diabetes workshop: developing strategies for the most...

Diabetes Workshop: Developing Strategies for the

Most Difficult Patients in Your Practice

Primary Care Internal Medicine October 21, 2019

Deborah J Wexler MD, MSc

Clinical Director, MGH Diabetes Center Associate Clinical Chief, MGH Diabetes Unit

1

Disclosures

• I am a member of the ABIM Diabetes, Endocrinology and Metabolism Exam Committee • November 2017–present • As is true for any ABIM candidate who has taken

the certification exam, I have signed a Pledge of Honesty in which I have agreed to keep the ABIM exam confidential

• No exam questions will be disclosed in my presentation

• I serve on Data Monitoring Committees for Novo Nordisk

• Spouse: APOLO1BIO, equity

Challenging diabetes issues

• Which second glucose-lowering medication?

• Which second glucose-lowering medication if the patient has atherosclerotic cardiovascular disease or chronic kidney disease?

• Insulin management in “Diabesity”

Case 1: Next-step medication after metformin

• 73 year old woman with central obesity (BMI 28 kg/m2, type 2 diabetes, hypertension, and smoking.

• HbA1c 7.8% on metformin 1000 mg twice per day. • Medications are hydrochlorothiazide, lisinopril, and

bupropion.

What are the treatment priorities?

• Smoking cessation

• Statins – Number needed to treat ~ 7- 44

• Blood pressure lowering – Number needed to treat ~12-30s for CVD event and mortality, depending on ACE

inhibition/agent/population

• Glycemic control – What we as endocrinologists spend a lot of time on – Number needed to treat depends on timing of treatment, outcome, and duration – Role of diet, exercise, and weight

What would you recommend for treatment of hyperglycemia?

• Referral to medical nutrition therapy?

– Lifestyle intervention?

• Does she need an additional medication? – If so, which one?

DECISION CYCLE FOR PATIENT CENTRED GLYCEMIC MANAGEMENT IN TYPE 2 DIABETES

GOALS OF CARE

• Prevent complications • Optimise quality of

life

ASSESS KEY PATIENT CHARACTERISTICS

CONSIDER SPECIFIC FACTORS WHICH IMPACT ON CHOICE OF TREATMENT

SHARED DECISION MAKING TO CREATE A MANAGEMENT PLAN

AGREE MANAGEMENT PLAN

IMPLEMENT MANAGEMENT PLAN

ONGOING MONITORING AND SUPPORT

REVIEW & AGREE MANAGEMENT PLAN

ADA-EASD Management of hyperglycemia T2DM 2018: Less focus on meds, more on approach

Davies MJ, D’Alessio DA, Fradkin J, Kernan WK, Mathie C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB. Diabetes Care 2018

Individualization of Glycemic Targets

American Diabetes Association Diabetes Care 2017;40:S48-S56

Individualization of Glycemic Targets

American Diabetes Association Diabetes Care 2017;40:S48-S56

20-30% of diabetes patients

have established vascular complications

Relationship between Glycemia and Complications

DCCT and UKPDS

Current Mean HbA1c (%)

Event Rate per

1000 Pt-Y

DCCT

UKPDS

43% reduction in risk for every 10%

decrease in HbA1c 37% reduction in risk

for every 1% decrease in HbA1c

©2005 David M. Nathan

Chart1

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5.55.5

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6.56.5

77

7.57.5

88

8.58.5

99

9.59.5

1010

10.510.5

1111

11.511.5

1212

DCCT

UKPDS

8

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10

10

18

15

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Sheet1

55.566.577.588.599.51010.51111.512

DCCT810183860105160

UKPDS51015234058

Glycemic targets Rationale Summary of A1C goal Fasting BG (mg/dl or

mmol/L)

ACP Overgeneralization from ACCORD, ADVANCE

7-8% in most, deintensify

ADA Long-term data from UKPDS

My general approach to glycemic targets

• HbA1c

Case 1: Next-step medication? Initial steps

• 73 year old woman with central obesity (BMI 28 kg/m2, type 2 diabetes, hypertension, and smoking.

