2022-2023

Dr. Omer Q. B. Al-lela

PhD in clinical pharmacy
ISPOR, ISOP member, ICIT

Diabetes Mellites (DM)

Introduction
1-Diabetes mellitus (DM) is a group of metabolic disorders characterized
by chronically elevated blood glucose (BG) and abnormal carbohydrate, fat,
and protein metabolism.

2-Without effective treatment, DM can lead to acute complications such as

diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome
(HHS).

3- Chronic hyperglycemia can cause microvascular, macrovascular, and

neuropathic complications.
Pathophysiology
1-Type 1 DM (5%–10% of cases) usually results from autoimmune destruction of
pancreatic β-cells, leading to absolute deficiency of insulin.

 It usually presents in children and adolescents but can occur at any age. The disorder
is believed to be initiated by exposure to an unknown environmental trigger in a
genetically susceptible individual.

 The autoimmune process is mediated by macrophages and T lymphocytes with

autoantibodies to β-cell antigens (e.g., islet cell antibody, insulin antibodies).

 After the initial diagnosis, a period of transient remission called the “honeymoon”
(20%) phase may occur, during which insulin doses can be reduced or withdrawn
before continued β-cell destruction requires lifelong insulin replacement therapy.
Development of Type 1 Diabetes
Pathophysiology
2-Type 2 DM (90%–95% of cases) is characterized by multiple defects:
• Impaired insulin secretion: β-cell mass and function are both reduced, and β-cell failure is
progressive.
• Reduced incretin effect: Normally, the gut incretin hormones glucagon-like peptide-1 (GLP-1) and
glucose-dependent insulinotropic peptide (GIP) are released and stimulate insulin secretion in
response to a meal. Patients with type 2 DM have a reduced incretin effect due to decreased
concentrations of or resistance to the effects of incretin hormones.
• Insulin resistance: This is manifested by excessive hepatic glucose production, decreased skeletal
muscle uptake of glucose, and increased lipolysis and free fatty acid production.
• Excess glucagon secretion: This occurs because type 2 DM patients fail to suppress glucagon in
response to meals because of GLP-1 resistance/deficiency and insulin resistance/deficiency, which
directly suppress glucagon.
• Sodium-glucose cotransporter-2 (SGLT-2) upregulation in the kidney: This increases
reabsorption of glucose by proximal renal tubular cells, which further contributes to
hyperglycemia.
Pathophysiology
Development of Type 2
Diabetes
Pathophysiology
3-Gestational diabetes (GDM) is DM that occurs in women during pregnancy.

4-Less common causes of DM (1%–2%) include maturity onset diabetes of the

young (MODY), genetic syndromes (eg, Down syndrome), endocrine disorders (eg,
acromegaly, Cushing syndrome), pancreatic exocrine dysfunction, infections, and
medications (eg, glucocorticoids, thiazides, niacin, atypical antipsychotics).

Complications
 Microvascular complications include retinopathy, neuropathy, and
nephropathy.

 Macrovascular complications include coronary heart disease (CHD), stroke, and

peripheral vascular disease.
Advanced Glycation End (AGE) products theory
Advanced Glycation End (AGE) products theory
Clinical presentation
Type 1 Diabetes Mellitus
1-Patients often have symptoms in the days or weeks preceding the
diagnosis. The most common initial symptoms are polyuria, polydipsia,
polyphagia, weight loss, fatigue, and lethargy.

2-Individuals are often thin and are prone to develop DKA in the absence of
an adequate insulin supply; many patients initially present with DKA.

3-Symptom onset can be triggered by infection, trauma, or psychological

stress.
Clinical presentation
Type 2 Diabetes Mellitus
1-Most patients are asymptomatic or have only mild fatigue at the time of
diagnosis. Many patients are incidentally found to have type 2 DM after routine
laboratory testing (eg, plasma glucose or A1C) or development of complications (eg,
myocardial infarction, stroke).

2-Because mild hyperglycemia may exist for years prior to the diagnosis,
microvascular and macrovascular complications are often present at the time of
diagnosis.

