Diabetes

mellitus
 Case tutorial
21-year-old patient (weight 80 kg) is given a diagnosis of T1D after the discovery of fasting
elevated glucose concentrations (average 326 mg/dL), and the patient has signs and
symptoms of hyperglycemia.

Which is the most appropriate correction of the dose of rapid-acting insulin before breakfast
for this patient? (Assume a TDI regimen of 0.5 unit/kg/day.)

A. 2 units.

B. 4 units.

C. 7 units.

D. 14 units.
 Answer
• TDI regimen of 0.5 unit/kg/day.)
• TDI =0.5 x 80 = 40 units
• “1800 rule”: 1800/TDI = milligrams per deciliter of glucose lowering
per 1 unit of rapid-acting insulin.
• 1800/ 40 = 45 mg/ dl
• BG now – BG target = 326- 130 = 196 mg/ dl
• 1 unit ………… 45 mg / dl
• X unit ………..196 mg / dl
= 4 units
 Therapeutic
management of T2D
Treatment of Type II DM
 Oral antidiabetic agents in Type 2 DM

Stepwise Addition of Medications

•Type 2 DM is a progressive disease, and the majority of patients will eventually
require combination therapy.
• A stepwise approach is recommended. For patients who have been
maximized on metformin therapy and have A1C levels above the target, a
second-line antihyperglycemic agent should be added.
•However, there is no clear-cut second-line agent that should be used. The ADA
Standards of Care identify six drug classes to consider in addition to metformin:
DPP-4 inhibitors, GLP-1 RAs, SGLT-2 inhibitors, sulfonylureas,
thiazolidinediones, and basal insulin.
Factors to be considered when
selecting an oral antidiabetic
•Patient-specific factors to consider when selecting a medication include the individualized
A1C target and presence of specific comorbidities (eg, ASCVD, heart failure, CKD, obesity).

• Drug-specific factors to consider include glucose-lowering efficacy, impact on other

comorbidities, impact on weight and hypoglycemia risk, side effect profile, ease of use, and
cost.
 Oral antidiabetic agents in Type 2 DM

1. Metformin (biguanide):
a. Mechanism of action:
i. Reduces hepatic gluconeogenesis.
ii. Increase insulin sensitivity
iii. Decrease intestinal absorption of glucose.
 Optimal first-line drug unless contraindicated
 Primarily reduces FBG values
 Adverse effects
a. Common: Nausea, vomiting, diarrhea (especially early)
b. Uncommon: Macrocytic anemia (caused by vitamin B12 deficiency); lactic acidosis
(uncommon but life threatening; use only in appropriate patients!)
 Metformin (biguanide):
Contraindications/precautions: (because of risk of lactic acidosis) :
i. Renal impairment: Serum creatinine 1.5 mg/dL or greater in men and 1.4 mg/dL or greater in
women or reduced creatinine clearance. Renal insufficiency increases risk of lactic acidosis.
ii. Age 80 years or older.
iii. High risk of cardiovascular event or hypoxic state.
iv. 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.
2. Sulfonylurea
Mechanism of action: stimulation of insulin secretion (insulin secretagogue).

a. First-generation agents seldom used today (e.g., chlorpropamide, tolbutamide).

b. Second-generation agents (e.g., glyburide, glipizide, glimepiride).

Adverse effects
a. Hypoglycemia
b. Weight gain

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).
 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. They require the presence of glucose to stimulate insulin secretion; as glucose levels
decrease to normal, stimulated insulin secretion diminishes. As monotherapy, they reduce
postprandial glucose excursions and reduce A1C by 0.8% to 1%.
d. Two currently available: Repaglinide and nateglinide.
e. Adverse effects: Hypoglycemia (though less than with sulfonylureas) and weight gain
 4. Thiazolidinediones (often called TZDs or glitazones):
a. Mechanism of action:
i. TZDs 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 indirectly. Insulin
must be present in significant quantities, and the drugs are referred to as “insulin sensitizers.”
a. Two agents available: Pioglitazone and rosiglitazone
b. Both drugs increase HDL-C, but pioglitazone has a more favorable effect in reducing LDL-C and TG
compared with rosiglitazone.
c. Adverse effects:
i. Fluid retention may occur, perhaps because of peripheral vasodilation and improved insulin
sensitization in the kidney with increased sodium and water retention. This may result in peripheral
edema, heart failure, hemodilution of hemoglobin and hematocrit, and weight gain.
Edema is dose related, and if not severe may be managed by dose reduction and use of spironolactone.
 4. Thiazolidinediones (often called TZDs or glitazones):
Cont’D

i. TZDs are contraindicated in patients with New York Heart Association Class III or IV
heart failure and should be used with caution in patients with Class I or II heart failure.

