Inpatient Diabetes Management for the Hospitalist

Haritha Katakam, MD Assistant Professor of Medicine Division of Hospital Medicine Emory University Hospital • No financial disclosures

• Thank you to Dr. Guillermo Umpierrez for his assistance in the preparation of this presentation A Snapshot of Diabetes

Accounts for 1 in 4 health care dollars in the U.S How do we screen for Diabetes and Hyperglycemia? 1

On Admission Assess all patients for a history of diabetes Obtain laboratory BG testing on admission

No history of diabetes No history of diabetes History of diabetes BG<140 mg/dl BG >140 mg/dl (7.8 mmol/L)

Start POC BG BG monitoring Initiate POC BG monitoring x 24-48h Check A1C if not done in last monitoring according to Check A1C 3 months clinical status

A1C ≥ 6.5% Umpierrez et al. J Clin Endocrinol Metabol 2012. [Slide courtesy of Umpierrez GE 2018] What are the glycemic targets in the hospital? 2

• Hyperglycemia in the hospital is defined as • BG> 140 mg/dL

• Insulin therapy should be started at a threshold of • BG>180 mg/dL

• Target glucose range in the hospital • BG 140-180 mg/dL is recommended for the majority of critically ill and non- critically ill patients • Premeal BG <140 mg/dL, random BG <180mg/dL

Diabetes Care in the Hospital: Standards of Medical Care in Diabetes 2018. AACE/ADA Consensus Statement on Inpatient Glycemic Control 2009. Outline

❖ Can we use non-insulin agents in the hospital?

❖ What is the optimal insulin regimen in the hospital?

❖ How do we choose a treatment regimen for discharge? Can we use non-insulin agents in the hospital? Case

A 67 year old male with PMH of CAD, ischemic cardiomyopathy with EF 45%, type 2 Diabetes, CKD stage 4, presents to the hospital with a CHF exacerbation. His home DM regimen includes metformin, sitagliptin. His last A1c is 7.0%. A random BG on admission is 160 mg/dL.

What is the best treatment regimen for his Diabetes while in the hospital? a) Continue Sitagliptin (DPP4-i)

b) Continue Metformin + correctional insulin

c) Start Empagliflozin (SGLT2 inhibitor)

d) Start Liraglutide (GLP-1 RA) What the guidelines tell us..

• Recommends: • Basal + bolus + correction • DPP-4 alone or in combination with basal insulin

• Discourages use of: • SSI alone • Premixed insulins • SGLT2 inhibitors • Noninsulin agents in most patients

Diabetes Care in the Hospital: Standards of Medical Care in Diabetes 2018. AACE/ADA consensus statement 2009. Debate on Insulin vs Non-insulin Use in the Hospital Setting Metformin • No evidence to support discontinuing metformin on admission

• Historically, a concern for lactic acidosis and changing renal function

• Cochrane review -> Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus • no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use

Pasquel FJ et al. Current Diabetes Reports (2019). Debate on Insulin vs Non-insulin Use in the Hospital Setting Sulfonylureas • Inpatient use not recommended due to risk of hypoglycemia • Insulin use has risk of hypoglycemia as well

Thiazolidinediones (TZDs) • Delayed onset of action • Potential for fluid retention, risk of CHF

Pasquel FJ et al. Current Diabetes Reports (2019). Dipeptidyl-Peptidase-4 (DPP-4) Inhibitors

Jiang J et al. Protein Data Bank. 2017. Sita-Hospital Trial

Basal + Basal + bolus sitagliptin

TDD of 0.4 u/kg Glargine once daily 0.15- 1/2 as glargine once daily 0.25 u/kg

1/2 divided as aspart or Renally dosed sitagliptin lispro with meals once daily

SSI AC+HS SSI AC+HS

Pasquel et al. The Lancet Diabetes Endocrinol 2017. Sita-Hospital Trial

% of Patients with Treatment failure (# Total insulin dose hypoglycemia of patients with 2 BG (units/day) P=0.45 >240mg/dl) P<0.001 50% P=0.54 40.0 40 31.0 40% 30.0 24.1 30% 30 26 22 20.0 20% 20 9% 12% 10% 10 10.0 0% 0 0.0 Sitagliptin-basal Sitagliptin-basal Sitagliptin-basal Basal-bolus Basal-bolus Basal-bolus