3-Most patients are overweight or obese with an elevated waist: hip ratio.
 Differences between Type1 and
Type2
Characteristics Type 1 Type 2
Percentage of 5–10% 90%
diabetic
population
Age at onset <30 yr; peaks at 12–14 yr; >40 yr,
Pancreatic Usually none Insulin present in low, “normal,”
function or high amounts
Pathogenesis Presence of islet cell Defect in insulin secretion;
antibodies suggests tissue resistance to insulin; ↑
autoimmune process hepatic glucose output
Family history Generally not strong Strong
Body habitus Lean Obesity (60-80%)
History of Often present Rare, except in circumstances
ketoacidosis of unusual stress (e.g., infection)
 Differences between Type1 and
Type2
Characteristics Type 1 Type 2
Clinical Moderate to severe Mild polyuria, fatigue; often diagnosed on
presentation symptoms that generally routine physical or dental examination
progress relatively rapidly
(days to weeks): polyuria,
polydipsia, fatigue, weight
loss, ketoacidosis
Microvascular No Common
complications at
diagnosis
Macrovascular Rare Common
complications at
or before diagnosis
Treatment MNT MNT
Physical activity Physical activity
Insulin Antidiabetic agents
Amylin mimetic Insulin
(pramlintide) Amylin mimetic (pramlintide)
Diagnosis
1-Normal fasting (no caloric intake for at least 8 hours) plasma glucose (FPG)
is 70–99 mg/dL. Impaired fasting glucose (IFG) is FPG 100–125 mg/dL.

2-Normal glucose tolerance based on a 2-hour post-load plasma glucose using

the equivalent of 75 g anhydrous glucose dissolved in water (oral glucose
tolerance test or OGTT) is <140 mg/dL. Impaired glucose tolerance (IGT) is
OGTT 140–199 mg/dL.

3-Normal A1C is 4%–5.6%. Increased risk of DM (prediabetes) is A1C 5.7%–

6.4%.
Diagnosis
4-Criteria for diagnosis of DM include any one of the following:
1. A1C ≥6.5% 2. FPG ≥126 mg/dL 3. OGTT ≥200 mg/dL 4. Random plasma
glucose ≥200 mg/dL with classic symptoms of hyperglycemia or hyperglycemic crisis.

5-In the absence of unequivocal hyperglycemia, a diagnosis using criteria 1 through 3

requires two abnormal test results from the same sample or in two separate test
samples.

6-Prediabetes is a condition of abnormal BG that is not sufficiently high to meet the

thresholds that define DM but often progresses to the diagnosis.

7-Screening for type 1 DM in asymptomatic children or adults is not recommended due

to low disease prevalence and the acute onset of symptoms.
Diagnosis
8-Screening for type 2 DM is recommended for asymptomatic adults who are
overweight (BMI ≥25 kg/m2) and have at least one other risk factor for developing
type 2 DM.

9-All adults, even those without risk factors, should be screened every 3 years
starting at 45 years old. Children at risk for developing type 2 DM should undergo
screening every 3 years starting at age 10 years.

10-Pregnant women should undergo risk assessment for GDM at the first prenatal
visit; those with multiple risk factors for type 2 DM should be tested as soon as
possible. All women (even if the initial test was negative) should undergo testing at
24–28 weeks’ gestation.
Treatment
1-Goals of Treatment: The primary goal is to prevent or delay progression of long-
term microvascular and macrovascular complications.

2-Additional goals are to alleviate symptoms of hyperglycemia, minimize

hypoglycemia and other adverse effects, minimize treatment burden, and maintain
quality of life.

3-General glycemic targets for most nonpregnant adults with DM are listed in Tab-1.
Table-1: Glycemic Target Recommendations for Most Nonpregnant Adults with Diabetes

4-Glycemic targets should be individualized. More stringent or less stringent goals may
be appropriate for some patients.
HbA1c
Treatment
Nonpharmacologic Therapy
1-Medical nutrition therapy (MNT) involves an individually tailored nutrition plan. Implement
a healthy meal plan that is moderate in calories and carbohydrates and low in saturated fat with all
of the essential vitamins and minerals. Target an initial weight loss goal of at least 5% in all type
2 DM patients who are overweight or obese through calorie restriction.

