diabetes family medicine board review no disclosures · sulfonylureas • mechanism: binds...

3/19/2015

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DiabetesFamily Medicine Board Review

Sarah Kim, MDAssistant Clinical Professor of Clinical Medicine, UCSF

Division of Endocrinology, SFGHMarch 19, 2015

No disclosures

Diabetes Test Topics• Majority Type 2 Diabetes (vs. Type 1)• Medications – mechanism of action,

contraindications • Standards of care (CVD risk reduction, etc)• Treatment of complications • Newest medications & recommendations

unlikely to be on the test

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Case #1

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64 yom with HTN, CAD, CHF and hyper-TG with a priorepisode of pancreatitis is found to have a random plasmaglucose of 205 mg/dl on labs obtained for another reason.An A1C was obtained and was 6.4%. The patient has nosymptoms such as polyuria, polydipsia or polyphagia.

Does he meet the criteria for the diagnosis of diabetes?

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Diagnosis of Diabetes & Pre-diabetesPre-Diabetes Criteria Diabetes Criteria*

Fasting Glucose 100-125 mg/dL ≥ 126 mg/dL2 hour post 75g OGTT

140-199 mg/dL ≥ 200 mg/dL

Random glucose N/A ≥ 200 with symptomsof hyperglycemia

HbA1c 5.7-6.4%** ≥ 6.5%**

*unless unequivocally hyperglycemic, results should be confirmed with another or repeat test**in absence of anemia or hemoglobinopathy

Diabetes Care, Vol 35, Supp 1, 2012

Case #1 continued

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You obtain a fasting BG which is 154 mg/dl confirming the diagnosis of diabetes mellitus for which he has a strong family history. You obtain further labs and plan to start treatment.

LABS: A1C = 6.4%, 140 111 284.5 28 1.5

MEDS: • furosemide 40 mg BID • KCl 20 meq• ASA 81 mg• lisinopril 40 mg• metoprolol 100 mg BID

EXAM: 100 kg; BMI 32; BP 145/95 sitting, 120/84 standing• Lungs: CTA • CV: S3 gallop• Ext: 1+ edema, feet with no

ulcerations, normal monofilament exam

Lipids: TC 350;LDL NC;HDL 22;TG 505

Case #1

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Which of the following medications would be the most appropriate initial therapy for this patient’s DM2?

A. metforminB. bromocriptineC. canagliflozinD. pioglitazoneE. glipizideF. exenatide

Case #1

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Which of the following medications would be the most appropriate initial therapy for this patient’s DM2?


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Non Diabetic

T2DM

T1DM

Beta Cell Loss in Diabetes Sulfonylureas• Mechanism: binds ATP-dependent K+ channels on

surface of beta cells� opening voltage gated Ca++ channels � release of insulin.

• Lower A1C 1-2%• Advantages

– Long history of use & cheap• Disadvantages

– Weight gain (≈ 2 kg)– Hypoglycemia– Must be renal-dosed and avoided in liver failure– Blunts ischemic preconditioning?

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Sulfonylureas2nd generation Duration Daily DoseGlipizide 6-12hr

(XL version= 24 hr)2.5-20mg once daily or 2 divided doses

Glyburide 20-24hr 2.5-10mg once dailyGlimepiride 24hr 2-4 mg once daily

1st generation Duration Daily DoseChlorpropamide 24-72 hr 250-500mg once dailyTolbutamide 6-12hr 500-2000 mg in 2-3

divided doses

U. Masharani and M. German, Ch 18 Pancreatic Hormones and Diabetes Mellitus. In: D Shoback and D Gardner (editors): Greenspan’s Basic and Clinical Endocrinology, 8th edi. McGraw Hill 2007.

