Therapy- T2DM
What is the usual reduction in A1C from bromocriptine?
0.1-0.5%
What is the usual reduction in A1C from bile acid sequestrant therapy?
0.5%
What is the usual reduction in A1C from α-glucosidase inhibitor therapy?
0.5-1.0%
What is the usual reduction in A1C from DPP-IV inhibitor therapy?
0.5-1.1%
What is the usual reduction in A1C from metformin therapy?
1-2%
What is the usual reduction in A1C from meglitinide therapy?
1-2% and 2-3% in combination
What is the usual reduction in A1C from sulfonylurea therapy?
1.5-2%
What is the usual reduction in A1C from TZD therapy?
1.5-2.5%
What is the most efficacious daily dose of repaglinide?
12mg
At what dose is the maximum A1C benefit achieved with 2nd generation sulfonylurea therapy?
50% of max dose
In which doses is metformin supplied?
500, 750, 850, and 1000 mg
When are patients at the highest risk of fractures on TZD therapy?
>2 years of therapy
Which agents are α-glucosidase inhibitors?
Acarbose (Precose) and Miglitol (Glyset)
What are the 1st generation sulfonylureas?
Acetohexamide (Dymelor), Chlorpropamide (Diabinese), Tolazamide (Tolinase), and Tolbutamide (Orinase)
What is the mechanism by which TZDs cause fractures?
Activation of PPAR-γ which inhibits bone formation and induces bone loss
What are "other" considerations for patients with T2DM?
Age, weight, sex, race, genetics, and comorbidities
What are contraindications of α-glucosidase inhibitors?
Any GI disease or symptom that causes GI disease
Why do 75-90% of patients with T2DM respond initially to sulfonylurea therapy?
As long as β cells remain then sulfonylureas will work
Which antidiabetics only affect fasting glucose levels?
Biguanides and Basal Insulin
What are the classes of oral antihyperglycemics?
Biguanides, TZDs, α-glucosidase inhibitors, DPP-4 inhibitors, Bile acid sequestrants, Dopamine agonists, and SGLT-2 inhibitors
Which antidiabetics increase the risk of pancreatitis due to the potential of increasing triglycerides?
Bile acid sequestrants
Which D2 agonist is an antidiabetic?
Bromocriptine Mesylate
Which comorbidities are taken into account in patients with T2DM?
CAD, HF, CKD, liver dysfunction, and hypoglycemia
Which agents are SGLT2 inhibitors?
Canagliflozin (Invokana), Dapagliflozin (Farxiga), and Empagliflozin (Jardiance)
What should NOT be administered to a patient with hypoglycemia that is on an α-glucosidase inhibitor?
Complex sugar because they cannot break it down so must administer simple sugar (glucose, lactose)
What are disadvantages of meglitinides?
Compliance may be a problem due to TID-QID dosing and *patients having a poor response to sulfonylurea therapy are NOT likely to respond if meglitinide is added onto therapy*
What are common side effects of colesevelam?
Constipation, dyspepsia, abdominal pain, and increased TGs
What is the place in therapy of TZDs for patients with HF?
Contraindicated in Class III or IV HF as they can cause fluid retention which may exacerbate or lead to heart failure and are not recommended in patients with symptomatic HF
Which class of antidiabetics is known to cause severe joint pain?
DPP-IV inhibitors
What is the MoA of metformin?
Decreased hepatic gluconeogenesis (primary MoA), improved glucose utilization and uptake in peripheral tissues, and decreased intestinal absorption of glucose
What are contraindications of SGLT2 inhibitors?
Dialysis, ESRD, hypersensitivity, eGFR <30 (Dapa and Cana) or <45 (Empa)
What are potential drug interactions of empagliflozin?
Diuretics and insulin
Meglitinides PK table
Dosed with meals and a snack so can be up to QID
What are contraindications of sulfonylureas?
Drug hypersensitivity (including inactive ingredients), T1DM, and DKA with or without coma
Which landmark study found that empagliflozin improves CV outcomes and mortality in T2DM?
EMPA-REG OUTCOME
When are α-glucosidase inhibitors beneficial for therapy?
Early stages of disease with only a mildly elevated A1C, relatively high blood glucose levels after meals, or relatively normal fasting blood glucose levels
What is the primary marker of metformin efficacy?
FPG 60-80 mg/dL
What are common side effects of bromocriptine?
Fatigue, dizziness, N/V/HA/D/C
What are precautions of SGLT2 inhibitors?
Genital mycotic infections, hypotension, renal impairment, hypoglycemia, LDL increase, elderly (cana), hyperkalemia (cana), and bladder cancer (dapa)
Which sulfonylurea is the best choice for patients with renal and liver dysfunction?
