1. Doc. Eglė Varanauskienė KMU Endokrinologijos klinika
Antsvoris, nutukimas ir širdies ir kraujagyslių ligų rizika. Nutukimo gydymo principai
Doc. Eglė Varanauskienė
KMU Endokrinologijos klinika

2. O. Rodeno “Balzakas” 3

5. Kardiometabolinis adipocitų išskiriamų medžiagų poveikis
↑ Lipoproteinlipazė
Hipertenzija
↑ IL-6
↑ Angiotenzinogenas
Uždegimas
↑ Insulinas
Aterogeninė
dislipidemija
↑ LRR
Adipose tissue
↑ TNFα
↑ Rezistinas
↑ Leptinas
↑ Adipsinas (Komplementas D)
Adverse cardiometabolic effects of products of adipocytes
This slide shows a more complete list of the bioactive substances secreted by adipocytes, that modulate insulin resistance and cardiovascular risk.
Lyon CJ, Law RE, Hsueh WA. Minireview: adiposity, inflammation, and atherogenesis. Endocrinology 2003;144:
Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92:
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:
↑ Laktatas
2 tipo CD
↓ Adiponektinas
↑ Plazminogeno aktyvatoriaus inhibitorius-1 (PAI-1)
Aterosklerozė
Trombozė
Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

6. Riebalinis audinys hipertrofuoja ir hiperplazuoja
Išskiriami uždegiminiai citokinai
Sumažėja gliukozės pasisavinimas
Kasa išskiria daugiau insulino
Hiperinsulinemija
Trigliceridai išskiriami į kraują
Širdies ir kraujagyslių ligos
Hiperglikemija
Didėja gliukozė kraujyje

7. Sekančio dešimtmečio uždaviniai
Pagrindiniai nepasiekti klinikiniai tikslai
Klasikiniai rizikos veiksniai
Nauji rizikos veiksniai
Metabolinis sindromas
Visceralinis nutukimas
DTL-C
TG
TNF IL-6
PAI-1
Gliuk
Insulin
 MTL-C
 AKS
Rūkymas
2TCD
Unmet clinical needs to address in the next decade
The adverse effects of cardiovascular prognosis of the classical cardiovascular risk factors, hypercholesterolaemia, hypertension and smoking, are well understood. Our increasing understanding of the pathophysiology of cardiovascular disease is now defining the importance of a range of new cardiovascular risk factors.
Among these, abdominal obesity, low HDL-C, hypertriglyceridaemia and the hyperglycaemia associated with insulin resistance are all recognised criteria for the diagnosis of the metabolic syndrome. However, a range of important novel risk factors or risk markers for cardiovascular disease are also associated with the metabolic syndrome, although not yet included within its definition. These include chronic, low-grade inflammation, and disturbances in the secretion of bioactive substances from adipocytes (‘adipokines’) that influence cardiovascular structure and function.
The cardiovascular risk factors associated with the metabolic syndrome, whether included within its diagnostic criteria or not, contribute to the progression of atherosclerotic cardiometabolic disease, and represent an important clinical need inadequately addressed by current therapies.
Kardiovaskulinės ligos

8. Visceralinis nutukimas didina ŠKL riziką nepriklausomai nuo KMI (HOPE)
Tercilė 1
Tercilė 2
Tercilė 3
Vyrai
Moterys
<95
95–103
>103
<87
87–98
>98
Liemens apimtis (cm):
1.4
1.35
1.29
1.27
1.2
1.17
1.16
1.14
Standartizuota reliatyvi rizika 1 1 1 1
Abdominal obesity predicted CVD independently of BMI in the HOPE Study
This analysis from the Heart Outcomes Protection Evaluation (HOPE) study evaluated the effects of abdominal obesity (tertiles of waist circumference) on the risk of all-cause or cardiovascular death, or MI in 6620 men and 2182 women followed for an average of 4.5 years. Results were adjusted for BMI, age, smoking, sex, previous MI, stroke, peripheral arterial disease, microalbuminuria, use of antiplatelet agents, diuretics, lipid-lowering agents, and anti-hypertensives, history of hypertension, diabetes, or total cholesterol >5.2 mmol/L, or HDL-cholesterol <0.9 mmol/L.
The risk of cardiovascular death, MI, or death from any cause increased in line with increasing tertiles of waist circumference, even after multivariate adjustment for cardiometabolic factors including BMI. These data from this major intervention study add to the growing database of evidence supporting an independent adverse effect of abdominal obesity on clinical cardiovascular outcomes.
Dagenais GR, Yi Q, Mann JF, Bosch J, Pogue J, Yusuf S. Prognostic impact of body weight and abdominal obesity in women and men with cardiovascular disease. Am Heart J 2005;149:54-60.
0.8
Mirting. ŠKL MI
Bendr.mirting.
Standartizuota pagal KMI, amžių, rūkymą, lytį, ŠKL, diabetą, DTL-C, Bendr.-C. ŠKL: širdies ir kraujagyslių ligos; MI: miokardo infarktas; KMI: kūno masės indeksas.
Dagenais GR et al. Am Heart J 2005;149:54-60.

9. Liemens apimties (cm) kvintilės
Visceralinis nutukimas susijęs su padidėjusia koronarinės širdies rizika
Liemens apimtis reikšmingai susijusi su padidėjusia, standartizuota pagal amžių KŠL rizika, nepriklausomai nuo KMI ir kitų kardiovaskulinės rizikos veiksnių
0.0
0.5
1.0
1.5
2.0
2.5
3.0
< < < < <139.7
1.27
2.06
2.31
2.44
p = 0.007
Reliatyvi rizika
Liemens apimties (cm) kvintilės
The prospective Nurses Health Study set out to assess the impact of factors such as waist circumference in determining risk of CHD in a cohort of 44,702 US female registered nurses, aged 40 to 65 years, recruited between 1986 and Study subjects were free of prior CHD at baseline.
During 8 years of follow-up, there was a direct, independent and continuous relationship between waist circumference and age-adjusted risk of CHD.
CHD: coronary heart disease; BMI: body mass index
Rexrode KM et al, 1998
Rexrode KM, Carey VJ, Hennekens CH et al. Abdominal adiposity and coronary heart disease in women. J Am Med Assoc 1998;280:1843–8.

10. Visceralinis nutukimas: viena iš pagrindinių ūmaus miokardo infarkto priežasčių
Kardiometaboliniai rizikos veiksniai, INTERHEART Study 60 49
Visceralinis nutukimas didina ŠKL riziką nepriklausomai nuo KMI 40
Rizika (%) 20 18 20
The INTERHEART Study was a case-control study involving 29,972 participants in 52 countries. The study examined the contribution of various cardiometabolic risk factors to the risk of a first acute myocardial infarction (AMI). The study quantified the relationships between risk factors and AMI through calculation of the population attributable risk (PAR), which measures the proportion of AMI among those who have the risk factor which would be eliminated if the risk factor was removed.
Dyslipidaemia (raised ApoB/ApoA1 ratio) and smoking were associated with the highest PAR. However, the PAR for abdominal obesity was greater than either diabetes or hypertension. BMI showed a modest correlation with the risk of AMI, but this was not significant when abdominal obesity was included in a multivariate analysis.
Abdominal obesity is therefore an important predictor of adverse cardiovascular outcomes in its own right. 10
Dislipidemija
Visceralinis
nutukimas
Hipertenzija
Diabetas
Yusuf S et al, 2004
Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937–52.

