What not to miss dm and cv disease 2013
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What Not To Miss... DM and CV disease 2013. Adam Wolfe, DO Medical Director, Primary Care MHMG IM Residency Director, Metro Health Hospital. Conflicts - none. Game Plan. New targets and role in therapy New cardiovascular data 2013 What not to miss… Comments and questions. Case #1- JM.

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What not to miss dm and cv disease 2013

What Not To Miss...DM and CV disease 2013

Adam Wolfe, DO

Medical Director, Primary Care MHMG

IM Residency Director, Metro Health Hospital


Conflicts none

Conflicts - none


Game plan

Game Plan...

  • New targets and role in therapy

  • New cardiovascular data 2013

  • What not to miss…

  • Comments and questions


Case 1 jm

Case #1- JM

  • JM is a 56 year old male with non-insulin requiring DM diagnosed 4 years ago, systolic HF (EF 25%), CAD (post LAD stent 3 years ago), Serum Cr = 1.1mg/dL

    • Current medications: metformin 850 mg BID, sitagliptin 100 mg daily, valsartan 80 mg BID, carvedilol 12.5 mg BID

    • A1C 1 month ago was 7.6%

    • Present BP: 142/86 mm Hg

    • No signs of retinopathy, + microalbumin on last urinary testing

    • Based on the above clinical findings, the next most appropriate therapy for the patient’s blood sugar control would be:


Case 1 cont

Case #1 (cont)

  • A) Continue present therapy

  • B) Increase Metformin therapy to 1000 mg twice daily

  • C) Add basal insulin therapy for FBS goal of 100 mg/dL

  • D) Initiate Invokana (canagliflozin)

  • E) Add Avandia therapy at 4 mg daily


Case 1 cont1

Case #1 (cont)

  • A) Continue present therapy

  • B) Increase Metformin therapy to 1000 mg twice daily

  • C) Add basal insulin therapy for FBS goal of 100 mg/dL

  • D) Initiate Invokana (canagliflozin)

  • E) Add Avandia therapy at 4 mg daily


New therapies in dm

New Therapies in DM

  • Considerations

    • Clinical efficacy

    • Weight effect

    • Hypoglycemia risk

    • Adverse interactions or effects

    • Cost

    • CV safety


Fda mandate on future dm trials

FDA mandate on future DM trials

  • In July 2008, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee met to discuss the role of CV assessment in the premarketing and postmarketing settings. The FDA determined that concerns about CV risk should be more thoroughly addressed during drug development; their newly issued guidelines will result in profound changes in the ways new antidiabetes drugs are evaluated and brought to market in the future

  • Continue to evolve safety data

  • Surrogate endpoints cannot replace large scale clinical trials looking at CV outcomes


New options in therapy

Expanding the physiology of DM in practice

New options in therapy


Physiology natural progression

Physiology - natural progression

Earlier Diagnosis +

Earlier Treatment +

Better Options =

Better Outcomes

Adapted: Nathan DM. N Engl J Med. 2002;347:1342-9


Ominous octet

‘Ominous Octet’

DeFronzo R et al. Diabetes. 2009;58:773-795.


What not to miss dm and cv disease 2013

Sites of Action

Secretagogues

Simulate insulin secretion

Alpha-glucosidase inhibitors

Inhibitcarbohydratebreakdown

Incretins

  • Insulin secretion

     Glucagon secretion

Incretins

Slow gastric emptying

MetforminThiazolidinediones

  • Glucose metabolism

Thiazolidinediones

  • Glucose metabolism

     FFA output

MetforminThiazolidinediones

Suppress glucose production

Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661–1669

Drucker DJ. MolEndocrinol. 2003;17:161–171


Canagliflozin invokana

canagliflozin (Invokana)

  • Approved March 29, 2013

  • New mechanism of action - SGLT2 inhibition

  • Dose related A1c reductions studied as monotherapy and in combination with SFU, DPP4, TZD, Basal Insulin

  • Weight loss associated (2.5-3 kg) and BP reduction

  • CV outcomes coming…CANVAS (2015)*


Renal targets

Renal Targets

Am J Renal Phys 280(1): F10-F18 2001


Mechanism of action sglt2 inhibitors

Mechanism of action – SGLT2 inhibitors

  • Inhibition of renal tubular Na+ glucose cotransporter reversal of glucose toxicity

    • Increased insulin sensitivity of skeletal muscle

    • Increased insulin sensitivity of liver

    • Decreased gluconeogenesis

    • Improved beta cell function


Dapagliflozin farxiga

Dapagliflozin (Farxiga)

  • FDA Approval Jan 8, 2014

  • 16 trials and over 9600 patients studied

  • Initially disallowed (2012) due to concerns for bladder malignancy marker

  • Dose related A1c reductions studied as monotherapy and in combination with SFU, DPP4, TZD, Basal


Clinical concerns

Clinical concerns…

Schernthaner G. et al. Diabetes Care 2013;36:2508-2515


The race for cv safety data 2013

The race for CV safety data - 2013


Case 2 mary

Case #2 - Mary

Mary is a 50-year-old woman who was diagnosed with T2DM 5 years ago.

