TUGAS CME

“SECONDARY PREVENTION OF CVD”

Pembimbing:

dr. Wahyu Djatmiko, Sp. PD

Disusun Oleh :

Tiara Zakiah Darajat G4A017086

SMF ILMU PENYAKIT DALAM

RSUD PROF. DR. MARGONO SOEKARJO

PURWOKERTO

2019
 LEMBAR PENGESAHAN

TUGAS CME

SECONDARY PREVENTION OF CVD

Disusun oleh:

Tiara Zakiah Darajat G4A017086

Diajukan untuk memenuhi syarat

mengikuti Kepaniteraan Klinik

di Bagian Ilmu PenyakitDalam

RSUD Prof. DR. Margono Soekarjo Purwokerto

telah disetujui dan dipresentasikan

pada tanggal: Desember 2018

Purwokerto, Desember 2018

Pembimbing,

dr. Wahyu Djatmiko, Sp. PD

Secondary Prevention of CVD

Sarah is a 58-year-old dental nurse, with a body mass index (BMI) of 31

kg/m2. She was diagnosed with type 2 diabetes mellitus (T2DM) around 8 years
ago, and she is currently taking metformin 1000 mg twice daily and glipizide 5 mg
four times daily. Sarah also has hypertension, as well as dyslipidemia. Just over 1
year ago, Sarah had a myocardial infarction (MI) and underwent coronary artery
revascularization. Today, Sarah is visiting her general practitioner for her regular
3-month follow-up visit; the doctor is concerned about Sarah's risk of having
another cardiovascular (CV) event.

Doctor: Come in.

Doctor: Ah, Sarah, please take a seat.

Patient: Thank you, doctor.

Doctor: How are you feeling?

Patient: I'm good -- nothing new.

Doctor: I've looked at your results for today, and I'm quite concerned.

Patient: Alright...

Doctor: Your glycated hemoglobin, or HbA1c, is 8.5%, which is slightly higher

than last time you were here. Your blood pressure is 150 over 90 mm Hg -- so that
first number is also a little higher than it should be. Your estimated glomerular
filtration rate is 53 mL/min/1.73 m2, which suggests that your kidney function has
started to decline. But I'm not going to worry too much about that at the moment.

Patient: OK.

Doctor: The statin has brought your low-density lipoprotein cholesterol, or LDL-C,
down to 3.1 mmol/L, or 120 mg/dL, but I would like to see it lower still. Your high-
density lipoprotein cholesterol, or HDL-C, is only 0.9 mmol/L, or 35 mg/dL -- and
that's the good cholesterol -- so we want it to be a little higher.

Patient: I see.
Doctor: Sarah, you have already had one heart attack, and all of these things are
putting you at great risk of having another one, or of having a stroke.

Patient: But I just don't know what to do, doctor.

Doctor: Well, one of the things that would help with your blood glucose, your blood
pressure, and your cholesterol is losing some weight. We have talked about this
before.

Patient: Yes, I know.

Doctor: I'm going to ask the nurse to sit down with you again to try to identify
specific things you can do in terms of your diet to lower your weight. I will also
give you a prescription to take part in an exercise program.

Patient: Alright, thank you.

Doctor: In the meantime, I would like to adjust your medication regimen.

Patient: What do you suggest?

Doctor: I think that we need to be more aggressive about controlling your blood
glucose, so I would like to add a medication called sitagliptin.

Patient: Does that do the same thing as the other diabetes medications?

Doctor: Not exactly -- it's a dipeptidyl peptidase-4, or DPP-4, inhibitor, which

means it blocks an enzyme in your intestine that causes glucose to increase.

Patient: I would take that with the other 2 medications, then?

Doctor: Yes. I would also like to protect your heart more by further lowering your
blood pressure. So I’m going to prescribe 5 mg a day of amlodipine, which should
help with that.

Patient: That's a lot of medicine.

Doctor: Yes, I know. But you're at very high risk of having another heart attack. If
you can get your weight down, as I said, that will help, and we may be able to cut
back on the medications. But I think we should go with this for now, and then see
where you are in 6 weeks' time.
Patient: Alright, doctor.

Since Sarah is at high risk for another CV event, CV risk factor management
is critical to her care. Which of the following CV risk factor goals/targets of therapy
is most appropriate for Sarah?

