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XII.B. Medical treatment

The manifested symptoms may be reduced separately in the following ways.

1. Diuretics

Aim: increase of the water release in the kidneys.

Active ingredients: hydrochlorothiazide and torasemide.

Pharmaceutical drugs: Hypothiazid, Brinaldix and Chlortalidon.

Effects: They increase the TG and cholesterol levels, decrease the HDL level, and hence are not suitable for long-term treatment. They are β-blockers (atenolol).

In small doses they decrease the BP.

2. Antihypertensives

Aim: the decrease of BP

a.β-receptor blockers

Aim: the inhibition of E and N, hormones which increase the BP.  

Effects: They enhance the TG and cholesterol levels and decrease the HDL level, and hence are not suitable for long-term treatment. They worsen the sugar and fat values.

b. α-receptor blockers

Pharmaceutical drugs: Prazosin, Terazosin, Doxasozin, Minipress retard and Cardura.

They are vasodilators. They ameliorate the insulin resistance.

c. Vasodilators

Effect: decrease of the BP.  

ACE inhibitors

Active ingredients: lisinopril, amlopidin, captopril, enalapril, quinalapril, ramipril, fosinopril, trandolapril, etc.

Effects: ACE produces A-II (a vasoconstrictor) in the lung and therefore increases the BP. The blockade of A-II causes a rapid and significant (20-40 mmHg) decrease of BP. 

ACE inhibitors enhances insulin sensitivity and improve microalbuminuria.

Ramipril inhibits the development of T2DM. These inhibitors decrease the PAI-1 level, improve the endothelial function and facilitate fibrinolysis. They improve the renal function.  

As ACE inhibitors exert their effects in the lung, they cause a long-term cough.

d. Angiotensin-2-receptor blocking agents (ARBs)

Pharmaceutical agents: Valsartannal, Irbesartannal, Losartannal, Candesartannal and Diovan.

Effects: They are A-II blockers (they inhibit aldosterone and endothelin production, but enhance NO production), and therefore decrease the BP.

 e. Angiotensin-1 (AT1) receptor blockers

Effects: They decrease the BP and the development of T2DM.

 f.  Ca2+-channel blockers

Active ingredients: dihydropyridine (DHP) preparations

Pharmaceutical drugs: Nifedipin,Amblodipin and Lacipil.

Effects: The increased influx of Ca2+ leads to enhanced myocardial contraction (e.g. coffee consumption). The blockade of these channels causes a decrease of the strength of the heart contraction.

They have no effect on albuminuria.  They decrease vasoconstriction, and hence decrease hypertension.

Active ingredients: non-DHP preparations

Pharmaceutical drugs: Nisoldipin.

They increase the risk of heart attack. They inhibit albuminuria.

They do not appear to influence the MetS.

g. Hormone replacement

It is not well understood, whether estrogen replacement should be recommended or not for women after the menopause.  

h. Imidazole agonists

Pharmaceutical drugs: Moxonidine (Cynt) and Rilmenidine (Tenaxum).

They are recommended in the initial phase of hypertension. Their side-effect is dry mouth.

i. Aldosterone inhibitors

Pharmaceutical drugs: Spironoladon and Verospiron.

They decrease the BP.

They enhance the K+ level.

3. Anticoagulants

a. Aspirin

Effects: It inhibits COX, and hence a decrease in the TXA2 level. It is not effective in developed T2DM.

b. Ticlopidine, clopidogrel and prasugrel

Effect: They inhibit the P2Y12 receptor

c. Abciximab

Effect: It inhibits GbIIb/IIIa.

d. E-5555 and SCH 530348

Effect: They inhibit PAR-1.

4. Cholesterol reducers

a. Statins

Active ingredients: atorvastatin, pravastatin, rosuvastatin or fluvastatin.

Effects: Statins (HMG-CoA reductase inhibitors) decrease the cholesterol, TG and LDL levels, enhance the HDL level, and hence decrease the risk of circulatory disorders. They also decrease the levels of the inflammatory marker CRP, testosterone and luteinizing hormone. They decrease the risk of the MetS and atherosclerosis. An anti-inflammatory effect, increases of fibrinolysis and the NO level, and an inhibitory effect on thrombotic processes have been described in the literature. The results of their use for CVD prevention are controversial.

 b. Fibrates

Pharmaceutical drug: Clofibrat (Myscleron)

Active ingredients: gemfibrozil, fenofibrat, bezafibrat and ciprofibrat,

Effects: They decrease the TG and cholesterol levels, and increase the HDL level.

They act through the PPARγ receptor.

They decrease the fibrinogen level.

They are vasodilators and decrease atherosclerosis.

Side-effect: Gallstones may develop and muscle pain may occur.

c. Nicotinic acid (Niacin)

Effects: It decreases the FFA, TG, cholesterol and LDL levels, and increases the HDL level.

There were earlier many side-effects, but there are much fewer with the new product (Niaspan).

As a side-effect, it increases prostaglandin D2 production, which causes vasodilatation and a burning sensation in the skin through its DP1 receptor. The DP1 antagonist laropiprant inhibits this effect.

d. Ion-exchange resins

Pharmaceutical drugs: Cholestipol (Colestid) and Cholestyramin (Questran).

They increase the LDL catabolism, and hence lead to a decrease of about 25-30% in the serum cholesterol level.

5. Anti-obesity medication

a. Orlistat (Xenical)

This is an artificially synthetized and modified derivative of the natural compound lipstatin produced by Streptomyces toxyricini. It binds to gastric and pancreatic carboxyl ester lipases in the intestinal lumen and inhibits lipid binding to these enzymes, thereby causing a 30% decrease of the absorption of fat from the food.

b. Sibutramine

This is a derivative of the amphetamine precursor ß-phenylethylamine, which was modified to reduce its addictive effect. It is a dopamine agonist. Sibutramine induces the satiety feeling by inhibiting the reuptake of monoamine precursors (catecholamines) in the hypothalamus.  It therefore increases postsynaptic signalization.

