Therapy of diabetes mellitus/PGS

Therapy of DM
The main purpose of the diabetes treatment is to achieve the long-term normoglycemia or at least to get as closer to its rates as possible (www.diab.cz). The treatment of the evry patient with diabetes must always include non-pharmacological measures, such as the elected diet and physical activity considering the age, type of the diabetes, patient's body mass and the presence of the other associated comlications. According to the situation, we select the diabetic diets with 175 g, 200 g or 225 g of sugars or the reducing diets (svačina a spol., 2008). Physical activity (for example walking for at least 30 minutes a day) is the essential part of the treatment. Pharmacological treatment differs according to the type of diabetes (Škrha, 2009). Type I diabetes requires insulin treatment from the beginning. Therapy of the type II diabetes immediately begins with metformin treatment together with lifestyle measurements. The further procedures are mentioned below. The self-evident part of the patient's complex treatment is therapy of the associated deseases.

Treatment plan for the type I DM
includes an individual diet regimen (regulated food consumption) accompanied by the appropriate lifestyle (everyday physical activity and the exclusion of smoking), targeted education of the patient and his family members, insulin treatment and therapy of the further diseases. The physiological basis of insulin treatment are intensive insulin regimens with insulin application at least three times a day. In these regimens are combined short-acting types of insulin, which are applicated before the main dishes, and one or two doses of long-acting types of insulin, which at least partially imitate physiological inuslin secretion (so-called prandial and basal insulin). In indicated cases it's necessary to think about an insulin pump application.

Inseparable part of the diabetes type I treatment is glycemia self-monitoring (self-contol), which is accomplished by the patient with help of the glycemic profiles and particular glycemia rates. The treatment of type I diabetes is provided either by a diabetologist or an internal medicine physician with relevant erudition. Treatment plan for the type II DM newly reccomends immediately after diagnosing and simultaneously wuth non-pharmacological measures to start the metformin treatment and add the others PGS in combination with it.

If the combination of all peroral antidiabetics and all measures is not enough to reach the required diabetes compensation, it's necessary to think about an appropriate insulin treatment. The part of the therapy is an individually suggested self-control of the glycemia. Controls of the patient with type II DM take place every 3-6 months, in case if the patient's condition doesn't require the other frequency. The details are mentioned in standards of medical care in type II diabetes (www.diab.cz).

Peroral antidiabetics
• biguanides (metformin) • derivatives of the sulfonylurea (glimepirid, gliklazid, gliquidon, glipizid and glibenclamid) • glinids (repaglinid) • substances with the incretin effect (exenatid, liraglutid, vildagliptin, sitagliptin) • thiazolidinediones (rosiglitazone, pioglitazone) • alpha-glucosidase inhibitors (akarbóza)

The main principle is to begin the treatment with the lower doses. If the effect is insufficient, the dose increases, however the usage of the combination of antibiotics with different mechanism of action is more prefered than the increasment of the dose to its maximum. Biguanides (bg) effect particularly the liver insulin resistance, less the peripheral insulin resistance. The only deputy of this group that is used in clinical practice is metformin, which has the lowest risk of lactate acidosis as the treatment complication. It's applicated in one or two doses per day and it doesn't cause the hypoglycemia. There are also fixed combinations su+bG (glibenclamid a metformin). In patients with type II DM it's appropriate to begin the metformin monotherapy with the application of the lowest dose once or twice a day. The chronic maintenance dose usually doesn't exceed 1700–2000 mg per day. If the metmorfin monotherapy doesn't reach the satisfying compensation, it's combinated with an antidiabetic agent of the other type, beginning with the lowest dose. Metmorfin if contraindicated in case of the renal insufficiency (creatinine above 130 umol/l), heart failure, dehydration and hypoxia or shock conditions. There're no age restrictions that can be contraindication for metformin treatment.

Sulfonylurea derivatives (su) increase the secretion of the insulin. They're added when metformin therapy is not enough for the required effect. In practice are used the second generation medicaments which differ in effect's rapidity, duration of the hypoglycemia, way of the elimination and the side effects. Here belong glimepirid, gliklazid, gliquidon, glipizid and glibenclamid. Su are given in the smallest possible doses once or twice a day. The main risk of the treatment is hypoglycemia, the treatment is also accompanied by the weight gain (less in glimepirid and the most in glibenclamid treatment).

