family medicine board review - ucsf cme · sulfonylureas • mechanism: binds atp-dependent k+...

Diabetes

Family Medicine Board Review

Sarah Kim, MD Assistant Clinical Professor of Clinical Medicine, UCSF

Division of Endocrinology, SFGH

March 10, 2016

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

Case #1

64 yom with HTN, CAD, CHF and hyper-TG with a prior episode of pancreatitis is found to have a random plasma glucose of 205 mg/dl on labs obtained for another reason. An A1C was obtained and was 6.4%. The patient has no symptoms such as polyuria, polydipsia or polyphagia.

Does he meet the criteria for the diagnosis of diabetes?

Diagnosis of Diabetes & Pre-diabetes

Pre-Diabetes Criteria Diabetes Criteria*

Fasting Glucose 100-125 mg/dL ≥ 126 mg/dL

2 hour post 75g OGTT

140-199 mg/dL ≥ 200 mg/dL

Random glucose N/A ≥ 200 with symptoms of 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

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 28

4.5 28 2.5

• 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

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

eGFR 44

Case #1

Which of the following medications would be the most

appropriate initial therapy for this patient’s DM2?

A. metformin

B. bromocriptine

C. colesevalem

D. pioglitazone

E. glipizide

F. exenatide

Case #1

Which of the following medications would be the most

appropriate initial therapy for this patient’s DM2?

A. metformin

B. bromocriptine

C. colesevalem

D. pioglitazone

E. glipizide

F. exenatide

Non Diabetic

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 dose reduced in renal and liver – Ongoing, unsettled debate on whether SU’s increase CV

mortality

Sulfonylureas

2nd generation Duration Daily Dose

Glipizide

6-12hr (XL version= 24 hr)

2.5-20mg once daily or 2 divided doses

Glyburide 20-24hr 2.5-10mg once daily

Glimepiride 24hr 2-4 mg once daily

1st generation Duration Daily Dose

Chlorpropamide 24-72hr 250-500mg once daily

Tolbutamide 6-12hr 500-2000 mg in 2-3 divided doses

Tolazamide 10-24hr 100-500mg daily

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)

– More expensive than SU

Meglitinides

Drug Duration of Action Daily Dose

Nateglinide 1.5 hr 60-120mg qAC

Repaglinide 3 hr 0.5-2mg qAC

Sulfonylureas Meglitinides

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) – Reputation for risk of lactic acidosis (risk=small/non-existent?)

Metformin

Biguanide Duration Daily Dosing

Metformin 7-12 hr • 1000-2250mg in 2-3 divided doses

XR version 24 hrs • 500-2000mg nightly

Metformin Contraindications:

• Renal insufficiency – PA still says creatinine ≥1.5 men, ≥ 1.4 in women or abnormal Cr Cl

– Will hopefully be updated

• End stage liver disease (ok in mild-mod cirrhosis)

• Iodinated contrast

– Discontinue within 48 hrs of exposure

• Excessive alcohol use-

• Elderly (≥80 yo unless normal renal function)

• Severe or acute CVD- particularly unstable CHF or AMI

Biguanides

Thiazolidinediones (TZD) • Activate PPAR-, 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 with

pioglitazone • Advantages:

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

Drug Duration Dosing

Pioglitazone 24 hr 15-45 mg qDay

Rosiglitazone 24 hr 4-8 mg qDay or BID

TZDs Adverse Event Frequency Increased Risk vs Placebo

Edema 5% 2 fold

Congestive Heart Failure 5% 2-7 fold

Weight Gain 60% +0.5-4 kg

Fractures 2-5% 2 fold

Bladder Cancer 0.3% 20%

Biguanides

SGLT2 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.

