Diabetes Workshop: Developing Strategies for the Most ...primarycareinternalmedicine2018.com/uploads/1/2/2/... · Clinical use of DPP-4 inhibitors • Tablet, but expensive • HbA1c

Diabetes Workshop: Developing Strategies for the

Most Difficult Patients in Your Practice

Primary Care Internal Medicine October 16 and 18, 2018

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

Challenging diabetes topics

• Glycemic targets

• When to consider use of newer drugs in type 2 diabetes

• Effective use of insulin in T2DM – Bonus case: complex insulin regimens

Case 1: New patient to you

• 73 year old woman with central obesity (BMI 28 kg/m2, type 2 diabetes, hypertension, and smoking. – Blood pressure is 144/92 mmHg – She has low HDL and high triglycerides (363

mg/dl) – 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

A1C Targets

• ACP Clinical Guideline, March 2018

• Guidance Statement 2 – “Clinicians should aim to achieve an HbA1c level

between 7% and 8% in most patients with type 2 diabetes”

• Other guidance statements: 1. Personalize HbA1c goals 3. De-intensify if HbA1c

Next steps for the patient in case 1?

• Smoking cessation

• Redouble efforts at diet and exercise – Dietitian and/or DSME referral

• Add a second medication?

• What is A1C target?

ADA: Individualize 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

55

5.55.5

66

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

5

10

10

18

15

38

23

60

40

105

58

160

Sheet1

55.566.577.588.599.51010.51111.512

DCCT810183860105160

UKPDS51015234058

Benefit of glycemic control diminishes with age and increasing comorbidity

Expected differences in lifetime incidence of specific complications for 60–64 year old and 75–79 year old patients by level of morbidity

Huang, et al. Ann Intern

Med. 2008: 149: 11–19.

My response to ACP • “Clinicians should aim to achieve an HbA1c level between 7%

and 8% in most patients with type 2 diabetes” – Not in most…this is applicable to the 20-30% of people with

CVD – Younger patients without complications could aim for

Case 2:

• 53 year old woman with central obesity (BMI 34 kg/m2, type 2 diabetes and hypertension.

• She desires weight loss. – Blood pressure is 144/92 mmHg – She has low HDL and high triglycerides (363

mg/dl) – HbA1c 7.8% on metformin 1000 mg twice per day. – Medications are hydrochlorothiazide, lisinopril,

and bupropion.

Next steps for patient in Case 2?

• Redouble efforts at diet and exercise – Dietitian and/or DSME referral

• What is A1C target?

• What are treatment priorities?

• Add a second medication?

Antihyperglycemic therapy in T2DM: general recommendations

Diabetes Care 2017 Jan; 40(Supplement 1): S64-S74.

Review of “newer” drugs

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

• Tablet, but expensive • HbA1c decrease of 0.43 to 1.4, average ~0. 7 • Weight-neutral • 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)

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

SGLT-2 inhibitors: from genetic phenotype to physiologic insight

• Familial renal glycosuria – Co-dominant mutation in sodium-glucose SLC5A2

co-transporter gene that encodes SGLT2 – Benign phenotype, for the most part

• Polyuria, enuresis, mild growth delay • Episodic dehydration and ketosis during starvation

Santer & Calado, Clin J Am Soc Nephrol 2010;5:133.

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.

SGLT2i: Clinical summary

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

on starting point • Weight reduction

– ~2.5 kg, stabilizes • Hypoglycemia only with

insulin or sulfonylurea • Decreased efficacy with

decreasing GFR – Contraindicated GFR< 30

ml/min

• Adverse effects – Mycotic genital infections

• Women > men

– Calciuria • Bone loss

– Rarely, euglycemic DKA • Especially with insulin

reduction in insulin-dependent people

• Trigger: stress (increased glucose demand) + ketosis + ongoing osmotic diuresis and glucosuriaDKA)

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

• DPP4 inhibitors – Elderly – CKD – Risk of

hypoglycemia • GLP1 receptor

agonists – Weight loss – High A1C as

alternative to basal or prandial insulin

• SGLT2-inhibitors – Weight loss – Men > women

• What if patients have CVD or CHF???