• HbA1c 7.8% on metformin 1000 mg twice per day. • Medications are hydrochlorothiazide, lisinopril, and

bupropion. – Referral to medical nutrition therapy and smoking cessation – Establish HbA1c target of

Case 1, continued

• 73 year old woman who presented with central obesity (BMI 28 kg/m2, type 2 diabetes, hypertension, and smoking. – The patient successfully quits smoking, and gains 15 lbs. – She returns for follow up. She has not been successful with lifestyle

change. • HbA1c is now 8.3%.

• Does she need an additional medication now?

– If so, which one?

Sequencing of glucose-lowering medication

Davies MJ, D’Alessio DA, Fradkin J, Kernan WK, Mathie C, Mingrone

G, Rossing P, Tsapas A, Wexler DJ, Buse JB. Diabetes Care 2018

Incretin agents

N. McIntyre et al.: Lancet 2:20-21, 1964.

• Incretin: a hormone released by nutrients in the gut that stimulates insulin secretion in the presence of hyperglycemia

• Incretin response is dysregulated in diabetes

Incretin effect

Glu

cose

mg/

dl

Plas

ma

insu

lin

time

http://edrv.endojournals.org/content/vol20/issue6/images/large/ef0690385001.jpeg

Glucagon like peptide-1 (GLP-1) and Dipeptidyl peptidase-4 (DPP-4) actions

Modified from Meier JJ Nature Reviews Endocrinology 4(2012)

Appetite suppression

Gut ↓GI motility

Clinical comparison of GLP-1 receptor agonist and DPP-4 inhibitors

GLP-1 Agonists DPP-4 Inhibitors Administration Injection Oral GLP-1 agonism >10x 2-3x Increase insulin secretion +++ _ Decrease glucagon secretion ++ ++ Gastric emptying Inhibited ~ Weight loss Yes No Nausea / vomiting Yes No Risk of pancreatitis No*Don’t use if history of

pancreatitis Yes, ARR 0.13%

Hypoglycemia With ins/SU/etc With ins/SU/etc

Clinical use of DPP-4 inhibitors

• HbA1c decrease of 0.43 to 1.4, average ~0. 7 • Weight-neutral • Tablet, but expensive…for now • Potential uses

– In older patients—when hypoglycemia is a concern – In chronic kidney disease—if insulin is not an option

• CHF risk increased with some DPP4 (saxa) • Otherwise, cardiovascular outcomes trials demonstrated safety

GFR (ml/min) > 50 30-49

Clinical use of GLP-1 receptor agonists Dose ∆ HbA1c ∆ Weight (kg) CVD +

Short-acting Exenatide 5-10 mcg bid -0.5 - -1.5 ~ -2.8 N/A Lixisenatide 20 mcg qd -0.80 -2.9 No

↑GI side effects, ↓gastric emptying, post meal glucose absorption

Long-acting Liraglutide 1.2-1.8 mg qd -1.5 ~ -3.2 Yes Exenatide LAR 2 mg qwk -1.9 -3.7 Partial Semaglutide 0.5-1 mg qwk -1.1, -1.4 -3.6, -4.9 Yes* Dulaglutide 1.5 mg qwk -1.4 -2.9 Pending

Generally, tachyphylaxis to GI side effects with prolonged GLP1 receptor stimulation

Sodium-glucose co-transporter-2 inhibitors

• SGLT2 – S1 PCT: High-capacity, low-affinity: 90%

glucose reabsorption • SGLT-2 upregulated in T2DM

– Increased glucose AND sodium reabsorpotion, leading to myriad adverse renal hemodynamic effects

• Blockade of SGLT-2 – Osmotic diuresis (glucosuria) – Lower blood pressure (2-5 mmHg) – Decreased uric acid – Self-limited glucose lowering – Self-limited weight loss

• Drugs – Canagliflozin, empagliflozin, dapagliflozin

Kalra S, Singh V, Nagrale D. Sodium-Glucose Cotransporter-2 Inhibition and the Glomerulus: A Review. Advances in Therapy. 2016;33(9):1502-1518.

