Update on Diabetes Medications and

Guidelines in Cardiopulmonary Rehab Setting

Objectives

 Learn about the impact of diabetes in the United States

 Review oral and injectable diabetes medications and

their role in diabetes management
 National Diabetes Estimates

• 25.8 million Americans (8.3% of the

US population)
• 7 million undiagnosed
• 79 million American adults aged 20
years or older qualify as being at
high risk to develop diabetes
(fasting glucose between 100 and
125)
• If the trend continues, 1-in-3
American adults will have diabetes
by 2050
CDC National Diabetes Fact Sheet 2011.
ADA diabetes Statistics 2013
• The 7th leading cause of death in the US
• The leading cause of blindness, renal failure
and nontraumatic amputations between the
age of 20-74
• Cost: U.S. national economic burden of pre-
diabetes and diabetes reached $245 billion in
2012, $218 billion in 2007 , $132 billion in
2002 vs. $44 billion in 1997
Making the Diagnosis
 Fasting Plasma Glucose Test
99 or below = Normal
100 to 125 = Pre-diabetes (impaired fasting glucose (IFG))
≥ 126 = Diabetes
 Oral Glucose Tolerance Test (OGTT)
2 hr plasma glucose result:
139 and below =Normal
140-199 = Pre-diabetes (impaired glucose tolerance (IGT))
200 and above = Diabetes
 Random Plasma Glucose Test
200 or more plus presence of symptoms (polydypsia/polyuria/polyphagia) =
Diabetes
 Results should be confirmed by repeating the
test on another day prior to diagnosis
 A1c ≥ 6.5% (new 2010 criteria for diagnosis)
 Classification of Diabetes

 Insulin-Dependent Diabetes Mellitus (Type I)

– High anti-beta cell antibodies
– Low plasma insulin concentration (determined by C-peptide levels)
– Usually lean and young patients but this trend in changing

 Non-Insulin-Dependent Diabetes Mellitus (Type II)

– Serum insulin levels normal or elevated but still have relative insulin
deficiency
– Metabolism does not respond properly to insulin= insulin resistance
– Usually obese (60-90%) and older but thins trend is changing
– Losing weight frequently brings glucose levels and insulin sensitivity
back under control
– Strong genetic linkage
 Classification of Diabetes (Cont.)
 Type 1.5 Diabetes (also known as slow onset type I or latent autoimmune diabetes
in adults)
– Patients do not immediately require insulin for treatment
– Little or no resistance to insulin
– Antibodies present (especially GAD65)
– Can be easily misdiagnosed as Type II since patients are older and respond to
oral medications except glitazones (since little or no insulin resistance) &
usually have good C-peptide levels
 Gestational Diabetes (GD)
– In most cases, slender and physically fit patients
– Approximately 4% of all pregnancies according to ADA
– 5-10% of women with GD are found to have type 2 diabetes
– Women with GD have 20-50% chance to develop diabetes in the next 5-10
years
Type 3 Diabetes??

 Alzheimer’s can be associated with low levels of

insulin in the brain is the reason why increasing
numbers of researchers have taken to calling it
Type 3 diabetes, or "Diabetes of the Brain“
 In Alzheimer’s, the brain, especially parts that
deal with memory and personality, become
resistant to insulin.  Research is ongoing and
there will be more to come on the link between
diabetes and the brain.
Risk Factors

 Family History
 Obesity: 20% over IBW or BMI > 27
 Age: over 45 years old
 History of impaired glucose tolerance or impaired fasting
glucose
 Hypertension
 HDL < 35 and/or TG > 200
 Smoking
 Race/Ethnicity
 Pregnancy
Clinical Practice Recommendations

 ADA  AACE
 Begin screening at age 45
 Begin screening at age 30
 Preprandial BG 70-130

 2 hr postprandial <180
 Preprandial BG 110

 Average bedtime BG 100-140

 2 hr postprandial <140
 A1c goal <7% for patients in
general, EAG= (28.7x A1c) - 46.7
(6%= 126 mg/dl, 7%= 154, 8%=  A1c goal <6.5%
183, 9%= 212, etc.)

