Case 3 A 50 year old female presents at the OPD with symptoms of fatigue,

increased thirst & frequent urination. Her family history is significant for obesity,
diabetes & hypertension. Two of her 4 children had birthweights of over 9 pounds.
PE revealed a BMI of 34, blood pressure of 150/90 mm Hg and there was noted
weakness of both upper & lower extremities. Lab tests reveal a random blood sugar
of 260 mg/dL which was confirmed with a fasting plasma glucose of 193 mg/dL.
Guide Questions
1. What is your diagnosis? Describe the mechanism in the development of the
disease.
TYPE 2 DIABETES MELLITUS is a heterogeneous syndrome
characterized by abnormalities in carbohydrate and fat metabolism. The
causes of type 2 diabetes are multi-factorial and include both genetic and
environmental elements that affect beta-cell function and tissue (muscle,
liver, adipose tissue, pancreas) insulin sensitivity. It is characterized by an
insulin resistance combined with a relative deficiency in insulin secretion
leading to an unused supply of glucose in the blood (hyperglycemia) and its
toxicities.
2. What drug should be used as initial therapy? Describe its mechanism of
action and expected adverse reactions expected.
The standard therapy for diabetic patients is intensive glycemic control
and targeting near-normal glucose control associated with comprehensive
self-management. In pharmacologic treatment, however, Metformin is a firstline consideration. Metformin decreases hepatic glucose output through the
activation of AMP-activated protein kinase (AMPK) and, to a lesser extent,
sensitizes peripheral tissues to insulin. The most common toxic effects of
metformin are gastrointestinal (nausea, vomiting, abdominal discomfort and
diarrhea) which occur in 20% of patients. These are dose-related, tend to
occur at the onset of therapy, and are often transient.
Also, since there is a mild dysfunction of the beta-cells in the pancreas,
insulin therapy may also be a choice for these patients.
3. In case of clinical failure with the above drug, what drug can be used as
second agent. Describe their mechanisms of action and adverse reactions
expected. Which one is preferred? Why?
If metformin doesnt work, then possible second line treatments would
be Sulfonylureas (less expensive, with risk of hypoglycemia) or
Thiazolidenediones (more expensive, no risk of hypoglycemia).
Sulfonuylurea insulin secretagogues (e.g., glipizide [Glucotrol],
glimepiride [Amaryl]) and nonsulfonylurea insulin secretagogues (e.g.
nateglinide [Starlix]) increase insulin secretion by closing potassium channels
on the surface of pancreatic beta cells. Hypoglycemia can occur with any
insulin secretagogue. Sulfonylureas can cause weight gain; this effect is less
common with nonsulfonylurea secretagogues.

Thiazolidinediones increase insulin sensitivity in peripheral tissues and,

to a lesser extent, decrease hepatic glucose production. These agents will not
cause hypoglycemia when used as monotherapy. Thiazolidinediones (TZDs)
are agonists of peroxisome proliferator-activated receptor gamma (PPAR) and
primarily enhance sensitivity of muscle and fat, and mildly of the liver, to
exogenous and endogenous insulin. TZDs lower fasting and postprandial
blood glucose levels.
Thiazolidenediones would be a good choice since it can be taken only
once a day, however, studies suggest that these types of drugs increase the
risk of cardiovascular complications, especially to person with a
cardiovascular disease already so the decision would be up to the doctor
giving the medicine and the situation of the patient.
4. Describe possible third and fourth line therapy including mechanisms of
action and adverse reactions associated.
1. Alpha glucosidase inhibitors competitively block the enzyme alpha
glucosidase in the brush borders of the small intestine, which delays
absorption of carbohydrates (absorbed in the mid and distal portions of
the small intestine instead). They primarily target postprandial
hyperglycemia without causing hypoglycemia. GI complaints, such as
bloating, abdominal cramps, flatulence, and diarrhea are the main side
effects.
2. Incretin-based therapies can be used as injections (GLP-1 analogs) or as
pills (DPP-4 inhibitors). All incretin-based medications carry increased risk
of acute pancreatitis. Patients must be warned about this risk and be
advised to stop taking these medications and seek medical evaluation if
acute abdominal pain develops.
3. SGLT-2 inhibitors are the newest group of medications approved for
treatment of diabetes mellitus. SGLT-2 is a protein acting as sodiumglucose co-transporter in the kidneys proximal tubules whose main
function is reabsorption of the filtered glucose from the urine back into the
circulation. It is responsible for about 90% of total glucose reabsorption.
Inhibition of this protein leads to the excretion of the glucose in the urine
at much lower blood glucose level than normal. The most common side
effects of SGLT-inhibitors are vaginal yeast infections and urinary tract
infections. The greatest risk is seen in female patients and those men who
are uncircumcised. Polyuria is also seen.