A. Glycated hemoglobin (HbA1c) <6.5%; systolic blood pressure (SBP) <150

mm Hg; low-density lipoprotein cholesterol (LDL-C) <3.0 mmol/L (<115
mg/dL)
B. HbA1c <7.0%; SBP <140 mm Hg; LDL-C <1.8 mmol/L (<70 mg/dL)
C. HbA1c <7.5%; SBP <130 mm Hg; LDL-C <1.8 mmol/L (<70 mg/dL)
D. HbA1c <7.0%; SBP <120 mm Hg; LDL-C <2.6 mmol/L (<100 mg/dL)

Hello, I'm Lars Rydén, Senior Professor of Cardiology at the Karolinska

Institute in Stockholm, Sweden. I want to comment on this patient and discuss her
management. This patient has obesity, T2DM, a history of cardiovascular disease
(CVD), and a number of other CV risk factors. Let us start with her HbA1c; it is
not well controlled. Her blood pressure (BP) is elevated, and she has an elevated
LDL-C and a low HDL-C. Looking at the kidney function, her estimated glomerular
filtration rate (eGFR) indicates adequate kidney function for now, but suggests that
some loss of function is occurring. Finally, her obesity has not been treated until
this time.

Obesity is a main risk factor for a number of noncommunicable diseases,

including CVD, T2DM, hypertension, coronary heart disease, and certain types of
cancers.[1,2] In addition, it also causes diverse psychological problems and
physical disabilities. Since the majority of people with T2DM are overweight or
obese, weight reduction is seen as a key therapeutic goal in the prevention and
management of T2DM.
 Multiple clinical trials have demonstrated the benefit of weight reduction in
diabetes prevention and therapy.[3] It is often difficult for patients to lose weight,
but clinicians should try to emphasize its importance. In patients with impaired
glucose tolerance, the occurrence of T2DM can be delayed with lifestyle
modifications, including weight reduction and physical activity.[4] For individuals
who have progressed to prediabetes, the Finnish Diabetes Prevention Study showed
that an intensive dietary and exercise program decreased the overall risk for diabetes
by 58%.[4] The LOOK-AHEAD study demonstrated that a loss of 5% to 10% of
body weight could improve overall fitness, reduce HbA1c levels, improve CVD
risk factors, and decrease the use of antihyperglycemic, antihypertensive, and lipid-
lowering medications after 1 year.[5]

European guidelines on CVD prevention in clinical practice state that

patients with documented CVD, on average, are at very high risk for recurrent CV
events and mortality.[6] Furthermore, CVD is the most common cause of death in
people with T2DM. It is therefore of critical importance to minimize the risk for
macrovascular complications by carefully managing modifiable CV risk factors in
patients with T2DM.[7] In this case, the physician recognizes that the patient is at
elevated CV risk despite treatment, and has proposed some therapeutic adjustments
to address this risk.
 Adding a DPP-4 inhibitor to the patient's antihyperglycemic medications, at
least, recognizes that her HbA1c is not well controlled and intensification of
glucose-lowering therapy is required. However, in order to reach a goal HbA1c of
less than 7.0%, an HbA1c decrease of more than 1.0% will be required, which is
likely greater than can be expected with a DPP-4 inhibitor.[8] The physician has
seen that the patient's BP requires some additional attention; the vaso-selective
calcium channel blocker, amlodipine, is a good choice. Certainly, the diet-and-
exercise program is essential for this patient, and the 6-week assessment is
appropriate. However, the patient's lipids are still elevated despite treatment.
Multiple randomized clinical trials have clearly demonstrated that LDL-C lowering
has a beneficial impact on CV events in patients with and without diabetes.[9] The
absolute benefit of LDL-C lowering is greater in patients with diabetes, since their
CV risk is much higher vs those without T2DM. A level of <1.8 mmol/L (or <70
mg/dL) is recommended in international guidelines.[9] Let us now return to the
patient to see how she has done after implementing some of these medication and
lifestyle changes.
Doctor: And have you been following the dietary recommendations that the nurse
gave you and regularly taking part in the exercise program?

Patient: Yes, I've made some adjustments to what I cook -- although I don't think
my husband is always crazy about it. And I go to the exercise sessions twice a week.
I actually feel better afterward, and I seem to have more energy some days.

