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

e-maileric.l.johnson@med.und.eduejohnson@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