Diabetes Mellitus

Lecture 2

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Learning Objectives: Lec 2

Explain the outcomes and clinical significance of UKPDS for patients with type 2 diabetes Discuss the 10 year post-trial UKPDS data Differentiate the presented diabetes care guidelines from the

ADA, AADE, and the PSW diabetes toolkit Compare and contrast the pharmacokinetic, adverse effect,

and drug interaction profiles of sulfonylureas, metformin, and alpha-glucosidase inhibitors Recommend appropriate therapeutic plans (including

monitoring parameters) for patients taking sulfonylureas, metformin, and alpha-glucosidase inhibitors

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Landmark Clinical Trial: UKPDS 33

United Kingdom Prospective Diabetes Study

Type 2 diabetes Subjects

median age: 54 n=3867 randomized newly diagnosed

Intervention: “intensive” therapy (insulin/sulfonylurea) vs. “conventional” therapy (MNT + exercise)

Primary endpoint: incidence of microvascular and macrovascular complications

Follow-up: median of 10 yrs

Lancet. 1998;352:837-853.

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UKPDS 33 Results

Results 25% decreased risk of microvascular endpoints 16% decreased risk of MI 24% decreased risk of cataract extraction 21% decreased risk of retinopathy at 12 yrs

Lancet. 1998;352:837-853.

UKPDS 34-Metformin study

Results Analysis #1 A1c

metformin: 7.4% conventional: 8.0%

diabetes related endpoint: 32% reduction with metformin diabetes-related death:

42% reduction with metformin all-cause mortality: 36%

reduction with metformin

Analysis #2: metformin had greater

effect than sulfonylureas or insulin for any of the three endpoints

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Lancet. 1998;352:854-865.

Primary endpoints: any diabetes-related endpoint, diabetes-related death and all-cause mortality

UKPDS: 10 years post-trial Tight BP control

follow-up BP control Differences @ 2 yrs @10 yrs: risk not sig.

Microvascular & macrovascularoutcomes

Tight BG control follow-up BG control A1c diff lost 1 yr post-trial RRR for DM-related endpt

& microvascular dzpersisted RRR for MI & death from

any cause: signif over time Continued benefit

metformin in overweight

6N Engl J Med. 2008;359. (10.1056/NEJMoa0806359)

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Type 2 Diabetes: Treatment Goals

Euglycemia Prevent morbidity/mortality from macrovascular

complications Tight control in most patients Improved QOL Prevent hypoglycemia Blood pressure control Lipid management Prevention of long-term complications

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Type 2 Diabetes: Treatment Options

Nonpharmacologic MNT Exercise

Pharmacologic Oral agents Metformin Sulfonylureas Glinides Acarbose/Miglitol TZD DPP4-inh SGLT-2 inh Combinations

Pharmacologic Injected Pramlintide GLP-1 agonists

Insulin Monotherapy Combination therapy

American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74

American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to Glycemic Treatment. Diabetes Care.2019;42(suppl 1):S94.

T2DM Treatment Framework: ASCVD, HF or CKD

11PSW Diabetes Toolkit

T2DM Treatment Framework:NO Heart or Kidney disease

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PSW Diabetes Toolkit

American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to Glycemic Treatment. Diabetes Care.2019;42(suppl 1):S93.

Non-Insulin AntihyperglycemiaMedications

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PSW Diabetes Toolkit

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Metformin (Glucophage®) Mechanism of action antihyperglycemic agent primary: decreased hepatic glucose production secondary: increased insulin sensitivity in muscle (not

clinically relevant per euglycemic clamp studies) does not promote pancreatic insulin release requires insulin for efficacy

How would you explain this to a patient?

Metformin:Place in Therapy Monotherapy obese patients dyslipidemia price efficacy vs.

sulfonylureas Combination therapy sulfonylureas insulin

What about type 1 diabetes patients?

What about pediatric patients?