Doctor: Good -- it seems to be helping. Your weight is down by a couple of kilos.

So, well done!

Patient: Thank you, doctor.

Doctor: Your BP is also quite a bit lower now -- down to 130 over 80 mm Hg,
which I'm comfortable with.

Doctor: There has been some improvement in your HbA1c since we added the
sitagliptin, but not a lot -- that has dropped to 7.8%. How have you been doing with
that?

Patient: It's been alright, on the whole. I've have had a couple of hypos -- I was
getting dizzy, and when I checked my blood sugar it was down around 4 mmol/L.

Doctor: Hmm, yes, that can happen sometimes -- when people are taking a
medication such as sitagliptin and their glucose starts to fall, it is easier to get hypos
if they are also taking a sulfonylurea like the glipizide that you're on.

Patient: I see.

What change would you be most likely to make to Sarah's antihyperglycemic

regimen at this time?

A. I would not make a change at this time, but would have the patient return in
3 months to recheck her HbA1c
B. Increase glipizide to 10 mg four times daily
C. Switch glipizide 5 mg four times daily to extended-release glipizide 20 mg
once daily
 D. Discontinue glipizide and sitagliptin and add a glucagon-like peptide-1
receptor agonist (GLP-1 RA) or sodium-glucose cotransporter 2 (SGLT2)
inhibitor

As we see, the changes to therapy introduced after the initial visit have resulted
in some improvements. For example, the addition of amlodipine to the angiotensin
receptor blocker, valsartan, and hydrochlorothiazide has resulted in good BP
improvement. Her HbA1c is also down, but remains elevated; the choice of a DPP-
4 inhibitor was perhaps not optimal. DPP-4 inhibitors are often selected as add-on
therapy to metformin and other glucose-lowering agents because they are well-
tolerated, orally administered, and convenient to use. However, as we see with this
patient, their HbA1c reduction is fairly modest (<1%); and their effects on weight
and CV risk are, in general, neutral.[8] In this patient, a better choice for additional
HbA1c reduction might have been a glucagon-like peptide-1 receptor agonist
(GLP-1 RA) or a sodium-glucose cotransporter 2 (SGLT2) inhibitor, as both types
of agents provide greater HbA1c reduction compared with DPP-4 inhibitors.
Moreover, GLP-1 RAs and SGLT2 inhibitors are associated with weight loss. Since
the patient has a history of clinical CVD, adding an agent that provides CV
protection against new ischemic events should be considered.[8]

Four large, CV outcome trials (CVOTs) have been conducted with GLP-1 RAs
in patients with T2DM and high CV risk or established CVD.[10-13] All of the
trials demonstrated CV safety of the active GLP-1 RA therapy. In addition, the
LEADER and SUSTAIN-6 trials found that treatment with either liraglutide (in the
LEADER trial) or semaglutide (in the SUSTAIN-6 trial) significantly reduced the
risk for the primary major adverse CV event (MACE) endpoint, a composite
endpoint of the first occurrence of death from CV causes, nonfatal MI, or nonfatal
stroke, compared with placebo, when added to conventional treatment.[11,12]
 Two large CVOTs have been conducted with SGLT2 inhibitors in patients
with T2DM and high CV risk: the EMPA-REG OUTCOME trial and the CANVAS
trial[14,15] demonstrated CV safety of their respective SGLT2 inhibitor.
Furthermore, treatment was associated with a significant reduction the risk for the
primary MACE endpoint compared with placebo.[14,15]

Based on the results of these and other CVOTs, a number of countries and
organizations are changing recommendations regarding the use of glucose-lowering
therapy in patients with clinical CVD. For example, the 2018 Clinical Practice
Guidelines from Diabetes Canada suggest using an antihyperglycemic agent with
demonstrated CV benefit, including liraglutide, empagliflozin, or canagliflozin.[16]
The 2018 American Diabetes Association, or ADA, Standards of Diabetes Care
recommend incorporating an agent proven to reduce MACE and CV mortality
(currently empagliflozin and liraglutide), after considering drug-specific and patient
factors.[8,17]
 For this patient, selection of a GLP-1 RA or an SGLT2 inhibitor might have
made it possible to discontinue the sulfonylurea (SU), due to the significant
glucose-lowering effect of these agents. Discontinuation of the SU is desirable since
the patient has complained of some hypoglycemic episodes. SUs stimulate the
release of insulin and are associated with a high risk for hypoglycemic episodes.
These hypos are more common in elderly people and may be associated with
arrhythmia, including serious ventricular ones.[18]