Adapted from Thomas and Cherney (2018) Diabetologia DOI 10.1007/s00125-018-4669-0

Physiological mechanisms implicated in improved renal function with SGLT2i

SGLT2i complement RAAS blockade, which decreases efferent arteriolar

tone, reducing glomerular pressure

In diabetes, glomerular hyperfiltration increased intraglomerular pressure • Increased reabsorption of glucose and

sodium (solute)

SGLT2 inhibitors • Reduce introglomerular pressure due to

increased distal sodium delivery Macula densa senses volume status

• ↑ tubuloglomerular feedback constricts afferent arteriole, lowering intraglomerular pressure

SGLT2i: Clinical summary

• Variable HbA1c reduction – -0.5% to 2.5%, depending on starting point

• Weight reduction

– ~2.5 kg, stabilizes with time

• Hypoglycemia only with insulin or sulfonylurea

• Decreased glycemic efficacy with decreasing GFR – Cana and empa label: eGFR>45, dapa, ertuga >60 – Contraindicated in eGFR< 30 ml/min – But, prevents progression of CKD above that threshold

SGLT2i: Adverse effects

• Mycotic genital infections – Women > > men – Fournier gangrene/necrotizing fasciitis: 1/10,000, not statistically significantly

increased from non SGLT2i users

• Urinary tract infection • Calciuria

– ? Bone loss increased fractures in CANVAS • Rarely, euglycemic DKA

– Especially with insulin reduction in insulin-dependent or insulin-deficient diabetes – Trigger: stress (increased glucose demand) + ketosis + ongoing osmotic

diuresis and glucosuriaDKA)

Dave CV Patorno E.JAMA Int Med 2019

Sulfonylureas—mechanism and clinical use

• ↑ insulin release from pancreatic beta cells

• Reduce HbA1c 1-1.5% • Side effects:

– Hypoglycemia – Weight gain – CVD concerns likely unwarranted

• Duration of action – Glyburide (long) – Glipizide and glimepiride (medium) – (Meglitinides also close SUR1 receptor but

are short-acting)

By Aydintay - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=5509829

Study SAVOR EXAMINE TECOS CAROLINA CARMELINA

DPP4-i saxagliptin alogliptin Sitagliptin linagliptin linagliptin Comparator placebo placebo Placebo sulfonylurea placebo

N 16,500 5,400 14,000 6,000 8,300

Results 2013 2013 2015 2017 2017

New evidence on sulfonylurea safety from DPP4-i CV outcome trials

• All showed cardiovascular safety • Saxagliptin had increased risk HF

• CAROLINA and CARMELINA were a unique pair

• Linagliptin was compared to placebo or a sulfonylurea,

glimepiride

CARMELINA: Linagliptin is safe compared to placebo CAROLINA: Glimepiride was as safe as linagliptin

Rosenstock. JAMA. 2019;321(1):69-79.

MACE: Linagliptin vs. Placebo Linagliptin vs. Glimepiride

Rosenstock. JAMA. 2019;322(12):1155-1166.

Equivalent cardiovascular safety

Sulfonylurea update from CV Outcome trials

• Higher rate of hypoglycemia and weight gain with glimepiride – Hypoglycemia

• 2.2% rate of severe hypoglycemia in glimepiride arm, compared to 0.1% in linagliptin

– Weight was increased, by 1.5 kg

• Equivalent CV safety – Unclear if CVD safety is applicable to glyburide or glipizide

Wexler DJ. Sulfonylureas on trial: The final verdict? JAMA 2019, published online September 19, 2019

Within-class sulfonylurea comparison of rates of death and CVD outcomes

Zeller M et al, JCEM 2010 95, 4993-5002.; Riddle MC, JCEM 2010

= glyburide

Limitation: Retrospective trial confounded by allocation bias Strengths: large cohort and bias may be minimized within drug class

Glyburide (glibenclamide) may be the bad actor…and is the one used most often in other trials

Sulfonylureas: My tips and tricks

• Use the lowest effective dose – To prevent to obligate snacking to avoid hypoglycemia – To minimize weight gain

• Strategy: variable dosing based on anticipated meal size and activity – Example: glipizide 5 mg before small meals, 10 mg before larger

meals – This may motivate some patients to eat smaller meals

• Reduce dose in CKD

Case 1: The choice!

• 73 year old woman with central obesity (BMI 28 kg/m2, type 2 diabetes, hypertension, and smoking; HbA1c is now 8.3%.