ADA= American Diabetes Association

AACE= American Association of Clinical Endocrinologists
Benefits of Reducing A1c by 1%

 Type I diabetes (DCCT)

-32% decrease in risk for retinopathy
-20% -27% decrease in risk for nephropathy
-30% decrease in risk for neuropathy
 Type II diabetes (UKPDS)
-10% decrease in risk in diabetes related death
- 6% decrease in all-cause mortality
-16% decrease in risk for MI
-25% decrease in microvascular complications
DCCT= Diabetes Control and Complications Trial

UKPDS= United Kingdom Prospective Diabetes Study

 A1C Goals Unmet in Majority of
Patients With Diabetes
10.0 12.4% have A1C >10%1

9.5

9.0 20.2% have A1C >9%3

A1C (%) 8.5

8.0 37.2% have A1C >8%

7.5
64.2% of patients with type 2
7.0
diabetes have A1C 7%2
6.5 ACE recommended target (<6.5%)4

6.0 Upper limit of normal range (6%)

5.5
1. Data from Saydah SH, et al. JAMA. 2004; 291:335-342
2. Calculated from Koro CE, et al. Diabetes Care. 2004; 27:17-20
3. Data from ADA. Diabetes Care. 2003; 26(suppl 1):S33-S50
4. Data from ACE. Endocrine Practice. 2002
 Diabetes Management

 Control of A1c, fasting glucose(FG) and postprandial

glucose levels (PPG) (DECODE study showed that PPG is
more predictive than AIC and FG for CV risk*)

 Hypertension-goal is <140/80 mmHg

 Dyslipidemia (General Guidelines):

*LDL<100 mg/dl
*HDL men >40 mg/dl, women >50 mg/dl
*Triglycerides<150 mg/dl

*Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE)

Review of Oral Hypoglycemic Meds

 Sulfonylureas
 Meglitinides
 Thiazolidinediones
 Biguanides
 Alpha-Glucosidase Inhibitors
 Dipeptidyl Peptidase IV inhibitors (DPP 4 inhibitors)
 Sodium Glucose Co-transporter 2 Inhibitor (SGLT-2
inhibitor)
 Combination Products
 Others: Welchol and Cycloset
Sulfonylureas
 Stimulate insulin production from pancreas
 Glyburide (Diabeta®, Micronase®, Glynase®), max. dose
20 mg/day
 Glipizide (Glucotrol®)-taken 30 min before eating, max.
dose 40 mg/day, (Glucotrol XL®)-may be taken with food,
max. dose 20 mg/day
 Glimipiride (Amaryl)-taken with food, max dose 8 mg/day
 Watch for renal dysfunction:
-Glyburide not recommended for CrCl<50 ml/min,
contraindicated for patients with severe renal failure
-Glimipiride < 30ml/min, start with 1 mg daily and adjust
-Glipizide < 10ml/min use a conservative dose & adjust
 Side effects-hypoglycemia, GI effects and sun sensitivity
Meglitinides

 Stimulate insulin production from pancreas

 Repaglinide (Prandin®)-Max. dose 4 mg tid-
qid
 Nateglinide (Starlix®)-Max. dose 120 mg tid
 To be taken 15-30 min before meals
 Skip doses for skipped meals
 Side effects: hypoglycemia and GI effects
Thiazolidinediones (TZDs)

 Decrease insulin resistance, promote skeletal

muscle glucose uptake
 Rosiglitazone (Avandia®)-taken with meals once or
twice daily. Max. dose 8 mg/day
 Pioglitazone (Actos®)-taken once daily. Max. dose 45
mg/day
 Monitor LFTs every 2 months for the first year of
therapy then periodically.
 Not recommended if LFTs >2.5 times upper limit or
for NYHA class III or IV CHF patients
 Side effects: Edema (secondary to plasma volume
expansion), GI effects, weight gain and back pain
Biguanides
 Decrease production of glucose in the liver, decrease
glucose absorption & improve insulin sensitivity
 Metformin (Glucophage®, Glucophage XR®, Fortamet®,
Riomet® (liquid metformin))- Max dose 2550 mg/day
 Used first line for obese diabetics
 May also be used for polycystic ovary syndrome (PCOS)
(Not FDA approved for that indication)
 Should be taken with food
 Contraindicated in symptomatic CHF patients and
renal patients (SCr >1.5 men, SCr>1.4 women)
 Must be discontinued for 48 hrs after any IV dye
procedure due to risk of lactic acidosis
 Side effects: Nausea, diarrhea and gas that tend to
improve with continued use
Alpha-Glucosidase Inhibitors