Pasquel et al. The Lancet Diabetes Endocrinol 2017. Sita-Hospital Trial

Pasquel et al. The Lancet Diabetes Endocrinol 2017. Safety and Efficacy of DPP4 Inhibitors and Basal Insulin in Hospitalized Patients with T2DM

References Design Patients and Main Findings Teaching Points Treatment Umpierrez (2013) 90 Med/Surg patients Randomized to: No differences in Patients with a with T2DM and • Sitagliptin alone glycemic control, randomization BG Pilot randomized random BG 140 - 400 • Sitagliptin + basal length of hospital stay >180 mg/dL treated study mg/dl treated with • Basal + bolus and hypoglycemia with sitagliptin alone diet, oral meds or events had higher mean daily low-dose insulin All groups received BG correctional insulin

Garg (2017) 66 non-ICU patients Randomized to: Non-inferior in mean Saxagliptin as single with T2DM and • Saxagliptin daily blood glucose therapy may be Randomized- HbA1C ≤7.5% on 0-2 • Basal + bolus control safe/effective in controlled trial oral meds patients with well Both groups received Lower glycemic controlled T2DM on Mean A1c ~ 6.5% correctional insulin variability with DPP-4 0–2 oral agents Pre-randomization BG

~ 155 mg/dL Table adapted from Gomez-Peralta et al. Diabetes Ther 2018. Safety and Efficacy of DPP4 Inhibitors and Basal Insulin in Hospitalized Patients with T2DM

References Design Patients and Main Findings Teaching Points Treatment Perez-Belmonte 454 non-ICU patients 2 groups: No differences in Linagliptin-basal insulin (2018) with T2DM with A1c • Linagliptin + Basal glycemic control, can be used safely and <8 %, BG <240 mg/dl, • Basal + bolus treatment failures, effectively in patients Retrospective diet controlled or on hypoglycemic with type 2 DM with observational study oral meds at home All groups received events, length of mild-mod correctional insulin stay, or hyperglycemia, on oral complications meds at home

Perez-Belmonte 240 non-ICU, non- Randomized to: No differences in Patients on linagliptin- (2019) cardiac surg patients • Linagliptin + Basal glycemic control, basal insulin had fewer with A1c <8%, BG • Basal + bolus treatment failures. hypoglycemic events <240 mg/dl, on oral (p<.001) and lower meds at home All groups received number of daily insulin correctional insulin injections (p<0.001)

Perez-Belmonte LM et al. Journal of Clinical Medicine 2018. Perez-Belmonte LM. Ann Med 2019. Dipeptidyl-Peptidase-4 (DPP-4) Inhibitors in the Hospital

3 • Good candidates • Hepatic metabolism • Type 2 DM, diet controlled or • Vildagliptin on oral meds, or low dose • Saxagliptin insulin (<0.6 u/kg) • Renal elimination • A1c < 8 • Sitagliptin • Mild to moderate • Saxagliptin hyperglycemia on admission (BG < 240 mg/dL) • Vildagliptin Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

insulin gastric secretion emptying GLPGLP--11 GIPRA glucagon secretion

hepatic peripheral Slide courtesy of Francisco J. Pasquel, MD, MPH glucose glucose Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 production uptake GLP-1 Receptor Agonists / Cardiovascular Studies

Leader Trial Sustained 6

Slide courtesy of Guillermo E. Umpierrez, MD LEADER TRIAL- Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marzo et al. N Engl J Med 2016. Slide courtesy of Guillermo E. Umpierrez, MD Semaglutide and Cardiovascular Outcomes in T2DM

Marso SP et al. N Engl J Med 2016. Slide courtesy of Guillermo E. Umpierrez, MD Exenatide Therapy for the Inpatient Management of Med/Surg Patients with Type 2 Diabetes