In treatment of patients with BMI below 25 kg/m2 are recommended rather short-acting medications (glipizide, gliclazide), which are also added in combination with primarily applicated metformin. Treatments begins with the lowest dose and in case of the insufficient compensation after a couple of weeks the dose increases (usually by two or three times). If patient's condition is not satisfactory, it's possible to choose longer-acting su (for example glibenclamide), but still more preferable are other PGS, particularly glimepiride or gliclazide. In younger DM type II patients with risk of cardiovascular desease is more convenient to use glimepiride, which in addition has lower risk of hypoglycemia and more suitable dosage once a day. Gliclazide is appropriate particularly in younger patients with manifistation of the DM before 55 years of life. In chronic therapy it is not recommended to exceed the moderate doses of PGS!!! (Glibenclamide 10 mg, Glipizide 10 mg, Gliclazide 160 mg, Gliclazide mR 60 mg, Glimepiride 2 mg). In derivative therapy it's important to pay attention to their side effects and drug interactions of su (especially in elder polymorbid patients). Increasement of the peroral antidiabetic dose in patient with glycemia rates about 15 mmol/l won't have any further effect, it's necessary to think of the fundamental change of the therapy. Glinids which affect the prandial glycemia increasement are fast-acting and have relatively short effect on insulin secretion, their effect is also more physiological than sulfonylurea derivatives, because they don't cause protracted hyperinsulinemia. They're applied before the main dishes three times a day, for example repaglinide 0,5 mg, 1 mg a 2 mg pill. Antidiabetics with incretin effect are applicated as derivatives or analogs of the glp-1 (glucagon like peptide-1), here belong exenatide or liraglutide (so-called incretin mimetics), or dipeptidyl peptidase IV inhibitors (dPP iv), which physiologically inactivates GlP-1 (so-called gliptins, for example vildagliptin and sitagliptin). This prospective group of medications improves insulin secretion by the glucose-dependent b-cell and has a lot of other effects (for example slower gastric evacuation, appetite suppression and so on). Medications are applicated in metformin or sulfonylurea derivatives combination therapy. Thiazolidinediones (glitazones) decrease insulin resistance, insulin secretion itself is not affected. Rosiglitazone (4 mg, 8 mg) or pioglitazone (15 mg, 30 mg tbl.) are applicated in combination therapy with metformin or sulfonylurea derivatives. In monotherapy they're not used. In treatment it can cause fluid retention, that's why glitazones are not applicated in patients with heart failure, edema and in pregnancy. This group of medicamentations usually has an amount of effects, many of them haven't been explained yet, and that is the reason why it's recommended to observe the patient consistently while using these medicaments.

Insulin analogs
inzulinová analoga se stále více používají v léčbě diabetu vedle humánních inzulinů. Působí jednak krátce (inzulin lispro, inzulin aspart či glulisin), jednak dlouze (inzulin glargin nebo inzulin detemir). První skupina ovlivňuje postprandiální glykémii rychleji a nevyvolává delší hyperinzulinémii jako humánní, rychle působící inzulin, kdežto druhá skupina se vyznačuje vyrovnanou hladinou inzulinu (tzv. bezvrcholový inzulin), která pak není tak často provázena hypoglykémiemi jako v případě nPH inzulinů. oba efekty se vhodně využívají u diabetiků, kteří nejsou úspěšně léčeni humánními inzuliny. Pro léčbu analogy u pacientů s dm 2. typu platí stejná zásada jako pro léčbu humánními inzuliny – pokud je to možné, tak vŽdy kombinujeme s léčbou metforminem. Řada studií prokázala, že prosté převedení na léčbu analogy humánních inzulinů sice nevede jednoznačně k lepším hodnotám HbA1c, ale že při stejné úrovni kompenzace výrazně snižuje riziko hypoglykémie, což má důsledky jak zdravotní, tak ekonomické. Analoga tak vytvářejí prostor pro zlepšení kompenzace DM, neboť u většiny pacientů je právě otevřená či skrytá obava z hypoglykémie nejzávažnější překážkou pro dosažení cílových hodnot glykémie a glykovaného hemoglobinu. samozřejmostí při podávání jak humánních inzulinů, tak inzulinových analog je jejich podávání pomocí inzulinových aplikátorů, což představuje přesnou a pro pacienty šetrnou metodu aplikace inzulinu.

