Care of the Patient with Diabetes in the Safety Net UCSF CME Care - - PDF document

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UCSF CME Care of Vulnerable Populations Elizabeth J. Murphy, MD, DPhil February 22, 2020

Care of the Patient with Diabetes in the Safety Net I have no financial interests or relationships to disclose.

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Case

3

43 yo Hispanic man with obesity and newly diagnosed DM2 (no CKD or CAD) presents to your clinic. He was recently seen seen in the ED with an A1C of 13 and glucose of

• 575. He got treated and was given a prescription for Lantus and metformin.

Now he comes to see you. He’s taking metformin and stopped soda but couldn’t afford his Lantus. Random BG 325. You decide he needs insulin and more orals meds. What do you do?

a) Switch him to NPH which is covered but feel badly about it. b) Happily switch him to NPH. c) Fill out a PA to get him glargine. d) Give him a coupon or get him free glargine some other way

Case

4

In addition to insulin and metformin you will add:

a) A sulfonylurea but feel badly about it b) Happily add a sulfonylurea c) I don’t like SU so I’ll use some combination of other oral meds if I don’t have to fill out a PA to get them d) I don’t like SU so I’ll use some combination of other oral meds even if I have to fill out a PA e) Add a GLP-1 analog f) None of the above. I’ll just start with insulin and metformin.

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A1C COST 10/2019

Sulfonylurea 1-2% $5 Metformin 1-2% $4 Pioglitazone 0.5-1.5% $20 Exenatide 0.5-1.5% $450 Canagliflozin 0.5-0.8% $330 Sitagliptin 0.5-0.8% $320 Acarbose 0.5-0.8% $30 $498 $731 $455 TZD GLP-1 agonist SGLT2i DPP-IVi

JAMA Intern Med. 2019;179(10):1376-1385. doi:10.1001/jamainternmed.2019.2396

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$- $50 $100 $150 $200 $250 $300 1995 2000 2005 2010 2015 2020

RETAIL PRICE HUMOLOG (LISPRO)

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A1C COST 10/2019

Sulfonylurea 1-2% $5 Metformin 1-2% $4 Pioglitazone 0.5-1.5% $20 Exenatide 0.5-1.5% $450 Canagliflozin 0.5-0.8% $330 Sitagliptin 0.5-0.8% $320 Acarbose 0.5-0.8% $30

Good Rx.com 10/2014

$498 $731 $455 TZD GLP-1 SGLT2i DPP-IV

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PIOGLITAZONE

• In some patients has profound A1C lowering without

hypoglycemia when used alone.

• It can take a month or more to see effects.
• Absolutely contraindicated in CHF.
• Long term adverse bone effects and may increase risk of

bladder cancer in men.

DPPIV Inhibitors

• Horrible at A1C lowering.
• Don’t have the weight loss benefits of GLP-1 agonists.
• May have unexpected AE
• If it’s not working don’t continue it.

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Concerns with Inexpensive DM Meds

• Metformin

– Renal failure, congestive heart failure, gastrointestinal side effects

• Sulfonylureas

– Increased cardiovascular risk – Hypoglycemia (low blood sugar)

• Insulins

– Hypoglycemia

DO SULFONYLUREAS INCREASE RISK OF CARDIOVASCULAR DISEASE?

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MEDPAGE TODAY

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Antonios Douros et al. BMJ 2018;362:bmj.k2693

Forest plot summarising the primary analysis and all sensitivity analyses

77,138

Metformin Monotherapy Users

25,699

Adding or switching to SU

13,217

Adding SU

9,800

Switching to SU

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0.5 2.5 4.5 6.5 8.5

Myocardial Infarction Adding SU Switching to SU Ischemic Stroke Adding SU Switching to SU CV Death Adding SU Switching to SU All Cause Mortality Adding SU Switching to SU

Adjusted HR (95% CI) Stopping Metformin Increases the Risk of Cardiovascular Disease Adding a sulfonylurea to metformin does not increase the risk of cardiovascular disease but replacing metformin with a sulfonylurea does

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GLARGINE (LANTUS) COMPARED TO NPH

a) Lowers A1C more b) Has less clinically significant hypoglycemia c) Both d) None of the above

Name Brand Name Status Manufacturer Cost glargine Lantus Sanofi $278-429 glargine Basiglar Biosimilar Lilly $235-331 glargine Lusduna Biosimilar Merck Not available glargine Toujeo U-300 Sanofi $295-393 detemir Levemir Novo Nordisk $446-465 degludec Tresiba Novo Nordisk $490-511 NPH (vial) Humulin Lilly NA-$474 NPH (pen) Humulin Lilly $301 NPH (vial) Novolin Novo Nordisk $24-144

