Pharmacotherapy of Diabetes: Part 2

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Diabetes Mellitus Part 2 Anas Bahnassi PhD CDM CDE 2 Week

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This is part two of the diabetes presentation aimed for pharmacists and allied health professional who are interested in tailoring special pharmaceutical care plans for diabetic patients.

Transcript of Pharmacotherapy of Diabetes: Part 2

Page 1: Pharmacotherapy of Diabetes: Part 2

Diabetes Mellitus Part 2

Anas Bahnassi PhD CDM CDE

2 Week

Page 2: Pharmacotherapy of Diabetes: Part 2

GLUCOSE ABSORPTION

α- glucosidase inhibitors

GLUCOSE PRODUCTION

Biguanides Thiazolidinediones

MUSCLE

PERIPHERAL GLUCOSE UPTAKE

Thiazolidinediones (Biguanides)

PANCREAS

INTESTINAL HORMONES

Incretin

ADIPOSE TISSUE LIVER

INTESTINE

Oral hypoglycemic agents sites of action

INSULIN Secretion

Sulfonylureas Meglitinides Insulin Amylin

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α-Glucosidase inhibitors

Drug Typical dosing Min and Max daily dose

Mean t1/2

Duration of Activity

Bioavailability , Metabolism, and

Excretion

Comments

Acarbose (Precose) 25, 50, 100 mg

25–100 mg with first bite of each meal. Begin with 25 mg; ↑ by 25 mg/meal every 4–8 weeks.

Minimum: 25 mg TID; Maximum dose is 50 mg TID if ≤60 kg; 100 mg TID if >60 kg.

2.8 hr Affects absorption of complex carbohydrates in a single meal

F = 0.5%–1.7%; extensively metabolized by GI amylases to inactive products; 50% excreted unchanged in the feces

Titrate doses slowly to avoid GI effects

Miglitol (Glyset) 25, 50, 100 mg

25–100 mg with first bite of each meal. Begin with 25 mg; ↑ by 25 mg/meal every 4–8 weeks.

Minimum: 25 mg TID Maximum: 100 mg TID

2 hr Affects absorption of complex carbohydrates in a single meal

Dose of 25 mg is completely absorbed; dose of 100 mg 50–70% absorbed; elimination by renal excretion as unchanged drug

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Biguanides

Drug Typical dosing Min and Max daily dose

Mean t1/2 Duration of Activity

Bioavailability , Metabolism, and

Excretion

Comments

Metformin (Glucophage) 500, 850, 1000 mg; 500 mg/mL liquid

Begin with 500 mg QD or /BID; ↑ by 500 mg QD every 1–2 weeks.

0.5–2.5 g BID or TID

Plasma, 6.2 hr Whole blood, 17.6 hr

6–12 hr F = 50%–60%; excreted unchanged in urine

Take with food. Avoid in patients with renal dysfunction or those who could be predisposed to lactic acidosis (e.g., alcoholism, CHF, severe respiratory disorders, liver failure)

Metformin extended-release (Glucophage XR) 500, 750, 1000 mg

500–1,000 mg/QD with evening meal; ↑ by 500 mg every 1–2 weeks.

1,500–2,000 mg QD

Active drug is released slowly

24 hr

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Nonsulfonylurea Insulin Secretagogues (Glinides)

Drug Typical dosing Min and Max daily dose

Mean t1/2

Duration of Activity

Bioavailability , Metabolism, and

Excretion

Comments

Repaglinide (Prandin) 0.5, 1, 2 mg

If HbA1c is <8% or if this is first drug, begin with 0.5 mg with each meal. For others, begin with 1–2 mg/meal.

0.5–4 mg with each meal (16 mg/day)/TID–QID

1 hr Cmax is at 1 hr; duration is approximately 2–3 hr

F = 56%; 92% metabolized to inactive products by the liver; 8% excreted as metabolites unchanged in the urine

Take only with meals. Skip dose if meal is skipped. Maximum dose per meal is 4 mg.