Patient-specific characteristics have to be taken into account in order to

select the most suitable add-on agent for this patient. Considering the comparable
effects GLP-1 RAs and SGLT2 inhibitors have on the HbA1c reduction, weight
loss, and the minimal risk for hypoglycemia, clinicians should weigh the potential
benefits and adverse events of each agent before choosing a specific one.[8,16,17]
It has been suggested that SGLT2 inhibitors may provide benefits on CV outcomes
via diminishing heart failure (HF) risk, whereas GLP-1RAs provide benefits on CV
outcomes via reduction of atherosclerosis progression; however, the exact
mechanisms are still yet unknown.[19,20]

It is also necessary to intervene to provide better control of the patient's

lipids in this case. The IMPROVE-IT trial demonstrated that the addition of
ezetimibe to statin therapy enhanced the impact of lipid lowering with a favorable
impact on CV events, including mortality.[21] This effect was, in principle, related
to the presence of diabetes, as patients without diabetes did not experience a similar
benefit.[22]

Intensifying Antihyperglycemic Therapy With a GLP-1 RA

Doctor: I would really like to continue to try to get your blood glucose much lower
-- that will reduce the chances of you having the severe problems that can occur
with diabetes, such as nerve pain and poor vision. It will also lower your risk of
having another heart attack or a stroke.

Patient: Yes, I understand.

Doctor: So here is what I would recommend: I think you should stop taking both
the glipizide and the sitagliptin that you started 6 weeks ago. Instead, I would like
you to try a newer medication, liraglutide.

Patient: Will I have to take this new medicine 4 times a day, like the glipizide?

Doctor: No, actually, this is an injection that you give yourself. It lasts for 24 hours,
so you only have to take it once a day.

Patient: An injection?

Doctor: Yes, it comes in a pen-like device. It's very easy, not like using a syringe.
Most people get used to it very quickly.

Patient: Oh, I see.

Doctor: The nurse can show you exactly how to do it.

Patient: Alright.

Doctor: This medication should be good for you, Sarah. It does several things at
once, including stimulating the secretion of your body's own natural insulin, as well
as slowing down the absorption of glucose by the intestine and reducing appetite as
an indirect effect of a delay in gastric emptying. So it lowers both fasting glucose
and the glucose spikes that occur after meals.

Patient: That sounds good.

Doctor: Yes. And together with the changes in your diet and the exercise program
that you're doing, liraglutide may also help you lose weight.

Patient: Oh, that would be nice.

Doctor: But we also need to do something about your cholesterol.

Doctor: Your tests show an LDL-C level of 3.0 mmol/L, or 116 mg/dL, which is
more or less the same as it was at your last visit. So I'm going to give you a
prescription for ezetimibe -- it's a medication that works with your statin to lower
LDL-C further.

Patient: Alright.

Doctor: I'm going to arrange for the nurse to speak to you about the liraglutide
injection, and then I'd like to see you again in about 2 months.

Patient: Of course. Thank you, doctor.

Doctor: Well, Sarah, I have good news for you.

Patient: Oh really?

Doctor: Yes. But first, I want to congratulate you -- you've lost 3 kg since your last
visit. That's wonderful!

Patient: Thank you. I'm feeling so much better.

Doctor: I'm sure you are. And your HbA1c is now down to 6.4%, or 46 mmol/mol,
which is a huge improvement. It's great. How have you been doing in terms of
giving yourself the injection each day?

Patient: Oh, I got used to that very quickly. But I was feeling quite nauseous early
on.
Doctor: Yes, that's not at all unusual with this medication. Are you still experiencing
any nausea?

Patient: No, it seemed to go away gradually.

Doctor: Good -- that's quite typical. Your blood pressure is okay -- 135 over 85 mm
Hg -- and your LDL-C is much better. It’s down to 1.8 mmol/L, or 70 mg/dL, and
I'm very happy with that.

