Agents that mimic/prolong incretin action

GLP-1 Receptor Antagonist

• Injectable, adjunctive therapy in persons with type 2 DM treated with metformin

• HbA1c reductions of 0.2–1.2%. Weight loss in the range of 2–3 kg occurs and contributes to the improvement of glucose control

Agents that mimic/prolong incretin action

GLP-1 Receptor Antagonist

• Soluble fatty acid-acylated GLP-1 analog.

• Half-life: approximately 12 hours, permitting once-daily dosing

Agents that mimic/prolong incretin action

GLP-1 Receptor Antagonist

• Approved in patients with type 2 DM who achieve inadequate control with diet and exercise and are receiving concurrent treatment

• Reduction of HbA1c of 0.8–1.5%; weight loss ranges from none to 3.2 kg

Agents that mimic/prolong incretin action

GLP-1 Receptor Antagonist

• A human GLP-1 dimer fused to human albumin

• Half-life: 5 days

• Steady state: reached after 4–5 weeks of once weekly administration

• Weight loss is much less common

Agents that mimic/prolong incretin action

GLP-1 Receptor Antagonist

• Two GLP-1 analog molecules covalently linked to an Fc fragment of human IgG4.

• The GLP-1 molecule has amino acid substitutions that resist DPP-4 action.

• Half-life: about 5 days

Agents that mimic/prolong incretin action

Adverse Effects

• Increase the risk of pancreatitis

• Severe abdominal pain

Contraindication

• Persons with a past medical or family history of medullary thyroid cancer or multiple endocrine neoplasia (MEN) syndrome type 2

Agents that mimic/prolong incretin action

GLP-1 Receptor Antagonist

• Renal impairment and acute renal injury reported

Agents that mimic/prolong incretin action

GLP-1 Receptor Antagonist

• Nausea and injection-site erythema reported

Agents that mimic/prolong incretin action

DPP-4 Inhibitors

• Oral bioavailability of over 85%

• Peak concentrations within 1–4 hours

• Half-life: 12 hours

• Hepatic metabolism is limited and mediated by CYP3A4 isoform and CYP2C8.

Agents that mimic/prolong incretin action

DPP-4 Inhibitors

Adverse Effects:

• Nasopharyngitis, upper respiratory infections, and headaches

• Hypoglycemia can occur when the drug is combined with insulin secretagogues or insulin

• Post-marketing reports of acute pancreatitis (fatal and nonfatal) and severe allergic and hypersensitivity reactions

Agents that mimic/prolong incretin action

DPP-4 Inhibitors

• Reaches maximal concentrations within 2 hours (4 hours for its active metabolite).

• Minimally protein bound and undergoes hepatic metabolism by CYP3A4/5.

• Excretion is by both renal and hepatic pathways.

• Plasma half-life is 2.5 hours

Agents that mimic/prolong incretin action

DPP-4 Inhibitors

Adverse Effects:

• Increased rate of infections (URT and urinary tract), headaches, and hypersensitivity reactions (urticaria, facial edema)

• May increase the risk of heart failure

Agents that mimic/prolong incretin action

DPP-4 Inhibitors

• Lowers HbA1c by 0.4–0.6% when added to metformin, sulfonylurea, or pioglitazone

Adverse Effects:

• Nasopharyngitis and hypersensitivity reactions (urticaria, angioedema, localized skin exfoliation, bronchial hyperreactivity).

• Risk of pancreatitis may be increased

Agents that mimic/prolong incretin action

DPP-4 Inhibitors

• Lowers HbA1c by about 0.5-0.6% when added to metformin, sulfonylurea, or pioglitazone

Adverse Effects:

• Reports of hypersensitivity reactions (anaphylaxis, angioedema, Stevens-Johnson syndrome).

• Cases of hepatic failure have been reported should be discontinued

Agents that mimic/prolong incretin action

DPP-4 Inhibitors

• Lowers HbA1c by about 0.5–1% when added to the therapeutic regimen of patients with type 2 diabetes

Adverse Effects:

• Upper respiratory infections, nasopharyngitis, dizziness, and headache

• Rarely cause hepatitis, and liver function tests should be performed quarterly in the first year of use (periodically thereafter)

Agents that inhibit glucose reabsorption

SGLT2 Inhibitors

• Reduces the threshold for glycosuria from a plasma glucose threshold of approximately 180 mg/dL to 70–90 mg/dL.

• It has been shown to reduce HbA1c by 0.6–1% when used alone or in combination with other oral agents or insulin.

• It also results in modest weight loss of 2–5 kg

Agents that inhibit glucose reabsorption

SGLT2 Inhibitors

• Usual dosage is 10 mg daily, but 5 mg daily is recommended initially in patients with hepatic failure

• Reduces HbA1c by 0.5–0.8% when used alone or in combination with other oral agents or insulin.

• It also results in modest weight loss of about 2–4 kg.

Agents that inhibit glucose reabsorption

SGLT2 Inhibitors

• Usual dosage is 10 mg daily, but 25 mg/d may be used

• Reduces HbA1c by 0.5–0.7% when used alone or in combination with other oral agents or insulin.

• It also results in modest weight loss of about 2–3 kg.

Agents that inhibit glucose reabsorption

• Main adverse effects are increased incidence of genital infections and UTI

Agents that inhibit glucose reabsorption

SGLT2 Inhibitors

• _________ and __________ caused a modest increase in LDL cholesterol levels

Agents that inhibit glucose reabsorption

SGLT2 Inhibitors

• Has been reported to cause a decrease in bone mineral density at the lumbar spine and the hip

Agents that inhibit glucose reabsorption

SGLT2 Inhibitors

• Had higher rates of breast cancer and bladder cancer

Agents acting by other/ill-defined mechanisms

• Islet amyloid polypeptide (IAPP, amylin) analog

• A 37-amino-acid peptide present in insulin secretory granules and secreted with insulin.

• It has approximately 46% homology with the calcitonin gene-related peptide

• Physiologically acts as a negative feedback on insulin secretion.

Agents acting by other/ill-defined mechanisms

• Rapidly absorbed after subcutaneous administration

• Peak within 20 minutes

• Duration of action is not more than 150 minutes

• Injected immediately before eating

• Dosages range from 15 to 60 mcg subcutaneously for type 1 patients and from 60 to 120 mcg for type 2 patient

Agents acting by other/ill-defined mechanisms

• At pharmacologic doses, IAPP reduces glucagon secretion, slows gastric emptying by a vagally mediated mechanism, and centrally decreases appetite

Adverse Effects:

• Hypoglycemia and gastrointestinal symptoms, including nausea, vomiting, and anorexia.

Agents acting by other/ill-defined mechanisms

• Presumed to involve an interruption of the enterohepatic circulation and a decrease in farnesoid X receptor (FXR) activation

Agents acting by other/ill-defined mechanisms

• Bile acid sequestrant and Cholesterol-lowering drug

• Approved as an antihyperglycemic therapy for persons with type 2 diabetes who are taking other medications or have not achieved adequate control with diet and exercise.

Agents acting by other/ill-defined mechanisms

Adverse Effects:

• Gastrointestinal complaints (constipation, indigestion, flatulence).

• It can also exacerbate the hypertriglyceridemia that commonly occurs in people with type 2 diabetes.

Agents acting by other/ill-defined mechanisms

• Dopamine Agonist

• In randomized placebocontrolled studies lowered HbA1c by 0–0.2% compared with baseline and by 0.4 0.5% compared with placebo.

Adverse Effects:

• The main adverse events are nausea, fatigue, dizziness, vomiting, and headache.