11. The MRC/BHF Heart Protection Study Rizikos sumažėjimas =24%
Reikšminga liekamoji kardiovaskulinė rizika pacientams, gydytiems statinais
The MRC/BHF Heart Protection Study 30
Placebas
Statinai 20
Rizikos sumažėjimas =24%
(p<0.0001)
19.8% statinais gydytų pacientų buvo reikšmingų KV įvykių per 5 metus
% Pacientai 10
Substantial residual cardiovascular risk in statin-treated patients
The MRC/BHF Heart Protection Study was one of the landmark trials that have established the place of statins in the management of hypercholesterolaemia. A population of 20,536 patients at high cardiovascular risk through the presence of coronary disease, other arterial disease or diabetes were randomly assigned to treatment with simvastatin or placebo for an average of 5 years.
The intervention was highly effective, with a significant reduction in the risk of cardiovascular events of 24%. However, a majority of cardiovascular risk remains unaffected after statin treatment, and almost 20% of patients in the statin group had a major cardiovascular event during the 5-year follow-up period.
Total cholesterol and LDL-C were markedly reduced by treatment with the statin (mean changes from baseline of –1.2 mmol/L [–46 mg/dL] and –1.0 mmol/L [–39 mg/dL], respectively). However, other lipid components, such as triglycerides of HDL-C impact importantly on cardiovascular risk and were changed only slightly in the study (mean changes from baseline of –0.3 mmol/L [–27 mg/dL] and 0.03 mmol/L [1 mg/dL], respectively).
We may need to look beyond effects on LDL-C to achieve greater results in the management of overall cardiovascular risk. 1 2 3 4 5 6
Stebėjimo metai
Heart Protection Study Collaborative Group, 2002
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.

12. Kodėl gydytojai negydo nutukimo?
Vaistai nekompensuojami
Sunku pakeisti elgesį
Nebuvo mokoma medicinos universitete
Tik pastaruoju metu įvertinta nutukimo rizika

13. Naujas požiūris gydant antsvorį ir nutukimą
Svoris
Pirmiausia svorio
korekcija
Dislipidemija Hipertenzija GTS

14. Nutukimo gydymo piramidė
Dieta
Fizinis aktyvumas
Gyvenimo būdo keitimas
Farmakoterapija
Chirurgija
Obesity treatment pyramid
The clinical approach to obesity can be viewed as a pyramid consisting of several levels of therapeutic options. All patients should be involved in an effort to change their lifestyle behaviors to decrease energy intake and increase physical activity. Lifestyle modification also should be a component of all other levels of therapy. Pharmacotherapy can be a useful adjunctive measure for properly selected patients. Bariatric surgery is an option for patients with severe obesity, who have not responded to less-intensive interventions. The number of obese patients who require a specific level of treatment decreases as one moves up the pyramid.

15. PSO rekomenduojama dieta
ANGLIAVANDENIAI : 50-60%
- pagrinde sudėtiniai angliavandeniai
RIEBALAI : 30%
- prisotinti 10%
- polinesotieji 10%
- mononesotieji 10%
- cholesterolis < 300 mg/day
BALTYMAI : 12-20%
NATRIS : < 6 g/dieną
- sergantys hipertenzija ir CD, < 3 g/dieną

16. Valios ugdymas

17. Alkoholis Alkoholis turi 7 kcal/g Alus 355 ml 160 kalorijų Vynas
Margarita
237 ml
270 kalorijų
Džinas su toniku
237 ml (džinas sudaro 51 ml)
190 kalorijų
1 taurelė likerio
60 ml
128 kalorijos
Energy content of alcoholic beverages
Alcohol intake can increase total energy intake because it provides 7 kcal per gram and often stimulates appetite. Alcohol consumption increases the number of calories in a diet and has been associated with obesity in both epidemiologic and experimental studies [1]. Therefore, ingestion of alcoholic beverages should be limited in patients trying to lose weight or maintain weight loss. The energy content of selected alcoholic beverages is shown on this slide. The total energy content (in kcal) of an alcoholic beverage can also be estimated by using the following formula: x proof of beverage x ounces of beverage.
National Institutes of Health, National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report. Obes Res 1998;6(suppl. 2):51S-209S.

18. Vaistai galintys sąlygoti svorio augimą
Psichotropiniai vaistai
Tricikliniai antidepresantai
Monoamino oksidazės inhibitoriai
Kai kurie SSRIs
Atipiniai antipsichotikai
Litis
Kai kurie antikonvulsiniai
-adrenerginių receptorių blokatoriai
Diabeto gydymui
Insulinas
Sulfonilšlapalo dariniai
Tiazolidinedionai
Aktyvus antiretrovirusinis gydymas
Tamoksifenas
Steroidiniai hormonai
Gliukokortikoidai
Gestagenai
Selected medications that can cause weight gain
Certain medications can cause weight gain and increase body fat, thereby making weight loss more difficult. This table presents a partial list of drugs and drug classes that contain medications associated with weight gain. These drugs differ in their propensity to increase body weight; some medications, such as the anticonvulsant valproic acid, can cause considerable weight gain of 15–20 kg, whereas other medications, such as the β-adrenergic receptor blocker propranolol, are associated with small and probably clinically insignificant weight gain. The mechanism responsible for medication-induced weight gain has not been carefully studied for most of these agents, but must be related to an increase in energy intake (e.g. antipsychotics and steroid hormones), a decrease in energy expenditure (e.g. β-adrenergic receptor blockers), a decrease in energy loss (e.g. decreased glucosuria from diabetes therapy), or a combination of these factors. Weight loss therapy can be facilitated by decreasing the dose or substituting the medication with another drug that has less weight gain potential, if possible.
Pijl H, Meinders AE. Bodyweight changes as an adverse effect of drug treatment. Drug Safety 1996;14:
SSRI=selective serotonin reuptake inhibitor

19. Gyvenimo būdo pakeitimas užtikrina ilgalaikį svorio sumažėjimą
Nieko nekeičiant
Laikantis dietos ir fiz. krūvio režimo
Svorio netekimas (%)
P <0.05
Dieta ir elgesį modifikuojantis gydymas
Long-term weight loss is improved with long-term maintenance therapy
Maintenance therapy is important for long-term weight management success after initial weight loss is achieved by diet and behavior therapy. In this study, Perri and colleagues [1] randomized obese subjects who lost weight after 5 months of diet and behavior modification therapy to “no maintenance” or a “maintenance program” that involved biweekly contact. At 1 year after initial weight loss was achieved, participants who received maintenance therapy maintained long-term weight loss, whereas those who did not receive maintenance therapy regained half of their lost weight.
Perri MG, McAllister DA, Gange JJ, et al. Effects of four maintenance programs on the long-term management of obesity. J Consult Clin Psychol 1988;56: 1 2 3 4 5 6 7 8 9 10 11 12
Laikas (mėn) 13 14 15 16 17
Perri et al. J Consult Clin Psychol 1988;56:529.

20. Fizinis aktyvumas

21. Vaistai nutukimo gydymui
“Daktare, ar nėra tokios vienos tabletės?”

22. (ir kiti rizikos veiksniai)
Kada ir kuo gydyti?
KMI
(ir kiti rizikos veiksniai)
Gydymas
(su gretutinėmis ligomis)
Farmakologinis
Chirurginis
≥ 40

23. FDA patvirtinti vaistai nutukimo gydymui
Generinis pavadinimas
Firminis pavad.
DEA vertinimas
Patvirtinta gydymui
Patvirtinimo metai
Orlistat
Xenical _
Ilgalaikis
1999
Sibutramine
Reductil IV
1997
Diethylpropion
Tenulate
Trumpalaikis
1973
Phentermine
Adipex, lonamin
Phendimetrazine
Bontril, Prelu-2
III
1961
Benzphetamine
Didrex
1960
Drugs approved by FDA for treating obesity
This table lists the medications approved by the United States Food and Drug Administration (FDA) for treatment of obesity; only sibutramine (Meridia) and orlistat (Xenical) have been approved for long-term use. All the approved medications act as anorexiants, with the exception of orlistat, which blocks the absorption of dietary fat. Anorexiants increase satiation (level of fullness, which regulates the amount of food consumed during a meal) or satiety (level of fullness after a meal, which determines frequency of eating), or both. Methamphetamine is also approved by the FDA for short-term use, but it is a DEA schedule II drug and should be avoided because of its abuse potential. Three anorexiant medications have been removed from the marketplace because of increased risks of either valvular heart disease (fenfluramine and dexfenfluramine) [1] or hemorrhagic stroke (phenylpropanolamine) [2] associated with their use.
Khan MA, Herzog CA, St Peter JV, et al. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med 1998;339:
Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000;343:

24. Sibutramino veikimo mechanizmas
 Sotumas
 Energijos netekimo sumažėjimas laikantis dietos
 Alkis
Rezistencija periferijoje ?
Širdis
Sibutramine is a novel agent for weight loss and maintenance.
It appears to act by:
Increasing satiety
Reducing hunger
Reducing the post-dieting decline in energy expenditure
In addition, because of its action involving the sympathetic nervous system, it might be expected that sibutramine would affect cardiovascular function, primarily heart rate and blood pressure.

