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Diabetes Update 2019: Beyond the A1c

Justin Moore, MD, FACP

June 6, 2019

2

Justin Moore, MD, FACP

Justin is an endocrinologist who left academic medicine in 2014 to do consulting work at the clinical-public health intersection with Double Arrow Metabolism. It's in this role that he serves as a consultant with Health ICT and chairs the Chronic Disease Alliance of Kansas. He's also an endocrinology consultant with RubiconMDand a volunteer endocrinologist with Guadalupe Clinic, where he tends to stop more medications than he starts. He believes chronic diseases should fall at the top of the patient's problem list at any given visit, not at the bottom. He believes that health is hard to define and harder to measure, but that it's easier to achieve than people think. He believes true health saves money. He's an evangelist for transportation by bicycle.

Disclosures

Old conversation

1. Your A1c level is too high

2. Your A1c level is too high

3. Your A1c level is too high

4. Sigh…let’s see about your blood pressure

Learning objectives

Outline the philosophy of a recent shift away from pure glycemic control toward holistic cardiovascular risk reduction

Appreciate a new focus on quality of life, mortality, and cost in diabetes guidelines

Describe the role of newer glycemic agents in cardiovascular risk reduction

Outline arguments in favor of bariatric surgery as a primary diabetes treatment modality

Case one

43 y/o obese male (BMI = 32.5 kg/m2), A1c = 5.8%

Despite your best efforts, his BMI continues to trend upwards and medication adherence is spotty

He does state a desire to lose weight and be healthier

What do you do?

Once upon a time…

DiagnosisProlonged

hyperglycemia

Retinopathy

Nephropathy

Neuropathy

Dialysis Blindness

Amputation

Premature death

Type 2 diabetes is an acknowledgement of retinopathy risk

Diabetes Care 2009, PMID: 19502545

PostprandialHyperglycemia

IGT Type 2DiabetesPhase I Type 2

DiabetesPhase II

Type 2 DiabetesPhase III

25

100

75

0

50

-12 -10 -6 -2 0 2 6 10 14

Once you’re diabetic, you’ve had pancreatic dysfunction for a very long time: -cell Loss Over Time in UKPDS

-c

ell

Fu

nct

ion

(%) b

y H

OM

A

Without Treatment Adjustment, A1C Rises ~0.2% to 0.3% Yearly

Diabetes 1995, PMID: 7589820

Patients treated with insulin, metformin, sulfonylureas

Years From Diagnosis

A1c 5.7-6.4%FPG 100-125 mg/dlOGTT 140-199 mg/dl

USPSTF: Persons aged 40-70 years with a BMI ≥25.0 kg/m2 (repeated every 3rd year)

Ann Intern Med 2015, PMID: 26501513

Who gets screened?

• Multicenter RCT: 3,234 enrollees

• Eligibility: Age > 25 + BMI > 24 kg/m2 + IGT + FPG > 95 mg/dL

•Follow-up: ~2.8 yrs (1.8-4.6); annual OGTT; semiannual FPG•

•Randomization:

Meformin850 BID

Intensive Lifestyle Changes*

Troglitazone400 QD# Placebo

NEJM 2002, PMID: 11832527

* 7% weight reduction; low-fat diet; 150 min/week exercise

# discontinued after 8 months due to hepatotoxicity

X

Mean age: 51 years (68% female, 45% ethnic minorities)Mean BMI: 34 kg/m2

Mean FPG: 107 mg/dL; 2-hr PG: 165 mg/dL; HbA1c: 5.9%

Diabetes Prevention Program (DPP)

NEJM 2002, PMID: 11832527

DPP: Incidence of type 2 diabetes

NNT for DPP: 7NNT for metformin: 14

https://nccd.cdc.gov/DDT_DPRP/Registry.aspx, accessed 3/9/18

Case two

65 year-old pt with 10 yr history of type 2 DM, A1c 7.7% on two well-tolerated oral agents

Should this patient’s glycemic regimen be intensified?

New ACP Guidance Statement1

1. Personalize goals for glycemic control in patients with type 2 diabetes on the basis of benefits and harms, patients' preferences, patients' general health and life expectancy, treatment burden, and costs of care.

2. Aim to achieve an HbA1c between 7% and 8% in most patients with type 2 diabetes.

ADA2: ≤7.0%

AACE3: ≤6.5%

3. Consider deintensifying therapy in patients who achieve HbA1c <6.5%.

4. Treat to minimize symptoms related to hyperglycemia and avoid targeting an HbA1c level in patients with a life expectancy less than 10 years.