• Pros and cons of each – DPP4-inhibitor? – SGLT2 inhibitor? – GLP-1 receptor agonist? – Sulfonylurea?

General reasons to consider costly new meds instead of older meds for glucose-lowering • DPP4 inhibitors

– Elderly – CKD – Risk of hypoglycemia

• GLP-1 receptor agonists

– Weight loss – High A1C as alternative to

basal or prandial insulin*

• SGLT2 inhibitors – Weight loss – Men > women

• Sulfonylurea – Inexpensive – Effective

• What if patients have CVD,

CHF, or CKD???

Case 2: Next-step medication in ASCVD

• 63 year old man with T2DM, coronary artery disease with BMI 36 kg/m2, taking metformin 1000 mg po bid and glipizide 10 mg po bid with HbA1c 8.1%....

• What is the next best medication? – What if he has CHF with EF 28%? – What if he has peripheral vascular disease?

Special populations: Atherosclerotic Cardiovascular and Chronic Kidney Disease

• Cardiovascular outcomes trials have revised our approach to diabetes in the setting of atherosclerotic cardiovascular disease

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwi1j6Whg_XTAhUHxRQKHdvtBpkQjRwIBw&url=https://en.wikipedia.org/wiki/Coronary_artery_disease&psig=AFQjCNHGml46PwG2KosZTa0MO9pTT3hTHQ&ust=1495045043631492

Study SAVOR EXAMINE TECOS CAROLINA CARMELINA

DPP4-i saxagliptin alogliptin Sitagliptin linagliptin linagliptin Comparator placebo placebo Placebo sulfonylurea placebo

N 16,500 5,400 14,000 6,000 8,300

Results 2013 2013 2015 2017 2017

Study LEADER ELIXA SUSTAIN 6 EXSCEL REWIND

GLP1-RA liraglutide lixisenatide semaglutide exenatide LR dulaglutide Comparator placebo placebo placebo placebo placebo

N 16,500 14,000 6,000 5,400 8,300

Results 2016 2015 2016 2018 2019

Study EMPA-REG CANVAS DECLARE NCT01986881

SGLT2-i empaglifozin canagliflozin dapagliflozin ertugliflozin Comparator placebo placebo placebo placebo

N 7300 4300 22,200 3900

Results 2015 2017 2019 2020

Cardiovascular Outcomes Trials in T2DM

Slide adapted from Silvio Inzucchi, Yale

Sequencing of glucose-lowering medication



Recommended next-step medication in presence of CVD, CHF, or CKD



GLP1-RA and SGLT2i have equivalent effect on major adverse cardiovascular event* rate

Zelniker TA et al Circulation 2019

1.01 (0.87, 1.19)

0.89 (0.80, 0.93)

Established atherosclerotic cardiovascular disease population

Multiple risk factor population REWIND 0.87 [0.74-1.02]

REWIND 0.87 [0.74-1.02]

*MACE: MI, stroke, CVD Death

SGLT2i, but not GLP1-RA, reduce hazard ratio of hospitalization for heart failure


0.69 (0.61, 0.79)

0.93 (0.83, 1.04)

GLP1-RA

SGLT2i

Summary: In presence of ASCVD…

• GLP1-RA or SGLT2i, depending on patient comorbidities and adverse effect profile – Peripheral vascular disease GLP1-RA

Because of observed increased risk of amputations associated with canagliflozin

– Desire for significant weight loss, HbA1c>9% GLP1-RA

– CHF SGLT2i

Case 3: Diabetes and chronic kidney disease

• 63 year old man with T2DM, hypertension, BMI 36 kg/m2, taking metformin 1000 mg po bid and glipizide 10 mg po bid with HbA1c 8.1%....

• And CKD, with creatinine 1.6 mg/dl and urine albumin-to-creatinine ratio of 402 mg/g creatinine

• Which medication is preferred?

Special populations: Diabetic kidney disease • Diabetic kidney disease definition

– Persistent albumin-to-creatinine ratio (ACR) > 30 mg/g (more than 3 months)

– Sustained reduction eGFR 300 mg/dl: Severely increased

*CKD stages (eGFR ml/min) 2 : 89-60 3a: 59-45 3b: 44-30 4 :29-15 5

Renal function over time on empagliflozin

Wanner C et al. N Engl J Med 2016;375:323-334.