25. Nutukimas didina simpatinį aktyvumą
Baroreceptoriai
Chemoreceptoriai
Metabareceptoriai
+++ +
Adipose tissue
Hipertenzija
Rezistencija insulinui
Organų-taik. pakenkimas
Leptinas?
GDS_ _TrofimukA_v7 25

26. Sibutraminas skirtingai veikia centrinį ir periferinį simpatinį aktyvumą
Baroreceptoriai
-blokada
“clonidine-like (-2)”
poveikis SNS
Stimuliuojami
periferiniai efektai
Adapted from Birkenfeld et al, Circulation 2002;106:

27. 6
Serotonino ir norepinefrino reabsorbcijos inhibitoriai: centrinis vs periferinis veikimas
Centr. veikimas
Pre-synaptinė
dalis
Post-synaptinė
dalis
Perif. veikimas
Į ‘ Clonidine-panašus (2)’ centrinis veikimas
Slopina norepinefrino reabsorbciją
Didina norepinefrino kiekį sinapsėje
Stimuliuoja pre-synaptinius 2-receptorius CNS neig. grįžt. ryšio principu
Mažina CNS simpatinę stimuliaciją
Mažina AKS, ŠSD & kontrakciją ir vazokonstrikciją
Didina norepinefrino ir serotonino koncentraciją
Veikiant per post-synaptinius -1, -1 ir -2 receptorius gaunamas efektas
Didina AKS, ŠSD & kontrakciją ir vazokonstrikciją
Didina energijos išeikvojimą
When a nerve impulse arrives at the pre-synaptic terminal of a neurone it causes a release of neurotransmitter into the synaptic cleft resulting in stimulation of receptors on the post synaptic membrane from where the nerve signal is perpetuated along the neurone. The neurotransmitter is removed from the synaptic cleft via an active reuptake mechanism. Additionally, the released transmitter is able to stimulate auto receptors on the pre-synaptic terminal which also assists in reducing further release of neurotransmitter. Therefore by blocking the active reuptake mechanism for the released neurotransmitter, sibutramine is able to prolong the action of the neurotransmitter in the synapse and therefore its activity at both pre and post synaptic receptors. In the CNS, the pre-synaptic effect lead overall to a reduction in sympathetic activity while in the periphery sympathetic activity is enhanced.
As we will see later this dual effect leads to the paradoxical effect we observe with sibutramine in patients with hypertension.
Based on this pharmacological effect what clinical effects do we see with sibutramine?

28. Kūno svorio pokytis (kg)
Gydymo Sibutraminu poveikis kūno svoriui, gydant pastoviai ir nepastoviai
Placebo
Nepastovus gydymas
Pastovus gydymas sibutraminu
Kūno svorio pokytis (kg)
Effect of continuous vs intermittent sibutramine therapy on body weight
The effectiveness of continuous versus intermittent sibutramine therapy in achieving weight loss was evaluated in a 48-week randomized, controlled trial in 1102 obese subjects [1]. Subjects entered a 4-week open-label run-in period during which they received 15 mg of sibutramine daily. Patients with a weight loss of at least 2% or 2 kg were randomized to receive sibutramine continuously (15 mg daily for 44 weeks), sibutramine intermittently (15 mg from weeks 1 through 12, 19 through 30, and 37 through 48, and placebo during the off-sibutramine weeks), or placebo. During the 44-week treatment period, overall weight loss was similar in patients receiving either continuous (3.8 kg; 4.0%) or intermittent therapy (3.3 kg; 3.5%) (P=0.28 continuous vs intermittent), whereas the placebo group gained weight (0.2 kg; 0.2%) (P<0.001 placebo vs either treatment group). Overall weight loss during the 48-week period was 7.9 kg and 7.8 kg in the continuous and intermittent groups, respectively, compared with 3.8 kg in the placebo-treated group. During intermittent therapy, weight increased rapidly each time active drug was changed to placebo and decreased when active drug was restarted. In addition, intermittent treatment was associated with less serious adverse events. The results from this study demonstrate that long-term treatment with intermittent sibutramine therapy can be just as effective as continuous therapy in achieving successful weight loss in those who have an initial positive response to sibutramine treatment.
Wirth A, Krause J. Long-term weight loss with sibutramine. JAMA 2001;286:
Pradinis
periodas 4 8 12 16 20 24 28 32 36 40 44 48
Laikas (sav)
Sibutramino dozė=15 mg/d.
Wirth and Krause. JAMA 2001;286:1331.

29. Sibutraminas ir visceraliniai riebalai: KT tyrimas L4-L5 slankstelių aukštyje
Visas abdominalinis
riebalinis audinys
Visceraliniai
riebalai
Poodiniai riebalai
% Sumažėjimas
1000
19%
17%
24%
750
cm2
500
Evidence from computed tomography studies show that fat loss with sibutramine occurs from the visceral compartment.
Van Gaal LF, Wauters MA, Peiffer FW, De Leeuw IH. Sibutramine and fat distribution: Is there a role for pharmacotherapy in abdominal/visceral fat reduction? Int J Obes Relat Metab Disord 1998; 22 (Suppl 1): S38-S40.
250
Prieš Po
Van Gaal LF, Int J Obes Relat Metab Disord 1998;22 (Suppl 1):S38-S41
***p < 0.001

30. Lipidų profilio pakitimai po 2 gydymo Sibutraminu metų (STORM)
Placebo (n=103)
Visi Sibutraminu gydyti ligoniai
(n=323)
Netekę >5%
svorio (n=235)
Netekę >10%
svorio (n=131) 25 15 5
Trigliceridai
LMTL-chol
% Pokytis
DTL-chol -5
These data from the STORM study confirm that the lipid effects are maintained in the long term (2 year data) and that the results are proportional to the degree of weight loss.
-15
-25
Abbott Laboratories data on file unpublished from STORM study

31. *P<0.001 lyginant su sibutramino grupe
2-metų gydymo Sibutraminu poveikis liemens apimčiai ir metaboliniams veiksniams (STORM)
Placebo
Gydyti Sibutraminu
20.7 20 -1
11.2 10
Vidut. % pokytis -2
-1.6 (-4.0 cm)
Vidut. pokytis (in.)
-3.75 -3
STORM: Reduced Waist Circumference Translates Into Improved Lipid Parameters Following Sibutramine Therapy
The ability of sibutramine to significantly decrease visceral adiposity and thus substantially lower triglyceride levels while raising HDL-cholesterol was demonstrated in STORM.
By enhancing the metabolic effects of diet, exercise, and behavior therapy, sibutramine specifically led to a mean reduction of 4 inches from the waist circumference versus 1.6 inches with placebo. The mean percentage of increase in HDL-cholesterol levels was 20.7% with sibutramine versus 11.2% with placebo. Triglyceride levels were lowered by 18.5% with sibutramine versus 3.75% with placebo.
Using risk equations based on the Framingham Heart Study, the investigators noted that the potential benefits of sibutramine on lipid abnormalities could confer cardiovascular benefits that would counteract any potential increases in blood pressure.
[[Reference James and Anderson]]
[[ Please note: Cannot verify statement regarding 22% visceral fat decrease in STORM, which was suggested by T. McDonnell. Another source available? If not, will have to delete. Add Van Gall reference from Int J Obesity.]]
-10 -4
-20
-18.5
-4.0 (-10.0 cm)
DTL-C*
TG*
Liemens apimtis
*P<0.001 lyginant su sibutramino grupe
James WPT, Lancet 2000; 356: Abbott Laboratories Data on File