ii. Weight gain of 4 kg is not uncommon; both fluid retention and fat accumulation play
roles in this effect. Rarely, rapid gain of a large amount of weight may necessitate
discontinuation of therapy.

iii. 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. α-Glucosidase inhibitors:

a. Mechanism of action: Slows the absorption of glucose from the intestine into the
bloodstream by slowing the breakdown of large carbohydrates into smaller
absorbable sugars.
b. Two agents available: Acarbose and miglitol.

d. Adverse effects:
i. Flatulence, diarrhea, abdominal pain.
ii. Increased liver enzymes observed with high doses of acarbose.
e. Contraindications/precautions: Inflammatory bowel disease, colonic ulcerations,
intestinal obstruction.
f. Efficacy:
Targets postprandial glucose excursions.
 6. Dipeptidyl peptidase-4 (DPP-4) inhibitors:

a. Mechanism of action: Inhibits the breakdown of glucagon-like peptide-1 (GLP-1)

secreted during meals, which in turn increases pancreatic insulin secretion, limits
glucagon secretion, slows gastric emptying, and promotes satiety.
b. drugs:
i. Sitagliptin
ii. Saxagliptin
iii.Linagliptin
iv. Vildagliptin
 6. Dipeptidyl peptidase-4 (DPP-4) inhibitors:
Adverse effects:
i. Upper respiratory and urinary tract infections, headache.
ii. Hypoglycemia with monotherapy is minimal, but increased frequency with concurrent sulfonylurea
therapy (can lower dose of sulfonylurea when initiating).
iii. Sitagliptin has had some post-marketing reports of acute pancreatitis, angioedema, Stevens-
Johnson syndrome, and anaphylaxis.

Contraindications/precautions:
iv. Previous hypersensitivity to the agents.
v. History of pancreatitis.
 7. Incretin Analogs:
a. GLP-1 analog:

a. Mechanism of action: Synthetic analog of human GLP-1 that binds to GLP-1 receptors,

resulting in glucose-dependent insulin secretion, reduction in glucagon secretion, and reduced

gastric emptying; promotes satiety.

b. Approved agents available (exenatide, liraglutide, dulaglutide, lixisenatide, and semaglutide).
Both agents available in prefilled, multidose syringes for subcutaneous injection.
c. Adverse effects:
i. Nausea, vomiting, diarrhea very common.
ii. Hypoglycemia common with concurrent sulfonylurea (consider reduction in sulfonylurea
dose if adding exenatide).
iii. Postmarketing reports of pancreatitis, acute renal failure, or impairment.
 a. GLP-1 analog: (Cont’D)

Contraindications/precautions:
i. Impaired renal function: CrCl less than 30 mL/minute.
ii. History of severe GI tract disorder.
iii.History of pancreatitis.
iv. For liraglutide: Contraindicated in patients with a personal or family history of
medullary thyroid carcinoma (adverse effect found in rodent studies but not in
humans).
 b. Amylin analog:

a. Mechanism of action: Amylin is cosecreted with insulin and has effects similar to GLP-1
described above.
b. Pramlintide is currently the only agent in this class available in the United States. Can be used
in either type 1 or type 2 DM as adjunctive therapy in patients receiving insulin.
i. Use of prefilled pens is strongly recommended when possible versus using a syringe and vial to
reduce risk of dosing errors.
ii. Cannot be mixed with insulin products, requires increased frequency of daily injections.
Efficacy:
Very effective at controlling postprandial glucose excursions.