CREDENCE Trial, 2019

• T2DM – A1C 6.5-12% – eGFR 30 to 300-5000 mg/dl – Stable dose of ACE inhibitor or

angiotensin receptor blocker • Outcomes

– Composite of ESRD, eGFR

CREDENCE Results: CVD and renal benefit

• 2.62 year follow up of 4,401 participants • Primary outcome: 43.2 vs. 61.2 per patient-year • Estimated NNT 22 for primary outcome, 28 for renal outcome, 40 for

major adverse cardiovascular events

SGLT2i-emerging evidence base Verma et al: Pumps, pipes, and filter: do SGLT2i cover it all?

CKD

SGLT2 inhibitors: tips and tricks

• Patient education – Maintain hydration

• Especially with high carbohydrate meals, which may prompt post-prandial diuresis

– Risk of euglycemic DKA

• Prescribing tips – Monitor blood pressure and orthostatic vital signs – If at or near BP goal, reduce doses of other blood pressure

medications and diuretics – Monitor renal function – Do not use in setting of peripheral vascular disease or ulcers

GLP1-RA also associated with improved renal outcomes

Dulaglutide (N/100 py)

Placebo (N/100 py)

HR (95%CI)

P

Renal Composite Outcome 3.47 4.07 0.85 (0.77, 0.93) 0.0004 Components of Composite First Macroalbuminuria a 1.76 2.29 0.77 (0.68, 0.87) 33.9 mg/mmol (300 mg/g); b any reported AE linked to acute renal failure

Between-group HbA1c difference 0.6% in REWIND....but liraglutide was also associated with improved renal outcomes

REWIND trial: After 5.4 years of dulaglutide

Gerstein HC Lancet June 9 2019

The upshot: SGLT2i better than GLP1-RA for renal endpoints…but both are beneficial


0.82 (0.75, 0.89)

GLP-1 RA

0.62 (0.58, 0.67)

SGLT2i

“Broad kidney endpoint:” new-onset macroalbuminuria sustained doubling of serum creatinine or a 40% decline in estimated glomerular filtration rate, end-stage kidney disease, or death of renal cause

Summary: management of hyperglycemia in CKD, for this patient • SGLT2i for albuminuric CKD, as long as eGFR>30 ml/min

– Product labeling for all SGLT2i: stop for eGFR

More on about metformin and CKD

• New FDA guidance (2016) in response to citizens’ petition – OK to continue to eGFR of 30 ml/min – Do not start at eGFR

EMPA-REG

Metformin No metformin

How does metformin compare to new meds? Unknown! New meds were added to metformin.

Metformin was background therapy in three-quarters of the participants in cardiovascular outcomes trials

CANVAS


SUSTAIN-6


LEADER


76.4% 74.0%

77.2% 73.2%

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Case 4: Diabesity

• 68 year old man with uncontrolled type 2 diabetes and obesity (BMI 43 kg/m2)

• Medications: metformin 1000 mg bid, dulaglutide 1.5 mg weekly, and glargine, 80 units nightly, recently increased from 60 units based on morning blood glucose above target with HbA1c 8.5%

• He becomes hungry and diaphoretic midday when he tries to eat less – He drinks a 16 oz soda to manage this symptom

• He has gained about 15 lbs since insulin dose has been increased

Thoughtful use of insulin in obesity with insulin resistance • Metformin in combination with insulin is beneficial in type 2 DM

compared to insulin alone – Better HbA1c: 0.6% (CI 0.3-0.9) – Better weight: 1.7 kg (CI 1.3-2.2) – Non-significant increase in hypoglycemia

• Other insulin-sparing agents can help – GLP-1 agonists, SGLT-2 inhibitors, even pioglitazone for extreme

insulin resistance

• Use the lowest effective insulin dose

Hemmingson B, BMJ 2012; 344 e1771

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiKgaHr_6bUAhVB0WMKHU4qADgQjRwIBw&url=http://atvb.ahajournals.org/content/27/11/2276&psig=AFQjCNE5IOU0bFZGnTRtrzuUKqfKEoLOBg&ust=1496762177248018

