College of Pharmacy

Fourth year. Clinical Pharmacy

Endocrine disorders: Diabetes Mellitus Part II
α-Glucosidase Inhibitors
1-Acarbose and miglitol delay the breakdown of sucrose and complex carbohydrates in
the small intestine, prolonging carbohydrate absorption.
2-Good candidates for these drugs are patients who are near target A1C levels with near-
normal FPG but high PPG levels.
3-The most common side effects are flatulence, abdominal pain, and diarrhea, which
can be reduced by slow dosage titration.
Meglitinides
1-Nateglinide and repaglinide stimulate insulin secretion from pancreatic β-cells by
binding to a site adjacent to the sulfonylurea receptor.
2-They are similar to sulfonylureas except that they have a faster onset and shorter
duration of action.
3-Similar to sulfonylureas, the main side effects are hypoglycemia and weight gain.
4-They may be a good option for patients with erratic meal schedules. However, multiple
daily dosing may decrease adherence.
5-Meglitinides should be taken by mouth with each meal.
Bile Acid Sequestrants
1-Colesevelam binds bile acid in the intestinal lumen, decreasing the bile acid pool for
reabsorption. Its mechanism in lowering plasma glucose levels is unknown, and its role in
therapy is unclear.
2-It reduces LDL-C in patients with type 2 DM by 12%–16. Patients with type 2 DM who
need a small reduction in A1C as well as additional LDL-C lowering may be
candidates for this agent.
3-The most common side effects are constipation and dyspepsia; colesevelam should be
taken with a large amount of water. Colesevelam has multiple absorption-related drug–
drug interactions.
Dopamine Agonists
1-Bromocriptine mesylate is FDA approved for treatment of type 2 DM. The mechanisms
by which it improves glycemic control are unknown but may involve improved hepatic
insulin sensitivity and decreased hepatic glucose output.
2-Its role in the treatment of type 2 DM is unclear.
Amylin Analogs
1-Pramlintide is a synthetic amylin analog that reduces glucagon secretion, slows gastric
emptying, and increases satiety. It was the first noninsulin agent approved for patients
with type 1 DM.
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2-It is used primarily in type 1 DM as adjunctive therapy for patients who are not
achieving PPG goals despite maximizing mealtime insulin doses.
3-It can also decrease weight and may allow for lower mealtime insulin doses.
Treatment of Hyperglycemia in Type 2 Diabetes
1-Upon diagnosis, set a patient-specific A1C target. Implement comprehensive lifestyle
modifications .
2-Initiate metformin as first-line therapy in patients without contraindications or
tolerability issues. Start with a low dose and titrate to the maximum effective dose over
time to improve tolerability.
3-If the initial A1C is close to goal (eg, ≤7.5%) consider initial treatment with lifestyle
modifications alone if the patient is motivated.
4-Consider starting two medications (metformin plus a second agent) if the initial A1C is
>1.5% higher than the target A1C.
5-Consider early introduction of basal insulin in patients with very high A1C levels
(>10%), symptoms of hyperglycemia, or evidence of catabolism (eg, weight loss).
6-See patients at least every 3 months if they are not meeting their goals and at least
every 6 months if they are meeting goals.
7-For patients maximized on metformin therapy but with A1C levels above the target, add a
second-line antihyperglycemic agent. The ADA Standards of Care identify six drug
classes to consider:
(1) DPP-4 inhibitors, (2) GLP1-RAs, (3) SGLT-2 inhibitors, (4) sulfonylureas, (5)
TZDs, and (6) basal insulin.
8-Recommendations based on patient-specific comorbidities and other factors include:
 Established ASCVD or CKD: SGLT-2 inhibitor (eg, empagliflozin) or GLP1-RA
(eg, liraglutide) with proven CV benefit.
 Established ASCVD and HF: SGLT-2 inhibitor with proven benefit in reducing HF
progression. Avoid TZDs in patients with HF.
 CKD (with or without ASCVD): SGLT-2 inhibitor with proven benefit in reducing
CKD progression.
 Need to minimize weight gain or promote weight loss in patients without
ASCVD or CKD: GLP1-RA or SGLT-2 inhibitor. If these agents cannot be used,
use a weight-neutral medication such as a DPP-4 inhibitor. Avoid sulfonylureas,
insulin, and TZDs due to weight gain.
 Compelling need to minimize hypoglycemia: DPP-4 inhibitor, GLP1-RA, SGLT-2
inhibitor, or TZD could be added to metformin.
11-If the A1C target is not achieved after 3 months of dual therapy or if the patient did not
tolerate the selected drug(s), then triple therapy is warranted, adding a drug from another
class.
12-People with type 2 DM can often be managed with oral medications for years before
injectable medications are needed.
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13-Insulin is recommended for extreme (A1C >10%) or symptomatic hyperglycemia.
Otherwise, GLP-1 RAs are preferred over basal insulin because they have equal or
superior A1C lowering efficacy and lead to weight loss instead of weight gain with a low
risk of hypoglycemia.
14-Basal insulin can be initiated if additional glucose lowering is needed after the GLP-1
RA dose has been maximized.
15-If the A1C target is not reached by maximally titrating basal insulin, PPG levels are
likely elevated and a GLP1-RA or SGLT-2 inhibitor should be considered if the patient
is not already taking one.
16-Prandial insulin is also an option. Titrate the dose over time to achieve target PPG
levels <180 mg/dL. A second or third injection can be added to the other meals if needed.
Treatment of Hyperglycemia in Type 1 Diabetes
1-All patients with type 1 DM require exogenous insulin. Achieving adequate glycemic
control usually requires intensive insulin regimens designed to provide insulin in a
manner that mimics normal physiologic insulin secretion, with consistent secretion of
insulin throughout the day to manage glucose levels overnight and in between meals (ie,
basal insulin), and bursts of insulin in response to glucose rises after ingestion of
carbohydrates (ie, prandial insulin).
2-Intensive insulin regimens can be given with either multiple daily injections (MDI) or
use of continuous subcutaneous insulin infusion (CSII) via an insulin pump.
3-A common MDI approach is one injection of long-acting insulin (eg, insulin glargine) for
the basal component and three injections of rapid acting insulin (eg, insulin lispro) for the
prandial component.
4-A less expensive option consists of two injections of intermediate-acting insulin (eg,
NPH insulin) and two injections of short-acting insulin (eg, regular insulin). However,
the ADA Standards of Care recommend that most patients should use rapid-acting insulins
rather than regular insulin to reduce the risk of hypoglycemia.
5-Insulin pump therapy or CSII infuses rapid-acting insulin to cover both the basal
and prandial insulin needs . The pump infuses a basal rate constantly throughout the day
and allows the patient to give bolus doses using a bolus dose calculator based on current
glucose levels, carbohydrate intake, and insulin on board.
6-The total daily insulin dose is divided to give 50% as basal insulin and 50% as
prandial insulin (distributed across meals). The insulin doses would then be adjusted
based on SMBG data. Ideally, patients should learn to count carbohydrates so they can
match their prandial insulin doses to their carbohydrate intake.
7-Patients should also SMBG before each meal or use continuous glucose monitoring
(CGM) to evaluate the insulin regimen and make treatment decisions. Bolus insulin
doses can be better individualized by using carbohydrate-to-insulin ratios (C:I ratios) and
correction factors (CF).

