Clinical Pharmacy

Endocrinology
Learning Objectives
• After the end of this lecture the students will be able to:
• Discuss therapeutic goals for blood glucose for a patient with
diabetes.
• Recommend non pharmacologic therapies, including meal
planning and physical activity, for diabetic patients .
• Compare oral agents used in treating diabetes by their mechanisms
of action, time of action, side effects, contraindications and
effectiveness.
DM treatment goals
• DM treatment goals include:
1. Reducing, controlling and managing long-term microvascular,
macrovascular and neuropathic complications.
2. Preserving β-cell function.
3. Preventing acute complications from high blood glucose
levels.
4. Minimizing hypoglycemic episodes.
5. Maintaining the patient’s overall quality of life.
DM treatment goals
• DM treatment goals include:
6. Glycemic therapy goals
• a. A1C less than 7.0% (AACE < 6.5%)
• Obtain every 6 months in patients at goal A1C and every 3
months in those over goal.
• b. FPG or premeal 70–125 mg/dL.
• Frequency of monitoring depends on regimen, type of DM, and
current glycemic control.
• c. Peak postprandial glucose (1–2 hours after a meal) less
than 180 mg/dL
General Approach to Therapy
• Type 1 Diabetes Mellitus
• Treatment of T1DM requires providing exogenous
insulin to replace the endogenous loss of insulin from the
nonfunctional pancreas.
• Ideally, insulin therapy mimics normal insulin physiology.
• The basal-bolus approach attempts to reproduce basal
insulin response using intermediate- or long-acting insulin,
whereas short- or rapid-acting insulin replicates bolus
release of insulin physiologically seen around a meal in
nondiabetics.
General Approach to Therapy
• As a rule, basal insulin makes up approximately 50% of the
total daily dose. The remaining half is provided with bolus
doses around three daily meals.
• Exact doses are individualized to the patient and the amount
of food consumed. T1DM patients frequently are started on
about 0.6 unit/kg/day, and then doses are titrated until
glycemic goals are reached.
• Most people with T1DM use between 0.6 and 1 unit/kg/day.
General Approach to Therapy
• Type 2 Diabetes Mellitus
• A number of new drugs and recommendations are available
to maintain tighter glycemic control.
• However, lifestyle modifications including education,
nutrition and exercise are paramount to managing the
disease successfully.
General Approach to Therapy
• Gestational Diabetes
• An individualized meal plan consisting of three meals and
three snacks per day is commonly recommended in GDM.
• The desired goals in these patients:
• Preventing ketosis.
• Promoting adequate growth of the fetus.
• Maintaining satisfactory blood glucose levels.
• Preventing nausea and other undesired GI side effects.
General Approach to Therapy
• Gestational Diabetes
• An abundance of glucose causes excessive insulin production by the
fetus, which if left uncontrolled, can lead to the development of an
abnormally large fetus.
• Infant hypoglycemia at delivery, hyperbilirubinemia and
complications associated with delivery of a large baby also may occur
when blood glucose levels are not controlled adequately.
• Insulin should be used when blood glucose levels are not maintained
adequately by diet and physical activity.
• Insulin detemir, insulin aspart, lispro and regular insulin carry
Category B safety ratings.
Non-pharmacologic Therapy
Nonpharmacologic Therapy
• Medical Nutrition Therapy
• MNT is considered an integral component of diabetes
management and diabetes self-management education.
• People with DM should receive individualized MNT,
preferably by a registered dietitian.
• MNT should be provided as an ongoing dialog customized to
take into account cultural, lifestyle and financial
considerations.
Nonpharmacologic Therapy
• The primary focus of MNT for patients with T1DM is matching
optimal insulin dosing to carbohydrate consumption.
• In T2DM, the primary focus is individualizing limits of
carbohydrates, saturated fats, sodium and calories.
• Carbohydrates are the primary contributor to post meal glucose
levels.
• The percentages of fat, protein and carbohydrate included in each
meal should be individualized based on the specific goals of each
patient
Nonpharmacologic Therapy
• Weight Management
• Moderate weight loss in patients with T2DM has been shown to
reduce cardiovascular risk, as well as delay or prevent the onset of DM
in those with prediabetes.
• The recommended primary approach to weight loss is therapeutic
lifestyle change (TLC), which integrates a 7% reduction in body
weight and an increase in physical activity.
• A slow but progressive weight loss of 0.45 to 0.91 kg (1–2 lb) per
week is preferred.
Nonpharmacologic Therapy
• Physical Activity
• Regular physical activity has been shown to improve blood glucose
control and reduce cardiovascular risk factors such as hypertension
and elevated serum lipid levels.
• Physical activity is also a primary factor associated with long-term
maintenance of weight loss and overall weight control. Regular
physical activity also may prevent the onset of T2DM in high-risk
persons.