Maya Fayfman et al. Dia Care 2019;42:450-456 SGLT-2 Inhibitors

SGLT-2 Inhibitors

Glucosuria Loss of calories Class Mechanism Advantages Disadvantages Cost SGLT-2 • Inhibits renal SGLT- • Use across • Genital mycotic High inhibitors 2 spectrum of DM infections • Increases stages • UTIs glucosuria • Weight loss • ? Dehydration •  BP • ? Renal effects Slide courtesy of Francisco J. Pasquel, MD, MPH The SGLT-2 Inhibitor Studies

•The EMPA-REG and CANVAS trials showed empagliflozin and canagliflozin reduced MACE outcomes (cardiovascular death, myocardial infarction or nonfatal stroke)1,2 •In DECLARE-TIMI58, dapagliflozin did not lower the rate of MACE, but lower rate of a composite of CV death or heart failure admission.

1. Zinman B et al. N Engl J Med. 2015;373:2117-2128. 2. Neal B et al. N Engl J Med. 2017;377:644-657. 3. Wiviott et al. NEJM 2018, on line November 2018 Slide courtesy of Guillermo E. Umpierrez, MD Primary Outcome: 3-point MACE (CV death, MI, stroke)

EMPA-REG (Empagliflozin) CANVAS (Canagliflozin) Dapagliflozin (DECLARE)

EMPA: 10.5% vs. PBO: 12.1% event per CANA: 26.9% vs. PBO: 31.5% event per DAPA: 8.8% vs. PBO: 9.4% event per 1000 patient-years (hazard ratio, 0.86; 1000 patient-years (hazard ratio, 0.86; 1000 patient-years (hazard ratio, 0.93; 95% CI, 0.74 to 0.99) 95% CI, 0.75 to 0.97) 95% CI, 0.84 to 1.03)

EMPA-REG (Empagliflozin) CANVAS (Canagliflozin) Dapagliflozin (DECLARE)

HR: 0.65; 95% CI, 0.50 to 0.85) HR: 0.67; 95% CI, 0.52 to 0.87) HR: 0.73; 95% CI, 0.61 to 0.88)

1. Zinman B et al. N Engl J Med. 2015;373:2117-2128. 2. Neal B et al. N Engl J Med. 2017;377:644-657. 3. Wiviott et al. NEJM 2018, on line November 2018

Slide courtesy of Guillermo E. Umpierrez, MD Case

What is the best treatment regimen for his Diabetes while in the hospital? a) Continue Sitagliptin (DPP4-i)

b) Continue Metformin + correctional insulin

c) Start Empagliflozin (SGLT2 inhibitor)

d) Start Liraglutide (GLP-1 RA) Can we use non-insulin agents in the hospital? 4

Recommended Promising Needs More Not Research Research Recommended What is the optimal insulin regimen in the hospital for non- ICU patients? Insulin Action

Breakfast Lunch Dinner

Aspart, Lispro or glulisine Insulin Insulin Action

Basal insulin

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342 [Slide courtesy of Umpierrez GE 2018] Total Daily Insulin Needs

“Scheduled” (SSI only uses this component)

Correction Total daily Bolus Basal Correction insulin needs (Prandial) Basal Prandial

Long-acting Rapid-acting insulin insulin

Moghissi ES et al. Endocr Pract. 2009;15(4):353–369. Umpierrez et al. J Clin Endocrinol Metabol. 97(1):16-38, 2012 [Slide courtesy of Umpierrez GE 2018] Case

A 53 year old female is pre-op for colectomy. She has an 12 year history of T2DM treated with metformin and premixed insulin 20u qAM and 14u qPM. Prior to surgery, a random BG is 224 mg/dL and A1C is 8.8%.

What is the best treatment regimen for her Diabetes wile in the hospital? a) Hold home meds, start Lantus + correctional insulin

b) Continue premixed insulin at 80% of home dose

c) Hold home meds, switch to NPH at weight based dosing What is the optimal insulin regimen in the hospital for non-ICU patients?