Treatment plan for the type II DM
není-li dostatečně účinná obvyklá monoterapie metforminem ani následná kombinace metforminu s derivátem sulfonylurey nebo ji nelze realizovat pro nesnášenlivost metforminu, je třeba rozhodnout buď o kombinaci s inzulinem, nebo ověřit účinnost kombinační léčby s thiazolidindionem (glitazonem) či nověji s inkretinovým mimetikem (včetně inhibitoru dPP-iv). volba inzulinového preparátu (humánní inzulin či analog, krátce či dlouze působící), jeho dávek i rozdělení v průběhu dne závisí na dosahovaných výsledcích ukazatelů kompenzace. o nasazení a vedení léčby inzulinem rozhoduje obvykle diabetolog nebo internista. Převod na léčbu inzulinem je nutný též v době řešení akutních situací (infekce, operace, úraz). Při dlouhodobé dekompenzaci dm 2. typu, kdy selhávají Pad, je třeba volit léčbu inzulinem či použít analoga inzulinu v kombinaci s PaD

Algorithm of the type II DM treatment and dispensarization
(Consensus of the american and european diabetic association 2008)

nedojde-li během 3 měsíců k dosažení Hba1c pod 5 %, přistoupíme k další alternativě léčby podle některé z šipek. metformin vynecháme, není-li snášen nebo je-li kontraindikován

Targets of the DM therapy
1. to normalize glycemia or at least to approximate its physiological rates

2. to prevent the development of the early or late complications

3. at the same time to treat the other related deseases and eventually to prevent them

Indicators of quality of the DM treatment
According to the achieved rates of the particular observed parameters it is possible to assess the compensation level as excellent, acceptable or unsatisfactory.

THE PLATE

glycemia in the capillary blood excellent acceptable unsatisfactory fasting / before food consumption (mmol/l) 4–6,0 6,0–7,0 > 7,0 1–2 hours after food consumption (mmol/l) 5–7,5 7,5–9,0 > 9,0 Glycated hemoglobin Hba1c (%)* (according to iFcc, od 1. 1. 2004) (according to dcct) < 4,5 < 6,5 4,5–6,0 6,5–7,5 > 6,0 > 7,5
 * according to DCCT (Diabetes Control and Complications Trial) se uplatňuje doporučení IFCC (International Federation of Clnical Chemistry) používané v ČR (viz též www.diab.cz).

the main indicator of successful DM compensation is either average glycemia assesed by glycated Hb (Hba1c), or postprandial glycemia.

if the target rates of the postprandial glycemia and glycated Hb are not achieved in mono- or PGS combination therapy in 6 months, it's appropriate to consult the patient with diabetologist about further treatment

Recommendations for levels of compensation
na základě výsledků posledních studií (zejména studie ACCORD) doporučují experti rozlišovat pacienty s dm 2. typu podle výše rizika vyplývajícího z intenzivní léčby diabetu (sklon k hypoglykémiím a přítomnost dalších komplikací, zejména iCHs) a také podle potenciálního přínosu těsné kompenzace pro pacienta. Je proto vhodné přizpůsobit cíle léčby individuálnímu profilu nemocné- ho. diabetiky s nízkým rizikem je nutné vést k těsnější kompenzaci (Hba1c do 4,5 %), kdežto diabetici s vyšším rizikem mohou mít cílové hodnoty Hba1c v pásmu mezi 5,3–6,0 % dle ifCC!

Therapy of the related deseases in type II DM
1. arterial hypertension treatment: achievement of the target rates of the blood pressure < 130/80 mmHg by the monotherapy or more often by the combination of the antihypertensive medications with different mechanism of action. The most preferable are acei and sartans, Ca channel blockers, then centrally-acting antihypertensive drugs, beta-blockers and diuretics. The most preferable antihypertensive medications are positive or neutral inotropic ones, here belong particularly the first three mentioned types of the aH.

2. dyslipidemia treatment: in predomination of the hypercholesterolemia - application of the statins, in hypertriglyceridemia - application of the fibrates. To achieve dyslipidemia compensation is necessary to combine statin and fibrates therapy though.

3. obesity treatment: in patients with bmi > 30,0 kg/m2 can be indicated sibutramine or lipase inhibitors (orlistat) in combination with regimen measures (diet and physical activity) and other combined pharmacotherapies.

4. treatment and prevention of the diabetic nephropathy (Ras inhibitors [angiotensin converting enzyme], sartans and aCei), consistent hypertension examination.