Meglitinides• Enhances insulin release like sulfonylureas• Repaglinide lowers A1C 1-1.5%; Nateglinide 0.2-0.6%• Advantages:

– Short acting (take 15 minutes prior to meals)– Repaglinide undergoes little renal clearance

• Disadvantages– qAC dosing– Hypoglycemia (less than sulfonylureas)– Expensive

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MeglitinidesDrug Duration of Action Daily DoseNateglinide 1.5 hr 60-120mg qACRepaglinide 3 hr 0.5-2mg qAC


SulfonylureasMeglitinides

Biguanides

Biguanides (Metformin)• Inhibits hepatic gluconeogenesis & increases peripheral insulin

sensitivity• Lowers A1C 1.5-2%• Advantages:

– Weight loss (0-2 kg)– Lowers TG, LDLc; Increases HDLc– No hypoglycemia when used alone– Long history of use and cheap – CVD and cancer benefit?

• Disadvantages– Majority of patients with GI side effects (titrate slowly)– Impaired B12 absorption (5% or more of patients)– Risk of lactic acidosis (very small)

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Metformin

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Biguanide Duration Daily DosingMetformin 7-12 hr • 1000-2250mg in 2-3 divided

dosesXR version 24 hrs • 500-2000mg nightly


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MetforminContraindications:• Renal insufficiency

– Creatinine ≥1.5 men, ≥ 1.4 in women or abnormal Cr Cl• End stage liver disease• Excessive alcohol use• Iodinated contrast

– Discontinue within 48 hrs of exposure• Elderly (≥80 yo unless normal renal function)• Severe or acute CVD- particularly unstable CHF or AMI


TZDs

Biguanides

Thiazolidinediones (TZD)• Activate PPAR-γ, improve insulin sensitivity by altering gene

transcription (takes 8-12 weeks for max effect)• Lower A1C 0.5-1.4%• CVD risk possibly increased with rosiglitazone & decreased

pioglitazone• Advantages:

– Improves decreases TG, increases in HDL (pioglitazone)– No hypoglycemia when used alone

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TZDsDrug Duration DosingPioglitazone 24 hr 15-45 mg qDayRosiglitazone 24 hr 4-8 mg qDay or BID


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TZDsAdverse Event Frequency Increased Risk vs Placebo

Edema 5% 2 foldCongestive Heart Failure 5% 2-7 fold

Weight Gain 60% +0.5-4 kgFractures 2-5% 2 fold

Bladder Cancer 0.3% 20%


TZDs

BiguanidesSGLT2 inhibitors

Sodium Glucose Co-Transporter 2 Inhibitors

• Sodium-glucose cotransporter 2 (SGLT2) plays a major role in renal glucose reabsorption in proximal tubule

• Renal glucose reabsorption is increased in type 2 diabetes

• Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose

J Intern Med. 2007;261:32-43.

SGLT1

(180 L/day) (900 mg/L)=162 g/day

10%

Glucose

No Glucose

S1

S3

Renal Handling of Glucose

SGLT2

90%

J Intern Med. 2007;261:32-43.Endocr Pract. 2008;14:782-790

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Glucosuria ↑ 52-85 g/day

FPG ↓ 16-30 mg/dL

PPG ↓ 23-29 mg/dL

Body weight ↓ 2.2-3.2 kg (↓ 2.5%-3.4%)

Urine volume ↑ 107-470 mL/day

Diabetes Care. 2009;32:650-657

Dapagliflozin: Glucosuric and Metabolic Effects SGLT2 Inhibitors

• Lowers A1C about 0.6-1% at max dose• No hypoglycemia when used alone or with metformin• Advantages

– Weight loss 2.5-4 kg– Decrease in SBP 5 mmHg

• Disadvantages– Increased mycotic genital infections in men (4%) and women

(10%) – UTIs (5%)– Bladder cancer concern– Polyuria, presyncope/sycope, fractures– Increases Cr, decreases eGFR (contraindicated in lower GFR),

hyperkalemia– $$$

SGLT2 InhibitorsDuration Dose

Canagliflozin* 24 hrs 100-300mg dailyDapagliflozin* 24 hrs 5-10mg dailyEmpagliflozin* 24 hrs 10-25 mg daily

* Renal dosing/contraindicated in renal failure

Case #1 continued

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64 yom with HTN, CAD, CHF and hyperTG with a prior episode of pancreatitis is found to have a random plasma glucose of 205 mg/dl on labs obtained for another reason. The patient has no symptoms such as polyuria, polydipsia or polyphagia.