 Slow the digestion and absorption of carbohydrates

 Acarbose (Precose®), Miglitol (Glyset®)
 Good for lowering post-prandial glucose
 Contraindicated in patients with cirrhosis ,colon
ulcerations, DKA, inflammatory bowel disease and
patients with bowel obstruction
 Usual dose 25,50 or 100 mg tid
 To be taken with first bite of meal
 Side effects: gas, diarrhea and abdominal pain (tend
to improve with continued use)
DPP- IV inhibitors : Januvia (sitagliptin),
Onglyza (saxagliptin), Tradjenta (linagliptin)
A relatively new class of oral antidiabetic drugs known as
dipeptidyl peptidase-IV (DPP-IV) inhibitors
The DPP-IV enzyme normally rapidly inactivates the gut
hormone (GLP-1) so that additional insulin secretion is not
prolonged more than necessary.
Slow the inactivation of that gut hormone, therefore
increase insulin release and decrease glucose release by the
liver-prolong homeostasis
May be taken with or without food
Low sugar reactions are rare since they work in a glucose
dependent fashion
Invokana® (canagliflozin)

 Drug Class: Sodium Glucose Cotransporter 2

Inhibitor (SGLT-2 inhibitor)
 Works by blocking the body’s reuptake of filtered
glucose in the kidneys leading to an increased
amount of urinary excretion of glucose
 A typical starting dose of canagliflozin is 100mg
orally once a day taken before the first meal
More on Canagliflozin…

 Doses can be increased to a maximum daily dose of

300mg/day
 Most common side effects: increased urination, and
increased urinary tract infections/genital yeast
infections in females
 May cause increased thirst, constipation and nausea
 Report symptoms of low blood pressure to Physician
Bile Acid Sequestrants:
Welchol® (colesevelam)

Decreases blood sugar in Type II diabetics by an

unknown mechanism. Originally used for high LDL
cholesterol
Main side effect is constipation. May cause
increased triglycerides
May interfere with absorption of other medications
and must be separated from them by at least 1 hour
Cycloset® (Bromocriptine)

 The first drug for type 2 diabetics that targets the body’s dopamine
activity
 Mechanism of Action: Generally unknown , but preclinical studies
have shown brain dopamine activity to be low in metabolic disease
states which may contribute to insulin resistance
 Indication: Treatment of type 2 diabetes most likely in combination
with all other existing agent
 Dosage : Initial dose 0.8 mg (one tablet) taken within 2 hours of
waking with food. Dose titration weekly by 0.8 mg until clinical
effectiveness or a maximum dose of 4.8 mg is reached
 Contraindications: Patients with syncopal migraines, pregnant
and nursing women, use with other dopamine receptor agonists
and pediatric patients
Bile Acid Sequestrants:
Welchol® (colesevelam)

Decreases blood sugar in Type II diabetics by an

unknown mechanism. Originally used for high LDL
cholesterol
Main side effect is constipation. May cause increased
triglycerides
May interfere with absorption of other medications and
must be separated from them by at least 1 hour
Combination Products

 Glucovance® = Glyburide + Metformin

 Metaglip® = Metformin+ Glucotrol

 Avandamet® = Avandia + Metformin

 Actoplus Met® = Actos + Metformin

 Avandaryl® = Avandia+ Amaryl

 Duetact® = Actos + Amaryl

 Janumet® = Januvia+ Metformin

 Prandimet ® = Prandin + Metformin

 Kombiglyze ® = Onglyza + Metformin
 Juvisync ® = Januvia + Zocor
Symlin® (Pramlintide)

