1. Diabetes Medications Update
Eric L. Johnson, M.D.
Assistant Medical Director
Altru Diabetes Center
Altru Health System
Associate Professor
Department of Community and Family Medicine
University of North Dakota
School of Medicine and Health Sciences
Grand Forks, ND

2. Disclosures
Off label use of some medications will be discussed

3. Objectives Assess knowledge of usual diabetes medications
Implement proper medication use per guideline management
Improve knowledge of side effects and contraindications of diabetes medications

4. 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

5. 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

6. Diabetes Diagnosis Normal <100 <140 <5.7
Category FPG (mg/dL) h 75gOGTT A1C
Normal < < <5.7
Prediabetes
Diabetes >126** > >6.5
Or patients with classic hyperglycemic symptoms with plasma glucose >200
** On 2 separate occasions
Diagnostic criteria for diabetes have changed.
Impaired fasting glucose (IFG) is a new term, defined as fasting plasma glucose between 110 and 125 mg/dL.
Diabetes is diagnosed at a serum glucose level of >126 mg/dL on at least two occasions.
For low risk individuals over the age of 45 years, the ADA recommends routine screening every 3 years with fasting glucose. OGTT are not recommended for screening.
Diabetes Care 35:Supplement 1, 2012

7. Natural History of Type 2 Diabetes
Uncontrolled Hyperglycemia
Obesity
IFG*
Diabetes
350 –
Fasting Glucose
Postmeal Glucose
300 –
250 –
Glucose (mg/dL)
200 –
150 –
100 –
50 –
250 –
Insulin Resistance
200 –
Relative Function (%)
150 –
100 –
-Cell Failure
-cell Function
50 –
0 –
-10 -5 5 10 15 20 25 30
Years of Diabetes
*IFG=impaired fasting glucose.
Copyright® 2000 International Diabetes Center, Minneapolis, USA. All rights reserved. Adapted with permission.

8. Decreased Incretin Effect
The Ominous Octet
Islet b-cell
Impaired
Insulin Secretion
Decreased Incretin Effect
Increased
Lipolysis
Islet a-cell
Increased
Glucagon Secretion
Insulin and appetite interact in the brain when neurotransmitters in the hypothalamus signal satiety in response to increased insulin.
Adding brain and neurotransmitter dysfunction to the pathogenic picture of type 2 diabetes gives us the ominous octet.
Increased Glucose
Reabsorption
Neurotransmitter
Dysfunction
Increased
HGP
Decreased Glucose
Uptake
DeFronzo Diabetes 2008 8

9. Goals of Glucose Management
Targets for glycemic (blood sugar) control in most non-pregnant adults
ADA
AACE
A1c (%)
<7*
≤6.5
Fasting (preprandial) plasma glucose
mg/dL
<110 mg/dL
Postprandial (after meal) plasma glucose
<180 mg/dL
<140 mg/dL
R36/p34/P1/L15
Both the ADA and the AACE recommend tight glucose control for persons with diabetes, although their definitions vary.
Despite the findings of two large-scale trials, the DCCT and UKPDS, a universally agreed-upon set of glucose management goals has yet to be defined. While almost every diabetes management guideline includes the hallmark variables of A1c and fasting plasma glucose, there are slight variations in specific target values. The American Diabetes Association (ADA) currently recommends a target A1c of <7%, while the American Association of Clinical Endocrinologists (AACE) suggests aiming for a value of 6.5% or lower. The ADA proposes a target range for fasting plasma glucose levels between 90 and 130 mg/dL, while the AACE recommends levels below 110 mg/dL. Postprandial plasma glucose recommendations put forth by the two organizations are <180 and <140 mg/dL, respectively.
In addition to these standard variables, there are other important aspects of diabetes management that deserve consideration. Other important issues identified in the two landmark trials, both medically and from a quality of life perspective, include reducing the frequency of hyperglycemic excursions, minimizing the risk of hypoglycemia, especially nocturnal, and minimizing weight gain. Addressing these issues could have an impact on patient motivation and/or treatment compliance, increasing the chance of attaining A1c and plasma glucose goals.
References:
American Diabetes Association. Standards of medical care in diabetes – Diabetes Care. 2006;29(suppl 1):S4-S42. Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement at ImplementationPositionStatement.pdf. Accessed January 6, 2006.
R5/pS10/T6
R2/p3/P2
*<6 for certain individuals
American Diabetes Association. Diabetes Care. 2012;35(suppl 1)
2011 9

