Diabetes
• 1 injection basal/1 injection bolus good 2 injection program- better than split basal
• 90/10 rule (90% basal, 10% bolus)• Start with largest meal of the day • Add other meal doses later (MDI-different formulas)
• Often stop TZD, always stop SU• Easy with pens
Other Insulins
Premix•70/30, 75/25, 50/50•Combine R or rapid acting with NPH or an “NPH-like” component•Certain applications may be appropriate•Limitation: change 2 insulins at once
U-500•Sometimes in severe insulin resistance
Severely Insulin Resistant
• 200-300+ units total daily dose • Obesity• Lipodystrophies• Donohue and Rabson–Mendenhall
Syndrome• Type a Insulin Resistance Syndrome and
HAIR-ANGarg NEJM 2004Semple et al Clin Endocrinol. 2010
Severely Insulin Resistant
• Consider occult infections (UTI, abcess, sinus, etc)
• Consider other inflammatory conditions (periodontal disease, etc)
Severely Insulin ResistantOptions:•U-500•Add Symlin•Add GLP-1 (exenatide now FDA approved with insulin)•Change/add “insulin sensitizing” agents•Bariatric Surgery•Sometimes pump- better absorption, maybe lower daily dose
Medication Combinations• Sulfonylureas: Virtually any in type 2• Metformin: Virtually any in type 2• TZD: Virtually any in type 2• Gliptins (DPP-IV): metformin, TZD, insulin
(sitagliptin),sulfonylureas• Insulin: metformin, TZD, sulfonylurea, amylin,
sitagliptin• Amylin: only in insulin regimens• Exenatide/Liraglutide: metformin, sulfonyureas,
TZD
Medication Indications
• Type 1 Diabetes: Insulin, amylin (amylin only in combination with insulin)
• Type 2 Diabetes: All oral agents, exenatide, liraglutide, amylin, insulin (amylin only in combination with insulin)
• Prediabetes: Case by case as discussed
Future Medications
• SGLT (sodium-glucose co-transporter) 1/2 inhibitors (i.e., Dapagliflozin)
• GPR (G-protein receptors)
• Ultralong acting insulins (i.e., degludec)
• Ultralong acting GLP-1 (i.e., bydureon)
• New P-PARS
Typical Type 2 Timeline
• Metformin at diagnosis
• Add something else
• Consider insulin if:
-Duration >5 years
-A1C>9
Summary
• Diabetes is common
• Understand Medications and Indications
• Type 1 diabetes: Insulin regimen (pumps)
• Type 2 diabetes: Lots of choices, but nearly all will need insulin eventually
Acknowledgements
• Jim Brosseau, M.D., M.P.H. Altru Diabetes Center• William Zaks, M.D., Ph.D., Altru Diabetes Center• Altru Diabetes Center Team• Melissa Gardner, Department of Family and Community
Medicine, UNDSMHS
Contact Info/Slide Decks/Media
[email protected]@altru.org
Facebook search “North Dakota Diabetes” on Facebook
Phone701-739-0877 cell
Slide Decks (Diabetes, Tobacco, other)http://www.med.und.edu/familymedicine/slidedecks.html
iTunes Podcasts (Diabetes) (Free downloads)http://www.med.und.edu/podcasts/ or iTunes>> search UND Medcast (
WebMD Page: (under construction)http://www.webmd.com/eric-l-johnson
Diabetes e-columns (archived): http://www.ndhealth.gov/diabetescoalition/DrJohnson/DrJohnson.htm
Case Studies
Case Study
• 54 y/o white male
• Diagnosed with type 2 diabetes after 2 fasting blood sugars of 154 and 142
• Also has high blood pressure and cholesterol disease (common in type 2)
Case Study
• Metformin 500 mg prescribed twice daily, titrated to 1000mg BID
• ASA 81 mg daily• Lisinopril 10 mg daily• Simvistatin 40 mg daily• Fish Oil 1000mg BID
Case Study
• Referred to Diabetes Educator and Dietician
• Recommend developing graduated exercise plan (exercise prescription)
• Six months after diagnosis, A1C = 6.8% (target <7%)
Case Study
• Three years later, patient’s A1C has risen to 8.4% (target <7%)
• Blood pressure and cholesterol effectively treated
• Now what?
Case Study
• Choices include– Adding a basal insulin once daily– Adding any other oral agent– Adding exenatide twice daily or liraglutide
once daily
• Any of these are good choices
• Choice may be made on individual factors
Case Study
• Patient chose additional oral agent (sitagliptin), but others would be OK
• A1C: 6 months later = 7.4% (target <7%) 3 years later = 8.1% (target <7%)
Now what?
Case Study
• Sitgliptin, metformin continued
• Basal insulin started with titration
• Eventually added bolus insulin with largest meal (90/10 rule)
• Likely will add bolus with other meals over time