LABS: A1C = 8.8%, 140 111 284.5 28 1.5

MEDS: • furosemide 40 mg BID • KCl 20 meq• ASA 81 mg• lisinopril 40 mg• metoprolol 100 mg BID

EXAM: 100 kg; BMI 32; BP145/94, 120/84 standing• Lungs: CTA • CV: S3 gallop• Ext: 1+ edema, feet with no

ulcerations, normal monofilament exam

Lipids: TC 350;LDL NC;HDL 22;TG 505

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Case #1

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Which choice below would be the most appropriate initial therapy for this patient’s DM2?


Case #2

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54 yow with DM2 diagnosed 7 years ago presents to you for f/u complaining of increasing hypoglycemia and several URIs. At your last visit you added sitigliptin (Januvia) to her medications for an A1C of 7.6% and persistent SMBG values in the 200s.

Which of the following statements is true? The addition of sitigliptin:A. Did not contribute to hypoglycemiaB. Should have been dose adjusted for renal insufficiencyC. Was not related to the increased number of URIsD. Typically results in a 1-2 kg weight loss

DM MEDS: metformin 1 gm BIDglyburide 10 mg dailysitagliptin 100 mg daily

LABS: A1C = 7.0%, 140 111 284.5 28 1.5

eGFR is 45 ml/min

Case #2

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54 yow with DM2 diagnosed 7 years ago presents to you for f/u complaining of increasing hypoglycemia and several URIs. At your last visit you added sitigliptin (Januvia) to her medications for an A1C of 7.6% and persistent SMBG values in the 200s.

Which of the following statements is true? The addition of sitigliptin:

A. Did not contribute to hypoglycemiaB. Should have been dose adjusted for renal insufficiencyC. Was not related to the increased number of URIsD. Typically results in a 2-3 kg weight loss

DM MEDS: metformin 1 gm BIDglyburide 10 mg dailysitagliptin 100 mg daily

LABS: A1C = 7.0%, 140 111 284.5 28 1.5

eGFR is 45 ml/min


GLP-1 AgonistsDPP-4 Inhibitorsα-glucosidase InhibitorsBile Acid Sequestrants

TZDs

Biguanides

SGLT2 inhibitors

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The Incretin Effect

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What Incretins Do

Incretins:-Enhance insulin secretion-Suppress glucagon secetion -Slow gastric emptying-Promote satiety

J Fam Med. October 2009 Vol. 58, No. 10

GLP-1 Analogs• Resistant to degradation by DPP4 and have a long half-

life• Lower HbA1C 0.5-1.5%• Advantages:

– Weight loss (2-3 kg); less hypoglycemia• Disadvantages:

– Injectable– GI Side Effects (nausea, vomiting)– Pancreatitis, medullary thyroid cancer?

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DPP-4 Inhibitors• Increases GLP-1 and GIP levels • Lowers A1C 0.5-0.8% • Use in conjunction with other oral hypoglycemic agents in DM2

or as monotherapy• Advantages:

– Oral, weight neutral• Disadvantages:

– $$– Increased incidence of URI, nasophyrngitis (mechanism?)

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Incretin-based therapiesGLP-1 Agonists Duration Daily DoseExenatide* 6hr

(ER version 1 wk)5-10mcg BID subcut. before meals(ER version 2 mg weekly)

Liraglutide 12-24 hr 0.6-1.8mg subcut. dailyAlbiglutide 1 wk 30-50 mg subcut. weeklyDulaglutide 1 wk 0.75-1.5mg weekly

DPP-4Inhibitors

Duration Daily Dose

Sitagliptin* 24 hr 25-100mg Daily Saxagliptin* 24 hr 2.5-5 mg DailyLinagliptin 24 hr 5 mg DailyAlogliptin* 24 hr 25 mg Daily