10. 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)

11. Goals of Glucose Management
Less stringent (<8) appropriate:
History of severe hypoglycemia
Limited life expectancy
Advanced complications or comorbid conditions
Longstanding difficult to control diabetes
American Diabetes Association. Diabetes Care. 2012;35(suppl 1)

12. 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)

13. A1C ~ “Average Glucose” A1C eAG % mg/dL mmol/L 6 126 7.0 6.5 140 7.8
Formula: 28.7 x A1C eAG
American Diabetes Association

14. Diabetes Medications

15. 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

16. Glucose-lowering Potential of Diabetes Therapies*
Treatment FPG ¯ HbA1C ¯
Sulfonylureas mg/dl 1-2%
Metformin mg/dl 1-2%
a-Glucosidase Inhibitors (Precose) mg/dl 0.5-1%
Repaglinade (Prandin) 60mg/dl 1.7%
Thiazolidinediones mg/dl 1-2%
Gliptins (Januvia,Onglyza) targets ppd %
*based on package insert data as monotherapy

17. Glucose-lowering Potential of Injection Diabetes Therapies*
Treatment FPG ¯ HbA1C ¯
Exenatide (Byetta) targets ppd 1-1.5%
Liraglutide (Victoza) targets ppd %
Pramlintide (Symlin) targets ppd 1-2%
Insulin Limited by %
hypoglycemia
*based on package insert data as monotherapy

18. ADA/EASD consensus algorithm Type 2
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%.
Tier 1: Well-validated core therapies
At diagnosis:
Lifestyle and MET
+ basal insulin
Lifestyle and MET + intensive insulin
Lifestyle +
MET
Lifestyle and MET+ SUa
Step 1
Step 2
Step 3
Tier 2: Less well-validated therapies/studies
Lifestyle and MET + pioglitazone
Lifestyle and MET + pioglitazone + SUa
No hypgglycemia No
edema/CHF
Bone loss
Lifestyle and MET + GLP-1 agonistb
Lifestyle and MET
+ basal insulin
No hypoglycemia No
Weight loss
Nausea/vomiting
aSU other than glyburide or chlorpropamide. bInsufficient clinical use to be confident regarding safety.
MET: metformin; SU: sulfonylurea. Nathan et al. Diabetes Care 2009;32(1):

20. 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

21. Oral Diabetes Medications

22. Sulfonylureas Oldest oral medications
Stimulate pancreas to secret more insulin
Effective, inexpensive
Glyburide, Glipizide, Glimiperide

23. 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

24. 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

25. 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

26. Thiazolidinediones (TZD’s)
Pioglitazone (Actos)
Rosiglitazone (Avandia)
Improves insulin resistance
Extremely low incidence of hypoglycemia
The role of TZD’s is rapidly diminishing

27. 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)

28. 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)

29. Gliptins’ Caveats, Benefits
Hypoglycemia if used with sulfonyurea or insulin
Nausea, rash
Benefits:
Few drug interactions; can be renally dosed

30. “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

31. Non-Insulin Injectable Medications

32. Glucagon-like Peptide-1 (GLP-1)
Gut hormone
Stimulates pancreas to secret insulin
Suppresses glucagon action
Many target organs
Weight regulation

33. 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

34. GLP-1 Caveats Nausea, vomiting Pancreatitis
Medullary thyroid carcinoma in rodents (liraglutide)
Hypoglycemia combined with sulfonylurea
Caution in renal or hepatic impairment

35. 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

36. 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

37. 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)