 Symlin (pramlintide) is an injectable synthetic analog of

human amylin, a hormone that is not present in diabetics.
 It slows gastric emptying, lessens after meals glucagon
secretion and suppress appetite
 May be given as a subcutaneous injection in Type I and
Type II diabetics as an add on therapy to meal time
insulin
 May cause Nausea/vomiting and add to risk of
hypoglycemia especially in type I diabetics
GLP-1 agonists: Byetta® (exenatide) ,
Victoza® (liraglutide) and Bydureon®
(exenatide LA)

Stimulate insulin secretion in a glucose-dependent

fashion
Slows the movement of food in the stomach (gastric
emptying).
Slows sugar (glucagon hormone) secretion during
hyperglycemia
May have some potential in stimulating regeneration of
the cells that make insulin (beta cells)
Over The counter Medications of
Concern with Diabetes

 Vitamins & Minerals

– Calcium 1000 - 1500 mg + Vitamin D daily
 Approximately 3 glasses of milk
– Multivitamin or additional supplements as needed to balance diet
 Decongestants (pseudoephedrine) - prolonged use can increase
blood pressure and decrease circulation

 Watch for sugar and alcohol content (especially in cough syrups)

 Many products are available sugar free and alcohol free-
Diabetic Tussin & Codimal DM
 Herbals and Nutraceuticals

 Consult doctor prior to use

 Check glucose before and after you take,
routinely for first few weeks, then periodically
 Use caution with all herbals, especially:
 Ginseng
 Ma Huang or Ephedra
 Glucosamine
 Ginger
 Nettle
 Garlic
Cholesterol Medications

 Total cholesterol goal is < 200, LDL<100, HDL for

men>45, for women>55 and triglycerides <150
 Have been shown to cut down on the incidence of
heart attacks and strokes in diabetics
 May delay the initiation of insulin in Type II diabetics
 Take at bedtime and avoid grapefruit and grapefruit
Juice
 Monitor liver function tests
 Side effects to tell the doctor about include: muscle
weakness, skin rash, nausea, vomiting, diarrhea and
loss of appetite
Cholesterol Medications (Cont.)

•Statins (Crestor, Zocor, Lipitor, etc.):

raise HDL; lower LDL
•Niacin: lowers LDL: increases HDL
•Bile Acid Resins (Questran, Welchol): lower
LDL
•Fibrates (Lopid, Tricor): lower
triglycerides; increase HDL
•Ezetimibe (Zetia): lowers LDL
Blood Pressure Medications

Blood pressure goal is 140/80 for diabetics (New 2013

goal ! (lower for some)
Blood pressure control has shown to decrease
cardiovascular disease, stroke, and kidney damage in
diabetics
Lifestyle changes may be adequate for some
Some diabetics are started on blood pressure medications
called ACE Inhibitors or Angiotensin Receptor Blockers
which offer kidney protection as well
There are many different classes of blood pressures
medications for your doctor to choose from
2012 ADA/EASD Guidelines for T2DM Management Algorithm
AACE/ACE Consensus Statement Endocrine Practice 2009; 15 (No. 6)
What to do when OADs fail to maintain
control in Type 2 diabetes

 Reemphasize that diet and exercise can

produce at most a 1% reduction from
baseline; maximum effect is at 3 months
 If on 2 first-line oral therapies, a third oral
agent will result in a further reduction of A1c
levels of only 1% or less
 Do not add a third oral agent if A1c> 9 %
since most patients will not reach target
level. It is time to consider insulin!
Insulin Fundamentals

Think about insulin therapy as

having three components:
1. Basal insulin : what you need when
not eating(between meals)
2. Prandial insulin: to cover food
3. Correction insulin: to fix abnormal
glucose levels
 Characteristics of Insulin