SSI

Basal + Basal + DPP-4 SSI inhibitor Basal bolus

Split NPH + mixed regular regimens Rabbit 2 Trial

Basal + SSI bolus

Blood glucose Units of Total daily dose (TDD) of AC+HS for glucose 0.4-0.5units/kg/day >140mg/dL mg/dl insulin >140-180 4 181-220 6 ½ TDD as glargine once 221-260 8 daily 261-300 10 301-350 12 ½ TDD divided as glulisine 351-400 14 with meals >400 16

Umpierrez et al. Diabetes Care 2007. RABBIT 2 Trial

Percentage of patients within the mean glucose target (140 mg/dl)

66%

38%

Figure 1—Changes in blood glucose concentrations in patients treated with glargine plus glulisine (●) and with SSI (○). *P 0.01; ¶P 0.05. Basal + bolus SSI

Umpierrez et al. Diabetes Care 2007. RABBIT 2 Trial

Figure 2—Mean blood glucose concentration in subjects who remained with severe hyperglycemia despite increasing doses of regular insulin per the sliding-scale protocol (○). Glycemic control rapidly improved after switching to the basal-bolus insulin regimen (●). P < 0.05.

Umpierrez et al. Diabetes Care 2007. • Worse glycemic control with SSI alone • Similar frequency of hypoglycemia SSI

Basal bolus Basal Plus Trial

Basal + Basal + SSI SSI Bolus + SSI

TDD of 0.5 units/ kg Glargine once daily ½ TDD as glargine once daily 0.25 units/kg

½ TDD as glulisine with meals SSI

SSI

Umpierrez et al. Diabetes Care 2014. Basal Plus Trial

% of Patients with hypoglycemia (BG< Treatment failures 70mg/dL) (two consecutive values or mean 50% daily BG>240 mg/DL) P=0.009 50% 40% P=<0.001 40% 30% 30% 20% 16% 19% 13% 20% 10% 10% 3% 0% 2% 0% 0% Basal + bolus Basal + SSI SSI Basal + bolus Basal + SSI SSI

Umpierrez et al. Diabetes Care 2014. • Worse glycemic control with SSI alone • Reduced frequency of hypoglycemia SSI

• Similar glycemic control Basal + • Similar frequency of SSI hypoglycemia Basal bolus DEAN Trial

NPH + regular Basal + bolus insulin

TDD of 0.4 U/kg TDD of 0.4 U/kg

1/2 TDD as detemir once 2/3 TDD before breakfast daily

1/2 TDD divided as aspart 1/3 TDD before dinner with meals

Umpierrez et al. J Clin Endocrinol Metab 2009. DEAN Trial

• RATES OF 240 Detemir + aspart HYPOGLYCEMIA 220 NPH + regular P=0.20 200 P=NS 180

160 BG, mg/dL BG, 140 32.9% 25.4% 120 100 Pre-Rx 0 1 2 3 4 5 6-10 BG Duration of Therapy, d BASAL + NPH + [Graph courtesy of Umpierrez GE 2018] BOLUS REGULAR [Graph courtesy of Umpierrez GE 2018]

Umpierrez et al. J Clin Endocrinol Metab 2009. Basal-Bolus with Insulin Analogs versus Human Insulin

Analogs Human p-value N=66 n=68 Mild Hypoglycemia 35% 38% p=0.68 (<70 mg/dL) Severe hypoglycemia 7.6% 25% p=0.08 (<40 mg/dL) Patients with n ≥2 10 16 p= 0.2 episodes, n (%)

Benitez et al. Endocrine Pract 2015. Basal bolus

NPH + • Similar glycemic control regular • Trend toward increased severe hypoglycemia (<40mg/dL) with human insulin Premixed Insulin Trial

Premixed human Basal + bolus insulin (70/30)