38. Insulin Therapies

39. Intensifying Treatment
Beta-cell function declines as Type 2 diabetes progresses
100
Diagnosis
Beta-cell decline exceeds 50% by time of diagnosis 75
Beta-cell function (%)
IGT
Insulin initiation 50
Postprandial Hyperglycemia 25
Type 2 Diabetes
Beta-cell function is tied to glycemic control
Type 2 diabetes is characterized by insulin resistance and the progressive loss of islet beta-cell function. Although the former is already established at diagnosis and changes little thereafter, beta-cell function continues to decline, leading to secondary failure of anti-hyperglycemic therapies.
In the UKPDS, glycemic deterioration was associated with progressive loss of beta-cell function.
Reference
Lebovitz H. Insulin secretagogues: old and new. Diabetes Rev 1999;7:
­12 ­8 ­4 4 8 12
Years from diagnosis
Lebovitz H. Diabetes Rev 1999;7: 39

40. 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

41. 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 41

42. Long-Acting Insulin Detemir (Levemir) Glargine (Lantus)
(Human NPH (N) )
Taken 1 or 2 times daily
“Basal” insulin

43. Rapid Acting Insulin Aspart (Novolog) Lispro (Humalog)
Glulisine (Apidra)
(Human Regular)
Taken with meals and snacks
“Bolus” insulin

44. Insulin Time Action Curves
140
Rapid (Lispro,Glulisine, Aspart)
120
100
Short (Regular) 80
Intermediate (NPH)
Insulin Effect 60 40
Long
(Detemir,Glargine) 20 2 4 6 8 10 12 14 16 18 20
Hours
adapted from R. Bergenstal, IDC

45. 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

46. 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 units/day

47. Adding Bolus Insulin in Type 2 Diabetes
Lispro (Humalog)
Aspart (Novolog)
Glulisine (Apidra)
Pen injectors
Why is bolus insulin important in Type 2?

48. Fasting and Postprandial Glycemic Excursions as a Function of A1C20 60 80 2
(7.3–8.4) 3
(8.5–9.2) 4
(9.3–10.2) 5
(>10.2) 1
(<7.3) 40
Contribution (%)
A1C (%) Quintiles
Postprandial hyperglycemia
Fasting hyperglycemia
Slide 17
The slide shows the relative contributions of postprandial and fasting hyperglycemia (%) to the overall diurnal hyperglycemia over quintiles of A1C1
These data were obtained from a study of 290 patients with type 2 diabetes conducted to determine the exact contributions of postprandial and fasting glucose increments to overall hyperglycemia1
The relative contribution of postprandial decreased progressively from the lowest to the highest quintile of A1C, while the relative contribution of fasting glucose increased gradually with increasing levels of A1C1
Therefore, the relative contribution of postprandial glucose excursions is predominant in fairly well-controlled patients, whereas the contribution of fasting hyperglycemia increases as diabetes worsens1
Reference
Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of A1C. Diabetes Care. 2003;26:
Monnier L et al. Diabetes Care. 2003;26:

49. 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

50. 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

51. Severely Insulin Resistant
units total daily dose
Obesity
Lipodystrophies
Donohue and Rabson–Mendenhall Syndrome
Type a Insulin Resistance Syndrome and HAIR-AN
Garg NEJM 2004
Semple et al Clin Endocrinol. 2010

52. Severely Insulin Resistant
Consider occult infections (UTI, abcess, sinus, etc)
Consider other inflammatory conditions (periodontal disease, etc)

53. Severely Insulin Resistant
Options:
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

54. 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

55. 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

56. 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

57. Typical Type 2 Timeline Metformin at diagnosis Add something else
Consider insulin if:
-Duration >5 years
-A1C>9

58. 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

59. 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

60. Contact Info/Slide Decks/Media
Facebook search “North Dakota Diabetes” on Facebook Phone cell Slide Decks (Diabetes, Tobacco, other) iTunes Podcasts (Diabetes) (Free downloads) or iTunes>> search UND Medcast ( WebMD Page: (under construction) Diabetes e-columns (archived):

61. Case Studies

62. 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)

63. 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

64. Case Study Referred to Diabetes Educator and Dietician
Recommend developing graduated exercise plan (exercise prescription)
Six months after diagnosis, A1C = 6.8% (target <7%)

65. Case Study
Three years later, patient’s A1C has risen to 8.4% (target <7%)
Blood pressure and cholesterol effectively treated
Now what?

66. Case Study Choices include Any of these are good choices
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

67. 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?

68. 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