High yield JVP findings

S1

S1 loud
- MS
- Hyperkinetic state ( anemia, thyrotoxicosis, beri beri )

S1 soft
- Valvular - Immobile MS, AR - regurgitant jet hitting the undersurface of MV
- LV - failure, hypertrophy
- Rhythm - AV block, LBBB

Split S1 ( M1-T1 )
- RV overload, hypertrophy
- Ebstein anomaly

Polyposis syndromes summary

Murmur and maneuver

4 big rules are all u have to remember
1) Preload = more blood more murmur, less blood less murmur
- Except MVP, MR and HOCM
- In MR, more blood SAME murmur, less blood less murmur
- MVP and HOCM more blood LESS murmur, less blood MORE murmur

2) Afterload
- Inverse relationship with EJECTION murmur - more afterload less ejection murmur and vice versa
- Direct relationship with REGURGITATION murmur - more afterload more regurgitation murmur

3) Inspiration increases all right sided murmur except ejection murmur ( PS )

4) Expiration increases ALL left sided murmur except MVP, MR and HOCM ( rule #1 applies )

New oral anticoagulants

Not the best in interpreting trials but well, this is a table i composed

Fair to say that in conclusion

1) New oral anticoagulants show promise in the prevention of stroke in non valvular AF with lower incidents of bleeding

2) Important to note that high dose Dabigatran can increase MI and GI bleed risk

3) This is an indirect comparison, a head to head trial is needed

References
Dabigatran versus Warfarin in Patients with Atrial Fibrillation
Stuart J. Connolly, M.D., Michael D. Ezekowitz, M.B., Ch.B., D.Phil., Salim Yusuf, F.R.C.P.C., D.Phil., John Eikelboom, M.D., Jonas Oldgren, M.D., Ph.D., Amit Parekh, M.D., Janice Pogue, M.Sc., Paul A. Reilly, Ph.D., Ellison Themeles, B.A., Jeanne Varrone, M.D., Susan Wang, Ph.D., Marco Alings, M.D., Ph.D., Denis Xavier, M.D., Jun Zhu, M.D., Rafael Diaz, M.D., Basil S. Lewis, M.D., Harald Darius, M.D., Hans-Christoph Diener, M.D., Ph.D., Campbell D. Joyner, M.D., Lars Wallentin, M.D., Ph.D., and the RE-LY Steering Committee and Investigators
N Engl J Med 2009; 361:1139-1151September 17, 2009DOI: 10.1056/NEJMoa0905561

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation
Manesh R. Patel, M.D., Kenneth W. Mahaffey, M.D., Jyotsna Garg, M.S., Guohua Pan, Ph.D., Daniel E. Singer, M.D., Werner Hacke, M.D., Ph.D., Günter Breithardt, M.D., Jonathan L. Halperin, M.D., Graeme J. Hankey, M.D., Jonathan P. Piccini, M.D., Richard C. Becker, M.D., Christopher C. Nessel, M.D., John F. Paolini, M.D., Ph.D., Scott D. Berkowitz, M.D., Keith A.A. Fox, M.B., Ch.B., Robert M. Califf, M.D., and the ROCKET AF Steering Committee for the ROCKET AF Investigators
N Engl J Med 2011; 365:883-891September 8, 2011DOI: 10.1056/NEJMoa1009638

Apixaban versus Warfarin in Patients with Atrial Fibrillation
Christopher B. Granger, M.D., John H. Alexander, M.D., M.H.S., John J.V. McMurray, M.D., Renato D. Lopes, M.D., Ph.D., Elaine M. Hylek, M.D., M.P.H., Michael Hanna, M.D., Hussein R. Al-Khalidi, Ph.D., Jack Ansell, M.D., Dan Atar, M.D., Alvaro Avezum, M.D., Ph.D., M. Cecilia Bahit, M.D., Rafael Diaz, M.D., J. Donald Easton, M.D., Justin A. Ezekowitz, M.B., B.Ch., Greg Flaker, M.D., David Garcia, M.D., Margarida Geraldes, Ph.D., Bernard J. Gersh, M.D., Sergey Golitsyn, M.D., Ph.D., Shinya Goto, M.D., Antonio G. Hermosillo, M.D., Stefan H. Hohnloser, M.D., John Horowitz, M.D., Puneet Mohan, M.D., Ph.D., Petr Jansky, M.D., Basil S. Lewis, M.D., Jose Luis Lopez-Sendon, M.D., Prem Pais, M.D., Alexander Parkhomenko, M.D., Freek W.A. Verheugt, M.D., Ph.D., Jun Zhu, M.D., and Lars Wallentin, M.D., Ph.D. for the ARISTOTLE Committees and Investigators
N Engl J Med 2011; 365:981-992September 15, 2011DOI: 10.1056/NEJMoa1107039