After serum Creatinine = 1.4 mg/dL, she stopped metformin and started SFU

Past Med History: non-smoker, longstanding hypertension, hyperlipidemia,

chronic kidney disease, sleep apnea, and osteoarthritis.

Recent LVEF = 45% by echocardiography

Family History: Mother died of CHF at age 70, Father died following an MI at age 50

Medications: ASA 81 mg/d, glimepiride 4 mg/d, lisinopril 20 mg/d, simvastatin 40 mg/d

On her physical exam, she is obese (BMI: 46.7 kg/m2) and has 2+ pitting edema. Her BP is 126/70 mm Hg. Her laboratory findings include the following: LDL: 90 mg/dL; HDL: 35 mg/dL; triglycerides: 170 mg/dL; HbA1c: 7.5%; creatinine: 1.4 mg/dL. Recent stress echocardiography demonstrated no evidence of ischemia


Which of the following is the next best therapy for mary

Which of the following is the next best therapy for Mary?

No change – follow-up 3 months

Discontinue SFU and re-initiate Metformin therapy

Add incretin agent to SFU therapy

Decrease SFU and add incretin agent

Discontinue SFU and initiate TZD

Discontinue SFU and initiate basal insulin therapy


Which of the following is the next best therapy for mary1

Which of the following is the next best therapy for Mary?

No change – follow-up 3 months

Discontinue SFU and re-initiate Metformin therapy

Add incretin agent to SFU therapy

Decrease SFU and add incretin agent

Discontinue SFU and initiate TZD

Discontinue SFU and initiate basal insulin therapy


Safety data

HISTORICAL LOOK

Safety data


Dcct edic intensive glucose control reduces long term cv risk

DCCT/EDIC: Intensive glucose control reduces long-term CV risk

N = 1441 with type 1 diabetes

0.12

0.12

42%

(95% CI 9%–63%)

P = 0.02

57%

(95% CI 12%–79%)

P = 0.02

0.10

0.10

0.08

0.08

Cumulative incidence of any first

CV event

Cumulative

CV death,

nonfatal MI,

stroke

Conventional

52 events

0.06

0.06

Conventional

25 events

0.04

0.04

Intensive

31 events

Intensive

11 events

0.02

0.02

0

0

0

5

10

15

20

0

5

10

15

20

Time (years)

Time (years)

N Engl J Med. 2005;353:2643-53.


Dcct and complications

DCCT and complications


What not to miss dm and cv disease 2013

Metformin – UKPDS data


Historical cardiovascular data

Historical Cardiovascular Data

  • (+) UKPDS – (2008) – 15% reduction in MI and 13% reduction in death in DM2 patients (1)

  • (-) ACCORD – (2008) – increased all-cause mortality for intensive control group (2)

  • (~) ADVANCE – (2008) – non-statistical difference of macrovascular events and mortality (3)

  • (~) VADT – (2009) – non-statistical difference of time to first majory CV event (4)

1. N Engl J Med 2008;359:1577-1589

2- N Engl J Med 2008; 358:2545-2559

3-N Engl J Med 2008; 358:2560-2572

4-N Engl J Med 2009; 360:129-139


First to market

first to market…


Alogliptin

alogliptin

N Engl J Med 2013; 369:1327-1335


Efficacy 14 trials with over 8000 patients

Efficacy – 14 trials with over 8000 patients


What not to miss dm and cv disease 2013

Cumulative Kaplan–Meier Estimates of the Time to tPrimary End-Point Event or Other Safety End Point.

N Engl J Med 2013;369:1327-1335


What not to miss dm and cv disease 2013

Major Safety End Points.

White WB et al. N Engl J Med 2013;369:1327-1335


Final thoughts on alogliptin

Final thoughts on alogliptin?

  • Improved A1C levels and durability in trials

  • More selective for DPP4 than other agents

  • No increase in CV events from EXAMINE

BMC Endocr Disord. 2013;13(9)


N engl j med 2013 369 1317 1326

N Engl J Med 2013;369:1317-1326

SAVOR SaxagliptinAssessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus


What not to miss dm and cv disease 2013

Kaplan–Meier Rates of the Primary and Secondary End Points.

Scirica BM et al. N Engl J Med 2013;369:1317-1326


What not to miss dm and cv disease 2013

Prespecified Clinical End Points.

Scirica BM et al. N Engl J Med 2013;369:1317-1326


If you can t imitate him don t copy him

“If you can’t imitate him, don’t copy him.”


What not to miss

What Not To Miss...

  • Avandia news – reinstated after readjudication of the RECORD data

  • Actos in IGT patients (ACT-NOW)

  • FDA Panel failed to approve insulin degludec (Tresiba) due to potential MACE. Ongoing CV trials being performed – look for DEVOTE data

  • ORIGIN – insulin glargine (2012) - retrospective

  • GLP cardiovascular data…

    • EXSCEL (2015), LEADER (2015)

  • Implications of lipid and HTN guidelines

Lancet. 2009;373:2125-2135

BMC Endocr Disord. 2009 Jul 29;9:17

Cardiovascular Diabetology 2011, 10:22 


Summary

summary

  • Continue to fight clinical inertia

  • New options for new clinical targets

  • Evolution of CV data for all agents

  • More focus on earlier diagnosis and treatment

  • Exciting times.


Questions

Thanks so much…

Questions?


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