It decreases the HbA1C level.

It has now been withdrawn from the commercial market, because it increased the risk of MI and stroke (Study in Overweight or Obese Subjects at Risk of a Cardiovascular Event – SCOUT-2010).

c. Rimonabant

This is an endocannaboid (CB-1) receptor blocker.

The increased activity of the CB system in obese patients leads to an enhanced food intake and fat accumulation.

Rimonabant selectively blocks CB-1 receptors both centrally and peripherally, and therefore normalizes the hyperfunction of the CB system.

It decreases the body weight, improves the lipid profile and decreases insulin resistance.

It has been removed from the European market because of its side-effect, depression.

6. Medical treatment of diabetes mellitus

a. Insulin sensitizers

i. PPARγ agonists

Active ingredients: Pioglitazone (Actos) is a TZD. It decreases insulin resistance, enhances insulin sensitivity and decreases the blood Glu level. It improves the lipid profile, increases the HDL, and decreases the LDL and TG levels. It diminishes inflammatory processes, because it lowers the levels of CRP, PAI-1, MCP-1, MMP-9 and sCD40L, but increases that of adiponectin. As a result of these changes, decreases occur in albuminuria, the BP, the thickening of the vessel walls and the endothelial dysfunction. 

Rosiglitazone (Avandia) decreases the risk of the development of circulatory disorders. Both drugs enhance the body weight and change the fat distribution.  They decrease the amount of visceral fat.

ii. Metformin

Active ingredient: Methylbiguanide.

Effects: It increases the level of adenosine monophosphate-activated protein kinase (AMPk), which stimulates the insulin sensitivity in the tissues and enhances fat oxidation. It decreases the ALT level and lipolysis. It causes a 10-20% decrease in the level of androgens. It decreases the level of LDL and enhances that of HDL. It decreases the blood Glu level. It leads to a slight weight loss. It decreases insulin resistance. It is recommended for obese and T2DM patients.

Side-effect: It has the risk of lactic acidosis.

iii. Glucagon-like peptide agonist (GLP-1 analog)

Liraglutide and exenatide increase pancreatic insulin production. They are incretin-like molecules. They enhance the insulin sensitivity in the tissues and decrease the body weight. They decrease the levels of ALT and AST, and the degree of fatty liver.

b. Insulin secretion enhancers

Effect: They bind to the  Kchannels of B cells and lead to insulin release.

Sulfonylurea derivatives: glipizide, glyburide, glimeparide, glibenclamide

Meglitinid derivatives – repaglanide and netiglamide

Gliclazid (Diaprel MR) and glimepiride (Amaryl) have beneficial effects on the heart.

Glibenclamid has the opposite effect on the heart, weakening the defensive ability of the heart.  

Some studies have reported that these agents increase the adiponectin level.

Glinid derivatives (phenylalanine derivatives):

            repaglinid (Novo-Norm) and nateglinid (Starlix).

These compounds enhance only the early fast insulin secretion, and hence they are termed oral insulin analogs.

c. Insulin analogs

glargin

d. Vitamin E

This decreases oxidative stress.  

It decreases the AST and ALT levels and fatty liver.

e. α-Glucosidase inhibitors

Acarbose and Glucobay

They decrease Glu absorption in the small intestine.

They lower the blood Glu and TG levels and the BP. They decrease the risk of DM and CVD.  

f. Insulin-like growth factors (IGF I and IGF II)

They decrease the blood Glu level. The drugs are currently undergoing testing.

g. Amylin

This peptide hormone is synthesized in the pancreatic B cells. It decreases the blood Glu level.  

The individual laboratory values should be taken into account in pharmacological therapy, and concomitant use of drugs should be minimized. The patients can be classified into different risk groups via their laboratory values and symptoms. 

The Framingham risk score:

            high risk (HR) (the 10-year risk of the disease is > 20%)

            moderately high risk (MHR) (the 10-year risk of the disease is 10- 20%)

            low-intermediate risk (LIR) (the 10-year risk of the disease is 6 - 10%)

            low risk (LR) (the 10-year risk of the disease is < 6%)

 

This has led to a general treatment proposal:

Control of coagulation

Aspirin            HR                   effective

                        MHR                probably effective

                        IR                     it depends on the individual (gender, age and bleeding predisposition)

                        LR                    not recommended because of the bleeding risk

Clopidogrel

Control of blood pressure

 (>140/>90 mmHg)

if diabetes is present too (>130/>80 mmHg)

ACE1 (ARB) drugs

beta-blockers and thiazides (although they have opposite effects on Glu tolerance, they are important because of the decreases in BP and CVD)

thiazides and Ca2+ antagonists

Decrease of cholesterol level

The most important is to decrease the LDL, and then the non-LDL and other cholesterols. The aim is then to increase the HDL and decrease CRP.  

The aim of statin use is to reach the next LDL level: for HR <100 mg/dl, for MHR < 130 mg/dl, for LR < 160 mg/dl), and for HR CRP< 3 mg/dl)

Niacin and fibrates enhance the effects of statin.

Treatment of diabetes mellitus

The most important are lifestyle changes (physical activity and diet)

At least 30 min of continuous physical activity per day  

A weight loss of 6-10% during 6 months

Daily Na+ intake < 65-100 mmol; daily K+ intake 90-120 mmol

A mediterranean diet is recommended: abundant fruits, vegetables, pulses, cereals, little alcohol, little meat, mainly unsaturated fatty acids.

Metformin treatment

TZD-s (pioglitazones), glinides and Acarbose treatment