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In which patients are insulin treatments ESSENTIAL?

Type I diabetes. These patients no longer have insulin and therefore you must treat them with insulin (making up for what they lack)
*they are indicated for late and progressive type ii diabetes that is not able to be controlled with non-insulin treatments and lifestyle changes


What are the bolus insulins used for prandial therapy?

• Humalog
○ Lispro
• Novolog
○ Aspart
• Glulisine
○ Aprida
• Inhaled insulin (Afrezza)
*these agents can be effectively used in insulin pumps


What is the time to onset of the bolus insulins? What is their clearance time?

These are rapid acting and should be used for prandial therapy
* Lispro, Aspart, Glulisine (Girls and Lads from sketchy)
*they lead to a 15minute or so onset of insulin action
*their peak action is about 1 hour
*their activity lasts 3-5 hours in total
*these agents can be effectivly used in insulin pumps


What are the short acting human insulins?

• Straight up regular insulin
• Humulin R
• Novolin R
○ Recombinant human insulin


When do you use intravenous insulin infusions?

• Think regular, recombinant insulin here
• Hyperosmolar hyperglycemic state
• Inpatient hyperglycemia in which glycemic control is desired, like peri-operatively and ICU patients
• IV insulin has immediate effect and rapid off-set (15 min or so)
• Thus no benefit to using a rapid acting IV agent


What is the usual dose of regular, recombinant insulin in hospital setting therapy?

• Hospital setting b/c regular insulin not often used in outpatient setting because of the difference in physiological timing
• 5-15 units is the usual dose
• This leads to clearance after 6-8 hours


What are the pharmacokinetic profiles of the short acting human insulins?

• Regular insulin (recombinant insulin)
• Not often used in outpatient b/c kinetics do not match well with physiologic needs
• 30 min before meals
• 30-60 minute onset with 2 hr peek
• Duration is 6-8 hours if used in normal doses
• 5-15 units are the normal dose


What are the "basal" insulins?

• These are the long acting ones that mimic the basal action of insulin in the body
• These are not prandial, but provide the insulin necessary to handle normal glucose fluctuations throughout the day
○ Remember thought that WELL CONTROLLED diabetes HbA1C is still 7%
• Glargine (Lantus)
• Detemir (Levemir)
• Degludec (Tresiba)
• Glargine U-300 (toujeo)


What makes the long acting insulins "long acting"

• They are formulated in a way that allows for less rapid dissolving and incorporation into the plasma
• Glargine has extra arginines that makes it precipitate in the subcutaneous neutral pH
○ Onset is 1.5 hr and 24 hour duration, taken once a day
• Detemir has an additional fatty acid chain which allows it to be more liphophilic and bind serum protein better, increasing duration of action to 12-20 hrs. usually taken 2X a day
• Degludec is the newest and has 42 hours of duration and is injected once daily


As far as drug mixing goes (insulin) what about NPH insulin vs. glargine?

• Glargine can't be mixed with other insulins because it's stored in an acidic manner
• NPH insulin and regular insulin CAN be mixed up in the same delivery stystem


What are the pharmacokinetics of NPH and Humulin insulin?

• NPH = neutral protamine Hagedorn
• The brand names are Humulin N, Novolin N
• Another word to look for is sophane
• Cloudy solution
• 1-3 hour onset with 6-8 hour peek
• Lasts 12-16 hours and is mostly used for the lunch-time peak in glucose


What is meant by "pre-mixed insulins"?

• Human: %NPH/%regular
○ Usually 70/30 or 50/50
• Humalog/regular is an option for the analogs
○ Humalog 75/25
§ Or 50/50
○ Novolog 70/30
• Allows for short term benefit for meals with longer action basal coverage
• Analog mixed - Injected 5-15 minutes before meal and have pharmacokinetics that are more physiologic than NPH/regular b/c of basal and spike mix


What is meant by basal bolus therapy?

• This includes the basal, prandial and correctional insulin needs
• You are mimicking with injection the normal insulin release of the body


Glargine, Detemir and NPH are used for what purpose?

• These are basal insulin medications
• Used for a patient to cover normal daily cyclical glucose spikes or hormone swings
• Suppresses hepatic glucose output and lowers overall glucose levels throughout the day
• Type 1 patients will develop DKA if they do not inject their basal insulin doses while type 2 patients will develop severe hyperglycemia but usually have enough endogenous insulin secretion to prevent ketoacidosis


If you wanted to start a patient on insulin therapy what is the estimate you can use to figure out the starting dose?