Nateglinide (Starlix) 60, 120 mg

120 mg TID 1–30 min before meals; 60 mg TID for patients with near-normal HbA1c at initiation.

60 or 120 mg TID

1.5 hr Onset, 20 min; peak, 1 hr; duration, 2–4 hr

F = 73%; metabolized to inactive products (predominantly) that are excreted in the urine (83%) and feces (10%)

Skip dose if meal is skipped.

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Thiazolidinediones

Drug Typical dosing Min and Max daily dose

Mean t1/2 Duration of Activity

Bioavailability , Metabolism, and

Excretion

Comments

Rosiglitazone (Avandia) 2, 4, 8 mg

4 mg QD; ↑ to 8 mg QD (or 4 mg BID)

4–8 mg daily in single or divided doses

3–4 hr Onset and duration poorly correlated with half-life because of mechanism of action. Onset at 3 weeks; max at ≥4 weeks. Offset likely to be similar

F = 99%; extensively metabolized in liver into inactive metabolites; excreted 2/3 in urine and 1/3 in feces

Food has no effect on absorption. BID dosing may have greater HbA1c lowering effect. No dose adjustments required in renal failure. Avoid in patients with liver disease and heart failure.

Pioglitazone (Actos) 15, 30, 45 mg

15–30 mg QD; ↑ to 45 mg QD. If used with insulin, ↓ insulin dose by 10%–25% once FPG <120 mg/dL.

15–45 mg QD

3–7 hr (16–24 hr for all metabolites)

Extensively metabolized in liver; 15%–30% excreted in urine, remainder eliminated in the feces

Food delays absorption but is not clinically significant. No dose adjustments required in renal disease. Avoid in patients with liver disease and heart failure.

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Nonsulfonylurea Insulin Secretagogues (Glinides)

Drug Typical dosing Min and Max daily dose

Mean t1/2

Duration of Activity

Bioavailability , Metabolism, and

Excretion

Comments

Repaglinide (Prandin) 0.5, 1, 2 mg

If HbA1c is <8% or if this is first drug, begin with 0.5 mg with each meal. For others, begin with 1–2 mg/meal.

0.5–4 mg with each meal (16 mg/day)/TID–QID

1 hr Cmax is at 1 hr; duration is approximately 2–3 hr

F = 56%; 92% metabolized to inactive products by the liver; 8% excreted as metabolites unchanged in the urine

Take only with meals. Skip dose if meal is skipped. Maximum dose per meal is 4 mg.

Nateglinide (Starlix) 60, 120 mg

120 mg TID 1–30 min before meals; 60 mg TID for patients with near-normal HbA1c at initiation.

60 or 120 mg TID

1.5 hr Onset, 20 min; peak, 1 hr; duration, 2–4 hr

F = 73%; metabolized to inactive products (predominantly) that are excreted in the urine (83%) and feces (10%)

Skip dose if meal is skipped.

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Second generation sulfonylurea

Drug Typical dosing Min and Max daily dose

Mean t1/2

Duration of Activity

Bioavailability , Metabolism, and

Excretion

Comments

Glimepiride (Amaryl) 1, 2, 4 mg

1–2 mg/QD initially; usual maintenance dose is 1–4 mg.

1–8 mg QD 9 hr 24 hr F = 100% completely metabolized by liver. Principal metabolite is slightly active (30% of parent compound). Excreted by the urine (60%) and feces (40%)

Probably safe in patients with renal failure, but low initial doses recommended for older patients and those with renal insufficiency. Incidence of hypoglycemia may be lower than other long-acting sulfonylureas

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Second generation sulfonylurea

Drug Typical dosing Min and Max daily dose

Mean t1/2

Duration of Activity

Bioavailability , Metabolism, and

Excretion

Comments

Glipizide (Glucotrol) 5, 10 mg

2.5 mg/QD in elderly, 5 mg QD in others; ↑ by 2.5 or 5 mg every 1–2 weeks.