Patient: Thank you, doctor -- I feel so relieved.

Doctor: You've done really well over the last few months. But please don't let up -
- you need to continue with the improvements that you've made with your diet, as
well as carrying on the exercise regularly.

Patient: Alright.

Doctor: I think you should continue the medications as they are, and I don't think I
need to see you again for about 3 months.

Patient: That sounds good -- I'll come back then.

What is the best strategy for reducing the incidence of nausea in patients who are
starting therapy with a GLP-1 RA?

A. Do not use the abdomen as an injection site

B. Use a slow dose titration of GLP-1 RA
C. Eat a large meal before the injection
D. Prescribe use of a concomitant anti-acid

The changes in therapy introduced during the last visit have resulted in
substantial improvements for this patient. With the addition of the GLP-1 RA,
liraglutide, the patient's HbA1c has been reduced and is now on target. In addition,
the patient has lost more weight.
 The underlying mechanisms that mediate the weight-reducing effects of
liraglutide are not clear, but are likely a combination of effects on the
gastrointestinal (GI) tract and the brain. Decreased appetite and increased satiety
are components.[23]

It should be underlined that initiation of a GLP-1 RA is, preferably,

performed with a stepwise increase in the dose with a time between successive steps
depending on the patient's reaction in order to decrease the incidence of nausea. GI
complaints disappear over time and are less frequent with a slow dose titration.[24]

People with T2DM, particularly those with evidence of CVD, are at high
risk for chronic kidney disease. Multiple CV outcomes trials, which I have
previously mentioned, have demonstrated improvements in cardio-renal outcomes
in patients with T2DM and high CV risk.

In the LEADER trial, renal complications were significantly lower in

patients treated with liraglutide vs placebo.[25] It is possible to start a GLP-1 RA
in patients with a reduced kidney function; caution must be used when using a
SGLT2 inhibitor.[26] In the EMPA-REG OUTCOME trial and the CANVAS
program, the incidence of worsening nephropathy was significantly reduced in
patients treated with an SGLT2 inhibitor vs placebo.[27,28]
 Renal effects, as well as the effects on CV outcomes, should be considered
by clinicians when selecting glucose-lowering medication for the management of
patients with T2DM and high CV risk.

In conclusion, since CVD continues to be the leading cause of death in

patients with T2DM, the prevention of CV events in patients with T2DM who have
already experienced a CV episode should be a primary objective when selecting
glucose-lowering therapy treatment. Recent clinical trials have increased our
understanding of the potential effects of drugs for T2DM on CV risk. Two types of
glucose-lowering agents, GLP-1 RAs and SGLT2 inhibitors, are available and have
demonstrated benefits on CV outcomes.

Management of patients with T2DM should be done in the context of a

comprehensive CV risk management strategy, which includes optimizing
management of the patient's weight, BP, and lipid profile.
Question 1 of 5

Sarah is a 58-year-old dental nurse with a body mass index (BMI) of 31

kg/m2. She was diagnosed with type 2 diabetes mellitus (T2DM) around 8 years
ago and is currently taking metformin 1000 mg twice daily and glipizide 5 mg once
daily. Sarah also has hypertension and dyslipidemia. Just over 1 year ago, Sarah
had a myocardial infarction (MI) and underwent coronary artery revascularization.
Today, Sarah is visiting her general practitioner for her regular 3-month follow-up
visit; the doctor is concerned about Sarah's risk of having another cardiovascular
(CV) event.

Since Sarah is at high risk for another CV event, CV risk factor management
is critical to her care. Which of the following CV risk factor goals/targets of therapy
is most appropriate for Sarah?

A. Glycated hemoglobin (HbA1c) <6.5%; systolic blood pressure (SBP) <150

mm Hg; low-density lipoprotein cholesterol (LDL-C) <3.0 mmol/L (<115
mg/dL)
B. HbA1c <7.0%; SBP <140 mm Hg; LDL-C <1.8 mmol/L (<70 mg/dL)
C. HbA1c <7.5%; SBP <130 mm Hg; LDL-C <1.8 mmol/L (<70 mg/dL)
D. HbA1c <7.0%; SBP <120 mm Hg; LDL-C <2.6 mmol/L (<100 mg/dL)