• 0.2 units/kg/day is the weight based method
• Titrated according to individual needs and circumstances
• Type 2, which has some insulin resistance in it, think more along the 0.5 units/kg/day for basal insulin


Describe the treatment paradigm of prandial insulin

• Used to metabolize nutrients in a meal or snack and cover the postprandrial rise in glucose
• The rapid-acting insulins are used for this
○ Humalog, novolog, apidra
○ Girls and Lads - Glulisine, Aspart and Lispro
• You can estimate the dose according to the carbohydrate to insulin ratio (C:I)
• Number of grams of carbohydrates that 1 unit of insulin is anticipated to cover for that individual
○ Insulin sensitive individuals may require a C:I ratio of 15:1 or 20:1
○ Resistant is more 10:1 or 8:1


How do you go about determining the dose of insulin for CORRECTION?

• Correctional doses of insulin are used to correct a high blood glucose level
• Humalog, novolg, apidra and inhaled insulin all used
• Usually added to a prandial insulin dose
• You determine the correction factor or sensitivity factor by dividing a constant, 1600, by their total daily dose of insulin
• The resulting number is the number of mg/dL that the blood glucose is expected to drop with each unit of insulin given as a correction dose
• Normal sensitivity might have a correction factor of 50
○ 1 unit of rapid acting insulin would be expected to drop the glucose by 50mg/dL
• Resistence might look like a correction factor of 20
○ 1 unit will drop glucose 20mg/dL


Describe the general, overall treatment paradigm of type 1 diabetes patients

• standard care is intensive multiple-dose insulin or basal bolus therapy
• This provides more physiologic replacement of insulin
• Allows for flexibility in timing, size and composition of meals
• Pre-meal doses can be fixed according to carbohydrate content of a given meal
• Must take into account lifestyle, motivation and preferences as well as cost
• Glargine injected once daily provides basal coverage for about 24 hours (detemir is 2X daily))
• Bolus dose is added to this before meal and additional correctional doses can be added as well according to correction factor
• Also think of the glucose pumps and the artificial pancreas


Describe the overall and general treatment paradigm for type 2 diabetes

• Essentially use insulin in patients who have not achieved good control before
• With data from home glucose monitoring, doses of rapid-acting insulin are added successively until glycemic control is achieved
• In this case though, consider the use of all non-insulins before starting insulin therapy
• Usually add insulin after 2-3 non-insulins are tried and are not effective in controlling the glucose target/goal
• In cases of severe insulin deficiency you should use insulin right away
• Fasting over 250, random over 300 and A1c over 10%
• Use insulin at first and see if you can titrate down or off
• Also use insulins in hyperglycemic hyperosmolar state or DKA
• Discharge with insulin and maybe taper with outpatient follow up


What are the different targets for treatment of diabetes?

• ADA recommends:
○ Less than 7% A1c
○ Fasting glucose - 70-130mg/dL
○ 2 hr post-meal glucose is less than 180mg/dL


What are the lifestyle recommendations made in the treatment of diabetes?

• Less calorie-dense foods
• More complex carbohydrates (as opposed to simple like high fructose corn syrup?)
• Higher fiber, lean proteins, smaller portions
• Increase physical activity
• Weight loss to normal range


What is metformin?

• Biguanide drug
• Potentiates the suppressive effect of insulin on hepatic glucose production
• Does not stimulate insulin secretion or increase circulating insulin levels
• Risk of lactic acidosis lower than a different drug in this class which is pulled off the market
○ But the risk still exists
• Use eGFR to guide use, since renal failure may precipitate lactic acidosis


What are the pros and cons to metformin use?

• Pros
○ Mechanism of action is more or less safe
○ No hypoglycemia
○ Inexpensive
○ No weight gain (slight weight loss)
○ Combinations are possible
§ Sulfonylureas
§ Thiazolidinediones
§ DPP-4 inhibitor
§ SGLT-2 inhibitor
• Cons
○ GI side effects - nausea, bloating, diarrhea
○ Risk of lactic acidosis - contrast media, CHF, renal insufficiency, liver disease


If metformin is not enough in your type 2 diabetes patient, and they have CV comorbidities, now what do you recommend?

• Add SGLT-2 or GLP-1RA to the regimen


You have a 51 year old woman with a 9yr histor of T2DM, A1c of 8.4% and is only on metformin right now. What additional therapies can be recommended at this point

• Again, have the lifestyle change conversation (always)
• Drugs (essentially just add another one)
○ Sulfonylurea
○ Thiazolidinedione
○ Basal insulin
○ GLP-1 receptor agonist
○ DPP-4 inhibitor
○ SGLT-2 inhibitor


What are the drug-specific considerations for thinking through additive glucose-lowering therapies?