32. Svorio sumažėjimas gydant sibutraminu, sergant 2 tipo diabetu
Kontrolė
Sibutraminas 15mg
(n=122)
Dieta 1
p<0.001
(n=114) -8
Svorio pokytis (%)
(n=65)
Sulfonilurea2
p<0.001
(n=69) -8
(n=68)
Metforminas3
(n=62)
p<0.001 -8 2 4 6 8 10 12
Mėn.
1. Kaukua JK, Pekkarinen TA, Rissanen AM.Int J Obes Relat Metab Disord 2004; 4: 600–5.
2. Serrano-Rios M et al Diabet Med. 2002; 19:
3. McNulty SJ et al Diabetes Care 2003; 26(1)

33. Mažėjant svoriui gerėja glikemijos kontrolė
Sib.
5-10%
Sib.
>10%
Placebo
-0.2
-0.22
-0.4
Change in HbA1c (mean)
-0.6
FDA kriterijus *
-0.8
-0.7 -1
* p <0.02
** p <0.0001
-1.2
-1.2 **
McNulty SJ, Ur E, Williams G for the Multicenter Sibutramine Study Group, Diabetes Care 26: , 2003

34. Sibutramine Cardiovascular OUTcomes Trial
Pirmas randomizuotas perspektyvinis tyrimas, kurio metu vertinama svorio netekimo ir palaikymo įtaka širdies ir kraujagyslių ligų (ŠKL) išeitims viršsvorį turintiems ar nutukusiems pacientams su padidinta ŠKL išsivystymo rizika.
Svorio korekcija apima svorio netekimą ir palaikymą, skiriant dietą, rekomenduojant didesnį fizinį aktyvumą gydant ir negydant sibutraminu
ŠKL išeitys - MI, insultas, širdies veiklos sustojimas po gaivinimo ir mirtis dėl ŠKL
The SCOUT trial is the first randomized trial to directly test the potential benefits of weight management on cardiovascular events in high risk overweight and obese patients.
Build 1: The SCOUT trial selects subjects at high risk (i.e., older overweight or obese patients) who have experienced a cardiovascular event already or have been diagnosed as having type 2 diabetes and another risk factor.
The specific events chosen as the trial’s endpoints are those selected in other cardiovascular outcomes trials and which are the biggest contributors to premature death and disability especially in the overweight and obese populations with pre-existing cardiovascular disease.
Torp-Pedersen et al. European Heart Journal doi: /eurheartj/ehm217

35. SCOUT tyrimas: apžvalga
European Countries
Belgium
Czech Republic
Denmark
France
Germany
Hungary
Italy
Poland
Portugal
Romania
Slovakia
Spain UK
Mexico
The study plan was to enrol 12,000 subjects to achieve 9,000 randomised over a period of 2 years based on an anticipated drop out rate of 25%. However, as you will see later, this percentage was in fact much lower. Over 300 centres across 16 countries were to participate in the study.
The aim was to complete the study when 2,160 specified cardiovascular outcome events had been reported and this was expected to occur approximately 3 years after the last subject was randomised.
In order to conduct this study it was important to select a high risk CV population of patients and the screening criteria were as follows:
Brazil
Australia
James WPT, Eur Heart J Supplement 2005: 7 (Suppl 7): L44-48

36. SCOUT tyrimas: vidutinis kūno svorio pokytis per pradinį 6-sav
SCOUT tyrimas: vidutinis kūno svorio pokytis per pradinį 6-sav. laikotarpį
Sav -6
Sav -4
Sav -2
Pradinis 1
Kūno svorio pokytis (kg) lyginant su pokyčiu po 6-sav -1 -2 -3 -4 -5
There was overall a steady reduction in weight over the 6 week lead-in period which is in keeping with previous results for treatment with 10mg of sibutramine.
Particularly encouraging is the degree of weight loss achieved, 2.2 kg, in a population containing a large percentage of diabetic subjects.
Build 1: Normally diabetic patients find it more difficult to lose weight than non-diabetic patients and yet they achieved similar weight loss to non-diabetics in this study.
Only 1171 (11%) of subjects either gained or failed to lose weight during the lead-in period -6
Svorio netekimas diabetu sergančių grupėje = 2.2kg -7 -8
Vidutinės reikšmės 5ta ir 95ta percentilės
Torp-Pedersen et al. European Heart Journal doi: /eurheartj/ehm217
Van Gaal et al IJO 2007;31:S168.Abstract T3:PO.254

37. SCOUT tyrimas: vidutinis liemens apimties ir kai kurių rodiklių pokytis per 6-sav. pradinį periodą2
1.5*** 1
Liemuo cm
Sist. KS mmHg
Diast. KS mmHg
ŠSD k/min
Pokytis -1
-1.0*** -2
As well as losing weight there was also a significant reduction in waist circumference of 2 cm.
As expected there was an increase in pulse rate of the order of 1.5 beats per minute again in keeping with previous data for sibutramine.
Interestingly there were median reductions in both systolic and diastolic blood pressure despite the rather modest degree of weight loss of 2.2 kg
Based on the previous hypothesis regarding the mechanistic effects of sibutramine on blood pressure, subjects were categorised according to their initial blood pressure and the data analysed for the effects of sibutramine.
-2.0*** -3
-3.0***
*** p<0.001 -4
Torp-Pedersen et al. European Heart Journal doi: /eurheartj/ehm217

38. Cochrane duomenų bazė: Sibutramino ilgalaikis efektas
RKT meta-analizė, Sibutraminas vs. placebo
3 tyrimai -- svorio netekimas per > nei 1 stebėjimo metus
2 tyrimai -- svorio palaikymas per 2 metus
Įtraukimas: suaug. KMI>30 ar KMI>27 + gretut. ligos
Neįtraukta: serg. CD ar blogai kontroliuojama AH
Rezultatai: 4.3 kg ( ) > svorio netekimas gydant sibutraminu
27% > pacientų išlaikė 80% pradinio kūno svorio per 2 metus gydant sibutraminu
Pašaliniai reiškiniai: nežymus ŠSD ir AKS padidėjimas
RKT – randomizuoti klinikiniai
tyrimai
Padwal, et al. Cochrane Database of Systematic Reviews, 2003.

39. Sibutraminas, arterinis kraujospūdis ir širdies susitraukimų dažnis
EU duomenų bazėje:
“Placebo-kontroliuojamuose klinikiniuose tyrimuose, gydant sibutraminu (dozė 1–30 mg), stebėtas sistolinio ir diastolinio kraujospūdžio padidėjimas 2–3 mmHg ramybės metu, ir širdies susitraukimų dažnio padidėjimas 3–7 k/min”

40. AKS ir ŠSD stebėjimas Pirmus 3 mėn.: kas 2 sav.
Tarp 4 ir 6 mėn.: kartą per mėn.
Po 6 mėn.: kas 3 mėn.
The next important issue is to undertake regular blood pressure and heart rate monitoring in all patients taking sibutramine.
In the first 3 months of treatment, monitoring is required every 2 weeks, with further monthly assessments during months 4-6 of treatment.
After this, monitoring should be undertaken every 3 months.
Sibutramine Summary of Product Characteristics (SmPC)

41. Kada nutraukti gydymą sibutraminu?
Jei ramybės ŠSD padidėja >10 k/min. ar Sist.KS/Diast.KS padidėja >10 mmHg 2 iš eilės einančių apsilankymų metu.
Jei AKS >145/90 mmHg dviejų iš eilės einančių vizitų metu, prieš gydymą buvus gerai hipertenzijos kontrolei.
Stebėti dėl progresuojančio dusulio, skausmo krūtinėje ar kulkšnelių edemos.
Finally, we should adhere to the accepted withdrawal criteria.
Sibutramine should be discontinued in patients experiencing a resting heart rate increase of more than 10 bpm or a rise in systolic or diastolic blood pressure of more than 10 mmHg at 2 consecutive visits.
Treatment should also be withdrawn in cases of previously well controlled hypertension who shift to a blood pressure of >145/90 mmHg at two consecutive visits, or in patients with signs of progressive dyspnoea, chest pain or ankle oedema.
Sibutramine Summary of Product Characteristics (SmPC)