2-Aerobic exercise can improve insulin sensitivity, modestly improve glycemic control, reduce
cardiovascular (CV) risk, contribute to weight control, and improve well-being. Physical activity
goals include at least 150 min/week of moderate intensity exercise spread over at least 3
days/week with no more than 2 days between activity. Resistance/strength training is
recommended at least 2 times/week for patients without proliferative diabetic retinopathy.

3-Patients must be involved in decision making and have strong knowledge of the disease and
associated complications.
Treatment (Insulin)
Pharmacologic Therapy
1-Insulin
Treatment (Insulin)
Pharmacologic Therapy
Insulin
1-The main advantage of insulin over other antihyperglycemic agents is that it can
achieve a wide range of glucose targets and the dose can be individualized based on
glycemic levels.

2-Disadvantages include the risk of hypoglycemia, need for injections, weight gain,
and treatment burden.

3-All commercial insulin preparations are produced using recombinant DNA

technology.

4-Most insulin products are administered subcutaneously (SC) for chronic diabetes
management, except for inhaled human insulin, which is a dry powder of regular
insulin that is inhaled and absorbed through pulmonary tissue.
Treatment (Insulin)
5-The most commonly used insulin concentration is 100 units/mL (U-100); more
concentrated insulins (U-200, U-300, U-500) may be considered for patients
requiring larger doses. U-500 regular insulin is reserved for patients with extreme
insulin resistance and is usually given two or three times a day.

6-The pharmacokinetics of insulin products is characterized by their onset, peak, and

duration of action (Table-2).
Treatment (Insulin)
Treatment (Insulin)
7-Basal insulin (or background insulin) refers to longer-acting insulins that regulate
BG levels in between meals by suppressing hepatic glucose production and
maintaining near-normal glycemic levels in the fasting state. Options include the
following insulins:
• NPH is the least ideal product because it has a distinct peak and a duration of
action much less than 24 hours and usually requires twice daily dosing.
• Detemir also has a peak and often lasts <24 hours; it can be given once daily in
some patients but should be dosed twice daily at low doses.
• Glargine and degludec are longer acting-agents that have no peak and are given
once daily.

8-All basal insulins can achieve similar A1C reductions if dosed and titrated properly,
but the longer-acting products have a lower risk of hypoglycemia (particularly
nocturnal hypoglycemia) and may result in less glucose variability. However, they are
more expensive.
Treatment (Insulin)
9-Bolus insulin refers to short- or rapid-acting insulins that cover meals (also
called prandial insulin) or glycemic excursions (also called correction insulin).

10-Basal insulin is the preferred and most convenient initial insulin formulation for
patients with type 2 DM, whereas patients with type 1 DM require a combination of
basal and bolus insulin to achieve adequate glycemic control.

11-Bolus insulin options include:

• Aspart, lispro, and glulisine, the rapid-onset, short-duration insulins
• Inhaled human insulin and fast-acting insulin aspart (Fiasp®), the ultra-rapid
onset insulins

12-Rapid-acting insulins offer a faster onset and shorter duration of action than
regular insulin, and ultra-rapid acting insulins offer an even faster onset; this may
more closely mimic prandial endogenous insulin release.
Treatment (Insulin)
13-Rapid-acting insulins have a modestly lower risk of hypoglycemia than regular
insulin.

14-Various premixed insulin products containing both a basal and a prandial

component are also available for patients who require fewer injections or a simpler
regimen (Table-2). However, these products are limited by fixed mixed
formulations, which can make it challenging to tailor the dosing regimen.

15-The insulin dose must be individualized. In type 1 DM, the average daily
requirement is 0.5–0.6 units/kg, with approximately 50% given as basal insulin and
the remaining 50% dedicated to meal coverage.

16-During the honeymoon phase, requirements may fall to 0.1–0.4 units/kg. Higher
doses are often needed during acute illness or with ketosis.
Treatment (Insulin)
17-Hypoglycemia is the most common adverse effects of insulin therapy. Insulin
also causes dose-dependent weight gain, which occurs predominantly in truncal fat.