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

Glucose

No Glucose

Renal Handling of Glucose

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

Endocr Pract. 2008;14:782-790

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

List JF, et al. 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 MF • Advantages

– Weight loss 2.5-4 kg – Decrease in SBP 5 mmHg – CV mortality benefit – Reduces albuminuria

• 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 Inhibitors

Duration Dose

Canagliflozin* 24 hrs 100-300mg daily

Dapagliflozin* 24 hrs 5-10mg daily

Empagliflozin* 24 hrs 10-25 mg daily

* Renal dosing/contraindicated in renal failure

Case #1 continued

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 28

4.5 28 2.5

• furosemide 40 mg BID

• KCl 20 meq

• ASA 81 mg

• lisinopril 40 mg

• metoprolol 100 mg BID

EXAM: 100 kg; BMI 32; BP145/94

• Lungs: CTA

• CV: S3 gallop

• Ext: 1+ edema, feet with no

ulcerations, normal monofilament

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

eGFR 44

Case #1

Which choice below would be the most appropriate

initial therapy for this patient’s DM2?

A. metformin

B. glyburide

C. canagliflozin

D. pioglitazone

E. glipizide

F. exenatide

Case #2

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 hypoglycemia B. Should have been dose adjusted for renal insufficiency C. Was not related to the increased number of URIs D. Typically results in a 1-2 kg weight loss

DM MEDS: metformin 1 gm BID glyburide 10 mg daily sitagliptin 100 mg daily

LABS: A1C = 7.0%, 140 111 28 4.5 28 1.5 eGFR is 45 ml/min

Case #2

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 hypoglycemia

B. Should have been dose adjusted for renal insufficiency

C. Was not related to the increased number of URIs

D. Typically results in a 2-3 kg weight loss

DM MEDS:

metformin 1 gm BID

glyburide 10 mg daily

sitagliptin 100 mg daily

LABS: A1C = 7.0%, 140 111 28

4.5 28 1.5

eGFR is 45 ml/min

GLP-1 Agonists DPP-4 Inhibitors α-glucosidase Inhibitors Bile Acid Sequestrants

Biguanides

SGLT2 inhibitors

The Incretin Effect

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?

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?)

Incretin-based therapies

GLP-1 Agonists Duration Daily Dose

Exenatide* 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. daily

Albiglutide 1 wk 30-50 mg subcut. weekly

Dulaglutide 1 wk 0.75-1.5mg weekly

DPP-4 Inhibitors

Duration Daily Dose

Sitagliptin* 24 hr 25-100mg Daily

Saxagliptin* 24 hr 2.5-5 mg Daily

Linagliptin 24 hr 5 mg Daily

Alogliptin* 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

α-Glucosidase Inhibitors

Duration Daily Dose

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

Miglitol 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

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 pioglitazone

B. Add basal insulin (NPH or glargine)

C. Add acarbose

D. 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 pioglitazone

B. Add basal insulin (NPH or glargine)

C. Add acarbose

D. Add saxagliptin

Case #3

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

At Diagnosis:

Lifestyle and Metformin

Basal Insulin Add

Sulfonylurea

Well-Validated Core Therapy for DM2

Basal Insulin

NPH Glargine Detemir

Pros 1. Variable dosing possible at different times of day

2. Can be mixed with other insulin types

1. Usually only one injection needed

2. Generally peakless

1. Variable dosing possible at different times of day

2. Mild peak

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

injection

1. Cannot be mixed with other insulin types

1. 2 injections/day 2. Cannot be mixed with

other insulin types

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

Total 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. NPH

Hypoglycemia ~17% less with glargine or detemir

Nocturnal 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

Basal Insulin Add

Sulfonylurea

Well-Validated Core Therapy for DM2

ADA Standards of Medical Care in Diabetes 2015

Less Well-Validated Buffet for DM2

Case #4

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 BID

NPH 20 units am, 10 units at bedtime

Regular 5 units before each meal

What would be the best next step for improving A1C?

A. Change NPH to glargine 30 units

B. Increase morning NPH dose to 25 units

C. Increase mealtime R insulin dose to 8 units before each meal

D. Increase dinnertime R insulin to 8 units

E. Change R to aspart insulin

Time Glucose Range

Fasting 105-130

Pre-Lunch 85-155

Pre-Dinner 92-145

Bedtime 170-280

Case #4

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 BID

NPH 20 units am, 10 units at bedtime

Regular 5 units before each meal

What would be the best next step for improving A1C?