Glipizide
What are the 2nd generation sulfonylureas?
Glipizide (Glucotrol, Glucotrol XL), Glyburide (Diabeta, Glynase, Micronase), Glimepiride (Amaryl)
Which sulfonylureas are the best choice for elderly patients concerned with hypoglycemia?
Glipizide and Glimepiride
Which sulfonylurea should NEVER be chosen for therapy?
Glyburide
What are contraindications of colesevelam?
History of bowel obstruction, serum TG >500 mg/dL, or a history of hypertriglyceridemia-induced pancreatitis
What are contraindications of sitagliptin?
History of serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema
What are contraindications of bromocriptine?
Hypersensitivity to ergot-related drugs, syncopal migraines (may precipitate hypotension and increase risk of syncope), and nursing women (may inhibit lactation)
What is the MoA of DPP-IV inhibitors?
Inhibit DPP-IV enzyme which increases active incretin levels and insulin release and also decreases glucagon secretion in a glucose-dependent manner
What is the MoA of α-glucosidase inhibitors?
Inhibit secretion of intestinal amylase and α-glucosidase action which delays breakdown of complex CHO into glucose and absorption of glucose to distal portion of the small intestine resulting in a reduction of "peak" postprandial blood glucose concentrations
Coadministration of rosiglitazone and ______ is not recommended due to a greater risk of myocardial ischemic events
Insulin
What is the MoA of bromocriptine?
Insulin resistance is associated with attenuation of dopaminergic tone in the hypothalamus and timed pulse bromocriptine increases dopaminergic tone
What are therapeutic options for weight management in T2DM?
Intensive lifestyle program, metformin, GLP-1 agonists, and consider LADA in lean patients
SGLT2 inhibitor PK table
KNOW CrCl and eGFR
Metformin AEs and CIs
Know who is at risk and should NOT be on metformin
What are side effects of meglitinides?
Less weight gain compared to sulfonylureas
Which antidiabetics affect fasting and postprandial glucose levels?
Long acting GLP-1 agonists, Sulfonylureas, and TZDs
What are beneficial effects of metformin therapy?
Low risk of hypoglycemia, weight neutral (up to 5kg loss), decreased TGs/LDL, increased HDL, decreased progression to diabetes, positive CV benefits in obese patients, and enhanced GLP-1 secretion
What are advantages of meglitinides?
Lower insulin exposure and potential for hypoglycemia, and dose may be omitted if a meal is skipped
What is the MoA of Sodium Glucose Cotransporter 2 (SGLT2) inhibitors?
Lowers renal threshold for glucose and increases urinary glucose excretion
What are examples of sex, ethnic, racial, and genetic differences in T2DM?
MODY & other monogenic forms of diabetes, Latinos have more insulin resistance, East asians have more β cell dysfunction, and gender may drive adverse effects
What are warnings and precautions of colesevelam?
May decrease absorption of fat-soluble vitamins and due to constipating effects is not recommended in patients at risk for bowel obstruction (gastroparesis, GI motility disorders, GI surgery), and can also reduce absorption of some drugs (separated by 4 hours if needed)
What is the most commonly prescribed antidiabetic?
Metformin (Glucophage, Glucophage XR, Glumetza, Fortamet)
How should HF be managed in T2DM?
Metformin (unless condition is unstable or severe), can use TZDs if stable or moderate HF but not in severe cases
How should CAD be managed in T2DM?
Metformin has CVD benefit (UKPDS) and avoid hypoglycemia
What is a major drug interaction of bromocriptine?
Metoclopramide which may diminish the effectiveness of bromocriptine which may diminish effectiveness of other therapies and so coadministration is not recommended
How should liver dysfunction be managed in T2DM?
Most drugs not tested in advanced liver disease, Pioglitazone may help steatosis, and insulin is the best option if disease is severe
What are drug interactions of dapagliflozin?
N/A
What are drug interactions of sitagliptin?
N/A
Sulfonylurea hypoglycemia may be potentiated by which other drugs?
NSAIDs, Clarithromycin, Salicylates, Sulfonamides, Chloramphenicol, Coumarins, Probenecid, MAOIs, β-blockers, Disopyramide, Fluoxetine, and Quinolones
What are the most common adverse reactions of sitagliptin?
Nasopharyngitis, URIs, HA
Which meglitinide elicits more of a physiological mealtime insulin secretion response? Why?