• Mechanism of action
• Glucose-lowering effectiveness
• Side effects
• Cost
• Convenience
• Pharmacokinetics
• Non-glycemic beneficial effects


What are the patient-specific considerations for thinking through additive glucose-lowering therapies?

• Baseline control
• Stage of diabetes
• Co-existing medical conditions
• Tolerability of side effects
• Social situation
• Financial situation
• Preference of therapy


If a DM patient has primarily a problem with insulin resistance, what are the drugs of choice?

• Metformin
• DPP-4i
• Insulin


How many times per year should A1c be measured in a diabetic patient?

• 2-4 times per year in ALL diabetic patients
• At that point you re-hash goals and talk about risk/benefit


How much of a reduction in A1c can the standard T2DM non-insulin drugs be expected to give you?

• Metformin - 1-2% reduction
• Every other drug but insulin will give you a 0.5% reduction
• The other exception is sulfonylureas, which can be expected to give you about the same reduction as does metformin


What are the Incretins?

• GLP-1 = glucagon-like peptide 1
○ Very effective for lowering glucose in diabetes
• GIP = gastric inhibitory peptide
○ Secreted by cells in GI tract in response to food intake
○ Augments insulin secretion only if blood glucose is elevated


What are incretins supposed to treat?

• The incretin effect
• This is the fact that there is insufficient insulin secretion AND insufficient glucagon supression in response to a meal in type 2 diabetes


What are all the ways that GLP-1 lowers glucose?

• Food intake will stimulate GLP-1 secretion from L cells of ileum
• This stimulates glucose-dependent insulin secretion and SUPRESSES postprandial glucagon secretion
• This leads to decreased hepatic glucose output, slowed gastric emptying and inhibited food uptake
• The end result is a normalized blood glucose


What is DPP-4 and why must it be inhibited?

• DPP-4 is what breaks down GLP-1
• DPP-4 = dipeptidyl peptidase 4
• Inhibit it to allow GLP-1 agonists to do their work of inhibiting glucagon secretion


What are the GLP-1 agonists you should know about?

• Exenatide
○ byetta
• Liraglutide
○ victoza
• Exenatide qwk
○ bydureon
• Albiglutide
○ tanzeum
• Dulaglutide
○ Trulicity


What are the pros and cons of GLP-1 agonists?

• Pros
○ Multiple mechanisms of action to lower postprandial glucose
○ Effects are glucose-dependent
○ Weight loss
○ Recent trial suggests CV benefit
• Cons
○ SC injections
○ Side effects
○ expensive


What are the DPP-4 inhibitors to know about?

• Sitagliptin
• Saxagliptin
• Linagliptin
• Alogliptin
○ Just remember the clips on the old hag's nose in the sketchy picture


What are the pros and cons to the use of DPP-4 inhibitors?

• Pros
○ Multiple mechanisms of action to lower postprandial glucose
○ Oral admin
○ Once daily admin
○ Weight neutral drugs
○ Combination pill with metformin
• Cons
○ Less potent glucose-lowering effect
○ Expensive
○ Side effects


What are the SGLT-2 inhibitors to know about?

• Sodium glucose co-transporter 2 is what is being inhibited - in proximal tubule
• Canagliflozin
○ invokana
• Dapagliflozin
○ farxiga
• Empagliflozin
○ Jardiance


What level of glucose can the normal kidney handle?

• Filtered glucose load of about 180 g/day
• Urinary glucose less than 0.5g/day
• Glucose reabsorption occurs in the proximal tubule though the action of SGLT1 and 2


What are the pros and cons of SGLT2 inhibitors?

• Pros
○ Novel mechanism for controlling glucose
○ Weight loss
○ Pill
○ At least 1 available as a combo pill with metformin
○ Recent trial suggesting CV benefit
• Cons
○ Increased risk for urinary tract and GU infections
○ Increased risk for low potassium
○ Expensive
○ Questionable long-term safety because they are new and not all that well studied far out


What is the mechanism of action for sulfonylureas?

• Close the ATP-sensitive K+ channels in the beta cell
• Closing of the potassium channels will depolarize the beta cell and lead to influx of calcium and secretion of insulin granules


What are the sulfonylureas to know?

• Glyburide
• Glipizide
• glimepiride


What are the pros and cons of the sulfonylureas for diabetes treatment?

• Pros
○ Inexpensive
○ Combos available
§ Metformin
§ Thiazolidinediones
• Cons
○ Weight gain
○ Hypoglycemia
○ Loses effectiveness with longer duration of diabetes
§ Since the beta cells are getting more and more burned out