A. Change NPH to glargine 30 units

B. Increase morning NPH dose to 25 units

C. Increase mealtime R insulin dose to 8 units before each meal

D. Increase dinnertime R insulin to 8 units

E. Change R to aspart insulin

Time Glucose Range

Fasting 105-130

Pre-Lunch 85-155

Pre-Dinner 92-145

Bedtime 170-280

Glycemic Goals in Diabetes

For 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 105-130

Pre-Lunch 85-155

Pre-Dinner 92-145

Bedtime 170-280

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

0600 0600

Time of day

100 B L D

Normal Plasma Insulin Profile

B=breakfast; L=lunch; D=dinner

0800 1800 1200 2400

Insulin

Basal insulin o Near-constant levels

o Important during night/between meals

o 50% or more of daily needs

Mealtime insulin o Limits hyperglycemia after meals

o Rise and peak post meal

o 10% to 20% of daily needs at

each meal

Types of Insulin

Basal Insulin Peak Duration

NPH 4-8 hrs 10-20hr

Glargine (U100, U300)

None 24 hr

Detemir Small 17-24 hr

Degludac U100, U200

None 42 hr

Bolus Insulin Peak Duration

Regular 2 hr 6 hr

Aspart 1 hr 3-4 hr

Lispro 1 hr 3-4 hr

Glulisine 1 hr 3-4 hr

Combination Insulin Composition

70%/30% 70% NPH 30% Regular or Aspart

75%/25%

75% NPH 25% Lispro

50%/50% 50%NPH 50% Lispro

0600 0800 1800 1200 2400 0600

Time of day

100 B L D

Basal-Bolus Insulin Treatment

Normal pattern

NPH NPH at bedtime

0600 0800 1800 1200 2400 0600

Time of day

100 B L D

Glargine

Normal pattern

0600 0800 1800 1200 2400 0600

Time of day

100 B L D

Glargine

Meal time insulin

Normal pattern

A 64 year old woman with DM presents with worsening glycemic control. Fasting glucose values are constantly above 200. She doesnt 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 agents

B. Start morning NPH or glargine, maintain sulfonylurea and

discontinue metformin

C. 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 agents

B. Start morning NPH or glargine, maintain sulfonylurea and

discontinue metformin

C. 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 compliance

b. Add pioglitazone 30mg daily to increase insulin sensitivity c. Contact the treating psychiatrist about possibly changing his

antipsychotic d. Add exenatide 10 mcg BID to assist with weight loss e. 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 compliance

b. Add pioglitazone 30mg daily to increase insulin sensitivity c. Contact the treating psychiatrist about possibly changing his

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

Case #6

Metabolic side effects of second generation antipsychotics

Most weight gain Less weight gain No weight gain

Olanzapine Quetiapine Aripiprazole

Clozapine Risperidone Ziprasidone

Iloperidone Lurasidone

Paliperidone

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 BID B. Begin pioglitazone 30mg daily C. Begin atorvastatin 40 mg daily D. Assure her that she has reached the LDL goal for diabetes

without medications E. 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 BID B. Begin pioglitazone 30mg daily C. Begin atorvastatin 40 mg daily D. Assure her that she has reached the LDL goal for diabetes

without medications E. Ask her about a family history of early MI

Case #7

Statin recommendations for DM

50 yom with DM2 x 8 yrs, HTN, and dyslipidemia has an A1c of 8.5%. He has a family history of early MI. Lowering HbA1c to ≤7% will NOT reduce his risk of developing:

A. Retinopathy B. Nephropahty C. Myocardial infarction D. Neuropathy

Case #8

50 yom with DM2 x 8 yrs, HTN, and dyslipidemia has an A1c of 8.5%. He has a family history of early MI. Lowering HbA1c to ≤7% will NOT reduce his risk of developing:

A. Retinopathy B. Nephropahty C. Myocardial infarction D. 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/site/misc/2016-Standards-of-Care.pdf

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