42. Arterinis kraujospūdis ir pulsas po 1 gydymo metų sibutraminu pacientams su gerai kontroliuojama arterine hipertenzija
Placebo
Sibutraminas
Sist. KS pokytis (mm Hg)
+1.5
+2.7
Diast. KS pokytis (mm Hg)
-1.3
+2.0 *
Pulso dažnio pokytis (ts/min)
4.9 *
Išbraukimas dėl hipertenzijos (%)
1.4
5.3
Blood pressure and pulse rate after 1 Y sibutramine therapy in patients with controlled hypertension
The risk of adverse effects with sibutramine therapy on blood pressure and pulse rate are no greater in patients with controlled hypertension than in patients who do not have hypertension. This table shows results from the sibutramine weight loss study reviewed previously, in which obese patients with medication-controlled hypertension were randomized to treatment with sibutramine or placebo for 52 weeks [1]. Sibutramine-treated patients had a trend toward an increase in systolic blood pressure and a statistically significant increase in diastolic blood pressure (2.0 mm Hg) and heart rate (4.9 beats/min) compared with placebo-treated patients (-1.3 mm Hg and 0.0 beats/min; P<0.05). This increase in systolic and diastolic blood pressures is similar to that reported in normotensive obese subjects. The incidence of a clinically significant increase in blood pressure (defined as increase in blood pressure of >10 mm Hg at three consecutive clinic visits) was similar in both treatment groups. The most common adverse event leading to discontinuation among patients receiving sibutramine was hypertension, which was reported in 5.3% of patients treated with sibutramine compared with 1.4% of those receiving placebo. These data demonstrate that sibutramine can be used safely in obese patients with controlled hypertension.
McMahon FG, Fujioka K, Singh BN, et al. Efficacy and safety of sibutramine in obese white and African American patients with hypertension. Arch Intern Med 2000;160:
*P<0.05 vs placebo.
McMahon et al. Arch Intern Med 2000;160:2185.

43. Gydymo Sibutraminu pašaliniai reiškiniai
Pacientai (%)
Pašalinis reiškinys
Placebo
Sibutraminas
Galvos skausmas
18.6
30.3
Burnos džiūvimas
4.2
17.2
Vidurių užkietėjimas
6.0
11.5
Nemiga
4.5
10.7
Galvos svaigimas
3.4
7.0
Hipertenzija
0.9
2.1
Tachikardija
0.6
2.6
Dažnas širdies plakimas
0.8
2.0
Adverse effects of sibutramine therapy
In placebo-controlled trials, the most common side effects reported with sibutramine use were dry mouth, constipation, and insomnia, which were usually mild and transient [1,2]. Because of its noradrenergic action, sibutramine treatment is associated with a dose-related increase in blood pressure and heart rate [1,2]. A dose of 10 to 15 mg/d causes an average increase in systolic and diastolic blood pressure of 2 to 4 mm Hg and an average increase in heart rate of 4 to 6 beats/minute. Some patients experience much larger increases in blood pressure or heart rate and require dose reduction or discontinuation of therapy. The use of sibutramine is contraindicated in patients with poorly controlled hypertension, coronary heart disease, congestive heart failure, arrhythmias, stroke, severe renal or liver dysfunction, or concomitant monoamine oxidase inhibitor therapy.
Bray GA, Blackburn GL, Ferguson JM, et al. Sibutramine produces dose-related weight loss. Obes Res 1999;7:
Smith I, on behalf of the members of the Sibutramine Clinical Study 1047 Team and Goulder MA. Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity. J Fam Pract 2001;50:
Meridia™ Package Insert, 2001.

44. Koks žalos:naudos santykis?
Sibutraminas, gydant viršsvorį turinčius/nutukusius pacientus: pašaliniai reiškiniai/saugumas
Galvos skausmas, pykinimas, vidurių užkietėjimas, nemiga ir burnos džiūvimas
Nežymus padidėjimas:
Sist.KS ir Diast.KS (2–3 mmHg)
ŠSD (3-7 k/min.)
Nedidelio laipsnio Sist.KS ir Diast.KS sumažėjimas vidutiniškai sumažėjus kūno svoriui (>5%)
While the majority of side effects were of little clinical concern, the effects on the CV system did result in the regulatory authorities requesting the monitoring of BP in patients but its use was not contraindicated in patients with controlled blood pressure. In normotensive patients, mean blood pressure was increased by 2-3 mmHg and pulse rate by 3-7 bpm
The unanswered question was therefore – what is the overall effect of sibutramine induced weight loss on clinical endpoints such as CV events and mortality or progression to diabetes.
Koks žalos:naudos santykis?
Padwal R et al, 2006 The Cochrane Collaboration.
Sibutramine Summary of Product Characteristics

45. Kam skirti Sibutraminą?
Pasirengusiems ilgalaikiams pokyčiams
Sutinkantiems laikytis dietos ir fizinio krūvio režimo programos
Kuriems reikia pagalbos programai vykdyti
Nenaudojantiems kitų serotonerginių vaistų (prozac etc.)
Jei vargina didelis apetitas ir nuolatinis užkandžiavimas

46. Kaip skirti Sibutraminą ? Nicos nuorodos
Skiriamas kaip bendros svorio mažinimo strategijos sudedamoji dalis pacientams, kurių KMI > 27 esant gretutinėms ligoms ar > 30, nesant gretutinių ligų.
Pastovus stebėjimas.
Skirti ilgiau nei 4 savaites, kai svorio sumažėjimas per mėn. sudaro 2 kg, ilgiau nei 3 mėn., jei svoris sumažėja 5%.
Stebėti AKS ir pulsą.
Rekomenduojamas gydymo laikas 12 mėn.

47. Orlistatas apsaugo nuo riebalų įsisavinimo ir absorbcijos prisijungdamas prie gastrointestinalinių lipazių
Žarnų spindis
Mukozinė ląstelė
LIPAZĖ
LIPAZĖ TG
Orlistatas RR
Orlistat prevents fat digestion and absorption by binding to gastrointestinal lipases
Orlistat is a chemically synthesized hydrogenated derivative of lipstatin (a natural product of Streptomyces toxyricini). Orlistat binds to gastric, pancreatic, and carboxylester lipases in the gut lumen and blocks the digestion of dietary fat by preventing lipase from interacting with its lipid target [1]. Inhibition of fat digestion decreases mixed micelle formation and absorption of long-chain fatty acids, cholesterol, and certain fat-soluble vitamins. Orlistat does not affect the action of systemic lipases or lipases located in other organ systems because it is minimally (<1%) absorbed from the gastrointestinal tract.
Drent ML, van der Veen EA. Lipase inhibition: A novel concept in the treatment of obesity. Int J Obes Relat Metab Disord 1993;17:
LIPAZĖ
Tulžies rūgštys
Micelė
TG=triglyceride; MG=monoglyceride; FA=fatty acid.