1Ann Intern Med 2018, PMID: 29507945; 2Clin Diabetes 2018, PMID: 29382975; 3Endocr Pract 2018, PMID: 29368965

J Clin Endocrinol Metab 2019, PMID: 30903688

Endo Society, European Society of Endocrinology, Gerontological Society of America, Obesity Society Consensus Guideline

Older Adults:

Standards of Medical Care in Diabetes - 2019. Diabetes Care 2019;42(Suppl. 1):S139-S147

ADA

Diabetes Care 2019, PMID: 30559227

ADA

Diabetes Care 2019, PMID: 30559227

What do we want from medical care?1. It makes you feel better

or

2. It makes you live longer

or

3. It saves money

Extremely tight glycemic control may not make patients feel better

Value Health 2012, PMID: 23244805

Extremely tight control does not save lives: ACCORD, ADVANCE, VADT, and UKPDS 33

NEJM 2008, PMID: 18539917; NEJM 2008, PMID: 18539917; NEJM 2009, PMID: 19092145; Lancet 1998, PMID: 9742976

ACCORD ADVANCE VADT UKPDS 33

N (age / BMI) 10,251 62 yrs 32 kg/m2 11,140 66 yrs 28 kg/m2 1791 60 yrs 31 kg/m2 3867 54 yrs 27.5 kg/m2

Follow-up Mean 3.5 yrs Median 5 yrs Median 5.6 yrs Median 10 yrs

Glycemic targets A1C <6.0% vs 7.0–7.9% A1C ≤6.5% vs “standard” A1C <6% vs 8-9%FPG <6 mmol/L (106 mg/dl vs

“best achievable”)

Mean Baseline A1C 8.3% 7.5% 9.4% 7.08%

Mean Endpoint A1C INT: 6.4% vs STD: 7.5% INT: 6.3% vs STD: 7.0% INT: 6.9% vs STD: 8.4% INT: 7.0% vs STD: 7.9%

Major macro- or microvascular event

N/A 0.9 (0.82-0.98), P=0.01 0.88 (0.74-1.05), P=0.140.88 (0.79-0.99), P=0.029*

*”Any DM-related endpoint”

Nonfatal MI / stroke, CV death

HR 0.9 (0.78-1.04), P=0.16 0.94 (0.84-1.06), P=0.32 N/A

0.79 (0.58-1.09), P=0.057

1.07 (0.68-1.69), P=0.72

0.94 (0.68-1.30), P=0.63

All-cause mortality HR 1.22 (1.01-1.46), P=0.04 0.93 (0.83-1.06), P=0.28 1.07 (0.81-1.42), P=0.62 0.94 (0.80-1.10), P=0.44

Nonfatal MIHR 0.76 (0.62-0.92), P=0.004 0.98 (0.77-1.22), P=NS 0.82 (059-1.14), P=0.24 0.79 (0.58-1.09), P=0.057

Hypoglycemic eventsa INT: 10.5% vs STD: 3.5%, P<0.001 INT: 2.7% vs STD: 1.5%, P<0.001 INT: 8.5% vs STD: 3.1%, P=0.000 INT: “increased” vs STD

Weight change> +10 kg, INT: 27.8% vs STD:

14.1%, P<0.001INT: -0.1 kg vs STD: -1.0 kg,

P=NSINT: +8.1% vs STD: 4.1%,

P=0.01INT: +2.9 kg vs STD, P<0.001

UKPDS 33

Only one (out of 21) endpoints in this landmark trial was positive:

Retinal photocoagulation Extremely tight glycemic control prevented ~1 laser

procedure per 330 patient years

Lancet 1998, PMID: 9742976

This observation is not isolated to the outpatient setting: NICE-SUGAR

Severe hypoglycemia (BG≤40 mg/dl):

206 (6.8%) in intensive group

15 (0.5%) in conventional group (P<0.001)

Death at 90 days: 829 patients (27.5%) in intensive group

751 (24.9%) in the conventional group died

OR 1.14; 95% CI, 1.02 to 1.28; P=0.02

No difference in:

Mechanical ventilation

Dialysis

Bloodstream infections

Median days in the ICU or hospital

NEJM 2009, PMID: 19318384

Meta-analysis confirms the lack of mortality benefitMeta-analysis of 29 RCTs totaling 8432 patients

No difference in mortality between tight glucose control and usual care

Increased risk of hypoglycemia (<40 mg/dl) in tightly controlled patients 13.7% vs. 2.5% (RR 5.13)

JAMA 2008, PMID: 18728267

Extremely tight glycemic control does not save you (or anyone else) money

25% of diabetics report skipping insulin doses due to cost2

1JAMA 2016, PMID: 27046369; 2JAMA Intern Med. 2019, PMID: 30508012

Annals of Int Med 2018, PMID: 29230472

More liberal glycemic targets save money

“Individualized control saved $13,547 per patient compared with uniform intensive control ($105,307 vs. $118,854), primarily due to lower medication costs ($34,521 vs. $48,763).”