TDD of 0.3-0.4 U/kg TDD of 0.3-0.4 U/kg

1/2 TDD as glargine once 60% TDD before breakfast daily

1/2 TDD divided as glulisine 40% TDD before dinner with meals

Bellido et al. Diabetes Care 2015. Premixed Insulin Trial

Bellido et al. Diabetes Care 2015. Premixed Insulin Trial - Treatment Protocol

Basal + Bolus Premixed insulin group Premixed insulin group Once daily adjustment of BG (mg/dl) (Morning dose adjusted (Evening dose adjusted basal insulin only according to BG value according to morning BG before lunch) value ) Based on fasting BG

<60 20 % 20 % 20 % 60-79 10 % 10 % 10 % 80-139 No change No change No change 140-179 10 % 10 % 10 % 180-249 20 % 20 % 20 % >250 30 % 30 % 30 %

Bellido et al. Diabetes Care 2015. Basal bolus

• Trial terminated early Split due to increased mixed frequency of regimen hypoglycemia in premixed insulin group Case

What is the best treatment regimen for her Diabetes wile in the hospital? a) Hold home meds, start Lantus + correctional insulin

b) Continue premixed insulin at 80% of home dose

c) Hold home meds, switch to NPH at weight based dosing • Similar glycemic control • Worse glycemic control • Similar frequency of with SSI alone hypoglycemia • Similar or reduced 5 • Total daily insulin dose and frequency of hypoglycemia # of insulin injections per SSI day were significantly lower in the sitagliptin-basal group Basal + • Similar glycemic control Basal + DPP-4 • Similar frequency of SSI inhibitor hypoglycemia Basal bolus

• Trial terminated early due Split • Similar glycemic control NPH + to increased frequency of mixed • Trend toward increased regular hypoglycemia in premixed regimens severe hypoglycemia insulin group (<40mg/dL) with human insulin What is the optimal insulin regimen in the hospital for non-ICU patients?

SSI

Basal + Basal + DPP-4 SSI inhibitor Basal bolus

Split NPH + mixed regular ? regimens Do the guidelines agree? PreferredSC IInpatientnsulin Adm iInsulinnistratio nRegimen

Scheduled (SSI only uses this component)

Correction

Total daily Bolus Basal Correction insulin needs (Prandial) Basal Prandial

Long-acting insulin Rapid-acting insulin

[Image courtesy of Umpierrez GE 2018]

Moghissi ES et al; American Association of Clinical Endocrinologists; AmDiabeteserican DCareiab eint ethes Hospital: Standards of Medical Care in Diabetes 2018. Association. Endocr Pract. 2009;15(4):353–369. AACE/ADA Consensus Statement on Inpatient Glycemic Control 2009. Umpierrez et al. Endocrine Society Guidelines. J Clin Endocrinol Metabol. 97(1):16-38, 2012Endocrine Society Clinical Practice Guideline 2012. Diabetes Care Guidelines 2018

• Recommends: • Basal + bolus + correction • DPP-4 alone or in combination with basal insulin

• Discourages use of: • SSI alone • Premixed insulins • SGLT2 inhibitors • Noninsulin agents in most patients

Diabetes Care in the Hospital: Standards of Medical Care in Diabetes 2018. Endocrine Society Clinical Practice Guideline 2012

For patients who are NPO For all other non-critically ill patients

Bolus Basal Correction Basal Correction (Prandial)

• Start with TDD 0.2-0.5 u/kg of insulin • Start with TDD 0.2-0.5 u/kg of insulin • 50% of TDD as Basal (glargine/detemir • 50% TDD as basal once daily or NPH twice daily) • 50% TDD divided with meals • Hold scheduled prandial insulin • Correction SSI AC+HS • Correction SSI q4-6hours

Endocrine Society Clinical Practice Guideline 2012. How do we choose a treatment regimen for discharge from the hospital? Case

45 YEAR OLD MALE

UNDERGOES SURGERY FOR DIABETIC FOOT INFECTION

A1c HOME MEDS: 8.0

GLIPIZIDE METFORMIN PMH: TYPE 2 DM Case

Post-operatively, Mr.S is receiving lantus 20 units daily, aspart 3 units with meals and correctional insulin. He is clinically stable and ready for discharge home.