Edoxaban versus Warfarin in Patients with Atrial Fibrillation
Robert P. Giugliano, M.D., Christian T. Ruff, M.D., M.P.H., Eugene Braunwald, M.D., Sabina A. Murphy, M.P.H., Stephen D. Wiviott, M.D., Jonathan L. Halperin, M.D., Albert L. Waldo, M.D., Michael D. Ezekowitz, M.D., D.Phil., Jeffrey I. Weitz, M.D., Jindřich Špinar, M.D., Witold Ruzyllo, M.D., Mikhail Ruda, M.D., Yukihiro Koretsune, M.D., Joshua Betcher, Ph.D., Minggao Shi, Ph.D., Laura T. Grip, A.B., Shirali P. Patel, B.S., Indravadan Patel, M.D., James J. Hanyok, Pharm.D., Michele Mercuri, M.D., and Elliott M. Antman, M.D. for the ENGAGE AF-TIMI 48 Investigators
N Engl J Med 2013; 369:2093-2104November 28, 2013DOI: 10.1056/NEJMoa1310907

DPP4 inhibitors vs GLP-1 agonists

1) GLP 1a provides pharmacological levels ( supraphysiological ) of GLP, DPP4-i provides physiological levels ( endogenous secretion ) of GLP

2) Incretins are secreted fro GI that enhances insulin secretion in glucose dependant manner ( = it will only enhance insulin secretion when there is high level of glucose in GI )

- 50% of postprandial insulin production is due to the action by incretins

3) 2 types of incretins - GLP-1 and GIP ( glucose dependant insulinotropic peptide )

4) Actions - enhance insulin secretion, block glucagon secretion and promote satiety by slowing gastric emptying ( as amylin )

5) Why is GIP not used? In T2DM the GIP response is impaired ( does not amplify insulin response ) and together with GLP-1 can antagonize the action of GLP-1 inhibiting glucagon

6) Native GLP-1 is subjected to DPP4 degradation and therefore has short half life

7) DPP4 inhibitors inhibit the enzyme of degradation -> depends on endogenous production; GLP-1a is resistant to DPP4 and causes supraphysiologic levels of GLP receptors stimulation 

8) DPP4i - 3 FDA approved - sitagliptin, saxagliptin and linagliptin

• Only linagliptin is not renally excreted

9) GLP-1a - exenatide, lixisenatide ( slow released form of exenatide ), liraglutide

• Former two are renally excreted
• Liraglutide is metabolized prior to excretion and no specific organs indicated for elimination

10) DPP4i - oral drug, GLP-1a - S/C injectable ( a peptide based hormone like insulin so prone to gastric enzymes degradation )

11) Benefits of GLP-1a over DPP4i

• Both are glucose dependant - so do not cause hypoglycemia ( except when + with S/U )
• Trials have shows that GLP-1a results in weight loss and better glycemic control ( lowers HbA1C more ) - due to supraphysiologic stimulation of GLP-1 receptors 

12) DPP4i is weight neutral ( limited by endogenous secretion )

13) Guidelines support use of either one in metformin failure patients

14) In pts with weight problem but HbA1C is 1-2% from the targe , GLP-1a is better even though only a small reduction of HbA1C is only needed 

• Weight loss provides better long term outcome

15) However, if patient has cardiac failure, weight loss causes increased mortality risk; in this subgroup of patients, DPP4i is better **

16) DPP4i is preferred if the patient has NO weight issues and only requires small reduction of HbA1c to target level ( and obese cardiac failure patient )

17) Most frequent side effect of GLP-1a is nausea, but can be overcome with incremental dosing approach

18) Remember DPP4i and GLP-1a is a team player; monotherapy ONLY when entry HbA1C is < 7.5% ; Once > 7.5%, need combined therapy with metformin

References

GLP-1 Receptor Agonists vs. DPP-4 Inhibitors for Type 2 Diabetes

S. Brunton

Int J Clin Pract. 2014;68(5):557-567

Evidence behind DM

Sometimes, to study a disease means we have to understand the evidence behind it.

DM has been a problem for every country in the world, we know about metformin ( Glucophage ), insulin, sulfonylureas but why are those used and still stand as an important components of tx even though many new medications have emerged ( exenatide, pramlitide, acarbose, the new DPP4 inhibitors and SGLT2 inhibitors )

These are the summaries of the landmark studies

Im not good in EBM but what i can conclude are :
1) UKPDS showed us the benefit of metformin in overweight patients

2) UKPDS-PTM showed us the benefit of early glycemic control ( = we have a window of opportunity to diagnose and treat DM and we must not miss this window; first 10 yrs of tx is important for future outcomes )

3) ACCORD trial showed us that aggressively lowering the HbA1C in high risk patients ( elders, with cardiovascular diseases ) does more harm than good

4) ADVANCE trial in contrast, showed that in LATE a target of 6.5% of HbA1C if achieved slowly over a few years, could provide good future outcomes

5) Gliclazide may have some role in late intervention ( In ADVANCE trial addition of gliclazide reduces the combined endpoint of micro and macrovascular events )

6) Insulin and sulfonylureas are used in UKPDS without any detrimental effect ( but these patients did not have pre-existing diabetic nephropathy )

Reference
Key landmark studies in the clinical management of type 2 diabetes: evolution or revolution?
D. R. Mat thews , Uni ted Kingdom
MEDICOGRAPHIA, Vol 33, No. 1, 22 2011