18-Injection site reactions may include redness, pain, itching, urticaria, edema, and
inflammation. SC administration can result in lipoatrophy or lipohypertrophy, which
can be prevented by routinely rotating injection sites.

19-Inhaled human insulin can cause cough and upper respiratory infections, and it
is contraindicated in chronic obstructive pulmonary disease and asthma due to
bronchospasm risk.

20-Because inhaled insulin has been associated with a small decline in pulmonary
function, patients should have spirometry tests performed at baseline, 6 months,
and annually thereafter.
2- Treatment (Biguanides)
Treatment (Biguanides)
Biguanides
1-Metformin decreases hepatic glucose production and enhances insulin sensitivity
in peripheral (muscle) tissues, allowing for increased glucose uptake into muscle
cells.

2-Metformin is recommended as first-line pharmacotherapy in patients with type 2

DM (unless a contraindication or intolerability exists) due to extensive experience,
high efficacy, minimal hypoglycemia risk, positive or neutral effects on weight,
potential positive impact on CV risk, manageable side-effect profile, and low cost.

3-It does not cause weight gain and may lead to a modest (2–3 kg) weight loss.

4-It has a low risk of hypoglycemia because it does not directly increase pancreatic
insulin secretion.
Treatment (Biguanides)
6-Metformin frequently causes GI side effects (diarrhea, abdominal discomfort,
stomach upset); these effects are usually dose-dependent, transient, mild, and can be
minimized with slow dose titration and taking metformin after meals.

7-Extended-release metformin may lessen some of the GI side effects.

8-Metformin may cause a metallic taste and may lower vitamin B12
concentrations; B12 levels or methylmalonic acid should be measured annually or if a
deficiency is suspected, with vitamin B12 supplementation given if indicated.

9-Lactic acidosis occurs rarely, usually in the setting of severe illness or acute
kidney injury. The risk may increase in moderate-to-severe renal insufficiency or
tissue hypoperfusion states such as acute heart failure (HF), excessive alcohol intake,
and hepatic impairment. Because symptoms are often nonspecific, the diagnosis
must be confirmed by laboratory measurement of high lactic acid levels and
acidosis.
Treatment (Biguanides)
10-Metformin is renally excreted and accumulates in renal insufficiency; it is
contraindicated in patients with eGFR <30 mL/min/1.73 m2.

11-Metformin initiation is not recommended in patients with eGFR 30–45

mL/min/1.73 m2 but can be continued with increased renal function monitoring; a
reduction of 50% of maximal dose may be warranted.

12-Due to the risk of acute renal failure with use of IV contrast dye, withhold
metformin therapy starting the day of the procedure and resume it 2–3 days later
if normal renal function has been documented.

13-Metformin can be used in combination with any other antihyperglycemic

therapy and is often continued when insulin therapy is initiated.

14-The target metformin dose is 1000 mg twice daily or 2000 mg daily if the
extended-release product is used. The minimal effective dose is 1000 mg/day.
3- Treatment (Sulfonylureas)
Treatment (Sulfonylureas)
Sulfonylureas
1-Sulfonylureas enhance insulin secretion by binding to the sulfonylurea receptor
SUR1 on pancreatic β-cells.

2-First-generation agents (chlorpropamide, tolazamide, and tolbutamide) are lower in

potency than second-generation drugs (glyburide, glipizide, and glimepiride), and
are rarely used due to a higher risk of adverse effects.

3-All sulfonylureas are equally effective in lowering BG when given in equipotent

doses.

4-Sulfonylureas are widely used because they have an extensive record of safety and
effectiveness, are given orally, and are inexpensive. However, current treatment
guidelines either discourage their use or suggest caution due to the risk of
hypoglycemia and weight gain. In addition, tachyphylaxis to the insulin secretion
effect occurs, leading to poor long-term durability of response in most patients.
Treatment (Sulfonylureas)
5-The most common side effect is hypoglycemia. Patients who
skip meals, exercise vigorously, or lose a substantial amount of
weight are more prone to hypoglycemia.

6-Sulfonylureas with long durations of action and those with

active metabolites should be used with extreme caution in
older patients and those with renal insufficiency due to the high
risk of hypoglycemia.