Weight loss medication is more effective with lifestyle intervention and meal replacements

• 150 adults with obesity randomly assigned to

– Intensive behavioral therapy (IBT) alone

– IBT plus liraglutide 3.0 mg daily

– IBT-liraglutide plus low-calorie meal replacements

• IBT – 21 sessions: 4 weekly, 10 every

other week, then monthly through month 12, adapted from the DPP

• Meal replacement – 1,000-1,200 liquid shake

divided into 4 servings plus frozen dinner (250-300 kcal)

• Compared to lira 3.0 alone from registration trial (NEJM 2015) Pi-Sunyer NEJM 2015; Wadden TA Obesity, Volume: 27, Issue: 1, Pages: 75-86, 13 November 2018

Lira 3.0 alone

-8

Insulin in diabesity: minimize dose • Ensure appropriate bolus dosing

– This patient should have had prandial insulin added at largest meal instead of continued increase in glargine dose

• Use the lowest effective dose: avoid excess basal insulin – Reduce insulin for exercise

• Avoid obligate snacking – Especially with premixed or peaking insulins

• Balance glycemic and weight goals • Consider concentrated insulins to improve absorption in patients on

high doses • But use them carefully

NPH: safe and effective in T2DM

Lipska K et al. JAMA. 2018;320(1):53-62. doi:10.1001/jama.2018.7993

At one year, 25,489 patients initiating basal insulin analog or NPH No increased risk of hypoglycemia

Equivalent glycemic control (HbA1c 9.4 to 8.2 with analogs, 7.9 with NPH)

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Basal insulin analogs vs. NPH • Evidence:

– 8 RCTs, ~2,300 patients (2006 Cochrane reviews and Meta-analyses) plus RCTs after 2006

• No difference in A1C, weight, severe hypoglycemia • Benefit

– Limited to lower incidence of non-severe & nocturnal hypoglycemia – Less weight gain with detemir vs. NPH in the evening (0.4-0.7 vs 1.6-1.9

kg) • Conclusion:

– Comparable net health benefit for insulin analogs vs. NPH – Patients with severe hypoglycemia may benefit from analogs

Cepac.icer-review.org/adaptations/diabetes

One-year budget impact of shift in insulin use from analog to NPH in New England

61

Cepac.icer-review.org/ adaptations/diabetes

Population: New England Medicaid enrollees

Switching from 80:20 to 20:80 ratio of analog to NPH insulin cut insulin costs by 40% $1.7 million in savings for every 1,000 patients switched

Alternate insulin delivery devices • Mechanical patch pump

– “V-Go”

• Great for patients with impaired vision or dexterity who require basal-bolus insulin

• Usually cheaper than insulin pens – Fill with vials (cheaper) – Fewer copays

Summary: Challenging diabetes management and potential approaches Condition Approach Elderly, frail, increased risk of hypoglycemia

• Raise glycemic targets • Avoid medications that cause hypoglycemia • Simplify regimen

Atherosclerotic CVD • GLP1-RA or • SGLT2 inhibitor (except in PVD)

CHF • SGLT2 inhibitor

CKD, GFR > 30 ml/min • SGLT2 inhibitor if UACR>300 mg/g, or GLP1-RA • Low dose metformin

ESRD • Stop metformin, SGLT2 inhibitor • Short-acting sulfonylurea or glinides • Dose insulin in the morning rather than bedtime

Obesity • Avoid excess basal insulin • Use insulin-sparing regimens • Behavioral intervention plus medication • Bariatric surgery

Key points

• There is now evidence to support the use of certain glucose-lowering medications in the presence of specific comorbidities – Athersclerotic cardiovascular disease: GLP-1 receptor agonist or

SGLT2-inhibitor – Albuminuric CKD: SGLT2-inhibitor

Next best steps

• Consider use of newer medications for specific indications

• Use tips and tricks to optimize use of lower-cost glucose lowering medications – Dose adjust sulfonylureas – Switch to NPH insulin

New References, 2018-2019 • Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of

hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-701.

• Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Furtado RHM, et al. Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus. Circulation. 2019;139(17):2022-31.

• Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-306.

• Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019.

• Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. 2019.

Questions? Comments? Cases?