Cardiovascular safety outcomes trials

• Mandated by FDA 2008 for all new diabetes drugs to demonstrate cardiovascular safety – But some got lucky!

• Generally enrolled participants with

established CVD or at high CVD risk to increase power – Results are most applicable to this population

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

SGLT-2-i empaglifozin canagliflozin dapagliflozin ertugliflozin Comparator placebo placebo placebo placebo

N 7300 4300 22,200 3900

Results 2015 2017 2019 2020

Large CV Outcomes Trials in Diabetes post-2008

✓

✓ ✓ ✓

✓

Slide adapted from Silvio Inzucchi, Yale

✓ ✓

✓

✓

LEADER

• 9,340 participants with A1C 8.7%

• High risk of CVD event – Based on age, cardiac risk factors, evident

cardiovascular disease

• Randomly assigned to placebo or liraglutide – Median daily dose in liraglutide arm was 1.78 mg

• SUSTAIN-6 had similar design

– Tested weekly semaglutide at 2 doses versus placebo Marso SP et al. N Engl J Med 2016.

LEADER Outcomes

Marso SP et al. N Engl J Med 2016.

Benefit apparent at 1 year

MACE ARR=1.9% over 3.9 yrs

(NNT~52)

CVD Death ARR=1.7% over 3.9 yrs

(NNT~59)

All-cause mortality

ARR=1.4% over 3.9 yrs

(NNT~71)

Study EMPA-REG CANVAS DECLARE NCT01986881

SGLT-2-i empaglifozin canagliflozin dapagliflozin ertugliflozin Comparator placebo placebo placebo placebo

N 7300 4300 22,200 3900

Results 2015 2017 2019 2020

Large SGLT-2 Trials post-2008

✓ ✓

• SGLT-2 Trials in patients with established CVD • EMPA-REG and CANVAS trials (NEJM) demonstrated cardiac

and renal benefit • Benefit strongest for those with established CVD

• Particularly with in patients with CHF and CKD

EMPA-REG Trial: SGLT-2

• 7,020 people with mean A1C ~8%

• Established cardiovascular or peripheral vascular disease

• Randomly assigned to placebo, empagliflozin 10 mg or 25 mg.

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

EMPA-REG Empagliflozin 10 or 25 mg vs placebo, A1C difference ~0.5

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

CVD benefit apparent at 3 months…

MACE ARR=1.6% over 3.1 yrs

(NNT~62)


(NNT~45)


(NNT~71)

All-cause death ARR=2.6% over

3.1 yrs (NNT~38)

Renal function over time on empagliflozin

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

EMPA-REG Renal Outcomes

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

Renal-replacement therapy HR 0.45 (0.21-0.97)

Total events=27

Composite renal outcome Doubling of creatinine with GFR

Effects of Canagliflozin on Cardiovascular, Renal, Hospitalization, and Death Events in the Integrated CANVAS Program

Neal B et al. N Engl J Med;377:644-657

Amputation 6.3 3.4

SGLT-2 inhibitors and heart failure

• Three ongoing trials of SGLT-2i for heart failure • Enrolling diabetes and non-diabetes patients • May be the drug of choice in heart failure and diabetes.

– Clinical pearl: reduce diuretics!