7-Weight gain is common (typically 1–2 kg). Patients with

sulfa allergy rarely experience crossreactivity with
sulfonylureas.
4- Treatment (TZDs)
Treatment (TZDs)
Thiazolidinediones (TZDs)
1-TZDs (Pioglitazone) bind to the peroxisome proliferator activator receptor-γ (PPAR-
γ) located primarily on fat and vascular cells, enhancing insulin sensitivity in muscle,
liver, and fat tissues.

2-Maximum effects may not be seen until 3–4 months of therapy.

3-TZDs are considered second- or third-line agents and can be used in combination
with metformin and other commonly prescribed medications for type 2 DM.

4-Pioglitazone decreases plasma triglycerides by 10%–20, whereas rosiglitazone

may increase LDL-C by 5%–15%. Both drugs increase HDL-C, but the magnitude
may be greater with pioglitazone.
Treatment (TZDs)
5-Fluid retention may occur due to peripheral vasodilation and improved insulin
sensitization in the kidney with increased sodium and water retention. This may
result in peripheral edema (4%–5% of patients with monotherapy; 15% or more when
combined with insulin), HF, hemodilution of hemoglobin and hematocrit, and weight
gain.

6-TZDs are contraindicated in patients with New York Heart Association Class III
or IV HF and should be used with caution in patients with Class I or II HF.

7-Weight gain is dose related and results from both fluid retention and fat
accumulation; a gain of 4 kg is not uncommon, and higher gains may require drug
discontinuation.

8-TZDs have also been associated with an increased fracture rate in the upper and
lower limbs of postmenopausal women. An increased risk of bladder cancer is
controversial.
5- Treatment (GLP1)
Treatment (GLP1)
Glucagon-like Peptide 1 Receptor Agonists (GLP1-RAs)
1-Dulaglutide, exenatide, exenatide XR, lixisenatide, liraglutide, and semaglutide
stimulate insulin secretion and suppress inappropriately high postprandial glucagon
secretion, decreasing hepatic glucose output. They also slow gastric emptying, increase
satiety, and cause weight loss (average 1–3 kg).

2-Short-acting agents (exenatide, lixisenatide) predominantly lower postprandial

glucose (PPG) levels, whereas long-acting agents (dulaglutide, liraglutide, exenatide
XR, semaglutide) lower both FPG and PPG, but with larger effects on FPG.

3-Evidence suggests that liraglutide and semaglutide have the highest A1C and
weight-lowering efficacy while exenatide and lixisenatide have the lowest.
Treatment (GLP1)
4-Liraglutide and semaglutide have demonstrated CV benefits in clinical trials.
Liraglutide is FDA approved to reduce the risk of major adverse CV events in adults
with type 2 DM and established atherosclerotic cardiovascular disease (ASCVD).

5-GLP1-RAs are not currently recommended as first-line agents but can be used as
monotherapy in patients who cannot tolerate or take first-line therapy.

6-They are recommended second-line agents for patients with established ASCVD or
chronic kidney disease (CKD) and those with a compelling need to avoid hypoglycemia
or to avoid weight gain or induce weight loss.

7-They can be used in combination with metformin, TZDs, sulfonylureas, SGLT-2

inhibitors, and basal insulin. They should not be used in combination with DPP-4
inhibitors due to similar mechanisms of action.
Treatment (GLP1)
8-The GLP1-RAs are administered SC.
9-The most common adverse effects of GLP1-RAs are nausea, vomiting, and
diarrhea. These effects are dose related, so dose titration is recommended. They usually
occur early in the treatment course and are mild and transient but may require drug
discontinuation in some patients. Instruct patients to eat slowly and stop eating
when satiated or nausea may worsen and cause vomiting.
10-Injection site reactions and hypersensitivity reactions (including anaphylaxis and
angioedema) have been reported.
11-Because GLP1-RAs enhance insulin secretion in response to food intake, the risk of
hypoglycemia is low when combined with metformin, SGLT-2 inhibitors, or a TZD.
However, hypoglycemia may occur when combined with a sulfonylurea or insulin.
6- Treatment (DDP-4)
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
Treatment (DDP-4)
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
1-Alogliptin, linagliptin, saxagliptin, and sitagliptin prolong the half-life of
endogenously produced GLP-1 and GIP, thereby increasing glucose-dependent
insulin secretion from the pancreas and reducing inappropriate postprandial
glucagon secretion, resulting in lower glucose levels without an increase in
hypoglycemia when used as monotherapy.