2.5–40 mg QD or BIDa

2–4 hr 12–24 hr Metabolized to inactive compounds

No special precautions daily dose >15 mg should be divided. Dose 30 min before meals

Glipizide extended–release (Glucotrol XL) 5 mg

5 mg/QD; ↑ by 5 mg every 1–2 weeks.

5–20 mg QD 4–13 hr 24 hr Use with caution in patients with preexisting GI narrowing owing to possible obstruction

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Second generation sulfonylurea

Drug Typical dosing Min and Max daily dose

Mean t1/2

Duration of Activity

Bioavailability , Metabolism, and

Excretion

Comments

Glyburide (Diabeta, Micronase) 1.25, 2.5, 5 mg

1.25 mg/QD in elderly, 2.5 mg QD in others; ↑ by 1.25 or 2.5 mg every 1–2 weeks.

1.25–20 mg QD or BID

4–13 hr 12–24 hr Metabolized to inactive/weakly inactive compounds; 50% excreted in urine and 50% in feces

Caution in elderly patients with renal failure and others predisposed to hypoglycemia. Daily doses >10 mg should be divided

Micronized Glyburide (Glynase presTab) 1.5, 3 mg

1.5 mg/QD; ↑ by 1.5 mg every 1–2 weeks.

1.0–12 mg QD 4 hr 24 hr Metabolized to inactive/weakly inactive compounds; 50% excreted in urine and 50% in feces

Daily doses >6 mg should be divided. ↑ bioavailability relative to original formulation. Resulted in reduced dose

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Incretin based therapy

Drug Typical dosing Min and Max daily

dose

Mean t1/2

Duration of Activity

Bioavailability , Metabolism, and

Excretion

Comments

GLP-1 receptor agonists/incretin mimetics

Exenatide (Byetta)

5 mcg SC BID; ↑ to 10 mcg SC BID after 1 month

5–10 mcg BID

2.4 hr Cmax is at 2.1 hr;

duration 10 hr

Glomerular filtration

Take within 60 min before morning and evening meal. Nausea usually subsides over time

DPP-4 Inhibitors

Sitagliptin (Januvia)

100 mg QD CrCl ≥30 to <50 mL/min: 50 mg QD CrCl <30 mL/min: 25 mg QD

100 mg QD

12.4 hr 24 hr F = 87%; ~79% excreted unchanged in urine.

Requires dose adjustment in renal insufficiency.

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Second generation sulfonylurea

Drug Typical dosing Min and Max daily dose

Mean t1/2

Duration of Activity

Bioavailability , Metabolism, and

Excretion

Comments

Pramlintide (Symlin)

Type 1 DM: 15 mcg SC before major meals; ↑by 15-mcg increments after minimum of 3 days Type 2 DM: 60 mcg SC before major meals; ↑ to 120 mcg after 3–7 days

Type 1: 15–60 mcg before major meals Type 2: 60 or 120 mcg before major meals

48 min Cmax is 20 minutes

F = 30%–40%; metabolized by kidneys

Reduce mealtime insulin dose by 50%. Titrate dose if no significant nausea.

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Potential combinations of antihyperglycemic agents

Eat healthy, Weight Control, Increase Physical Activity

Metformin Proceed to 2-drug combination if A1c goals are not reached

Metformin +

Sulfonylurea Thiazolidinedione DDP-4 Inhibitors GLP-1 receptor agonist Basal insulin

(SU) (TZD) (DPP-4-I) (GLP-1-RA)

Metformin +

Sulfonylurea Thiazolidinedione DDP-4 Inhibitors GLP-1 receptor agonist Basal insulin (SU) (TZD) (DPP-4-I) (GLP-1-RA)

+TZD +SU +SU +SU +TZD or DPP-4-I or DPP-4-I or TZD or TZD or DPP-4-I or GLP-1-RA or GLP-1-RA or insulin or insulin or GLP-1-RA

Consider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas

Consider beginning at this stage in patients wih very high A1C (eg, ≥9%).

