Diabetes Management: Lifestyle And Oral Agents

Front 1

Goals of Medical nutrition therapy: 4

Back 1

*Achieve and maintain
1) Blood glucose as normal as safely possible
2) Lipid profile that reduces vascular risk
3) Blood pressure as normal as safely possible (<130)

4) Prevent or slow the development of diabetes complications (retinopathy, neuropathy, nephropathy)

*Individualizing therapy--each pt is unique

Front 2

MNT Recommendations: Carbohydrates--

Back 2

*Generally 45-65% of diet

*Prefer carbs from fruits, vegetables, whole grains, legumes, low-fat milk

*Monitor carbs
-Carbohydrate counting
-Exchanges (1ex = 15g CHO)
-Experience-based estimation
-Glycemic index?

Front 3

MNT Recommendations: Fat and cholesterol--

Back 3

*Total dietary fat < 30%

*Limit saturated fat to <7% of total calories
Also minimize trans fats

*Limit dietary cholesterol < 200 mg/d

Front 4

MNT Recommendations: Protein--

Back 4

*Generally 15-20% of energy requirements

*“Good-quality” sources (provide all 9 essential amino acids): milk, cheese, soy, MEAT.

Front 5

Exercise: Benefits: 4

Back 5

*Improve blood glucose control
-Exercise increases movement of GLUT4 to cell surface in skeletal muscle
-Exercise improves insulin sensitivity (mechanisms still being defined)

*Reduce cardiovascular risk

*Contribute to weight loss

*Improve well-being

Front 6

Exercise recs for DM patients:

Back 6

*At least 150 minutes/week of moderate intensity aerobic physical activity (50-70% of maximum heart rate)

[MHR= 220 - age]

*Resistance training 3x/week

Front 7

Weight loss recs:

Back 7

*Modest (5-10%) weight loss reduces insulin resistance in overweight/obese individuals

*The key is CALORIE-RESTRICTION, not nutritional content

*The best “diet” is one that a patient can maintain longterm!

*Physical activity is an important component in maintenance of weight loss

Front 8

Pathophysiology of Type 2 DM: 3

Back 8

1) Insulin resistance

2) Defective insulin secretion

3) Other issues: Defective glucagon regulation

Front 9

UKPDS (study): Progressive Deterioration in b-Cell Function Over Time--

Back 9

50% loss of ß cells at diagnosis of DM2.

Front 10

Insulin Secretory Pathway in the Pancreatic b-Cell:

Back 10

*Sulfonylurea receptor is near Katp channel; causes release of insulin.

Front 11

Sulfonylureas: 3 TO REALLY KNOW

Back 11

INSULIN SECRETAGOGUES!
*“First-generation”
-Tolbutamide
-Chlorpropamide
-Tolazamide
-Acetohexamide

*“Second-generation”
-Glyburide**
-Glipizide**
-Glimepiride**
-More potent
-Fewer side effects
-Fewer drug interactions

**=most important ones

Front 12

Side effects of sulfonylureas: 2

Back 12

Hypoglycemia
Weight gain

Of the 2nd-generation SUs, GLYBURIDE causes the most hypoglycemia

Front 13

Short-acting insulin secretagogues: diagram--

Back 13

*Netaglinide binds to the same site as sulfonylureas
*Repaglinide binds a different site

Front 14

Describe short-acting insulin secretagogues:
"best" one?
what's a main drawback to these?

Back 14

*Shorter duration of action
-Take 3x/day with meals

*Major action is to lower postmeal glucose excursions
-REPAGLINIDE also lowers fasting glucose
-REPAGLINIDE lowers A1c more than nateglinide

*Hypoglycemia and weight gain
-Less than sulfonylureas

*Significantly more expensive than sulfonylureas

Front 15

Biguanides structure:

Back 15

METFORMIN FREAK!!!!

Front 16

How does metformin work? 2

Back 16

1) Metformin works primarily by increasing insulin sensitivity in the liver
2) Decrease hepatic gluconeogenesis

Front 17

Treatment With Metformin in Type 2 Diabetes-- plasma glucose levels throughout the day--

Back 17

*MAIN ACTION IS TO INCREASE INSULIN SENSITIVITY AND DECREASE LIVER GLUCONEOGENESIS IN LIVER

Front 18

Metformin side effects:

Back 18

*Gastrointestinal distress
-Minimized by slow titration of dose and administration with food

*Some interference with vitamin B12 absorption, usually not clinically meaningful

*Does NOT cause weight gain
*Does NOT cause hypoglycemia (used alone)

Front 19

Metformin's serious complication:

Back 19

*Lactic Acidosis!!!

*Serious metabolic complication due to metformin ACCUMULATION

*Incidence of 0.03 cases per 1,000 patient-years but fatal in ~50% of cases

*Risk RISES with increasing RENAL dysfunction and advancing AGE.

Front 20

Metformin Prescribing Considerations: when should you not Rx it? 7

Back 20

*Metformin should be avoided in
-renal dysfunction (what degree??)

-Uncompensated CHF

-Use of iodinated contrast materials for radiologic studies (“hold” for 48 hours)

-acute or chronic metabolic acidosis, INCLUDING DKA (but that occurs in DM1 only, and DM1 patients SHOULD NOT be Rxd Metformin, so this should be a non-issue)

-Significant hepatic dysfunction

-Alcohol abuse (etoh damage to liver)

-Acute serious illness

Front 21

UKPDS: Effects of Intensive (Metformin) Treatment:

Back 21

*Intensive = Metformin + a SU or insulin
*Bottom line--Metformin works

Front 22

Metformin: other uses--

Back 22

*Improves ovulatory function in women with polycystic ovary syndrome

*Decreases risk of progression to diabetes in patients with prediabetes (used off-label for this purpose)

Front 23

Structures of Thiazolidinedione Agents:

Back 23

*Pioglitazone still used.