2-They do not alter gastric emptying, cause nausea, have significant effects on
satiety, or cause weight gain/loss.

3-There are no clear differences in efficacy among agents in the class.

DPP-4 inhibitors are considered second- or third-line therapy.
Treatment (DDP-4)
4-Advantages include once-daily dosing, oral administration, weight
neutrality, low risk of hypoglycemia, and good tolerability. However, they
have less A1C lowering efficacy than other second-line medication classes and
are expensive.

5-Adverse effects are uncommon and include stuffy, runny nose; headache;
and upper respiratory tract infections. The labeling of saxagliptin and
alogliptin includes information about increased risk of hospitalizations for
HF. The FDA has also issued a warning on the risk of severe joint pain with
DPP-4 inhibitors.

6-Pancreatitis appears to be an established but rare safety concern.

7- Treatment (SGLT-2)
Sodium-Glucose Cotransporter-2 Inhibitors
Treatment (SGLT-2)
Sodium-Glucose Cotransporter-2 Inhibitors
1-Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin reduce plasma glucose
by preventing the kidneys from reabsorbing glucose back into the bloodstream,
leading to increased glucose excretion in the urine.

2-SGLT-2 inhibitors lower both FPG and PPG . Renal impairment decreases the
efficacy of SGLT-2 inhibitors.

3-SGLT-2 inhibitors are second-line agents that can be added to metformin or other
second-line agents. They are not recommended as first-line agents but can be used as
monotherapy in patients who cannot tolerate or take first-line therapy.

4-They are unlikely to cause hypoglycemia unless combined with medications such as
sulfonylureas, meglitinides, or insulin.
Treatment (SGLT-2)
Sodium-Glucose Cotransporter-2 Inhibitors
5-Both empagliflozin and canagliflozin reduced major adverse CV events in large
clinical trials, and empagliflozin is FDA approved to reduce the risk of CV death in
adults with type 2 DM and established ASCVD.
6-The most common adverse effect is genital mycotic infections, which are more
common in women and uncircumcised men. There is also a slightly increased risk of
urinary tract infections. Polyuria, dehydration, dizziness, or hypotension may occur
because of the osmotic diuresis effects.
7-Concomitant diuretic use may increase the risk of orthostatic hypotension and
electrolyte abnormalities. Other potential safety concerns include ketoacidosis,
amputations, fractures, and Fournier gangrene.
8- Treatment (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.
9- Treatment (Meglitinides)
9- Treatment (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, initiated at a low dose, and
titrated over time until glycemic control is achieved.
10- Treatment (Bile Acid Sequestrants)
10- Treatment (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%. Colesevelam is weight

neutral and has a low risk of hypoglycemia. 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.
11- Treatment (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. Common side effects include nausea,
vomiting, constipation, fatigue, headache,
dizziness, and asthenia. Somnolence and
orthostatic hypotension may also occur.
12- Treatment (Amylin Analogs)
12- Treatment (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.

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.

4-The most common adverse effects are nausea, vomiting, and anorexia. It does not
cause hypoglycemia when used alone, but hypoglycemia can occur when used with
insulin.

5-To minimize the risk of severe hypoglycemia, empirically reduce the mealtime
insulin dose by 30%–50% when pramlintide is initiated.
Treatment of Hyperglycemia in
Type 2 Diabetes
Treatment of Hyperglycemia in Type 2 Diabetes
1-Upon diagnosis, set a patient-specific A1C target. Implement comprehensive
lifestyle modifications with MNT, physical activity, weight loss if obese, smoking
cessation, and psychologic support upon diagnosis and reinforce them at every visit.
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).
Treatment of Hyperglycemia in Type 2 Diabetes
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. At those times, check an A1C level,
assess medication adherence, and reinforce lifestyle recommendations. Add additional
therapy if glucose targets have not been met.