*renal dosing required

α-Glucosidase Inhibitors• Reversible competitive inhibition of a-glucosidase �

difficulty breaking down disaccharides and complex carbs• Lowers A1C 0.5-0.8% by improving postprandial glucose• Advantages:

– No hypoglycemia when used alone; weight neutral• Disadvantages:

– GI SE, flatulance; TID dosing• Caution with hypoglycemia, sucrose is ineffective

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α-Glucosidase InhibitorsDuration Daily Dose

Acarbose 4 hr 75-300mg in 3 divided doses with mealsMiglitol 4 hr 75-300mg in 3 divided doses with meals


Bile Acid Sequestrant• Colasevelam• Approved for years for cholesterol lowering• Lowers HbA1C 0.4% (mechanism largely unknown)• Advantages:

– Lowers LDLc• Disadvantages:

– GI side effects (bloating, cramping, constipation)– Increases triglycerides (avoid if TG >500)– Impairs absorption of fat soluble vitamins, digoxin, warfarin,

thiazides, beta blockers, thyroxine, phenobarbital

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HbA1c Lowering by Non-Insulin Medications

Drug AIC lowering when used as monotherapy

Metformin 1.5-2%Sulfonylureas 1-2%Thiazolidinediones 0.6-1.5%GLP-1 Agonists 0.5-1.5%Meglitinides 0.5-1.5%SGLT2 inhibitors 0.6-1%Lifestyle 0.5-0.8%DPP4 inhibitors 0.5-0.8%α-glucosidase inhibitors 0.5-0.8%Bile acid sequestrant 0.4%Bromocriptine < 0.2%

You are asked to see a 72 year old man with CHF (NYHA class III) with previously well controlled DM2, but now a HbA1c of 9.1%. He is on glyburide and metformin at max doses.What is the most appropriate change to his regimen?A. Add pioglitazoneB. Add basal insulin (NPH or glargine)C. Add acarboseD. Add saxagliptin

Case #3

You are asked to see a 72 year old man with CHF (NYHA class III) with previously well controlled DM2, but now a HbA1c of 9.1%. He is on glyburide and metformin at max doses.What is the most appropriate change to his regimen?A. Add pioglitazoneB. Add basal insulin (NPH or glargine)C. Add acarboseD. Add saxagliptin

Case #3

Nathan DM et al. Diab Care 2009;32:193-203

At Diagnosis:Lifestyle and Metformin

Add Basal Insulin

Add Sulfonylurea

Well-Validated Core Therapy for DM2

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Basal InsulinNPH Glargine Detemir

Pros 1. Variable dosing possibleat different times of day

2. Can be mixed with other insulin types

1. Usually only one injection needed

2. Generally peakless

1. Variable dosing possibleat different times of day

2. Mild peak

Cons 1. 2 injections/day2. Peaks 6-8 hrs after

injection

1. Cannot be mixed with other insulin types

1. 2 injections/day2. Cannot be mixed with

other insulin types

HbA1C ≤7% No difference between NPH, Glargine, and DetemirTotal Dose No difference between NPH, Glargine, and Detemir

Cost(www.drugstore.com)

$ $$ $$

Cochrane Database of Systematic Reviews (2009) Issue 2. Art No CD006613

Hypoglycemia with basal insulin

Glargine or Detemir vs. NPHHypoglycemia ~17% less with glargine or detemirNocturnal Hypoglycemia ~35% less with glargine or detemir

Cochrane Database of Systematic Reviews (2009) Issue 2. Art No CD006613

* Driven by studies with aggressive titration strategies

Nathan DM et al. Diab Care 2009;32:193-203

At Diagnosis:Lifestyle and Metformin

Add Basal Insulin

Add Sulfonylurea

Well-Validated Core Therapy for DM2

ADA Standards of Medical Care in Diabetes 2015

Less Well-Validated Buffet for DM2

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Case #4

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66 yom with DM2 for 5 years started on insulin 2 years ago but still can’t get A1C below 8.0%. Patient reports no symptomatic lows.