Extra slides: concentrated insulins

Background: Insulin absorption • Rate of absorption of insulin

– Directly proportional to dose

• At high doses, volume injected can be large

Fast S L O W

Glargine has dose-dependent peak and duration of action

Wang Z. Diabetes Care 2010; 33:1555

Doses 2.0 units/kg 1.5 units/kg 1.0 units/kg 0.5 units/kg

Placebo

Lower doses do not even last 24 hours

Vast majority of T2D on

Lispro kinetics are also dose-dependent

Lispro injection Δ 50 units, obese T2DM □ 30 units, obese T2DM

• 10 units, healthy subject ○ 10 units, obese T2DM

Gagnon-Auger, Diabetes Care 2010; 33:2502-2507

Subjects: 6 healthy (age 23, BMI 22 kg/m2) and 7 with obesity and T2DM (age 60, BMI 38 kg/m2, studied with

euglycemic clamp

Conclusion: lispro absorption and glucose lowering action are delayed with higher doses and in obesity/T2DM

….but worth noting: these higher doses are unusual, even in obese patients

Concentrated insulin is more potent for a given volume

• Nomenclature and general principles – U-100 = 100 units in 1 ml

• NPH, R, lispro, aspart, glulisine, glargine, detimir, degludec U-100

– U-200 = 200 units in 1 ml • Lispro U-100, degludec U-200

– U-300 = 300 units in 1 ml • Glargine U-300

– U-500 = 500 units in 1 ml • R U500

• Same potency may be delivered in smaller volume, leading to improved absorption

U-500 R: the original concentrated insulin

• At relevant (high) doses, compared to Regular U-100, Regular U-500 has – Blunted peak – Longer duration of action

• Humulin R U-500

• Peak 4-6 hours • Duration of action 10-16

hours • BID or TID dosing

depending on dose • Similar to NPH (blue line) de la Pena, Diabetes Care. 2011

Dosing U-500 R

• Error-prone • Especially if dosed in a U-100 syringe • Ideally, instructions should be written

in volume and equivalent U-100 units – 0.15 ml on U-100 syringe, equivalent to

75 units • Stable up to 28 days in pre-filled

syringes • New U-500 pen

• Expensive • But costs less per unit than high-dose

U-100 • May be more effective due to improved

absorption

VA prototype U-500 syringe U-100 syringe

Abraham K. Usability Testing, PSQH 2013 Lull J. Am Pharm Assoc 2013

U-500 R Meta-analysis • Meta-analysis of 9 studies including

310 patients, most with type 2 DM, using subcutaneous U-500 – HbA1c decrease: 1.59% – Weight increase: 4.4 kg – Total daily dose increase: 59 units

• Findings from continuous subcutaneous insulin infusion – Similar A1C improvement – No significant weight gain or dose

change – Kinetics challenging

Reutrakul J. Diabetes Sci Technology 2012 PMID 22538155

HbA1c

Weight

Transitioning to U-500 R

• Does patient have uncontrolled diabetes on >200 units of insulin per day?

• First, redouble efforts at diet, exercise, and insulin-sparing medications

• Then, try administering U-100 insulin in divided doses to optimize absorption kinetics – For example, dose basal insulin twice daily and give prandial insulin rather

than relying on basal insulin alone. – Instead of glarigine 200 units, try NPH 75 units bid and prandial insulin 25

units before breakfast and dinner

If U-500 R is started • In uncontrolled patient, convert total daily dose to U-500 R dose

equivalent: – For example, Total daily dose 200 units of U-100 insulin = 0.40 ml of U-500 R

• If dosed twice daily: – Pre-meal breakfast / dinner injections (60%/40%) U-500 R 0.24 ml (~120 U-100 units) before breakfast U-500 R 0.16 ml (~80 U-100 units) before dinner

• If dosed three times per day, especially higher doses – Premeal (40%/30%/30% or 40%/35%/20%) U-500 R 0.16 ml before breakfast U-500 R 0.08 ml before lunch U-500 R 0.08 ml before supper

• Titrate based on response

Other concentrated insulins

• Glargine U-300 (Toujeo)