Nonpharmacologic Therapy
• Before initiating a physical activity program, patients should undergo
a detailed physical examination, including screening for microvascular
or macrovascular complications that may be worsened by a particular
activity.
• Walking, swimming and cycling are examples of low-impact
exercises that could be encouraged.
• Recommended physical activity goals for patients with T2DM include
150 minutes per week.
Oral Diabetes Agents in Type 2 DM
Metformin (biguanide)
• a. Mechanism of action: Reduces hepatic gluconeogenesis. Also
favorably affects insulin sensitivity and, to a lesser extent, intestinal
absorption of glucose
• b. Dosing
• i. Initial: 500 mg once or twice daily (once daily with extended-release
formulation)
• ii. Maximal daily dose: 2000 mg/day.
• iii. Can increase at weekly intervals as necessary
• iv. Small initial dosage and slow titration secondary to GI disturbances
Metformin (biguanide)
• c. Adverse effects
• i. Common: Nausea, vomiting, diarrhea, epigastric pain
• ii. Less common: Decrease in vitamin B12 levels, lactic acidosis
(rare)
• Signs or symptoms of lactic acidosis include acidosis, nausea,
vomiting, increased respiratory rate, abdominal pain, shock and
tachycardia.
Metformin (biguanide)
• d. Contraindications/precautions:
• i. Renal impairment (contraindicated because of increased
risk of lactic acidosis):
• Serum creatinine 1.5 mg/dL or greater in men and 1.4 mg/dL or
greater in women or reduced creatinine clearance (CrCl)
• Would discontinue or not initiate if CrCl less than 30 mL/minute.
Metformin (biguanide)
• ii. Age 80 years or older (use caution and carefully assess renal
function)
• iii. High risk of cardiovascular event or hypoxic state
• iv. Hepatic impairment
• v. Congestive heart failure (especially if prone to exacerbations)
• vi. Interrupt therapy if undergoing procedures using iodinated contrast
dye because of risk of nephrotoxicity. Reinitiate after 48 hours and
after normal serum creatinine concentrations are achieved.
Metformin (biguanide)
• e. Efficacy
• i. 1%–2% A1C reduction
• ii. Some benefit in TG reduction and weight loss
• iii. Considered first-line therapy unless contraindicated.
2. Sulfonylureas
• a. Mechanism of action:
• Bind to receptors on pancreatic beta-cells, leading to membrane
depolarization, with subsequent stimulation of insulin secretion
(insulin secretagogue)
• b. First-generation agents seldom used today (e.g., chlorpropamide,
tolbutamide)
• c. Second-generation agents (e.g., glyburide, glipizide, glimepiride).
• Dose titration: Can increase at weekly intervals as necessary
2. Sulfonylureas
• d. Adverse effects
• i. Common: Hypoglycemia, weight gain
• ii. Less common: Rash, headache, nausea, vomiting, photosensitivity
• e. Contraindications/precautions
• i. Hypersensitivity to sulfonamides
• ii. Patients with hypoglycemic unawareness
• iii. Poor renal function (glipizide may be a better option than glyburide
or glimepiride in elderly patients or in those with renal impairment
because drug or active metabolites are not renally eliminated)
2. Sulfonylureas
• f. Efficacy
• i. 1%–2% A1C reduction
• ii. Note: For this and all medications used to treat hyperglycemia,
the absolute decrease in A1C is larger for higher baseline A1C
values and smaller for lower A1C values.
2. Sulfonylureas
3. Meglitinides
• a. Mechanism of action:
• Very similar to that of sulfonylureas in increasing insulin secretion
from the pancreas but with a more rapid onset and shorter
duration of activity
• b. Glucose-dependent activity
• c. Two currently available: Repaglinide and Nateglinide
3. Meglitinides
• d. Dosing
• i. Repaglinide
• (a) Initial: 0.5–1 mg 15 minutes before meals
• (b) Maximal daily dose: 16 mg
• (c) Can be increased in weekly intervals if needed.
• ii. Nateglinide
• (a) 120 mg before meals
• (b) 60 mg if A1C near goal
3. Meglitinides
• e. Adverse effects:
• Hypoglycemia (though less than with sulfonylureas), weight gain, upper
respiratory infection
• f. Contraindications/precautions
• i. Hypersensitivity
• ii. Caution in concomitant use of repaglinide and gemfibrozil: Can lead
to greatly increased repaglinide levels
• g. Efficacy
• i. 0.5%–1.5% A1C reduction (repaglinide reduces A1C more than nateglinide)
• ii. Most effective on postprandial glucose excursions
4. Thiazolidinediones (TZDs or glitazones)
• a. Mechanism of action
• i. Peroxisome proliferator-activated receptor γ-agonist
• ii. Increases expression of genes responsible for glucose
metabolism, resulting in improved insulin sensitivity
4. Thiazolidinediones (TZDs or glitazones)
• b. Two agents available: Pioglitazone and rosiglitazone
• i. In September 2010, the FDA initiated restricted access to
rosiglitazone secondary to continued concerns about its
cardiovascular safety. Rosiglitazone was restricted to patients unable
to attain glycemic control with other agents and when pioglitazone is
not used for medical reasons.