What makes our patients live longer?

Am J Prev Med. 2010, PMID: 20494236

We don’t do a great job of treating co-morbidities in type 2 diabetes

For patients with DM and CVD: 41% of American adults meet secondary prevention

standards• HTN is most poorly controlled (worse than smoking)

• Others: ASA, statin use1

Diabetic patients who get their “diabetes-adjacent” risk factors controlled have a life expectancy similar to non-diabetic patients2

1Navar AM. Secondary prevention of CVD in patients with T2DM: international insights from the TECOS trial. Accessed 10/14/18 at:https://www.healio.com/endocrinology/diabetes/news/online/%7B1810fdf4-6b06-4097-9fda-3fa06300bc6b%7D/most-adults-with-diabetes-cvd-do-not-meet-secondary-prevention-targets; 2NEJM 2018, PMID: 30110583

Goals for diabetic patients

BP (automated cuff or self-monitored): 130/80 mmHg1

Office-measured/HEDIS: 140/90 mmHg

Lipids: DM alone: moderate-intensity statin* for 30% LDL reduction2

DM +ASCVD: high-intensity statin** +/- other agents to get LDL <70 mg/dl AND Icosapent ethyl 2 grams BID if elevated triglycerides3

Aspirin 75-162 mg/d or clopidogrel 75 mg/d if ASCVD

*atorvastatin (10–20 mg), rosuvastatin (5–10 mg), simvastatin (20–40 mg)**atorvastatin (40–80 mg) or rosuvastatin (Crestor; 20–40 mg)

1Hypertension 2017, PMID: 29133356; 2JAMA 2019, PMID: 30715135; 3Diabetes Care 2019, PMID: 30559226

Composite of CV death, nonfatal MI, nonfatal stroke, revascularization, or unstable angina

NNT for 2g BID icosapent ethyl = 21

NEJM 2018, PMID: 30110583

SDOH Alert: What predicts suboptimal treatment?Female sex

African‐American race

Age <55

Low income

Comorbid depression

Diabetes Obes Metab 2019, PMID: 30609214

Most patients not appropriately getting statins have simply never been offered a statin

59.2% reported never being offered

10.1% declined

30.7% had discontinued therapy

Most people are willing to try: 67.7% of those never offered

59.7% who discontinued

J Am Heart Assoc 2019, PMID: 30913959

Case three

54 year old female with a history of NSTEMI

BP well-controlledOn appropriate statin

doseOn anti-platelet therapyA1c 9.7% on metformin

alone, with some effort toward dietary moderation

Which glycemic drug do we use next?

Don’t forget about diabetes education

Or go to: https://professional.diabetes.org/erp_list_zip

Meta-analysis: 26% reduction in all-cause mortality at 1.8 years in type 2 diabetes patients (RR: 0.74, 95 %CI 0.60–0.90, P = 0.003)

Endocrine 2017, PMID: 27837440

The glycemic agents that prevent death don’t do it by lowering blood sugars

BMJ 2018, PMID: 30021781

The glycemic agents that prevent death don’t do it by powerfully lowering blood sugars. SGLT-2 inhibitors:

NEJM 2015, PMID: 26378978

This is not a class effect

All-cause mortality reduction: Empagliflozin

Canagliflozin

No mortality reduction: Dapagliflozin1 (but data

to support renal protection down to an eGFR of 45 ml/min)2

Ertugliflozin (VERTIS-CV data pending)

1N Engl J Med 2018, PMID: 304156022https://www.clinicaltrials.gov/ct2/show/NCT02413398, accessed 3/4/19

NEJM 2016, PMID: 27295427

The glycemic agents that prevent death don’t do it by powerfully lowering blood sugars. GLP-1 agonists:

“For patients with type 2 diabetes and other cardiovascular risk factors, metformin is the first-line treatment. GLP-1R agonists and SGLT-2 inhibitors may now be considered to help reduce CVD risk.”