Front 24

TZDs/Glitazones:

Back 24

*Improve insulin sensitivity in adipose tissue and skeletal muscle

-Concentration of PPARγ is high in adipose tissue but low in skeletal muscle

-TZD’s interact with PPARγ in the cell nucleus (intranuclear), and certain genes are expressed

-Decreased insulin resistance

Front 25

Back 25

*TZD action

Front 26

TZD side effects:

Back 26

*Fluid retention/edema
*Weight gain

*Congestive heart failure
Especially in combination with insulin

*Increased risk of heart attack (rosiglitazone)
*Increased risk of fractures
*Increased risk of bladder cancer?

*Hepatotoxicity (troglitazone)

*Expensive

*No hypoglycemia (when used alone)

Front 27

TZDs: Other uses--

Back 27

*Used in PCOS
-Less frequently than Metformin

*Used in DM prevention in high risk patients
-Less frequently than Metformin

*Role in treatment of Nonalcoholic Steatohepatitis?

Front 28

Alpha-glucosidase inhibitors:

Back 28

*Competitively inhibit (1) alpha-glucosidase enzymes in brush border of small intestine; and (2) pancreatic alpha-amylase

*Delay the breakdown of oligosaccharides to monosaccharides

*Take 3x/daily with meals

*Delayed glucose absorption results in lower postprandial hyperglycemia

Front 29

Alpha-glucosidase inhibitors: Side effects--

Back 29

*GI side effects
-Undigested carbohydrate that enters large intestine is metabolized by bacteria to short-chain fatty acids, hydrogen, carbon dioxide and methane
-FLATULENCE is very common

*No weight gain

*No hypoglycemia (when used alone)

Front 30

Antihyperglycemic Agents: Major Sites of Action (the story as of 2006)--

Back 30

*Know sites of action

Front 31

The Incretin Effect in Healthy Subjects:

Back 31

ORAL intake promotes higher release of insulin than IV glucose= incretin effect

Front 32

The Incretin Effect in Subjects Without and With Type 2 Diabetes:

Back 32

*Incretin effect is blunted in DM2 as compared to DM1

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Front 34

Back 34

Both insulin secretion and glucagon suppression are impaired in type 2 diabetes after a meal--GLP 1

Front 35

Effects of GLP-1:

Back 35

*This is an Incretin--helps cause incretin effect.

Front 36

Decreased Postprandial Levels of the Incretin Hormone GLP-1 in Patients With Type 2 Diabetes:

Back 36

dark line= pre-diabetic pt

Front 37

Role of Incretins in Glucose Homeostasis:

Back 37

DPP-IV breaks down GLP-I

Front 38

Mechanism of Action of DPP-IV Inhibitors:

Back 38

Front 39

DPP-4 inhibitors (SitaGLIPtin, SaxaGLIPtin, LinaGLIPtin):

Back 39

*No hypoglycemia when used alone

*No weight gain

*May need dose adjustment if taking drugs that inhibit CYP3A4/5 or if renal dysfunction

*More nasopharyngitis and URIs in clinical trials

*Hypersensitivity reactions?

*Pancreatitis?

*More expensive

*New drug, so long term side effects UNKNOWN

Front 40

Colesevelam:

Back 40

*Bile-acid-binding resin

*Used as LDL-lowering therapy

*Mechanism by which it lowers blood sugar is under investigation

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Back 41

NORMAL

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Back 42

Colesevelam ACTION TO LOWER LDL.

Front 43

Colesevelam: Side effects--

Back 43

*GI side effects (esp. constipation)

*Worsen hypertriglyceridemia

*Reduce absorption of fat-soluble vitamins

*Reduce absorption of drugs (inc. levothyroxine and OCPs)

Front 44

Bromocriptine:

Back 44

*Quick-release formulation

*Pulse of DA agonist to brain centers regulating peripheral fuel metabolism

*Reduce postprandial glucose without increasing insulin

Front 45

Bromocriptine: Cautions--

Back 45

*Typical side effects: nausea, dizziness (orthostasis), somnolence

*Potential to exacerbate psychosis

*Other concerns
-Highly bound to serum proteins
-CYP3A4-metabolized

Front 46

Oral Agents 20 years ago--

Back 46

Sulfonylureas
Biguanides

Front 47

Oral Agents available now:

Back 47

*Sulfonylureas
*Metformin
*Thiazolidinediones
*Short-acting insulin secretagogues
*DPP4 inhibitors
*Alpha-Glucosidase inhibitors
*Colesevelam
*Bromocriptine

Front 48

Sites of Action of:
SUs
short acting insulin secretagogues
a-glucosidase inhibitors
biguanides
TZDs
bromocriptine
Colesevelam
DPP4 inhibitors

Back 48

SUs: ß cells--have own receptor, near Katp channel

Short acting insulin secretagogues: ß cells--bind same site as SUs, except Repaglinide, which has its own binding site.

a-glucosidase inhibitors: alpha-glucosidase enzymes in brush border of small intestine; and pancreatic alpha-amylase

Biguanides: Liver

TZDs: PPARγ in adipose tissue and skeletal muscle

bromocriptine: BRAIN

Colesevelam: Intestines--bile acid binding

DPP4 inhibitors: Intestines