Check-up of the type II DM patient
Glycemia every check-up

Hba1c once in three months until the compensation of the DM, then once in six months

Blood pressure every check-up

serum lipids once in 6 months in treatment, once in two years in case of the normal rates

Weight or BMI every check-up

Na,K,Cl, creatinine, uric acid once a year

tsH in case of thyreopathy suspicion

urea chemical tests + sediment once a year

microalbuminuria/proteinuria once a year (repeat twice in case of positive result)

bacteriological tests of urea once in six months

lower extremities inspection every check-up

eye examination once a year


 * the internal investigation is provided by the physician in preventive care examination once a year

ECG once a year

orientational neurological examination once a year

Interní vyšetření zaměřené na postižení velkých cév a známky ischemické choroby srdeční, dolních končetin a CNS (cílená anamnéza a objektivní vyšetření včetně poslechu krkavic, stehenních tepen a palpace periferních tepen). Nález při interním vyšetření vede k indikaci dalších laboratorních vyšetření (krevní obraz, enzymy apod.).

Poškození cílových orgánů respektive SOP
SubklinicKé orgánové poškození a interpretace výsledků:

nález hraničních nebo mírně abnormálních hodnot vztahujících se k funkci ledvin (viz níže) má vést k intenzivnější léčbě diabetu a arteriální hypertenze tak, aby bylo dosaženo co nejlepších hodnot kompenzace.

• mírný vzestup sérové koncentrace kreatininu (m 115–133, Ž 107–124 µmol/l) • nízká glomerulární filtrace (< 60 ml/min/1,73m2, ≤ 1,0 ml/s/1,73 m2) • mikroalbuminurie (30–300 mg/24 h nebo poměr albumin/kreatinin m 2,5–25, Ž 3,0–30 g/mol kreat.)

Target rates of lipids in patients with diabetes
(According to the common recommendations of nine czech expert associations for prevention of the coronary artery disease in adulthood, years 2005-2008)

lipids target rates in DM patients

total cholesterol < 4,5 mmol/l

ldl-cholesterol < 2,5 mmol/l

triglycerides < 2,0 mmol/l

Hdl-cholesterol > 1,0 mmol/l

in patients with high risk (diabetes + manifesting cardiovascular desease) is desirable to reach ldl-cholesterol rate < 2,0 mmol/l.

Pharmacotherapy of diabetic dyslipidemia
Hypercholesterolemia (↑ ldl-cholesterol) Hgm Coa reduktase inhibitors (statins) third generation fibrates biliary tract sequestrants

Combined hyperlipidemia (↑ ldl + ↑ vldl) Hmg Coa reductase inhibitors (statins) (in case of persisting hypertriglyceridemia fibrates in combination with statins) acipimox

isolated hypertriglyceridemia (↑ vldl ± chylomicrons) fibrates acipimox omega 3 fish oils


 * LDL – low-density lipoprotein; VLDL – very low-density lipoproteins

prognosis is serious for all age groups. There is no "mild" diabetes. It's impossible to prevent macrovascular complications in DM II patients without medical intervention. Prognosis of the each patient with DM is worsen in case of kidney deseases (albuminuria, dysfunction, infection, renal insufficiency), which accelerate the development of the cardiovascular stroke. Proliferative reinopathy progressively decreases visual perception.

Preventive measures
high level of physical activity, weight reduction at least by 5–10 % and maintenance of this body mass, restriction of the animal fats consumption, restriction of the consumption of secondary processed meat (smoked meat, pastes, minced meat, fastfood), definite effect also has restriction of drinking juice. Manifestation of DM is not connected with consumption of sugars. Risk of type II DM can be decreased by higher consumption of plant fats, nuts, fibres, coffee and fish meat. Significant effect on type II DM manifestation has pharmacotherapy. DM manifestation is about 30 % lower in hypertonic patients treated with ace inhibitors and about 10–25 % lower in hypertonic patiens treated with sartans and ace inhibitors. In obese non-diabetic patients or patients with glycemia disorder while fasting or with glucose tolerance disorder were accomplished the preventative medication tests with metformin, acarbose, orlistat, rosiglitazone amd pioglitazone. All these substances signally decreased the manifestation of the type II DM. Type II DM is a desease which can be prevented; it's important to pay attention to the obese patients with diabetes in family anamnesis. The best results in the prevention of DM in obese were achieved by the bariatric surgery, when DM risk decreases by 40×. In patients with type II DM the desease can disappear in 90 % of the cases.

Qualification requirements
Treatment of the patients with an uncomplicated type II DM is provided by general practitioner, internist or diabetologist in ordination with the required equipment and the ensured laboratory biochemical tests of blood and urea parametres in the accredited laboratory. The general practioner must have the ensured connection with diabetes ordination. Patients with type I DM or complicated type II DM are treated by the diabetologist. Cooperation with neurology, eye, cardiac and angiosurgery department is self-evident.