Circulation. 2019, PMID: 30879355

Diabetes Care 2019, PMID: 30559227

Diabetes Care 2019, PMID: 30559227

Insulin is being demoted

But nothing is free

“New use of SGLT-2 inhibitors was statistically significantly associated with amputation compared with sulfonylureas, metformin, or thiazolidinediones1

Is this an effect of diuretics in general?2

Also roughly 2x risk of DKA3

1JAMA Int Med 2018, PMID: 30105373; 2http://diabetes.diabetesjournals.org/content/67/Supplement_1/2221-PUB, accessed 10/3/18; 3BMJ 2018, PMID: 30429136

“Patients taking an SGLT2 inhibitor (e.g., canagliflozin, dapagliflozin, empagliflozin, ertugliflozin) should seek medical care if they notice tenderness, redness, or swelling in the area of the genitals or perineum and have a fever over 100.4 degrees Fahrenheit or feel generally unwell. If Fournier's gangrene is suspected, clinicians should discontinue SGLT2 inhibitor treatment, immediately start the patient on broad-spectrum antibiotics, and perform surgical debridement as necessary.”

N = 12

https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm618908.htm, accessed 9/11/18

Diabetes Care 2019, PMID: 30559227

But seriously, nothing is free

Case four

35 year-old patient with BMI 41 kg/m2, A1c 11%, on >200 units insulin/day along with metformin

What’s the next step?

1https://www.medpagetoday.com/meetingcoverage/obesityweek/76371, accessed 11/16/18;2JAMA 2015, PMID: 25562267

We’ve long known that bariatric surgery reduced mortality as much as 66%1

1-5 years: HR 0.45 [95% CI, 0.36-0.56]2

5-14 years: HR 0.47 [95% CI, 0.39-0.58]

Bariatric surgery reduces microvascular risk

Ann Intern Med 2018, PMID: 30083761

Who qualifies for bariatric surgery? BMI ≥ 35 kg/m2

≥1 co-morbidity related to obesity: Type 2 DM Refractory HTN (≥140/90 on maximal doses of ≥3 meds Refractory hyperlipidemia (unacceptable lipids with diet and max

doses of meds) Obesity-induced cardiomyopathy “Clinically significant” obstructive sleep apnea Obesity-related hypoventilation/Pickwickian syndrome Pseudotumor cerebri (documented idiopathic intracerebral

hypertension) Severe arthropathy of spine and/or weight-bearing joints if obesity

prohibits surgical management of joint dysfunction NAFLD without evidence of active inflammation

Unsuccessful medical treatment for obesity

Ann Intern Med 2018, PMID: 30083761

Which procedure is best?SOS Study: Over 26-year follow-up, 40.7% of

bands revised vs. 7.5% of gastric bypass

JAMA Surg 2019, PMID: 30601881

Again, nothing is free

Increased suicidality1

Increased risk of pre-term birth, SGA, and possibly stillbirth/neonatal death2

Possibly increased alcohol abuse in RYGB patients3

Decreased bone mineral density4

Hospitalizations roughly double (7.9% vs 3.9%) over six years5

Five-fold decrease in the risk of hormone-related cancers (breast, prostate, endometrial) but ~2x risk of colorectal cancer6

1Am J Med 2010, PMID: 20843498; 2BMJ 2013, PMID: 24222480/NEJM 2015, PMID: 25714159; 3JAMA 2012; PMID: 22710289; 4BMJ 2012 PMID: 22867649; 5JAMA 2012, PMID: 22990271; 6Br J Surg 2018, PMID: 30003539

New conversation

1. You’re at risk of diabetes. Let’s do something about it.

2. How is it taking xx medications per day?

3. What’s your blood pressure?

4. How easy is it to take your cholesterol medication?

5. Is your daily aspirin causing problems?

6. Has an eye doctor looked in your eyes in the last couple years?

7. Have you seen the dentist in the last six months?

8. Can I see your feet?

9. Let’s check your urine for protein.

10. Now: about that A1c level.

Conclusions

Diabetes guidelines are moving away from pure glycemic control Toward QoL, cardiovascular risk reduction

The Diabetes Prevention Program is now a CMS-covered intervention

Diabetes education is an under-recognized intervention for prolongation of life

SGLT2 inhibitors and GLP1 agonists are likely the preferred second agents for glycemic control moving forward (but $$$)

Bariatric surgery should be offered to any diabetic person with a BMI >35 kg/m2

Questions?

doublearrowmetabolism.com

justin@doublearrowmetabolism.com