DM Meds: Metformin 1 gm BIDNPH 20 units am, 10 units at bedtimeRegular 5 units before each meal

What would be the best next step for improving A1C?A. Change NPH to glargine 30 unitsB. Increase morning NPH dose to 25 unitsC. Increase mealtime R insulin dose to 8 units before each mealD. Increase dinnertime R insulin to 8 unitsE. Change R to aspart insulin

Time Glucose RangeFasting 105-130Pre-Lunch 85-155Pre-Dinner 92-145Bedtime 170-280

Case #4

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66 yom with DM2 for 5 years started on insulin 2 years ago but still can’t get A1C below 8.5%. Patient reports no symptomatic lows.

DM Meds: Metformin 1 gm BIDNPH 20 units am, 10 units at bedtimeRegular 5 units before each meal

What would be the best next step for improving A1C?A. Change NPH to glargine 30 unitsB. Increase morning NPH dose to 25 unitsC. Increase mealtime R insulin dose to 8 units before each mealD. Increase dinnertime R insulin to 8 unitsE. Change R to aspart insulin

Time Glucose RangeFasting 105-130Pre-Lunch 85-155Pre-Dinner 92-145Bedtime 170-280

Glycemic Goals in DiabetesFor Most Adults:• Fasting Glucose 70-130 mg/dL• Peak Post-Prandial Glucose <180 mg/dL• HbA1c ≤7.0%

• Glycemic goals differ in:– pregnancy (lower goals) – children, limited life expectancy, hypoglycemia unawareness,

significant cardiovascular disease (higher goals)

Diabetes Care (2011) 34: s11-s61

Time Glucose Range

Fasting 105-130Pre-Lunch 85-155Pre-Dinner 92-145Bedtime 170-280

Polonsky KS et al. N Engl J Med. 1988;318:1231-1239

0600 0600Time of day

20

40

60

80

100B L D

Normal Plasma Insulin Profile

B=breakfast; L=lunch; D=dinner0800 18001200 2400

Insulin µU/mL

Basal insulino Near-constant levelso Important during night/between mealso 50% or more of daily needs

Mealtime insulino Limits hyperglycemia after mealso Rise and peak post meal o 10% to 20% of daily needs at

each meal

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Types of Insulin

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Basal Insulin Peak DurationNPH 4-8 hrs 10-20hrGlargine None 24 hrDetemir Small 17 -24 hr

Bolus Insulin Peak DurationRegular 2 hr 6 hrAspart 1 hr 3-4 hrLispro 1 hr 3-4 hrGlulisine 1 hr 3-4 hr

Combination Insulin Composition70%/30% 70% NPH

30% Regular or Aspart75%/25% 75% NPH

25% Lispro50%/50% 50%NPH

50% Lispro0600 0800 18001200 2400 0600

Time of day

20

40

60

80

100B L D

Basal-Bolus Insulin Treatment

Normal pattern

µU/mL

NPHNPH at bedtime

0600 0800 18001200 2400 0600Time of day

20

40

60

80

100B L D


Glargine

Normal pattern

µU/mL

0600 0800 18001200 2400 0600Time of day

20

40

60

80

100B L D


Glargine

Meal time insulin

Normal pattern

µU/mL

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A 64 year old woman with DM presents with worsening glycemic control. Fasting glucose values are constantly above 200. She doesn’t check BS at other times of the day. Medicines include metformin 1 g BID and glipizide 10 mg BID. A1C 9.1%.Of the options listed below, which is the most appropriate therapy for this patient?A. Start morning NPH or glargine and discontinue all oral agentsB. Start morning NPH or glargine, maintain sulfonylurea and

discontinue metforminC. Start bedtime NPH or insulin glargine, discontinue metformin

and continue sulfonylurea.D. Start bedtime NPH or glargine, maintain oral agents

Case #5

A 64 year old woman with DM presents with worsening glycemic control. Fasting glucose values are constantly above 200. She doesn’t check BS at other times of the day. Medicines include metformin 1 g BID and glipizide 10 mg BID. A1C 9.1%.Of the options listed below, which is the most appropriate therapy for this patient?A. Start morning NPH or glargine and discontinue all oral agentsB. Start morning NPH or glargine, maintain sulfonylurea and

discontinue metforminC. Start bedtime NPH or insulin glargine, discontinue metformin

and continue sulfonylurea.D. Start bedtime NPH or glargine, maintain oral agents

Case #5

67 yom has had DM2 for 2 yrs treated with metformin and glipizide. He also has schizophrenia and started olanzapine 3 months ago. Since then, he gained 20 lbs and his HbA1c increased from 6.0 � 8.0%.