What is the best medication regimen for discharge? a) Resume home oral meds - glipizide and metformin

b) Resume home oral meds and lantus 10 units daily

c) Resume home oral meds and lantus 20 units daily

d) Continue lantus 20 units daily and aspart 3 units with meals Endocrine Society Guidelines 6

Recommend using admission A1c to tailor treatment regimen at discharge

• A1c < 7 – continue home regimen

• A1c 7-9 – intensify treatment by adding/increasing oral agents or insulin

• A1c > 9 – start basal bolus regimen

Endocrine Society Clinical Practice Guideline 2012. Hospital Discharge Algorithm Based on Admission HbA1c

A1C < 7% A1C 7%-9% A1C >9%

Home OAD + Home OAD + 80% of inpatient Home OAD or 50% of glargine 80% of glargine basal bolus insulin regimen total daily dose total daily dose regimen

Umpierrez et al. Diabetes Care 2014. Change in HgbA1c at 4 weeks / 12 weeks

12 A1c < 7% A1c 7-9% A1c >9% 11.5 11

9 9.1

8 7.9 8.1 7 7.2 7.1 6.6 6.3 6 6.2

4 Admission 4 weeks after D/C 12 weeks after D/C

Umpierrez et al. Diabetes Care 2014. Change in HgbA1c at 4 weeks / 12 weeks

Change in A1c for Entire Cohort Discharge plan included: 10 • Diabetes education prior to discharge 9 8.67 • Glucose diary log 8 7.86

Hgb A1c Hgb 7.26 • Telephone calls every 2 weeks 7 • Clinic visit at 1 and 3 months to adjust 6 Admission 4 weeks after D/C insulin doses 12 weeks after D/C

Umpierrez et al. Diabetes Care 2014. Rates of Hypoglycemia (BG<70 mg/dL)

P = 0.27 50% P = 0.039 • Patients discharged home on a 44% basal + bolus regimen had an 40% increased rate of hypoglycemia 30% 30% 25% 22% 20%

10%

0% Discharge treatment regimen OAD only OAD + glargine basal + bolus glargine alone

Umpierrez et al. Diabetes Care 2014. Case

Post-operatively, Mr.S is receiving lantus 20 units daily, aspart 3 units with meals and correctional insulin. He is clinically stable and ready for discharge home.

What is the best medication regimen for discharge? a) Resume home oral meds - glipizide and metformin

b) Resume home oral meds and lantus 10 units daily

c) Resume home oral meds and lantus 20 units daily

d) Continue lantus 20 units daily and aspart 3 units with meals Under Consideration: ADA Standards of Medical Care in Diabetes - 2018

Monotherapy Me ormin

A1C not at goal

Dual therapy

ASCVD? Add agent with evidence of CV risk reduc on: Yes - SGLT2-I (empagliflozin or canagliflozin) - GLP1-RA (liraglu de) No

Slide courtesy of Guillermo E. Umpierrez, MD Choice of Meds After Metformin Monotherapy and Cost

Slide courtesy of Francisco J. Pasquel, MD, MPH Outline

❖ Can we use non-insulin agents in the hospital?

❖ What is the optimal insulin regimen in the hospital?

❖ How do we choose a treatment regimen for discharge? Outline

❖Can we use non-insulin agents in the hospital?

Recommended Promising Needs More Not Research Research Recommended Outline

❖What is the optimal insulin regimen in the hospital? Outline

❖How do we choose a treatment regimen for discharge?

Use admission A1c to tailor treatment regimen at discharge

• A1c < 7 – continue home regimen

• A1c 7-9 – intensify treatment by adding/increasing oral agents or insulin

• A1c > 9 – start basal bolus regimen Inpatient Diabetes Management for the Hospitalist

Thank You! Any Questions?

Haritha Katakam, MD Please contact me at [email protected] with any questions or feedback!