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8-Pramlintide is indicated as adjunctive treatment in patients with type 1 DM who are
not achieving glycemic targets despite optimization of mealtime insulin.
9-Assess patients every 3 months if uncontrolled and every 6 months if controlled.
Patients on intensive insulin therapy should SMBG at least four times daily, before meals
and at bedtime.
10-Patients should also test before exercise, prior to critical tasks such as driving, and
if symptoms of hypoglycemia occur. SMBG is crucial during times of intercurrent illness
or stresses for early detection and prevention of DKA.
11-Current guidelines recommend CGM in patients with type 1 DM who are not
meeting glycemic goals. They are also recommended in patients with hypoglycemia
unawareness to better detect and prevent hypoglycemic events.
Common insulin regimens.
(A) Multiple-component insulin regimen consisting of one injection of long-acting insulin
(detemir, glargine degludec) to provide basal glycemic coverage and three injections of
rapid-acting insulin (aspart, lispro, glulisine) to provide glycemic coverage for each meal.
(B) Insulin regimen consisting of two injections of intermediate-acting insulin (NPH) and
rapid-acting insulin (aspart, lispro, glulisine), or short-acting regular insulin.
(C) Insulin administration by insulin infusion device. The basal insulin rate is decreased
during the evening and increased slightly prior to the patient awakening in the morning.
Rapid-acting insulin (aspart, lispro, or glulisine) is used in the insulin pump.
Hypoglycemia
1-Hypoglycemia is a common complication of some diabetes medications.
2-The severity of hypoglycemia is classified as follows:
 Level 1 (hypoglycemia alert value; ≤70 mg/dL: May not cause symptoms but should
be treated with a fast-acting carbohydrate and may need medication dose
adjustment.
 Level 2 (clinically significant hypoglycemia; <54 mg/dL: Serious, clinically
important hypoglycemia
 Level 3 (severe hypoglycemia): Associated with cognitive impairment requiring
external assistance for recovery and can be life threatening.
3-Initial autonomic symptoms include tachycardia, palpitations, sweating, tremors, and
hunger. Neuroglycopenic symptoms often occur with BG <60 mg/dL and can include
cognitive impairment, confusion, behavioral changes, anger, irritability, blurred vision,
headaches, seizures, and loss of consciousness.
4-Some patients have hypoglycemia unawareness and are unable to detect the early
warning symptoms of hypoglycemia; they are at increased risk for the serious sequelae
associated with severe hypoglycemia.
5-SMBG and CGM can be useful in preventing hypoglycemia. Patients must be
educated to understand situations that increase risk of hypoglycemia (eg, delaying meals,
during or after exercising, or fasting).
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6-Treatment of hypoglycemia requires ingestion of carbohydrates, preferably glucose.
Patients should carry a source of fast-acting glucose with them at all times and use the “rule
of 15” for proper treatment:

 First use SMBG to confirm BG <70 mg/dL and then ingest 15 g of fast-acting
carbohydrates such as 1/2 cup (4 oz or 125 mL) of milk, juice, or soda; 1 tablespoon
of honey; hard candy; jelly beans; or glucose tablets.
 Repeat SMBG in 15 minutes; if the BG is <70 mg/dL, repeat the process.
 Once the BG is normalized, eat a snack or meal that includes complex
carbohydrates and protein to prevent further hypoglycemic episodes.
7-If the patient is unconscious, give IV glucose or glucagon injection. Glucagon increases
glycogenolysis in the liver and may be given in any situation in which IV glucose cannot be
rapidly administered.
8-A glucagon kit should be prescribed and readily available to all patients on insulin
who have a history of or high risk for severe hypoglycemia. It can take 10–15 minutes
before glucose levels start to rise, and patients often vomit.
9-Position the patient on the side with the head tilted slightly downward to avoid
aspiration.
10-Clinicians should monitor hypoglycemia at every visit.
11-Reevaluate the treatment regimen of patients with frequent or severe hypoglycemia to
minimize future episodes.
Complications and Comorbidities
Diabetic Ketoacidosis (DKA)
1-In patients with type 1 DM, DKA is usually precipitated by omitting insulin, infection,
or acute illness with resultant increases in cortisol, catecholamines, glucagon, and growth
hormone.
2-Patients may be alert, stuporous, or comatose at presentation. Diagnostic laboratory
values include hyperglycemia, anion gap acidosis, and large ketonemia or ketonuria.
3-Patients have fluid deficits of several liters and significant sodium and potassium deficits.
Treatment requires restoration of intravascular volume with normal saline followed by
hypotonic saline to replace free water, potassium supplements, and insulin given by
continuous IV infusion.
4-Rapid correction of the glucose (a decrease >75–100 mg/dL/hr) is not recommended
because it has been associated with cerebral edema, especially in children. Continue the
insulin infusion until the urine ketones clear and the anion gap closes.
5-Give long-acting insulin 1–3 hours before discontinuing the insulin infusion. Perform
hourly bedside monitoring of glucose and frequent monitoring of potassium (every 2–4
hours).

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6-Treatment with bicarbonate to correct the acidosis is generally not needed and may
be harmful.
7-It is essential to correct the underlying situation or medical condition that precipitated
DKA.
Hyperosmolar Hyperglycemic State (HHS)
1-HHS is a potentially life-threatening acute complication of diabetes associated with
very high glucose concentrations, typically >400 mg/dL.
2-It usually occurs in older patients with type 2 DM or in younger patients with prolonged
hyperglycemia and dehydration or significant renal insufficiency.
3-The patient presentation is similar to DKA, but HHS patients usually have much
higher BG, elevated serum osmolality, and little to no ketonuria or ketonemia.
4-HHS typically evolves over several days to weeks, whereas DKA evolves much faster.

5-Large ketonemia is not usually seen because residual insulin secretion suppresses
lipolysis. Infection or another medical illness is the usual precipitant.
6-Fluid deficits are often greater and BG levels higher (sometimes >1000 mg/dl) in
patients with HHS than in patients with DKA.

7-BG should be lowered very gradually with hypotonic fluids and low-dose insulin
infusions (1–2 units/hr).
Macrovascular Complications
1-Macrovascular complications (eg, CHD, stroke) are the leading causes of death in
people with diabetes.
2-The ADA recommends low-dose aspirin therapy (75–162 mg daily) in all patients with
established ASCVD. Clopidogrel may be used in patients allergic to aspirin.
3-The role of antiplatelet therapy for primary CV prevention is unclear because the benefits
may be offset by a higher risk of bleeding; some practice guidelines recommend aspirin
if the 10-year risk of a CV event is >20%.
4-In patients with established ASCVD, use of a GLP1-RA or an SGLT-2 inhibitor
should be strongly considered.

5-For all patients whose BP exceeds 120/80 mm Hg, the ADA recommends dietary
changes, physical activity, and weight loss in overweight or obese patients.
6-Drug therapy using agents proven to reduce CV events should be started for BP >140/90
mm Hg. A combination of two medications should be used for BP >160/100 mm Hg.
7-Initiate high-intensity statin therapy in all patients with diabetes and preexisting ASCVD
regardless of baseline lipid levels. In the absence of ASCVD, prescribe a moderate-
intensity statin to all patients with type 1 or type 2 DM over the age of 40.