Nateglinide because it has a more rapid onset and shorter duration of action than repaglinide
Alogliptin CIs, DIs, AEs, and warnings
Note: A lot more side effects
2nd generation sulfonylurea PK table
Note: Hepatic metabolism and renal excretion
α-glucosidase inhibitor PK table
Note: Max dose based on weight
Bromocriptine PK table
Note: Must dose at the same time every morning
DPP-IV Inhibitor PK table
Note: Weight neutral
What are drug interactions of colesevelam?
Phenytoin (decreased levels), Warfarin (decreased INR), and TSH (increased levels)
Which TZD is typically not prescribed at the maximum dose? Why not?
Pioglitazone because the side effects are detrimental for bladder cancer
What is a major benefit of TZD therapy on β cells?
Preservation of β cells for 1-2 years
Which factors have beneficial effects on sulfonylurea therapy?
Recently diagnosed (<5 years), 40 years of age or older, weight within 110-160% of IBW, FBG <200 mg/dL, <40 units/day of insulin or none at all
What are additional risks for older adults with T2DM?
Reduced life expectancy, higher CVD burden, reduced GFR, AEs from polypharmacy, and more likely to be compromised from hypoglycemia
Which agents are meglitinides?
Repaglinide (Prandin) and Nateglinide (Starlix)
What are drug interactions of canagliflozin?
Rifampin, Ritonavir, Phenobarbital, Phenytoin, and Digoxin
Which agents are TZDs?
Rosiglitazone (Avandia) and Pioglitazone (Actos)
What are contraindications of meglitinides?
Same as sulfonylureas but also gemfibrozil interaction
What is the MoA of meglitinides?
Same as sulfonylureas but also the extent of insulin release is glucose dependent and diminishes at low glucose levels
What are the two types of oral antidiabetics?
Secretagogues and Antihyperglycemics
What are side effects of sulfonylureas?
Side effects characteristic of increased insulin production
Which agents are DPP-IV inhibitors?
Sitagliptin (Januvia), Saxagliptin (Onglyza), Linagliptin (Tradjenta), and Alogliptin (Nesina)
What is the MoA of sulfonylureas?
Stimulate insulin release from β cells in pancreas and bind to specific receptor on β cell closing an ATP-dependent K channel which depolarizes the cell membrane and opens Ca channel to increase intracellular [Ca] which releases insulin
What is the MoA of secretagogues?
Stimulate release of insulin from pancreas, which may decrease hepatic gluconeogenesis and insulin resistance
Which classes of oral antidiabetics are secretagogues?
Sulfonylureas and Meglitinides
Coadministration of bile acid sequestrants with which agents can lead to a greater increase in triglycerides?
Sulfonylureas and insulin
What is the major difference between sulfonylureas and meglitinides?
Sulfonylureas are long acting and meglitinides are short acting
Why is colesevelam not recommended in pediatric patients?
Tablet size
What is the utility of incretins in T2DM
Target multiple defects of T2DM, lack hypoglycemia, favorable effects on weight, augment β cell function, and may affect disease progression through β cell preservation
How can GI side effects of α-glucosidase inhibitors be limited?
Titration
T/F: A majority of T2DM patients are overweight or obese
True
T/F: B12 levels are not tested upon initiation of metformin unless a deficiency is already present
True
T/F: Colesevelam should only be used if clearly needed during pregnancy and does NOT require dosage adjustment in hepatic or renal impairment
True
T/F: DPP-IV inhibitors do NOT inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses and also do NOT affect satiety or gastric emptying
True
T/F: Pioglitazone can be used with caution in patients with a prior history of bladder cancer but NOT patients with active bladder cancer
True
T/F: SGLT2 inhibitors can cause DKA leading to hospitalization but there is only a temporal association
True
T/F: Repaglinide is more potent than nateglinide
Tue
How long can it take to achieve a full effect from TZDs?
Up to 12 weeks
How long can it take for metformin therapy to be effective?
Up to 8 weeks but a majority of patients see benefits sooner
Is there any benefit of utilizing the maximum dose of metformin?
Using the maximum dose does not provide additional benefit and only causes more side effects
What are limitations of TZD therapy?
Weight gain (fluid retention, fat accumulation, CHF exacerbation, macular edema, cost, CV disease, fractures, and bladder cancer
What are non-pharmacological treatments for T2DM?
Weight optimization, healthy diet, and increased activity level
When should α-glucosidase inhibitors be administered?
With first bite of a meal
Which antidiabetics only affect postprandial glucose levels?
α-glucosidase inhibitors, DPP-4 inhibitors, Dopamine agonists, Meglitinides, Short acting GLP-1 agonists, Amylinomimetic (pramlintide), SGLT2 inhibitors, and Bolus insulin