Certain noninsulin agents may be continued with insulin

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A case approach to type-2 diabetes

L.H. is a 45-year-old, moderately overweight, Mexican-American (height, 5 feet 5 inches; weight, 160 lbs; BMI 26.6 kg/m2). She was treated for recurrent monilial infections, when noted glucosuria on routine urinalysis. On 2 separate occasions: her FPG was 150 mg/dL and 167 mg/dL. L.H. denies any symptoms of polyphagia or polyuria, although lately she has been more thirsty than usual. She does complain of lethargy and often takes afternoon naps.

Other medical problems include HTN, which is well controlled on lisinopril 20 mg/day, and recurrent monilial infections, which are treated with fluconazole. She has given birth to four children (birth weights, 7, 8.5, 10, and 11 lb) and was told during her last pregnancy that she had “borderline diabetes.”

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A case approach to type-2 diabetes

She currently works as a loan officer in a local bank and spends her weekends “catching up on her sleep” and reading. L.H. has been smoking one pack of cigarettes per day for 20 years and drinks an occasional glass of wine

She drinks at least two regular sodas daily and has “large” glass of orange juice every morning. Her family history is significant for a sister, aunt, and grandmother with type 2 diabetes; all have “weight problems.”

Laboratory assessment reveals an FPG of 147 mg/dL (normal, 70–100); fasting plasma triglycerides of 400 mg/dL (normal, <150 mg/dL); and an HbA1c of 9.2% (normal, 4%–6%). All other values (including the complete blood count, electrolytes, LFTs, and renal function tests) are within normal limits. L.H. is given the diagnosis of type 2 diabetes.

L.H.'s mother is alive and well at age 77; her father died of a heart attack at age 47.

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What features in L.H.'s history and physical examination are consistent with this diagnosis?

FPG concentration of 126 mg/dL or higher on more than one occasion An elevated HbA1c, High BMI with central obesity Age greater than 40 Family history of diabetes Mexican American descent. Delivering large babies, (undiagnosed gestational diabetes)

Mild signs and symptoms of hyperglycemia (including increased thirst and lethargy), recurrent monilial infections, hypertriglyceridemia, and indications of CVD (hypertension) also are typical in patients with type 2 diabetes

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What should the goals of therapy be for L.H. ? Which biochemical indices should be monitored?

Eliminating acute symptoms of hyperglycemia Avoiding hypoglycemia Reducing cardiovascular risk factors Preventing or slowing the progression of both microvascular and macrovascular diabetic complications.

Biochemical indices that should be followed to monitor L.H.'s response to therapy include fasting, postprandial, and preprandial blood glucose concentrations, HbA1c values, fasting triglyceride levels, as well as LDL and HDL cholesterol concentrations. Initial metabolic goals for L.H. should be an HbA1c value of <7%, an FPG of <130 mg/dL, postprandial glucose concentrations below 180 mg/dL, LDL-cholesterol below 100 mg/dL, and triglycerides below 150 mg/dL.

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How should L.H. be managed initially?

Lifestyle changes that will minimize insulin resistance and risk for CVD. Overweight (BMI 25.0–29.9) or obese (BMI ≥30.0) type 2 individuals need to be on lower calorie, low-fat, low-cholesterol diet. Regular exercise Smoking cessation Aggressive management of dyslipidemia and hypertension.

When signs and symptoms are mild, diet and exercise alone can correct glucose intolerance. SMBG monitoring and patient education.

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Diabetes type-2 initial treatment

Lifestyle + Metformin

Basal insulin SU, TZD

Further adjustments and more drugs

Metformin is favored as a first-choice agent for overweight, type 2 diabetics as long as there are no contraindications to its use.

This is because metformin lowers blood glucose by decreasing hepatic glucose output and insulin resistance (indirectly) without causing weight gain or hypoglycemia. Metformin also has beneficial effects on plasma lipid concentrations as well.