What should you do to help improve his diabetic control?a. Have a home health nurse assist him with medication

complianceb. Add pioglitazone 30mg daily to increase insulin sensitivityc. Contact the treating psychiatrist about possibly changing his

antipsychoticd. Add exenatide 10 mcg BID to assist with weight losse. Switch from glipizide to glyburide

Case #6

67 yom has had DM2 for 2 yrs treated with metformin and glipizide. He also has schizophrenia and started olanzapine 3 months ago. Since then, he gained 20 lbs and his HbA1c increased from 6.0 � 8.0%.

What should you do to help improve his diabetic control?a. Have a home health nurse assist him with medication

complianceb. Add pioglitazone 30mg daily to increase insulin sensitivityc. Contact the treating psychiatrist about possibly changing his

antipsychotic medication d. Add exenatide 10 mcg BID to assist with weight losse. Switch from glipizide to glyburide

Case #6

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Metabolic side effects of second generation antipsychoticsMost weight gain Less weight gain No weight gainOlanzapine Quetiapine AripiprazoleClozapine Risperidone Ziprasidone

Iloperidone LurasidonePaliperidone

49 yow with DM2 is seeing you for follow up. Her A1c is 7.3% on metformin, glyburide and significant lifestyle modifications that she has made over the years. She has HTN and albuminuria for which she takes lisinopril. Her recent lipid panel reveals a Tchol of 200, LDL of 90, HDL of 39, TG 190.

How do you respond to her lipid panel?A. Begin colasevelam 1875 mg BIDB. Begin pioglitazone 30mg dailyC. Begin atorvastatin 20 mg dailyD. Assure her that she has reached the LDL goal for diabetes

without medicationsE. Ask her about a family history of early MI

Case #7

49 yow with DM2 is seeing you for follow up. Her A1c is 7.3% on metformin, glyburide and significant lifestyle modifications that she has made over the years. She has HTN and albuminuria for which she takes lisinopril. Her recent lipid panel reveals a Tchol of 200, LDL of 90, HDL of 39, TG 190

How do you respond to her lipid panel?A. Begin colasevelam 1875 mg BIDB. Begin pioglitazone 30mg dailyC. Begin atorvastatin 20 mg dailyD. Assure her that she has reached the LDL goal for diabetes

without medicationsE. Ask her about a family history of early MI

Case #7 Statin recommendations for DM

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50 yom with DM2 x 2 yrs, HTN, and dyslipidemia has an A1c of 7.5%. He has a family history of early MI.

Lowering HbA1c to ≤7% will NOT reduce his risk of developing:A. RetinopathyB. NephropahtyC. Myocardial infarctionD. Neuropathy

Case #8

50 yom with DM2 x 2 yrs, HTN, and dyslipidemia has an A1c of 7.5%. He has a family history of early MI.

Lowering HbA1c to ≤7% will NOT reduce his risk of developing:A. RetinopathyB. NephropahtyC. Myocardial infarctionD. Neuropathy

Case #8

“Tight control” trials• 1977 UKPDS (DM2) *• 1983 DCCT (DM1) * • 2000 VADT (DM2)• 2001 ADVANCE (DM2) *• 2001 ACCORD (DM2)

*showed that tight control lowers microvascular complications

My go-to diabetes resource• American Diabetes Association Clinical Practice

Recommendations– Standards of Medical Care in Diabetes

http://care.diabetesjournals.org/content/36/Supplement_1/S11.full

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diabetes family medicine board review no disclosures · sulfonylureas • mechanism: binds...

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