b. Adverse effects:
iii.Black box warning for severe hypoglycemia, especially in patients with type 1 DM.
iv. Nausea, vomiting, anorexia, headache.
 8. SGLT-2 inhibitor
a. Mechanism of action: Increases urinary glucose excretion by blocking normal reabsorption in

the proximal convoluted tubule; has some effect on delaying GI glucose absorption

b. Approved agents: Canagliflozin, Dapagliflozin, Empagliflozin and Ertugliflozin

c. Adverse effects
i. Increased urination
ii. Urinary tract infections
iii. Genital mycotic infections (more common in females)
iv. Hypotension
v. Increased hypoglycemia risk with concomitant insulin or insulin secretagogue
vi. Possible increased bone fracture risk, decreased bone mineral density, and foot or leg
amputation with canagliflozin
 8. SGLT-2 inhibitor (cont’D)
d. Contraindications and precautions

i. Significant renal impairment (varies by agent, as stated earlier)

ii. Suggested to ensure euvolemia before initiating agent, given its diuretic effect

especially in older adults, patients with existing renal impairment or already low

blood pressure, or patients receiving diuretics

iii. Consider factors that could predispose the patient to acute kidney injury (e.g., low

blood volume, chronic kidney insufficiency, heart failure, or medications that could alter
 9. Bile acid sequestrant

a. Mechanism of action

i. Bile acid sequestrant used primarily for cholesterol management. Colesevelam

ii. Used in conjunction with insulin or oral DM medications

 10. Bromocriptine
a. Mechanism of action: Not clearly understood. Agonist for dopamine receptor D2 is
thought to reset circadian rhythm, which can reduce caloric intake and storage.
b. Adverse effects: Nausea, somnolence, fatigue, dizziness, vomiting, headache, orthostatic
hypotension, syncope
c. Contraindications and precautions
i. Can limit the effectiveness of agents used to treat psychosis or exacerbate psychotic disorders
ii. Should not be used in nursing mothers or patients with syncopal migraines
iii. Concomitant use with dopamine antagonists (e.g., neuroleptic agents) can limit the efficacy of
both agents.
 Addition of Injectable Medications
•People with type 2 DM can often be managed with oral medications for years before
the addition of insulin is needed. Insulin is recommended for patients with extreme
(A1C>10% [0.10; 86 mmol/mol Hb]) or symptomatic hyperglycemia.

•Otherwise, GLP-1 RAs are preferred over insulin by the ADA as the first injectable
agent. GLP-1 RAs have demonstrated equal or superior A1C lowering efficacy
compared to basal insulin and lead to weight loss instead of weight gain with a
low risk of hypoglycemia.
DM complications
• A. Hypoglycemia
• B. Diabetic ketoacidosis (DKA)
• C. Hyperosmolar hyperglycemic state (HHS)
• D. Nephropathy
• E. Retinopathy
• F. Neuropathy
• G. CVD with DM
Diabetic ketoacidosis (DKA)
 Diabetic ketoacidosis (DKA)
 More common in type 1 DM but can occur in type 2 DM.
 Usually occurs because of a precipitating factor that considerably stresses
the body, resulting in increased counter-regulatory hormones:
• a. Inappropriate (including nonadherence) or inadequate insulin therapy and
infection are the two most common causes.
• b. Other causes: Myocardial infarction, pancreatitis, stroke, drugs (e.g.,
corticosteroids)

 Results in significant hyperglycemia, dehydration, and ketoacidosis

 Common signs/symptoms: Polyuria, polydipsia, vomiting, dehydration,
weakness, altered mental status, coma, abdominal pain, Kussmaul respirations,
tachycardia, hyponatremia and hyperkalemia.
Management of DKA
Case
1. A patient weighing 65 kg with symptoms of hyperglycemia and a fasting
glucose concentration of 298 mg/dL is given a diagnosis of type 1 diabetes
(T1D). The patient’s physician asks for a recommendation of an appropriate
starting dose of basal insulin and estimates the total daily insulin (TDI)
needs of 0.4 unit/kg/day. Which recommendation is most appropriate?
•A. 13 units of insulin detemir.
•B. 13 units of insulin aspart.
•C. 26 units of insulin glargine.
•D. 26 units of insulin glulisine