Rapid acting Insulin such as Novolog, Humalog or Apidra

Onset: 10-15 min Peak: 30-90 min Duration: 6-8 hrs

Fast acting Insulin such as Novolin R or Humulin R

Onset : 30 min Peak : 2-4 hrs Duration 8-12 hrs

Intermediate Acting Insulin such as Novolin N or Humulin N

Onset :1-2 hrs Peak: 4-12 hrs Duration 18-24 hrs

Basal (long acting Insulin) such as Lantus or Levemir

Onset: 1-2 hrs No Peak Duration: Up to 24 hrs

Mixed Insulin such as Humulin or Novolin 70/30, Novolog Mix 70/30,

Humalog 75/25, Humalog 50/50
Treatment of Hypoglycemia

Things to inform patients:

What is an insulin reaction (hypoglycemia) and how
is it treated??
 Blood glucose becomes too low (below 70 mg/dl for
most people)
 Signs - cold sweat, dizziness, fatigue, nausea,
hunger, vision changes, rapid heart rate
 Treatments - glucose tablets (3-4), glass of milk, juice
(1/2 cup), soft drink (1/2 can)
 Test your glucose again after 15 minutes, and repeat
treatment if still below 70 mg/dl
 Notify your physician!!
 Recommendations:
Medical Nutrition Therapy (MNT)

 Individuals who have prediabetes or diabetes should

receive individualized MNT as needed to achieve
treatment goals, preferably provided by a registered
dietitian familiar with the components of diabetes MNT
 In general,
– Carbs 45-65%of total daily calories
– Fats 25-35% of total daily calories (<7% saturated)
– Protein 12-20 % (kidney disease <10%)
 Lose weight if body mass index (BMI)>25

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S21.

 ADA Recommendations: Physical
Activity

 Advise people with diabetes to perform at least 150

min/week of moderate-intensity aerobic physical
activity (50–70% of maximum heart rate), spread
over at least 3 days per week with no more than 2
consecutive days without exercise
 In absence of contraindications, people with type 2
diabetes should be encouraged to perform
resistance training at least twice per week

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S25.

Why Exercise?
 Challenges!!

HEALTH CARE
LOGIC!!
Process and Assessment
Interventions
 Diabetes Complications…. and
Cardiac Rehab
 People with DM are 2-4 times more likely to have CV
disease, hypertension and dyslipidemia
 People with DM are susceptible to autonomic
neuropathy so may be less likely to have symptoms
during exercise (such as angina to reflect myocardial
ischemia)
 People with DM may have developed long-term
complications that may make rehab more challenging
such as peripheral vascular disease and significant
claudication
 Glucose Monitoring in
Cardiac Rehab

• No evidence-based guideline on a specific number of times

blood glucose should be measured in the CPR setting

• Glucose monitoring establishes patterns for glucose response and

potentially prevent hypoglycemia

• Glucose monitoring determines how often a individual should

tests BG based on his/her medications, co-morbid conditions,
medical history, meal plan, time of exercise, and history of
hyperglycemia and hypoglycemia

• Glucose monitoring assess patient’s knowledge and ability to

perform accurate blood glucose checks
Pre Exercise Hypoglycemia Care

Journal of Cardiopulmonary Rehabilitation and Prevention 2011;32:101-112

 Post Exercise Hypoglycemia Care

Journal of Cardiopulmonary Rehabilitation and Prevention 2011;32:101-112

Pre Exercise Hyperglycemia for
Patients with Type 1 Diabetes

Journal of Cardiopulmonary Rehabilitation and Prevention 2011;32:101-112

Pre Exercise Hyperglycemia for
Patients with Type 2 Diabetes

Journal of Cardiopulmonary Rehabilitation and Prevention 2011;32:101-112

Post Exercise Hyperglycemia Care

Journal of Cardiopulmonary Rehabilitation and Prevention 2011;32:101-112

In Summary…
 Regular exercise helps maintain appropriate BG levels
and is a primary indication in the management of DM
 The cardiopulmonary rehab setting represents an
excellent opportunity for health care providers to
monitor and manage DM
 Aerobic and strength training exercise may trigger
hypoglycemia in people with DM
 Collaboration between health care providers is key for
success!!
THANK YOU!

QUESTIONS???

Rhanania1@iuhealth.org