Good Rx.com 2018 and 5/2019

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Insulin Degludec

• Has a much longer duration of action than glargine
• More flexible about what time of day it is given
• May be useful in patients with DM1 with poor med adherence

who might not remember to take insulin every day to prevent DKA

Name Brand Name Status Manu-facturer Cost aspart Novolog Novo Nordisk $300-560 aspart Fiasp Novo Nordisk NA-$294 glulisine Apidra Sanofi $423-551 lispro Humalog Lilly $178 -$334 lispro (vial) Admelog Biosimilar/ Interchangeable Sanofi $470-239 lispro “generic” Lilly NA - $137 R (vial) Humulin Lilly $99-155 R (vial) Humulin Novo Nordisk NA-$144 R (pen) Humulin Lilly $578 R (pen) Kwikipen U-500 Lilly ? $540

Good Rx.com 2018 and 5/2019

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Name Manufacturer Cost 70/30 70 N/30 R Novo Nordisk/Lilly $300-560 70/30 70 N/30 aspart (Novolog) Novo Nordisk NA-$294 75/25 70N/25 lispro (Humalog) Lilly $423-551 50/50 50N/50R Novo Nordisk/Lilly $178 -$334 lispro (vial) Biosimilar/ Interchangeable Sanofi $470-239 R (pen) U-500 Lilly ? - $540

Good Rx.com 2018 and 5/2019

Advantages of Insulin Analogues – in DM2

§ Rapid acting insulin

• Better mimics human physiology
• Improved A1C
• Fewer lows

§ Long acting analogues

• Fewer lows
• Less of a peak
• Take fewer shots in basal bolus
• Better A1C

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Advantages of Insulin Analogues – in DM2

§ Rapid acting insulin

• Better mimics human physiology?
• Improved A1C
• Fewer lows

§ Long acting analogues

• Fewer lows
• Less of a peak
• Take fewer shots in basal bolus
• Better A1C

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Cochraine Review

NPH versus Basal Analogues

• 6 studies comparing glargine to NPH
• 2 studies comparing detemir to NPH
• A1C and adverse effects did not differ in a clinically relevant way.
• No difference for severe hypoglycemia
• Statistically significant lower rates of nocturnal hypoglycemia

with glargine/detemir with target glucose < 100

• No effect on mortality, morbidity, QOL

Horvath et al, Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD005613. DOI: 10.1002/14651858.CD005613.pub3

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ED visits or Hospital Admissions for Hypoglycemia with Basal Insulin Analogs vs NPH in Type 2 Diabetes

• JAMA. 2018;320(1):53-62. doi:10.1001/jama.2018.7993

1.48 1.26 NPH Insulin Analogs

Reduction in A1C

*

• JAMA. 2018;320(1):53-62. doi:10.1001/jama.2018.7993

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Advantages of Insulin Analogues – in DM2

§ Rapid acting insulin

• Better mimics human physiology?
• Improved A1C
• Fewer lows

§ Long acting analogues

• Fewer lows (clinical relevance???)
• Less of a peak ?
• Take fewer shots in basal bolus (depends)
• Better A1C

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Advantages to NPH

• Can be used as a bridge to correct once daily basal dose timing.
• It can be adjusted twice a day allowing for more rapid titration

to goal

• Allows for more basal insulin in the day for snackers
• Allows for more basal insulin during the day for steroid induced

hyperglycemia which preferentially results in peripheral insulin resistance

• Allows for less basal insulin at night with renal failure/cirrhosis
• May be more affordable for patients

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Viewpoint July 4, 2017

Human Insulin for Type 2 Diabetes

An Effective, Less-Expensive Option

Kasia J. Lipska, MD, MHS1; Irl B. Hirsch, MD2; Matthew C. Riddle, MD3

• JAMA. 2017;318(1):23-24. doi:10.1001/jama.2017.6939

E d i t

• r

i a l J u l y 3 , 2 1 8

Revisiting NPH Insulin for Type 2 Diabetes

Is a Step Back the Path Forward?