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-Patient-specific factors to consider in medication selection include the individualized

A1C target and presence of comorbidities (eg, ASCVD, HF, CKD, obesity).
Treatment of Hyperglycemia in Type 2 Diabetes
9-Drug-specific factors to consider include glucose-lowering efficacy, impact on
comorbidities, effect on weight and hypoglycemia risk, side-effect profile, ease of use,
and cost.

10-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.
Treatment of Hyperglycemia in Type 2 Diabetes
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.

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.
Treatment of Hyperglycemia in Type 2 Diabetes
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.
Treatment of Hyperglycemia in Type 1 Diabetes
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-Insulin pump therapy can provide more precise glucose control and allow greater
flexibility and fine-tune tailoring.
Treatment of Hyperglycemia in Type 1 Diabetes
7-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.

8-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).
Treatment of Hyperglycemia in Type 1 Diabetes
9-Pramlintide is indicated as adjunctive treatment in patients with type 1 DM who
are not achieving glycemic targets despite optimization of mealtime insulin.

10-Pramlintide may improve glycemic control and minimize weight gain caused
by insulin, but its use is limited by adverse effects such as nausea and vomiting,
modest glucose improvements, increased injections and cost, and increased risk of
hypoglycemia.

11-Assess patients every 3 months if uncontrolled and every 6 months if

controlled. Obtain an A1C and adjust treatment as needed. Patients on intensive insulin
therapy should SMBG at least four times daily, before meals and at bedtime.
Treatment of Hyperglycemia in Type 1 Diabetes
12-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.

13-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.
Only one formulation of short-acting insulin is used.

(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 and is
associated with falls, injury, motor vehicle accidents, decreased quality of life, and
increased risk of developing dementia, CV events, arrhythmias, and death.

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.
Hypoglycemia
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).
Hypoglycemia
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.
Hypoglycemia
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. Ask the patient about the
frequency, severity, and timing of hypoglycemic events, need for assistance by others, or the
need to administer glucagon. Reevaluate the treatment regimen is very important.
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 GH.

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-Constant infusion of a fixed insulin dose and administration of IV glucose when the BG
level decreases to <250 mg/dL are preferred over titrating the insulin infusion based on the
glucose level.
Complications and Comorbidities
 Diabetic Ketoacidosis (DKA)
5-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.

6-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 hrs).

7-Treatment with bicarbonate to correct the acidosis is generally not needed and may be
harmful.

8-It is essential to correct the underlying situation or medical condition that precipitated
DKA. Metabolic improvement is manifested by an increase in serum bicarbonate and pH.
Complications and Comorbidities
 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.
Complications and Comorbidities
 Hyperosmolar Hyperglycemic State (HHS)

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).
Complications and Comorbidities
 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 (Exenatide…..) or an SGLT-2 inhibitor
(Empagliflozin) 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.
Complications and Comorbidities
 Macrovascular Complications
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. In patients <40
years of age, a moderate intensity statin may be appropriate for patients with multiple CV
risk factors.

8-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 (Antiplatelet) 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.
Complications and Comorbidities
 Microvascular Complications

Efforts to improve glucose control significantly reduce the risk of

developing microvascular complications and slow their
progression.

1. Nephropathy
2. Retinopathy
3. Neuropathy
Complications and Comorbidities
 Nephropathy:
1-Albuminuria is a marker of renal damage and can be predictive of end-stage renal
disease. 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 side effects. Three or
more antihypertensives are often needed to reach goal BP.
Complications and Comorbidities
 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.
Complications and Comorbidities
 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 can be severe and debilitating. Improved glycemic control,
discontinuation of medications that slow gastric motility, and use of
metoclopramide or low-dose erythromycin may be helpful.
Complications and Comorbidities
• 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-SMBG provides an opportunity to adjust medications, food intake, or physical activity

and enables patients to detect hypoglycemia.

3-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.

4-The optimal frequency of SMBG in patients with type 2 DM on oral agents is

controversial.

5-At each visit, ask patients with type 1 DM about the frequency and severity of
hypoglycemia.
Evaluation of therapeutic outcomes
6-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.

7-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).
TQ