A drawback to metformin is that it requires multiple daily dosing and its dose also must be titrated to minimize GI effects. After the dose is established, it is possible to use a long-acting product that can be dosed once daily.

Renal function tests should be evaluated before the drug is initiated.

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L.H. is started on metformin 500 mg BID with food and instructed to increase her dosage to 500 mg Q AM and 1,000 mg Q PM after 1 week. Three days after starting metformin, she phones the clinic complaining of nausea and diarrhea. She admits to taking her doses on an empty stomach. How should L.H.'s symptoms be addressed? GI disturbances such as diarrhea, bloating, anorexia, abdominal discomfort, nausea, and metallic taste often dissipate with time and can be minimized by initiating metformin in a single, 500- or 850-mg dose at breakfast or with the patient's largest meal of the day. Consistently taking metformin with food significantly minimizes the GI side effects. The dosage should be slowly increased (e.g., 500 mg/day every 2 weeks) until the appropriate clinical effect is achieved or the patient is taking the maximum dose (1,000 mg twice daily or 850 mg three times a day).

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How should metformin therapy be monitored in L.H.?

L.H. should be encouraged to perform SMBG. Have an HbA1c test performed quarterly until goals achieved. Additional evidence may include an improved lipid profile and some weight loss. Initially, it is important to follow GI problems

L.H. should be warned to bring to the attention of her physician any sudden symptoms of shortness of breath, weakness, and malaise (Lactic Acidosis). A baseline SrCr, LFTs, and complete blood count should be obtained . Lifestyle changes that will minimize insulin resistance and risk for CVD.

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What are the advantages and disadvantages of SMBG tests? When and how often should L.H. be instructed to test her blood glucose concentrations?

We often recommend SMBG for motivated type 2 patients who are learning to adjust their carbohydrate intake and portion sizes and want to measure how well medications and lifestyle changes are working to improve their glucose control.

Initially, we may suggest testing four times daily before meals and at bedtime for 1 week so that the patient can observe his or her glucose profiles. Later, once the desired HbA1c has been achieved, we recommend a minimum of testing blood glucose twice daily, but at various times to evaluate fasting glucose concentrations

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Treatment algorithm for type-2 diabetes

Lifestyle modifications + Metformin

Diagnosis

HbA1c≥7

No

Yes

Add glitazone No hypoglycemia

Add sulfonylurea Least expensive

Add basal insulin Most effective

HbA1c≥7 HbA1c≥7 HbA1c≥7

Intensify insulin

Add glitazone

Add Insulin Add

Sulfonylurea

yes yes yes yes

Intensive insulin + metformin ± glitazone

HbA1c≥7

yes

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Treating diabetes under special circumstances

Circumstance Avoid Consider

Patients with decreased renal function

Acarbose Long-acting SFUs (e.g., glyburide) Metformin

Glipizide Glimepiride Insulin Glinides (Repaglinide/ nateglinide) Sitagliptin Thiazolidinediones

Patients with impaired liver function

Acarbose Metformin Thiazolidinediones ? SFUs (severe liver dysfunction)

Insulin Repaglinide Exenatide Sitagliptin Miglitol

Patients who are obese or gaining excessive weight

Insulin Sulfonylureas Repaglinide ? Thiazolidinediones

Acarbose Miglitol Metformin

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Treating diabetes under special circumstances

Circumstance Avoid Consider

Patients with preexisting edema

Thiazolidinediones SFUs Glinides Exenatide Sitagliptin

Patients with heart failure Thiazolidinediones Metformin

SFUs Glinides Exenatide Sitagliptin Insulin

Patients experiencing hypoglycemia due to irregular eating patterns

Insulin Long-acting SFUs

Acarbose Metformin Repaglinide/nateglinide Thiazolidinediones Exenatide Sitaglipin

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Pharmacottherapy Anas Bahnassi PhD CDM CDE

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