Matthew J. Crowley, MD, MHS1,2; Matthew L. Maciejewski, PhD1,3,4

J A M A . 2 1 8 ; 3 2 ( 1 ) : 3 8

• 3

9 . d

• i

: 1 . 1 1 / j a m a . 2 1 8 . 8 3 3

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The Sunshine Act

2018

Starting Insulin

• On average 3 year delay between needing and starting insulin
• Insulin resistance

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Insulin Start Groups

• 2 hr “insulin introduction” groups
• Facilitated by advance practice nurses and patients on insulin
• First hour addressing fears, myths
• Second hour hands on teaching, mock injection

A1C Reduction

8.0% 8.5% 9.0% 9.5% 10.0% 10.5% 11.0% Insulin group Usual Care Baseline 6 months

*

Spanish Group

**

8.0% 8.5% 9.0% 9.5% 10.0% 10.5% 11.0% Insulin group Usual Care Baseline 6 months

English Group

** * * P < 0.05 compared to baseline ** P < 0.001 compared to baseline Kuo et al, J Clin Nurs. 2017, 1705-1713. doi: 10.1111/jocn.13577.

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http://bit.ly/InsulinIntro-Spa http://bit.ly/InsulinIntro-Eng

INSULIN INTRO VIDEO ENGLISH INSULIN INTRO VIDEO SPANISH

1980s 9% Before DCCT, UKPDS Sulfonylurea Insulin 1990s 8% After DCCT + Metformin 1997 + TZD 7% After DCCT, UKPDS

Glycemic Targets Over the Years

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N Engl J Med 2005;353:2643-2653

DCCT/EDIC - Cumulative Incidence CVD Outcomes

42% reduction in CVD risk 57% reduction in risk of nonfatal MI, stroke or CVD death

8.0 v 8.1 % A1C [----------------------------------------------] 7.2 v 9.1 % A1C

At 30 y Follow up 30% reduction in CVD risk 32% reduction in risk of nonfatal MI, stroke or CVD death

1980s 1990s 1997 9% Before DCCT, UKPDS Sulfonylurea Insulin 8% After DCCT + Metformin + TZD 7% After DCCT, UKPDS

Glycemic Targets Over the Years

2006 + Incretin ? 6% 7% After ACCORD 2008 + Mortality

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• Enhance glucose mediated insulin release
• GLP-1 is low in DM2
• Delays gastric emptying
• Short half life

GLP-1 GLP-1 Agonists

• Lower A1C
• Lead to weight loss
• Significant GI SE

Liraglutide (Victoza GLP-1): CV outcomes

Marso SP et al. N Engl J Med 2016;375:311-322

CV Death HR 0.78*

Marso SP et al. N Engl J Med 2016;375:311-322

1° Outcome HR 0.87* Nonfatal Stroke, NS Nonfatal MI, NS

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Marso SP et al. N Engl J Med 2016;375:311-322 Marso SP et al. N Engl J Med 2016;375:311-322

Liraglutide (Victoza): CV outcomes

Death HR 0.85* HF Hosp, NS

GLP-1 Agonists Trade Name Indication Cost/month

(Good Rx.com 10 2019)

Abliglutide Tanzeum NA exenatide Byetta/Bydureon

• 1. Glucose control

$731/$691 dulaglutide Trulicity

• 1. Glucose control
• 2. Reduce risk of major CV events

in patients with established CVD or multiple CV risk factors

$657 liraglutide (a) Victoza (b) Saxenda

• 1. Glucose control
• 2. Reduce risk of major

cardiovascular events in patients with established CVD.

• 1b. Chronic weight management

$955 $1243 semaglutide Ozempic (b) Rybelsus

• 1. Glucose control
• 1b. Glucose control

$773 $770 (2/2020)

GLP-1 Agonists Indications in Adults (with DM2)

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SGLT1

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

10%

Glucose

No Glucose S1 S3

Renal Handling of Glucose

SGLT2

90% Lots of Glucose

Canvas Trial

Ne Neal et al, N Engl J Med 2017; 377:644-657 DOI: 10.1056/NEJMoa1611925.

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V V Pe Perkovic et et al. N En Engl J J Me Med 2019;380:2295-2306. 2306.

Canagliflozin and Renal and Cardiovascular Outcomes

CV Death - HR 0.78* Death – HR 0.83 ESRD- HR 0.68* HD, Tx, Death HR 0.72*

Zinman B et al. N Engl J Med 2015;373:2117-2128.

Empagliflozin (SGLT2): CV and Mortality Benefit

Death – HR 0.68* CV Death HR 0.62* Hosp HF – HR 0.65* Primary Outcome– HR 0.86*

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• Ejection fraction of 40% or less
• 60% of enrolled WITHOUT Diabetes
• ACE/ARB/ARNI 94%, beta-blocker 96%, mineralocorticoid

receptor antogonist 71%

Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. NEJM. 9/19/19.