• Degludec U-200 (Tresiba) – Also has U-100 formulation

Bottom line for practice: Use concentrated insulins carefully

• U-500 R: Observational data in T2DM: – HbA1c 0.68% improvement – Hypoglycemia measured by ICD-9

• Incidence increased from 6.7% to 11.9% • 0.23 to 0.39 events/patient/year

• U-500 R: Randomized controlled trial in T2DM

– 24 weeks, open-label – Testing twice daily vs. three times per day U-500

• Equivalent HbA1c reduction: slightly more than 1% • Less hypoglycemia in TID regimen • 5 kg weight gain

Eby El. BMJ Open Diabetes Res Care 2015 PMID: 25969741 Hood RC. Endocr Pract 2015. PMID: 25813411

��Diabetes Workshop: �Developing Strategies for the �Most Difficult Patients in Your Practice�DisclosuresChallenging diabetes issues Case 1: Next-step medication after metforminWhat are the treatment priorities? What would you recommend for treatment of hyperglycemia? ADA-EASD Management of hyperglycemia T2DM�2018: Less focus on meds, more on approachSlide Number 8Slide Number 9Slide Number 10Glycemic targets�My general approach to glycemic targetsCase 1: Next-step medication? Initial steps Case 1, continued Sequencing of glucose-lowering medicationSlide Number 16Incretin agents Glucagon like peptide-1 (GLP-1) and �Dipeptidyl peptidase-4 (DPP-4) actionsClinical comparison of GLP-1 receptor agonist and DPP-4 inhibitorsClinical use of DPP-4 inhibitorsClinical use of GLP-1 receptor agonists Sodium-glucose co-transporter-2 inhibitorsSlide Number 23SGLT2i: Clinical summary SGLT2i: Adverse effectsSulfonylureas—mechanism and clinical useNew evidence on sulfonylurea safety from DPP4-i CV outcome trialsCARMELINA: Linagliptin is safe compared to placebo�CAROLINA: Glimepiride was as safe as linagliptin�Sulfonylurea update from CV Outcome trialsWithin-class sulfonylurea comparison of rates of death and CVD outcomesSulfonylureas: My tips and tricksCase 1: The choice!General reasons to consider costly new meds instead of older meds for glucose-loweringCase 2: Next-step medication in ASCVDSpecial populations: Atherosclerotic Cardiovascular and Chronic Kidney DiseaseCardiovascular Outcomes Trials in T2DMSequencing of glucose-lowering medicationSequencing of glucose-lowering medicationRecommended next-step medication in presence of CVD, CHF, or CKDGLP1-RA and SGLT2i have equivalent effect on major adverse cardiovascular event* rateSGLT2i, but not GLP1-RA, reduce hazard ratio of hospitalization for heart failureSummary: In presence of ASCVD…Case 3: Diabetes and chronic kidney disease Special populations: Diabetic kidney diseaseRenal function over time on empagliflozin CREDENCE Trial, 2019CREDENCE Results: CVD and renal benefit SGLT2i-emerging evidence baseSGLT2 inhibitors: tips and tricksGLP1-RA also associated with improved renal outcomesThe upshot: SGLT2i better than GLP1-RA for renal endpoints…but both are beneficialSummary: management of hyperglycemia in CKD, for this patient More on about metformin and CKDHow does metformin compare to new meds? �Unknown! New meds were added to metformin.Case 4: DiabesityThoughtful use of insulin in obesity with insulin resistanceWeight loss medication is more effective with lifestyle intervention and meal replacements Insulin in diabesity: minimize doseNPH: safe and effective in T2DMBasal insulin analogs vs. NPHOne-year budget impact of shift in insulin use from analog to NPH in New EnglandAlternate insulin delivery devicesSummary: Challenging diabetes management and potential approaches Key pointsNext best stepsNew References, 2018-2019Questions? Comments? Cases? Extra slides: concentrated insulins Background: Insulin absorptionGlargine has dose-dependent peak and duration of actionLispro kinetics are also dose-dependentConcentrated insulin is more potent �for a given volumeU-500 R: the original concentrated insulinDosing U-500 RU-500 R Meta-analysisTransitioning to U-500 RIf U-500 R is startedOther concentrated insulins Bottom line for practice: �Use concentrated insulins carefully

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