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Metformin: Efficacy Decrease A1c by 1.0 to 2.0% similar primary failure rate to sulfonylureas lipids ? Effect from glycemic control fractions TG decrease 16% LDL decrease 8% total cholesterol 5% HDL increase 2%

No weight gain

Non-DM Metformin Benefits Decreased cancer risk

BMJ. 2005;330:1304-1305 Diabetes Care. 2006;29:254-258 PLoS One. 2013;8(8):e71583

Decreased breast cancer incidence Journal Clinical Oncology 2012

Decreased colorectal cancer risk Diabetes Care. 2011; 34(10):2323-2328.

Neuron growth & improved memory (mice) Cell Stem Cell. 2012;11(1):23-35.

Increased survival in men with prostate cancer J Clin Oncol. 2013;31(25):3069-3075.

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Metformin Benefits: CV UKPDS Diabetes Care epub 12.10.12 Type 2 DM & CAD Randomized: glipizide vs metformin Results:Median f/u 5 years CV outcomes: HR 0.54 (metformin)

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Metformin: Toxicity

GI* metallic taste diarrhea nausea vomiting Anorexia

No hypoglycemia (monotherapy) Interaction with TSH

How to manage the GI side effects?

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Metformin Toxicity Lactic acidosis Rare complication 50% fatal

Symptoms Feeling weak, tired or uncomfortable Unusual muscle pain Trouble breathing Feeling cold, dizzy, or lightheaded Sudden onset of a slow or irregular heartbeat “flu-like” symptoms

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Metformin Toxicity Lactic acidosis Contraindicated Kidney impairment (see slide 27 regarding dosing) Hepatic disease & alcohol abuse Respiratory insufficiency Hypoxemic condition Cardiovascular collapse Acute MI Septicemia

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Metformin Toxicity

Lactic acidosis Radiological studies with iodinated contrast

materials Hold doses for 48 hours after procedure Restart after kidney function back to normal

Use with caution in older adults Age-related decline in kidney function

Metformin Dosing Tablet strengths available

“Regular” release 500 mg, 850 mg, 1000 mg

“XR” formulation (Glucophage XR®, Glumetza®) 500 mg, 1000 mg

Initial “Regular” 500 mg once daily with

breakfast x 5-7 days then 500 mg BID

“XR” Glucophage XR:500 mg

once daily with evening meal Glumetza: 1000 mg once

daily with evening meal25Diabetes Care. 2006;29(8):1969

Metformin Dosing Titrate weekly to biweekly (monthly in older

adults) 500 mg incrementsMin effective dose: 1500 mg per dayMax dose: 1700 mg vs 2000 mg vs. 2550 mg

26Also see in Canvas: metformin titration

Metformin Dosing: Kidney Impairment

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JAMA. 2014;312(24):2668-2675.

PSW Diabetes Toolkit

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Sulfonylurea Responders

Recent diagnosis (within 5 years) 110-160% IBW fasting glucose < 200 mg/dl insulin < 40 units/day > 40 years old

Note: opposites of each of these points are relativecontraindications to sulfonylureas

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Sulfonylureas:

MOA: Increase insulin secretion by direct stimulation

of the pancreas Efficacy: Decrease A1c by 1.0 to 2.0%

How would you explain MOA to a patient?

Sulfonylureas: Place in Therapy

PSW Diabetes Toolkit

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ADA

AACE

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Sulfonylureas: Contraindications

Type 1 diabetes Pregnancy (?) or lactation Hypersensitivity ? Sulfa allergy

Severe renal or hepatic dysfunction Acute stressors

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Sulfonylureas: Failure Primary failure 30-40% fail maximum doses Why? MNT nonadherence Severe beta cell impairment

Secondary failure progressive: 1 month to several years 5-10% per year add another agent consider switch to insulin

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Toxicity: Sulfonylureas

Hypoglycemia* consider potency & duration of action worst agents glyburide chlorpropamide

risk factors age kidney function nutrition dose excretion

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Toxicity: Sulfonylureas Gastrointestinal nausea fullness heartburn

Dermatologic pruritus Rash

Weight gain*

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Toxicity: Sulfonylureas

Hematologic reports: leukopenia, agranulocytosis,

thrombocytopenia, hemolytic & aplastic anemia

SIADH hyponatremia

Vision possibly due to changes in blood glucose change in lens

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Sulfonylureas: First Generation

Drug Duration Active Metab?