CREDENCE Trial

• Canagliflozin (SGLT2i) vs placebo in patients with T2DM and albuminuria – On max ACE inhibitor

• Stopped early (July 16, 2018) for meeting

efficacy criteria for prevention of progression of diabetic kidney disease

EMPA-REG OUTCOME

Metformin No metformin

If new drugs are so great, shouldn’t they be the first drug in people with CVD? No. Background metformin therapy in ¾ CVOT participants

CANVAS


SUSTAIN-6


LEADER


76.4% 74.0%

77.2% 73.2%

Slid

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8

If the new drugs are so great, why not use them all the time? • Clinical trial results may not be generalizable

to those without CVD – Patients may not derive the same benefit, and

may have different risks: • Example: calciuria from SGLT2i could cause

osteoporosis over the long term – We know that all glucose-lowering drugs improve

microvascular complications by virtue of their effect on glycemic control

• COST

Cost of glucose lowering drugs, c. 2015 …but it is worse now! • www.goodrx.com/, accessed Jan 3, 2015 (lowest

price for New Haven, CT postal code 06510)

Courtesy of Silvio Inzucchi, www.goodrx.com/, accessed Jan 3, 2015 (lowest price for New Haven, CT)

Chart1

Liraglutide 1.8mg QD

Glargine 50U QD (pen)

Canagliflozin 300mg QD

Sitagliptin 100mg QD

NPH 50U QD (vials)

Pioglitazone 45mg QD

Glipizide 10mg BID

Metformin 1000mg QD

Cost for 30 days

Cost for 30 days of therapy

611.46

356.84

316.83

316.71

138

14.02

4

4

Sheet1

Cost for 30 days

Liraglutide 1.8mg QD$611

Glargine 50U QD (pen)$357

Canagliflozin 300mg QD$317

Sitagliptin 100mg QD$317

NPH 50U QD (vials)$138

Pioglitazone 45mg QD$14

Glipizide 10mg BID$4

Metformin 1000mg QD$4

Bottom line for clinical practice

• Two GLP-1 receptor agonists and two SGLT2 inhibitors have demonstrated cardiovascular benefit in populations at very high cardiovascular risk – ADA changed guidelines to prefer medications with

cardiovascular benefit in patients with CVD – Benefit is likely related to non-glycemic effects of the

medications • This patient does not have CVD, but desires weight

loss. – GLP1 receptor agonists and SGLT2 inhibitors are also

preferred for patients prioritizing weight loss – They are most effective combined with behavior change

The approach: start metformin, then:

Choose a medication with demonstrated cardiovascular

benefit to add to metformin

New-onset diabetes, without overt CVD

Type 2 diabetes, diagnosed CVD (or CKD or CHF)

• Choose among many options based on patient priorities and preferences,

cost, and characteristics of medications

• Await results of GRADE Trial (2021)

8. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2018 American Diabetes Association

Diabetes Care 2018 Jan; 41 (Supplement 1): S73-S85. https://doi.org/10.2337/dc18-S008

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjz0v31j_LQAhWHxVQKHZIHD0sQjRwIBw&url=https://www.nhlbi.nih.gov/health/health-topics/topics/heartattack&psig=AFQjCNFYT45cEB84Hn9AjOz8PHmZfHHr4A&ust=1481751296196953http://care.diabetesjournals.org/content/41/Supplement_1/S73http://care.diabetesjournals.org/content/41/Supplement_1/S73https://doi.org/10.2337/dc18-S008

Case 3

• 52 year old woman with T2DM and BMI 36 kg/m2 – Medications

• Metformin • Dulaglutide 1.5 mg weekly • Glipizide 10 mg twice per day

– HbA1c persistently >9%

• What next?

Fatty liver Insulin resistance

Obesity impairs hepatic insulin signaling

• Gluconeogenesis is not

suppressed

• In type 2 diabetes, very high doses of basal insulin are required to suppress hepatic glucose output

• Small amounts of weight loss lead to big improvements in diabetes control (and reduction in insulin dose, which is then permissive for weight loss)

Thoughtful use of insulin in T2DM with obesity • Insulin is required when diabetes progresses

• Many replacement regimens are possible

– Little evidence for one insulin regimen vs. another – None have tested initiating insulin in combination with

medical nutrition therapy

• Many overweight people are very susceptible to insulin-associated weight gain – Especially when insulin is increased to very high doses and

not given physiologically

Insulin in obesity: minimize dose • Patient goals: self-management education re:

– Maintain or redouble efforts at diet and exercise, including dietitian referral at time of insulin initiation

– Mindful eating – Reduce dose in anticipation of physical activity – “Live within your dose”

• Provider goals

– Appropriate bolus dosing – Avoid excess basal insulin and reduce insulin for exercise – Avoid obligate snacking

• Especially with premixed insulins – Balance glycemic control with weight goals – Consider concentrated insulins (U500, U300) to improve

absorption in patients on high doses

Meta-analyses of other glucose-lowering medications with insulin • Using metformin in combination with insulin is

beneficial in type 2 DM vs. insulin alone – Better HbA1c: -0.6% (CI -0.3 to -0.9) – Better weight: -1.7 kg (CI -1.3 to -2.2) – Non-significant increase in hypoglycemia (RR 2.4, 0.5-11)

• Using GLP-1 RA as add-on to basal insulin compared to prandial insulin – Better HbA1c: -0.48% (-0.67 to -0.30) – Better weight loss: -2.6 kg (CI -3.32 to -1.89) – Lower risk of hypoglycemia (RR 0.52, 0.42-0.64)

Hemmingsen B, BMJ 2012; 344 e1771

Wysham CH, Postgraduate Medicine 2016;129; 436-445

Other long-acting insulins, including concentrated

Degludec (Tresiba) 3 ml prefilled Flextouch pen U-200: Max dose 160 units U-100: Max dose 80 units

Glargine ~ Basaglar Glargine U-300 (Toujeo)

NPH: safe and effective in T2DM

Lipksa 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)

Prob

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nt

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

49

Cepac.icer-review.org/ adaptations/diabetes

Population: New England Medicaid enrollees

Bonus case: Multiple daily injections

• 53 year old woman with long-standing type 1 diabetes and hypothyroidism – On stable levothyroxine – HbA1c range 6.8-8.1 over the last 2-3 years,

mostly in 7% range, last HbA1c was 7.3%. – No retinopathy; early cataract; no other

complications, urine microalbumin undetectable.

• Wants to lose weight.

Bonus case: insulin regimen

• Diabetes medications: – Glargine 22 units at bedtime – Lispro

• With meals: 1 unit to 10 grams of carbs PLUS • Correction factor of 1 unit for every 50

mg/dl>150 mg/dl – How do you interpret this?

• Usually 3-10 units per meal

History

• Lifestyle: – Just started exercising again – Treadmill x 30 min 3 mornings per week – Line dancing one evening per week – No alcohol

• Exam

– Well appearing – BP: 143/78 mmHg, P 76, Weight: 194 lbs / 88 kg. BMI: 31 kg/m2 – Background retinopathy, nl foot exam

Date B L S Bed Comments Time Treadmill Line Dancing BS 186 66 280 395 Ins Aspart 4 Aspart 4 Aspart 4 Aspart 3 Glargine 22

Time BS 44 164 311 57 Ins Aspart 6 Aspart 3 Aspart 4

Time Treadmill BS 61 115 114 Ins Aspart 5 Aspart 3 Aspart 4 Glargine 22

Time Treadmill 40 at 3 pm Line dancing BS 40 188 248 147 Ins Aspart 4 Aspart 3 Glargine 22

Time BS 280 212 247 204 Ins Aspart 5 Aspart 8 Aspart 9 Glargine 22


Time Walk 5-6 pm BS 150 178 33 66 Ins Glargine 12

Aspart 4 Aspart 4 Aspart 9 Glargine 9

SMBG log

1. What do you look for when reviewing SMBG logs?

2. How do you assess hypoglycemia?

Hypoglycemia evaluation

• Important questions for all people on medications that cause hypoglycemia: – Do you get low blood sugars? – At what level do you sense them? – What are your symptoms?