48. Orlistatas dietinių riebalų absorbciją mažina maždaug 30%
Vidut. fekal. riebalai (g/dieną)
Orlistatas120 mg 3/kd 30 25 20 15 10
Fecal fat as an endpoint
Obese 1800 calories, 60 grams
120 mg tid
Rapid onset of effects and rapid cessation
Led to dose modelling 5 -5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Tyrimo dienos
Guerciolini, Int J Obesity 1997; 21 (Suppl. 3): S12-23 11

49. Ilgalaikis gydymo Orlistatu poveikis kūno svoriui
-4.1 kg
Placebo
Svorio pokytis (kg)
-6.9 kg
Effect of long-term orlistat therapy on body weight
This figure shows the results of a 4-year randomized controlled trial, conducted in over 3000 obese subjects, that compared orlistat therapy plus lifestyle intervention with placebo therapy plus lifestyle intervention [1]. The lowest body weight was achieved during the first year, and was greater in the orlistat-treated group (11% weight loss) than in the placebo-treatment group (6% weight loss). Subjects regained weight during the remainder of the trial, so orlistat-treated subjects had lost 6.9% and placebo-treated subjects had lost 4.1% of their initial body weight at the end of 4 years. Orlistat therapy also resulted in a 37% reduction in the cumulative incidence of new-onset type 2 diabetes, primarily by preventing the development of diabetes in patients who had impaired glucose tolerance.
Torgenson JS, Boldrin MN, Hauptman J, et al. XENical in the prevention of diabetes in obese subjects (XENDOS) study. Diabetes Care 2004; 27:
Orlistatas
P<0.001 vs placebo 52
104
156
208
Savaitės
Torgenson et al. Diabetes Care 2004;27:155

50. Ką gydyti Orlistatu? Kai reikia pagalbos programos vykdymui
Pasirengusius ilgalaikiams pokyčiams
Sutinkančius laikytis dietos ir fizinio krūvio režimo programos
Kai reikia pagalbos programos vykdymui
Kuriems netinka sibutraminas (depresija, išreikšta ŠKL, etc)
Kurie sutinka su “tam tikrais nepatogumais”

51. Kombinuotas gydymas 3 nedidelės apimties tyrimai
34 moterys po 1 gydymo sibutraminu metų (vidut. svorio sumažėjimas 11.6%) randomizuotos į dvi grupes: S+O ar S+placebo 16 sav. periodui
89 moterys randomizuotos į tris grupes: dieta+O, dieta+S, ar diet+O+S 6 mėn. periodui
86 pacientai randomizuoti į S, O, S+O, ar dietinę grupes 12 sav.
Gydant vien Sibutraminu gauti tokie pat rezultatai, kaip ir gydant kombinuotai & geresni nei gydant vien Orlistatu
Wadden et al. Obes Res, 2000.
Kaya et al. Biomed Phamacother, 2004.
Sari et al. Endocrin Res, 2004.

52. Vaistai svorio mažinimui
Vaistas Dozė Veikimas Pašaliniai reiškiniai
Sibutraminas 5, 10, 15 mg Norepinefrino, ↑ ŠSD ir AKS
(Reductil) Pradėti nuo 10 mg/d, dopamino ir didinti dozę iki 15 mg serotonino reabsorbcijos
ar mažinti iki 5 mg inhibitorius.
Orlistatas 120 mg Inhibuoja pankreatinę Mažėja riebaluose
(Xenical) 120 mg 3/d lipazę, mažina tirpstančių vitaminų
prieš valgius riebalų absorbciją absorbcija; liuosi viduriai ir “riebios
kelnaitės”.
The drugs used to promote weight loss have been anorexiants or appetite suppressants. Two new drugs are sibutramine (Meridia) and orlistat (Xenical). Sibutramine and orlistat are FDA-approved drugs for weight loss.
Very few trials longer than 6 months have actually been done with any of these new drugs.
These drugs are associated with adverse health effects, including an increase in heart rate and blood pressure for sibutramine and, for orlistat, a decreased absorption of fat-soluble vitamins.
Ephedrine, caffeine, and fluoxetine have also been tested for weight loss but are not approved for use in the treatment of obesity. Mazindol, phentermine, benzphetamine, and phendimetrazine are approved for only short-term use for the treatment of obesity.
Herbal preparations are not recommended as part of a weight loss program. These preparations have unpredictable amounts of active ingredients and unpredictable and potentially harmful effects.

53. Gydymas metforminu paskatina kūno riebalų persiskirstymą
Selektyvus visceralinių riebalų netekimas
Svoris (kg)
Kūno masės indeksas (Kg/m2)
Bendri kūno riebalai (L)
Bendri poodiniai riebalai (L)
Pilviniai poodiniai riebalai (L)
Visceraliniai riebalai (L)
Liesoji kūno masė
Pokytis nuo
pradinio
- 3.3
- 1.2
- 2.8
- 2.1
- 0.6
% sumažėjimas
nuo pradinio 4% 9% 7%
11%
15%
Be pokyčių p
reikšmė
0.006
0.014
0.025
0.013
0.01 NS
Metformin-induced alterations in body composition
Recent studies suggest that visceral fat is most strongly associated with insulin resistance and increased cardiovascular risk, while subcutaneous fat is associated with a lower risk of poor cardiovascular outcomes.
Seven obese type 2 diabetic patients (mean BMI 29 kg/m2) received their maximally tolerated dose of metformin for 6 months in this study. The amount of visceral and subcutaneous fat was measured in each patient using computed tomography and dual-energy x-ray absorptiometry techniques.
On average, body weight was reduced by 3.3 kg (p<0.008). However, a larger decrease in visceral fat was observed, compared with subcutaneous fat (mean reductions of 15.7% [p=0.01] and 7% [p=NS], respectively).
Metformin treatment is therefore associated with a redistribution of visceral fat that is consistent with its beneficial effects on insulin resistance and clinical outcomes.
Kurukulasuriya R, Banerji MA, Chaiken R, Lebovitz H. Selective decrease in visceral fat is associated with weight loss during metformin treatment in African Americans with type 2 diabetes [abstract]. Diabetes 1999;48: A315.
Vidutiniai dydžiai. Gydymo trukmė: 6 mėn.
Kurukulasuriya R et al. Diabetes 1999;48:A315

54. Metforminas, lyginant su kitais vaistas
150 moterų, KMI >30
Sibutramine 10 mg p/o 2/d (didesnė už įprastinę dozė)
Orlistat 120 mg p/o 3/d
Metformin 850 mg p/o 2/d
Visose grupėse – gyvenimo būdo keitimas
Nėra placebo grupės
6 stebėjimo mėn.
KMI ↓ %
Liemens apimties ↓ %
Sibutramine
13.57
10.43
Orlistat
9.09
6.64
Metformin
9.90
8.10
Gokcel A, et al. Diab Obes Metab 2002.

55. Vaisto parinkimas nutukimo gydymuiNE
Svarbi kaina?
Sibutramine kontraindikuotinas? NE
Sibutramine
TAIP
TAIP
Serga CD ar rezistencija insulinui?
Orlistat
TAIP NE NE
Gydomas metforminu?
Metformin
Yra depresija?
TAIP
TAIP/NE
Exenatide
Bupropion

56. 2 tipo cukrinis diabetas - multihormoninis sutrikimas: istorinė perspektyva
b ląstelės
1925
2000
1975
1950
a ląstelės
Atradimas
Insulino analogai
Insulino pompa
Žmogaus insulinas
Zinc insulinas
NPH insulinas
Insulinas
Amilinas
Amilino analogai
patvirtintas (2005)
Pramlintidas
Gliukagono
antagonistai
Gliukagonas
GLP-1
Exenatide
Sitagliptinas
(2005)
(2007)
GLP-1 analogai
Exendin-4 ir
L ląstelės
Major discussion point:
The hormonal management of diabetes is less than a century old, with the first use of insulin in 1922 and the discovery of glucagon in 1923.
It was not until the 1980s that glucagon-like peptide 1 (GLP-1) and amylin were identified.