Doses per Day

Cautions

Tolbutamide Short No BID-TID, ac

disulfiram

Acetohexamide Intermed, prodrug

Kidney failure

Tolazemide Intermed Partially Once-BID Kidney failure

Chlorpropamide Long Yes Once daily Disulfiram, SIADH, hypoglycemia, kidney failure, elderly

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Sulfonylureas: Second Generation

Glyburide DiaBeta®, Micronase®, generic Tablet strengths: 1.25 mg, 2.5 mg, 5 mg dosingmax: 20 mg/day (effective max dose: 10 mg/d)Once daily to 10 mg then BID

duration of activity hypoglycemia weakly active metabolites caution: elderly, kidney dysfunction “75/50 rule”

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Glyburide Interactions NSAIDs Clarithromycin Salicylates Sulfonamides Etc.

Newer agents: Disopyramide Fluoxetine Quinolones

Interaction with antacids: Al-Mg: increases

absorption rate & peak serum [glyburide] Separate by ≥2 hr

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Sulfonylureas: Second Generation

Micronized glyburide Glynase PresTab® Tablet strengths: 1.5 mg, 3 mg, 6 mg dose nonequivalence Re-titrate Once daily to 6mg/day then BID

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Sulfonylureas: Second Generation

Glipizide Glucotrol®, Glucotrol XL®,

generic Tablet strengths: 5 mg, 10

mg no active metabolites food effect Dosing: Once daily to 10 mg then

BID (regular release) Once daily (for XL) max: 40 mg/day (effective

max: 20 mg/day) “75/50 rule”

Interactions with antacids Mg, NaHCO3 Increase rate of glipizide

absorption, max BG effect reduction

Separate doses by ≥2 hr

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Sulfonylureas: Second Generation

Glimepiride Amaryl® Tablet strengths: 1mg, 2 mg, 4 mg compare to glyburide dosing: 1-2 mg once daily with meal max 8mg/day

Dosage adjustments: Kidney failure: start with 1 mg daily (active metabolites) Hepatic dysfunction: start with 1 mg daily

Similar drug interactions to glyburide

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Sulfonylureas: Titration

Non-elderly every 1-2 weeks endpoint blood glucose goal achievementmax effective dose

Elderly consider slower titration

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Acarbose (Precose®) Mechanism of action reversible inhibition of intestinal alpha-glucosidase Delays breakdown of complex carbohydrates Slows glucose absorption

No systemic absorption Efficacy lowers postprandial glucose 50-60mg/dl

(monotherapy) lowers postprandial glucose 85mg/dl (with

sulfonylurea) decreases A1c 0.7 to 1.0%

How would you explain MOA to a

patient?

AGi: Place in Therapy

PSW Diabetes Toolkit

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ADA

AACE

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Acarbose Toxicity GI* fermented carbohydrates in colon cramps, flatulence, abdominal distention,

borborygmus, diarrhea additive with metformin

Hepatic unknown mechanism Very high doses monitor LFTs

No weight gain or loss

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Acarbose: Drug Interactions

Lack of monotherapy hypoglycemia Possible hypoglycemia with sulfonylureas Hypoglycemia treatment glucose tablets milk (lactose)

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Acarbose: Dosing Tablet strengths available: 25 mg, 50 mg, 100

mg Take with first bite of meal Initial: 25 mg once or twice daily increasing to

TID Titration 25 mg increments 4-8 week intervals

Maximum Patient weight < 60kg 50 mg TID

Weight > 60 kg 100 mg TID

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Miglitol (Glyset®)

Same MOA as acarbose Same tablet strengths available, dosing &

monitoring Maximum dosing 100 mg TID

Kidney dysfunction Avoid if SCr more than 2.0 or CrCl < 25

mL/min