• 80 mg/dl No problem • 50 mg/dl with adrenergic symptoms not great • 30 mg/dl with confusion very bad • 110 mg/dl altered set point with chronic

hyperglycemia – Implications for treatment targets

• Must be relaxed in the setting of hypoglycemia unawareness

Date B L S Bed Comments Time Treadmill Line Dancing BS 186 66 280 395 Ins Aspart 4 Aspart 4 Aspart 4 Aspart 3 Glargine 22

Time BS 44 164 311 57 Ins Aspart 6 Aspart 3 Aspart 4

Time Treadmill BS 61 115 114 Ins Aspart 5 Aspart 3 Aspart 4 Glargine 22

Time Treadmill 40 at 3 pm Line dancing BS 40 188 248 147 Ins Aspart 4 Aspart 3 Glargine 22



Time Walk 5-6 pm BS 150 178 33 66 Ins Glargine 12

Aspart 4 Aspart 4 Aspart 9 Glargine 9

Proposed changes to insulin regimen

1. What adjustments would you make to the glargine dose? 2. What adjustments would you make to lispro at meals and bedtime? 3. Glycemic targets?

Weight loss on insulin

• Use lowest effective dose – Do not feed the insulin!

• Reduce prandial insulin for exercise

• Combine with insulin-sparing agents

– Reduce dose

Key points and Next Best Steps

• Key points – Individualize HbA1c targets for patients with type 2 diabetes – Consider use of GLP-1 receptor agonists or SGLT2

inhibitors in patients with established cardiovascular disease

– Best practice with insulin requires using the lowest effective dose with dose adjustment for hypoglycemia and weight gain

• Next best steps

– Consider endocrinology consultation to help optimize the glucose-lowering medication regimen

Your cases and questions?

��Diabetes Workshop: �Developing Strategies for the �Most Difficult Patients in Your Practice�DisclosuresChallenging diabetes topicsCase 1: New patient to youWhat are the treatment priorities? A1C TargetsNext steps for the patient in case 1?Slide Number 8Slide Number 9Benefit of glycemic control diminishes with age and increasing comorbidityMy response to ACPCase 2: Next steps for patient in Case 2?Slide Number 14Review of “newer” drugsIncretin 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 SGLT-2 inhibitors: from genetic phenotype to physiologic insight Sodium-glucose co-transporter-2 inhibitorsSGLT2i: Clinical summary General reasons to consider costly new meds instead of older meds for glucose-loweringCardiovascular safety outcomes trialsLarge CV Outcomes Trials in Diabetes post-2008LEADERLEADER Outcomes Large SGLT-2 Trials post-2008EMPA-REG Trial: SGLT-2EMPA-REG Empagliflozin 10 or 25 mg vs placebo, A1C difference ~0.5Renal function over time on empagliflozin EMPA-REG Renal Outcomes Slide Number 34SGLT-2 inhibitors and heart failureCREDENCE TrialIf new drugs are so great, shouldn’t they be the first drug in people with CVD? No.If the new drugs are so great, why not use them all the time? Cost of glucose lowering drugs, c. 2015 …but it is worse now! Bottom line for clinical practiceThe approach: start metformin, then: Case 3Obesity impairs hepatic insulin signalingThoughtful use of insulin in T2DM with obesity Insulin in obesity: minimize doseMeta-analyses of other glucose-lowering medications with insulinOther long-acting insulins, including concentrated NPH: safe and effective in T2DMOne-year budget impact of shift in insulin use from analog to NPHBonus case: Multiple daily injections Bonus case: insulin regimenHistory SMBG logHypoglycemia evaluationProposed changes to insulin regimenWeight loss on insulinKey points and Next Best StepsYour cases and questions?

Documents

Diabetes Workshop: Developing Strategies for the Most ...primarycareinternalmedicine2018.com/uploads/1/2/2/... · Clinical use of DPP-4 inhibitors • Tablet, but expensive • HbA1c