57. β - ląstelių funkcija mažėja nežiūrint 2 tipo cukrinio diabeto gydymo
Progresuojantis β - ląstelių funkcijos
Mažėjimas dar prieš diagnozę
100
Ligos gydymo modifikavimas 80
Slide 13
Beta-Cell Function Declines Regardless of Intervention in Type 2 Diabetes1
This slide shows results from the UKPDS, which investigated beta-cell function of patients with type 2 diabetes who were still on their initial therapy—metformin, a sulfonylurea, or diet—at 6 years.
The trends show that beta-cell function, as measured by the homeostasis model assessment beta-cell function (HOMA-B) declined over time regardless of therapy.
Indeed these data can be extrapolated to show that the progressive loss of beta-cell function (dashed line) begins years before the diagnosis of type 2 diabetes mellitus is made.
For all patients, beta-cell function was assessed using HOMA-B, a mathematical formula that uses the fasting insulin and glucose measurements to assess the degree of beta-cell function (and insulin resistance) that would account for a given person’s set of fasting insulin and glucose levels. 60
β - ląstelių funkcija (%)* 40
Sulfonilkarbamidai 20
Dieta
Inkretinų funkcija
Metforminas –5 –4 –3 –2 –1 1 2 3 4 5 6
Metai po diagnozės
*Beta-cell function measured by homeostasis model assessment (HOMA).
Adapted from UKPDS 16 Group. Diabetes. 1995;44:1249–1258.
Reference:
1. UK Prospective Diabetes Study Group. U.K. Prospective Diabetes Study 16: Overview of 6 years’ therapy of type II diabetes: A progressive disease. Diabetes. 1995;44:1249–1258.

58. Iš kur kilo pavadinimas “INKRETINAI”?
“Hormonai, gaminami žarnyne, skatinantys insulino sekreciją priklausomai nuo gliukozės koncentracijos”
In ● cret ● in
Intestine Secretion Insulin
Major discussion point:
INtestine
SeCRETion
INsulin
Creutzfeldt W, Ebert R. New developments in the incretin concept. Diabetologia. 1985;28:
Creutzfeldt. Diabetologia. 1985;28:565.

59. Gliukozė veninėje plazmoje (mmol/l) Venous plasma glucose (mmol/l)
“Inkretinų efektas”
Sveiki (n=8)
Gliukozė per os (50 g/400 ml)
Izoglikeminė i/v gliukozė 20 20 * 15 15
Veikiant inkretinams po valgio išsiskiria 60% insulino
Gliukozė veninėje plazmoje (mmol/l)
Venous plasma glucose (mmol/l) 10 10 5 5
–10 –5 60
120
180
–10 –5 60
120
180 80
Normalus inkretinų veikimas 80 60 60
Diminished incretin effect
IR insulinas (mU/l) 40
IR insulin (mU/l) 40 20 20
–10 –5 60
120
180
–10 –5 60
120
180
Laikas (min)
Time (minutes)
*p0.05 vs. po valgio Adapted from Nauck M et al Diabetologia 1986;29:46–52.
References
Vilsbøll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia 2004;47:357–366. 
Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 2004;145:2653–2659.
Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004;287:E199–E206.
Nauck M, Stöckmann F, Ebert R et al. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986;29:46–52.

60. ©2005. American College of Physicians. All Rights Reserved.
GLP-1 veikimas
Stimuliuoja nuo gliukozės
priklausomą insulino sekreciją
Maistas…
Slopina gliukagono sekreciją
DISCUSSION POINTS:
Upon ingestion of meals containing carbohydrates and fats, GLP-1 is secreted from the L-cells in the intestine. This secretion of GLP-1 sets off a collection of actions which work in concert to help regulate glucose homeostasis:
Glucose dependent enhancement of insulin secretion
Suppression of inappropriately high glucagon secretion
Slowing of gastric emptying
Exogenous GLP-1 reduced food intake, and improved insulin sensitivity, in both animal studies and a 6-week study in patients with type 2 diabetes.
In animal studies, exogenous GLP-1 increased beta-cell mass through beta-cell proliferation and neogenesis.
SLIDE BACKGROUND:
[This is an animated slide]
Lėtina skrandžio evakuaciją
Iš žarnyno L-ląstelių
išskiriamas GLP-1
Mažina alkį
Didina jautrumą insulinui
llgalaikis efektas tiriant gyvūnus…
GLP-1:
Didina β-ląstelių masę
ir jų efektyvumą
Drucker DJ. Curr Pharm Des 2001; 7: Drucker DJ. Mol Endocrinol 2003; 17:
© American College of Physicians. All Rights Reserved.

61. GLP-1 insulinotropinis veikimas priklauso nuo gliukozės
Ca2+
Gliukozė
Nuo voltažo priklausomas
Ca2+ siurblys
K/ATP
siurblys
DISCUSSION
The combination of glucagon-like peptide 1 (GLP-1) activity and glucose-stimulated insulin secretion results in increased insulin secretion
The presence of the GLP-1-activated pathway delays the repolarisation of the membrane, allowing a longer period of calcium (Ca2+) influx
The increased concentration of intracellular Ca2+ results in even greater insulin release
BACKGROUND
The stimulatory action of GLP-1 on insulin secretion is glucose dependent and requires the presence of normal or elevated concentrations of the sugar
↑ATP/ADP
Ca2+
cAMP
ATP
Gliukozės pernešėjas
Insulino
išskyrimas
Insulino
granulės
GLP-1
receptorius
Kasos β ląstelė
Gromada J, et al. Pflugers Arch – Eur J Physiol. 1998;435: ; MacDonald PE, et al. Diabetes. 2002;51:S434-S442.

62. insulinas -ląst gliukozė GLP-1 GIP
skatina insulino sekreciją
-ląst
gliukozė
insulinas
GLP-1
GIP
Greitai inaktyvuoja dipeptidyl peptidazė IV
maistas

63. Atsparus degradacijai inkretinų mimetikas (GLP– 1)
Exenatide
Atsparus degradacijai inkretinų mimetikas (GLP– 1)

64. Exenatide Patvirtintas FDA: Vaistų klasė: Indikacijos gydymui: Dozė:
2005 m., balandžio 28 d.
Vaistų klasė:
Glucagon like peptide-1 analogas (GLP-1)
Indikacijos gydymui:
2 tipo CD gydymas pacientams, kurie gydomi:
Metforminu (MET)
Sulfonilkarbamidais (SK)
Kombinuotu gydymu (MET & SK)
Dozė:
5 mcg po oda 2 k/d
10 mcg 2 k/d po 1 mėn.
GLP-1: Most recognized incretin binds to specific receptors on beta cells to stimulate insulin release. Low GLP-1 in T2DM (impaired secretion of incretin hormones.
Short t1/2=<2 min
Degraded by dipeptidyl peptidase IV(DPP-IV)
Exenatide: resistant to DPP-IV inactivation
Metabolism- Minimal systemic; glomerular filtration w/ proteolytic t 1/ hours Peak plasma- 2.1 hours
Excretion: Urine (majority of dose)
Kinetics independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 hours post-dose. 64

65. Gyvenimo būdas + metforminas
ADA/EASD nuorodos (2006)
Gyvenimo būdas + metforminas
Pridėti SK
+ bazinį insuliną
Pridėti glitazoną
Jei HbA1c  7%
Toliau intensyvinti insuliną ar + bazinį insuliną + metforminą ± ↑jautrumą insulinui
Intensyv. insuliną
Pridėti
Exenatide
Guidelines support an early, intensive approach to the management of Type 2 diabetes.
The American Diabetes Association and the European Association for the Study of Diabetes (ADA–EASD) have produced a consensus algorithm for the management of hyperglycaemia in Type 2 diabetes.
This emphasises the value of early and intensive treatment and proposes that an HbA1c  7% “should serve as a call to action to initiate or change therapy”. Treatment should aim to bring glycaemic control “as near to normal as possible” (e.g. HbA1c < 6%) where practical, appropriate and free of significant hypoglycaemia or at a minimum decrease it to < 7% for most patients.
The structure of the algorithm and selection of therapies takes into account the long-term progressive nature of Type 2 diabetes. The algorithm emphasises:
Achievement and maintenance of normal glycaemic goals
Initial therapy with lifestyle intervention and metformin
Rapid addition of medications, and transition to new regimens, when target glycaemic goals are not achieved or sustained
Early addition of insulin therapy in patients who do not meet targets.
Link to next slide:
Let’s summarise what we have learned
Reference
Nathan DM et al. Diabetes Care 2006; 29: 1963–1972.
Pridėti Exenatide
Bailey C et al. Br J Diabetes Vas Dis 2006; 6: 147–148.