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8-In patients <40 years of age, a moderate intensity statin may be appropriate for patients
with multiple CV risk factors.
9-A fibrate (eg, fenofibrate), omega-3 fatty acid, or niacin can be added for patients with
marked hypertriglyceridemia.

10-Peripheral arterial disease can lead to claudication, nonhealing foot ulcers, and limb
amputation. Smoking cessation, statin therapy, good glycemic control, and antiplatelet
therapy are important strategies. Cilostazol may be useful in select patients to reduce
symptoms. Revascularization surgery can be considered in some situations. Perform foot
examinations during each face-to-face patient encounter and a yearly monofilament test to
assess for loss of protective sensation to identify high-risk patients.
Microvascular Complications
Efforts to improve glucose control significantly reduce the risk of developing microvascular
complications and slow their progression.
Nephropathy:
1-Albuminuria is a marker of renal damage. The ADA recommends screening for
albuminuria upon diagnosis in persons with type 2 DM.
2-Screening with type 1 DM should begin with puberty and after 5-years’ disease
duration.

3-BP control is important for preventing and slowing progression of nephropathy.

ACE inhibitors and ARBs can slow the progression of renal disease in patients with
diabetes.
4-Diuretics are often necessary due to volume expanded states and are recommended
second-line therapy.
5-The ADA recommends a BP goal <140/90 mm Hg in patients with nephropathy but a
lower target (eg, <130/80 mm Hg) if it can be achieved without undue burden or side
effects. Three or more antihypertensives are often needed to reach goal BP.
Retinopathy:
1-Patients with diabetes should have routine dilated eye examinations to fully evaluate
the retina.
2-Early background retinopathy may reverse with improved glycemic control and
optimal BP control. More advanced retinopathy will not fully regress with improved
glycemia, and aggressive BG reductions may acutely worsen retinopathy.
3-Laser photocoagulation has markedly improved sight preservation. Intravitreal
antivascular endothelial growth factor (VEGF) therapy is also highly effective for sight
preservation.
4-Bevacizumab (used off-label) and ranibizumab are anti-VEGF monoclonal
antibodies, and aflibercept is a VEGF decoy receptor.

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Neuropathy:
 Peripheral neuropathy is the most common complication in patients with type 2
DM. Paresthesias, numbness, or pain are the predominant symptoms. The feet are
involved far more often than the hands. Improved glycemic control is the primary
treatment and may alleviate some symptoms. Pharmacologic therapy is
symptomatic and includes low-dose tricyclic antidepressants (nortriptyline or
desipramine), duloxetine, gabapentin, pregabalin, venlafaxine, topical capsaicin,
and tramadol.
 Gastroparesis. Improved glycemic control, discontinuation of medications that slow
gastric motility, and use of metoclopramide or low-dose erythromycin may be
helpful.
 Diabetic diarrhea is often nocturnal and frequently responds to a 10- to 14-day
course of an antibiotic such as doxycycline or metronidazole. Octreotide may be
useful in unresponsive cases.
 Orthostatic hypotension may require mineralocorticoids (eg, fludrocortisone) or
adrenergic agonists (midodrine).
 Erectile dysfunction is common, and initial therapy should include a trial of an oral
phosphodiesterase-5 inhibitor (eg, sildenafil, vardenafil, or tadalafil).
Evaluation of therapeutic outcomes
1-Measure A1C every 3–6 months to follow long-term glycemic control for the
previous 2–3 months.
2-For patients with type 1 DM, SMBG is typically performed 4–6 times per day—prior
to food intake and physical activity and at bedtime.
3-The optimal frequency of SMBG in patients with type 2 DM on oral agents is
controversial.

4-At each visit, ask patients with type 1 DM about the frequency and severity of
hypoglycemia.

5-Screen for complications at the time of diagnosis and thereafter as follows:

 Obtain yearly dilated eye exams in type 2 DM and an initial exam in the first 5 years
in type 1 DM, then yearly.
 Assess BP at each visit.
 Examine the feet at each visit. Screen for pedal sensory loss annually.
 Screen for albuminuria at the time of diagnosis in patients with type 2 DM and 5
years after diagnosis in type 1 DM. At least once a year, assess urinary albumin
(urine albumin-to-creatinine ratio) and eGFR in all patients with type 2 DM and in
patients with type 1 DM for at least 5 years.
 Check fasting lipid panel annually if the patient is on lipid-lowering therapy.
6-Administer an annual influenza vaccine and assess for administration of the
pneumococcal vaccine and hepatitis B vaccine series along with management of other
CV risk factors (eg, smoking).
Reference: Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 11th Edition. 2021.