Sarah has a longer life expectancy but has had a relatively long duration of
T2DM (8 years) and is taking multiple glucose-lowering medications. According
to the American Diabetes Association (ADA)/European Association for the Study
of Diabetes (EASD), the most appropriate HbA1c target for her would be <7.0%
(53 mmol/mol). The most recent ADA guidelines recommend a target blood
pressure (BP) of <140/90 mm Hg, although the ADA guidelines also have a
recommendation for a goal BP of <130/80 mm Hg in patients with T2DM and high
risk for CV disease (CVD), if the targets can be achieved "without undue treatment
burden." In patients at very high CV risk, such as Sarah, with documented CVD, an
LDL-C goal of <1.8 mmol/L (70 mg/dL) or a reduction of at least 50% from
baseline is recommended.

Question 2 of 5
 At the time of her initial visit, Sarah was taking metformin 1000 mg twice
daily and glipizide 5 mg four times daily. Her physician recommended adding a
dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin 100 mg once daily, to her
antihyperglycemic regimen. After 6 weeks of sitagliptin therapy, Sarah's HbA1c
decreased from 8.5% to 7.8%.

What change would you be most likely to make to Sarah's antihyperglycemic

regimen at this time?

A. I would not make a change at this time, but would have the patient return in
3 months to recheck her HbA1c
B. Increase glipizide to 10 mg four times daily
C. Switch glipizide 5 mg four times daily to extended-release glipizide 20 mg
once daily
D. Discontinue glipizide and sitagliptin and add a glucagon-like peptide-1
receptor agonist (GLP-1 RA) or sodium-glucose cotransporter 2
(SGLT2) inhibitor

It would be most appropriate to discontinue glipizide and sitagliptin and add a

GLP-1 RA or SGLT2 inhibitor. Continued treatment with sitagliptin would likely
not lower the HbA1c to the goal of <7.0%. GLP-1 RAs and SGLT2 inhibitors
provide greater HbA1c reduction compared with DPP-4 inhibitors and are
associated with weight loss. In addition, since the patient has a history of clinical
CVD, adding an agent that provides CV protection, such as a GLP-1 RA or SGLT2
inhibitor, should be considered.

Question 3 of 5

What is the best strategy for reducing the incidence of nausea in patients who are
starting therapy with a GLP-1 RA?

A. Do not use the abdomen as an injection site

B. Use a slow dose titration of GLP-1 RA
C. Eat a large meal before the injection
D. Prescribe use of a concomitant anti-acid
 GLP-1 RAs provide clinically important reductions in HbA1c, as well as cardio-
renal protection in patients with T2DM at high CV risk. The most common adverse
event associated with GLP-1 RAs is nausea. Initiation of a GLP-1 RA is, preferably,
performed with a stepwise increase in the dose with a time between successive steps
depending on the patient's reaction in order to decrease the incidence of nausea. In
general, gastrointestinal (GI) complaints disappear over time and are less frequent
with a slow dose titration. In addition, in order to avoid nausea, patients can be
advised to eat slowly and consume smaller meals throughout the day.

Treatment with which of the following novel glucose-lowering agents, in their

respective cardiovascular outcome trials (CVOTs), has demonstrated an
improvement in renal outcomes vs placebo in patients with type 2 diabetes (T2DM)
and high cardiovascular (CV) risk?

A. Liraglutide only

B. Liraglutide and empagliflozin only

C. Canagliflozin and empagliflozin only

D. Canagliflozin, Answer: Canagliflozin, empagliflozin, and liraglutide

Multiple CV outcomes trials have demonstrated improvements in cardio-

renal outcomes in patients with T2DM and high CV risk. In the LEADER trial,
renal complications were significantly lower in patients treated with liraglutide vs
placebo. In the EMPA-REG OUTCOME trial, the incidence of worsening
nephropathy was significantly reduced in patients treated with empagliflozin vs
placebo. Most recently, the CANVAS study demonstrated that canagliflozin
treatment was associated with a reduced risk for sustained loss of kidney function,
attenuated estimated glomerular filtration decline, and a reduction in albuminuria.
Renal effects, as well as the effects on CV outcomes, should be considered by
clinicians when selecting glucose-lowering medication for the management of
patients with T2DM and high CV risk. empagliflozin, and liraglutide