• ii. In November 2013, the FDA removed some prescribing and
dispensing restrictions for rosiglitazone after evaluating clinical trial
data. The impact of this change and the availability of the agent is
unknown.
4. Thiazolidinediones (TZDs or glitazones)
• c. Dosing
• i. Pioglitazone
• (a) Initial: 15 mg once daily
• (b) Maximal daily dose: 45 mg
• ii. Dose titration is slow, and the maximal effect of a dose change may
not be observed for 8–12 weeks.
4. Thiazolidinediones (TZDs or glitazones)
• d. Adverse effects
• i. Weight gain
• ii. Fluid retention (particularly peripheral edema), worse with insulin
use. Edema less responsive to diuretic therapy.
• iii. Risk of proximal bone fractures; use caution in patients with
existing osteoporosis
4. Thiazolidinediones (TZDs or glitazones)
• iv. Small risk of bladder cancer with pioglitazone
• v. Increased risk of heart failure (Boxed warning).
• vi. Both agents have been withdrawn from some countries in
Europe.
4. Thiazolidinediones (TZDs or glitazones)
• e. Contraindications/precautions
• i. Hepatic impairment
• ii. Class III/IV heart failure
• iii. Existing fluid retention
• f . Efficacy
• i. 0.5%–1.4% A1C reduction
• ii. Both drugs increase HDL-C, but pioglitazone has a more favorable effect in
reducing LDL-C and TG compared with rosiglitazone.
5. Dipeptidyl Peptidase-4 Inhibitors
• Sitagliptin, saxagliptin, vildagliptin and linagliptin.
• MECHANISM OF ACTION
• The DPP-4 inhibitors inhibit the degradation of GLP-1 on entering
the GI vasculature, thus increasing the effects of these endogenous
incretins on first-phase insulin secretion and glucagon inhibition.
• ADVERSE EFFECTS
• The most commonly reported side effects with sitagliptin and
saxagliptin include increased risk of infection (nasopharyngitis,
upper respiratory tract infection, urinary tract infection) and
headache
5. Dipeptidyl Peptidase-4 Inhibitors
• EFFICACY
• In monotherapy clinical trials versus placebo, sitagliptin lowers fasting
glucose by 12 mg/dL and A1C by 0.6% to 0.7% compared with baseline.
• DOSAGE AND CLINICAL USE
• DPP-4 inhibitors are mainly used as add-on therapy in combination
with sulfonylureas, biguanides, TZDs, and insulin (sitagliptin only);
however, both are approved for use as monotherapy.
• Sitagliptin may be initiated at 100 mg taken once daily with or without
food. Saxagliptin is dosed at 5 mg daily regardless of meals. Renal
function should be assessed before initiation of either agent.
5. Dipeptidyl Peptidase-4 Inhibitors
• In patients with moderate renal insufficiency (ClCr 30–50
mg/dL), the dose for sitagliptin should be reduced to 50 mg
once daily, and in severe renal insufficiency (ClCr<30mg/dL)
or for those in end-stage renal failure requiring dialysis, the
sitagliptin dose is 25 mg once daily.
6. Selective sodium dependent glucose
cotransporter-2 inhibitor
• Canagliflozin , Dapagliflozin, Empagliflozin
• MECHANISM OF ACTION
• Inhibition of SGLT2 in the proximal tubules reduces reabsorption
of filtered glucose and lowers the renal threshold for glucose which
together cause increased urinary excretion of glucose and decreased
plasma glucose concentrations.
• ADVERSE EFFECTS
• Hyperkalemia, genitourinary infection, hypovolemia, renal
insufficiency, hypotension, polyuria, mild hypoglycemia
6. Selective sodium dependent glucose
cotransporter-2 inhibitor
• Efficacy:
• Typical A1c reductions are 0.5% to 1%
• Contraindication:
• All of them contraindicated if CrCl < 30 mL/min.
• Dapagliflozin not recommended if CrCl < 60 mL/min.
Patient-centered approach to antihyperglycemic therapy in type 2 diabetes as per the American Diabetes Association/
European Association for the Study of Diabetes.
 Take home messages
• Medical nutrition therapy and physical activity are
cornerstones to the treatment of diabetes.
• Metformin is the first-line therapy for type 2 diabetes unless a
patient has a contraindication to its use or is unable to tolerate
this agent. It should be added at diagnosis along with lifestyle
changes.