66. Rizikos veiksnių pokytis (%) lyginant du exenatide gydymo būdus su pradiniu lygiu
Rizikos veiksnys
Exenatide LAR
1 k/sav (%)
Exenatide
2 k/d (%)
Bendr. cholesterolis (mmol/L)
-0.31
-0.10
DTL (mmol/L)
-0.02
-0.03
MTL (mmol/L)
-0.13
+0.03
Sist. AKS (mm Hg)
-4.7
-3.4
Diast. AKS (mm Hg)
-1.7
Svoris (kg)
-3.7
-3.6
Drucker DJ et al. Lancet 2008;available at: 66

67. REZIUME Gydant vaistais stebimas vidutinis svorio sumažėjimas
Vaistai nutukimo gydymui nepakeičia dietos ir fizinio aktyvumo
Nutraukus gydymą dažnai svoris vėl didėja
Dauguma vaistų nutukimui gydyti nekompensuojami
Vaistas
Svorio netekimas
Sibutramine
4-5 kg
Phentermine
3-4 kg
Orlistat
2-3 kg
Metformin
2 kg
Exenatide
Bupropion
Fluoxetine
Mixed
Topamax
6-7 kg
Rimonabant

68. Amilino analogas Symlin (pramlintide)
Sintetinis β – ląstelių hormono analogas
Mažina gliukagono sekreciją po valgio
Didina sotumą, lėtina skrandžio evakuaciją
Kontraindikuotinas esant gastroparezei
Gali sukelti hipoglikemiją

69. (vaistas neskiriamas) Pramlintide: Effects on weight
Pramlintide: poveikis svoriui
Segantys 2 tipo diabetu
Dozės
nustatymas
Stebėjimas
(vaistas neskiriamas)
Dozės palaikymas
Svorio
Pramlintide: Effects on weight
Aronne et al conducted a randomized, double-blind, placebo-controlled weight-loss trial of pramlintide in 204 obese subjects (BMI kg/m[2]).
The study design consisted of a 1-week placebo lead-in, a 4-week nonforced dose escalation phase (during which pramlintide was initiated at 60 mcg tid and increased every 3 days up to a maximum of 240 mcg tid), a 12-week maintenance phase (during which patients received either 120, 180, or 240 mcg tid, based on the dose achieved during the escalation phase), and finally an 8-week nontreatment follow-up.
At week 16, the placebo-corrected weight loss in the intention-to-treat (ITT) population was 6 lbs (using LOCF).
Laikas (sav)

70. Svorio mažėjimo reikšmė rizikos veiksniams
HbA1c
Arter. KS
Bendras Chol
DTL Chol
Trigliceridai 1 1 2 2 3 3 3 3
Impact of weight loss on risk factors
Weight losses of 5%-10% have been shown to have a significant impact on several aspects of the metabolic syndrome, including well-recognized risk factors for cardiovascular disease and diabetes. For example:
Wing and colleagues at Brown University evaluated the effect of modest weight loss in 114 patients with type 2 diabetes. Those who lost 5% or more of their baseline weight showed statistically significant decreases in serum HbA1c levels [4].
The Trial of Antihypertensive Interventions and Management Study found that weight losses of 5% or more produced reductions in diastolic pressure that were equivalent to those produced by a single dose of antihypertensive medication [3].
Numerous studies have shown that weight losses of 5%-10% improve total cholesterol, LDL-to-HDL ratio, and the ratio of total-to-HDL cholesterol [1]. In one study, weight reduction of just 5.8% was associated with a 16% reduction in total cholesterol, an 18% increase in HDL cholesterol, and a 12% decrease in LDL cholesterol [1]. More recently, Ditschunheit and colleagues documented significant decreases in total cholesterol, triglycerides, and VLDL in obese patients with baseline hyperlipidemia who maintained a weight loss of 7.6% [2].
Blackburn G. Ob Res 1995;3(Suppl2):211S-216S.
Ditschunheit HH, et al. Lipoprotein responses to weight loss and weight maintenance in high-risk obese subjects. Eur J Clin Nutr 2002;56:
Mertens IL, Van Gaal LF. Overweight, obesity, and blood pressure: The effects of modest weight reduction. Ob Res 2000;8(3):
Wing RR, et al. Long-term effects of modest weight loss in Type 2 diabetic patients. Arch Intern Med 1987;147: 4
1. Wing RR et al. Arch Intern Med. 1987;147:
2. Mertens IL, Van Gaal LF. Obes Res. 2000;8:
3. Blackburn G. Obes Res. 1995;3 (Suppl 2):211S-216S.
4. Ditschunheit HH et al. Eur J Clin Nutr. 2002;56:

71. Svorio pokyčių įtaka Apnea- Hypopnea Indeksui (AHI)
AHI vidut. pokytis (atvejai/val.)
Effect of weight change on apnea-hypopnea index (AHI)
Overweight and obesity are associated with impaired pulmonary function, obstructive sleep apnea, and the obesity hypoventilation syndrome. Each of these conditions improves with weight loss. This figure shows the relationship between weight change and the apnea-hypopnea index (AHI; the number of apnea and hypopnea events per hour of sleep) in 690 middle-aged men and women participating Wisconsin Sleep Cohort Study [1]. All subjects were followed longitudinally for 4 years. The data demonstrated that changes in AHI were related in a dose-response fashion to changes in body weight. A 10% weight loss was associated with a 26% decrease in the AHI, whereas a 10% weight gain was associated with a 32% increase in the AHI. Furthermore, a 10% increase in weight was associated with a sixfold increase in the odds of developing moderate-to-severe sleep-disordered breathing, defined as an AHI 15 events per hour of sleep. Improvements in sleep apnea and obesity hypoventilation are maintained with persistent weight loss, but relapse occurs in those who regain lost weight.
Peppard PE, Young T, Palta M, et al. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA 2000;284:
-20 to <-10 (n=22)
-10 to <-5 (n=39)
-5 to <+5 (n=371)
+5 to <+10 (n=179)
+10 to +20 (n=79)
Svorio pokytis (%)
Peppard et al. JAMA 2000;284:3015.

72. Elgesio pokyčių, dietos ir medikamentų poveikis gydant nutukimą
Tik vaistas
Vaistas ir elgesio pokyčiai *
Svorio pokytis (%) *
Vaistas, elgesio pokyčiai ir dieta
Additive effects of behavior and diet therapy with pharmacotherapy for obesity
The use of pharmacotherapy alone is not as effective as pharmacotherapy given in conjunction with a comprehensive weight management program. The effect of adding behavior modification therapy and a portion-controlled diet with meal replacements to the pharmacologic treatment of obesity were compared in a 1-year study of 53 obese women randomized to 3 treatment groups: (1) medication alone (sibutramine 10–15 mg daily), (2) medication plus behavior modification therapy, or (3) medication plus behavior modification plus a 1000 kcal/d portion-controlled diet that consisted of 4 servings daily of a nutritional supplement and an evening meal of a frozen food entrée, a green salad, and a serving of fruit (combined treatment). All groups were prescribed a low-calorie diet and regular exercise regimen. Maximum weight loss was achieved by 6 months in all groups, and was significantly different between groups. At 12 months, subjects in the medication-alone group lost significantly less weight (4.1% of initial body weight) than the medication plus lifestyle group (10.8%) or the combined treatment group (16.5%); P<0.05 for both comparisons. In addition, after 1 year, more subjects in the two groups that involved lifestyle modification lost ≥5% or ≥10% of their initial body weight compared with subjects treated with medication alone (P<0.05 for both comparisons). These results suggest that drug treatment for obesity should only be provided in conjunction with other standard weight management approaches; drug treatment alone exposes patients to the full risks and costs of treatment without the full benefits.
Wadden TA, Berkowitz RI, Sarwer DB, et al. Benefits of lifestyle modification in the pharmacologic treatment of obesity. A randomized trial. Arch Intern Med 2001;161: 2 4 6 8 10 12
Laikas (mėn.)
*P<0.05 vs tik gydymas vaistais.
Wadden et al. Arch Intern Med 2001;161:218.