DAPA-HF

Diabetes Medications and Heart Failure 5 2

DapaHF N Engl J Med 2019; 381:1995-2008 DOI: 10.1056/NEJMoa1911303

HF Hospitalization HR 0.70* Death HR 0.83* CV Death HR 0.82*

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SGLT2 Inhibitors - Indications in Adults with DM2

SGL2 Inhibitors Trade Name FDA Approved Indications Cost/mth

(Good rx.com 10/2019)

canagliflozin Invokana

1. Glucose control 2. Reduce risk of major CV adverse events in patients with established CVD 3. Reduce risk of ESRD, doubling of creatinine, CV death, hospitalization for HF - in patients with diabetic nephropathy with albuminuria

$498 dapagliflozin Farxiga*

1. Glucose control 2. Reduce risk of hospitalization for HF in patients with CVD or CV risk factors

$485 empagliflozin Jardiance+

1. Glucose control 2. Reduce the risk of CV death in patients with established CVD

$476 ertuglifozin Steglatro

1. Glucose control

$287

*Forxiga is approved in Europe for DM1

SGLT-2 Inhibitors

• Increase in UTI and genital

infections

• Increase in fractures
• Maybe increased amputations
• Maybe increased Fournier’s

gangrene

• Increased rates of euglycemic

DKA

• Lower glucose
• Lower blood pressure
• Lead to weight loss

++

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Euglycemic Ketoacidosis

What we think we know

• Patients at increased risk for DKA are at increased risk of

ketoacidosis

• Reported precipitants are things that result in relative

insulin deficiency OR promote ketones

• Reduction or stopping insulin
• Severe acute illness/stress (e.g. surgery)
• Dehydration
• Extensive exercise
• Low carbohydrate diets/poor PO intake/fasting
• Excessive alcohol intake

Euglycemic Ketoacidosis

What we think we know

• Ketoacidosis can still occur several days after the SGLT2i is

stopped

• Normal urine ketones might be misleading so check plasma

ketones if concerned.

• Symptoms are similar to DKA with n/v, lethargy, abdominal

pain but the glucose is relatively normal

• Treat with insulin and carbohydrates to correct relative insulin

deficiency and dampen glucagon response

• For now would avoid use in hospital
• More common in woman

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Diabetes Subtypes

• Type 1 Diabetes
• Type 2 Diabetes
• Ketosis Prone Type 2 Diabetes
• LADA: Latent Autoimmune Diabetes in Adults
• Post pancreatitis diabetes.

SGLT-2 Inhibitors

• Increase in UTI and genital infections
• Increase in fractures
• Maybe increased amputations
• Maybe increased Fournier’s gangrene
• Increased rates of euglycemic DKA
• Lower glucose
• Lower blood pressure
• Lead to weight loss

++

• Reduce hospitalization for CHF
• Reduce renal failure
• Reduce death

+++++

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1980s 9% Before DCCT, UKPDS Sulfonylurea Insulin 1990s 8% After DCCT + Metformin 1997 + TZD 7% After DCCT, UKPDS

Glycemic Targets Over the Years

2006 + Incretin ? 6% 7% After ACCORD 2008 + Mortality 2016 7-8% After CV trials +SGLT2

A1C Targets

• < 7% - A reasonable goal for many nonpregnant adults. A
• < 6.5% - might be reasonable for select patients C
• < 8% (“less stringent A1C goals”) may be appropriate if: (B)

– h/o severe hypoglycemia – limited life expectancy – advanced micro or macrovascular complications – extensive comorbid conditions – longstanding DM and can’t get to goal despite trying really, really hard

ADA Diabetes Standards of Care 2019

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Summary

• SGLT-2 Inhibitors and GLP-1 agonists provide significant CV

benefit in subgroups of patients. This appears to be independent of tight glucose control.

• SGLT-2 Inhibitors provide significant renal benefit.
• SGLT-2 Inhibitors have CHF benefit in everyone (with or

without diabetes)

• SGLT-2 Inhibitors have significant SE that providers should

be on the lookout for.

• NPH is good stuff and SU are not bad stuff.
• Continued attention to glucose control is required to

prevent microvascular complications.

Summary

• The advent of a lot of newer and expensive diabetes

medications have yet to improve overall diabetes care

• For patients with Type 2 Diabetes, there are no proven

clinically significant advantages to insulin analogues.

• GLP-1 analogues and SGLT2i have significant cardiovascular and

renal benefits.

• SGLT2i are probably best thought of as drugs for CKD and CHF

with some A1C lowering.

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