THERAPY 13

Orlistat puts the squeeze on obesity

-Andy Bond-

Obesity is linked with a range of other cardiovascular disease risk factors, including dyslipidaemia, insulin resistance, type 2 (non-insulin-dependent) diabetes mellitus and hypertension. Orlistat ['Xenical'; Hoffmann-La Roche) is a novel non-systemically acting anti-obesity agent that inhibits gastrointestinallipases and prevents the absorption of about one-third of dietary fats. Results from the orlistat phase m clinical research programme, presented at the International Congress on Vascular Disease Prevention [Glasgow, UK; May 1998], suggest that obese patients treated with orlistat for 1 year achieve clinically significant weight loss and show marked improvements in several cardiovascular risk factors.

The effect of 1 year of orlistat treatment on weight loss in obese patients was reported by Professor Luc Van Gaal from the University Hospital Antwerp, Edegem, Belgium. He presented data from a pooled analysis of 5 large, multicentre, randomised, double-blind, placebo-controlled trials conducted in Europe and the US.

What's on the menu? Each of the 5 studies involved a 4-week, single­

blind, lead-in period. During this time, all patients received placebo and were placed on a mildly hypo­caloric diet (500-800 kcal daily deficit) designed to provide 30% of calories as fat. On completion of this lead-in period, patients were stratified according to weight loss (~ 2kg or > 2kg) and randomised to receive orlistat 120mg 3 times daily or placebo for 1 year. Patients continued with the hypocaloric diet during the double-blind treatment period. In the 2 studies conducted in the US, patients also participated in a weight reduction behaviour modification programme.

A total of 1561 obese patients (BMI 2843 kglm2)

who were randomised to receive orlistat and 1119 who received placebo were evaluable for intent-to-treat analysis. The majority of patients were Caucasian women aged 40-65years.

Oinically meaningful results After I year of treatment, orlistat recipients had

lost significantly more weight than placebo recipients (9.2 vs 5.8% of initial bodyweight, respectively). Also, a significantly greater proportion of orlistat, compared with placebo, recipients lost> 5% (70 vs 52%, respectively) or >10% (42 vs 23%, respectively) of their initial bodyweight. Modest weight loss of ~ 5% is associated with clinically meaningful improvements in cardiovascular disease risk profiles, commented Professor Van Gaal.

Almost twice as many orlistat recipients. compared with placebo. recipients shifted from an obese category (BMI of ~ 30 and < 35) at randomisation to a pre-obese status (BMI of < 30) after 1 year of treatment (61 vs 36% of patients, respectively).

Measuring the success Recipients of orlistat also achieved a significantly

greater reduction in waist circumference (an indicator of abdominal visceral obesity) than placebo recipients (-6.6 vs 4 .lcm. respectively). This is important. as the accumulation of abdominal visceral fat is a major cardiovascular disease risk factor.

1173-832419811145-000131$01.00° Adl. InWMtlonal LlmIt8d 11K18. All rlghta .--we:!

Quality of life during treatment was also con­sidered by Professor Van Gaal, who said that orlistat-treated patients reported a greater decline in overweight distress, less depression and more satisfaction with treatment than placebo recipients.

Lipid profiles improved Compared with placebo, orlistat significantly

improved several lipid parameters, according to additional data obtained from the pooled analysis of studies said Dr Michael Davidson from the Chicago Center of Clinical Research, Illinois, US .

Similar improvements in serum lipids occurred for all patients during the 4-week placebo lead-in period. However, compared with placebo recipients. orlistat recipients had significantly greater improvements in total cholesterol and LDL-cholesterollevels, LDL:HDL ratio, and lipoprotein(a). apolipoprotein A-I and apolipoprotein B levels after I year of treatment [see table].

Effects of orlistat on lipid profiles after 1 year's treatment

Mean c:hange Lipid parameter from value at rllndomillation

Orllw.t Placebo recipients recipients

Total cholesterol (mean percentage change)

-1 .98 +4.60

LDL-choIesterol (mean percentage change)

-423 +4.n

LOL:HDL ratio (mean percentage change)

-0.37 ~.20

Trlglycertdes (mean percentage change)

+1.34

Upoproteln(a) (m!¥L)

+11.72

ApoIipoprotein A·1 (mgll.)

+40.14

"NS = not significant

+2.87

+15.18

+70.65

+72.24

p value

<0.001

< 0.001

< 0.001

NS'

0.079

0.005

<0.001

In the subgroup of patients who had raised LDL-cholesterol values (~ 3.362 mmollL) at randomisation, more than twice as many orlistat compared with placebo recipients had normal LDL-cholesterollevels after I year (32 vs 14% of patients, respectively). said Dr Davidson.

Inpharma-11 JulllKl8 No. 1145

14 THERAPY

Conversely, significantly more placebo than orlistat recipients moved from a normal LDL-cholesterol level to an elevated value after 1 year (25 vs 12% of patients, respectively).

Dr Davidson highlighted the finding that orlistat had a beneficial effect on total and LDL-cholesterol levels that was independent of the effect on weight loss. This is likely to be as a direct result of the inhibition of fat absorption by orlistat.

BP effects additional Orlistat also had a favourable impact on BP in

patients with raised BP levels. Patients with elevated diastolic BP (~ 90mm Hg) at baseline had significant reductions in BP with orlistat, compared with placebo administration (reductions of 7.9 vs 5.5nun Hg, respectively). Similarly, systolic BP was significantly lowered in orlistat, compared with placebo, recipients who had raised (~ 140mm Hg) baseline levels (reductions of 10.9 vs 5.lmm Hg, respectively).

Glycaemic control enhanced Several glycaemic parameters were improved

with orlistat treatment, according to Dr Hermann Toplak from the Medizinische Klinik, Graz, Austria. In a 2-year study of obese non-diabetic patients, orlistat significantly prevented the development of impaired glucose tolerance (IGT) and type 2 diabetes, as diagnosed by oral glucose tolerance test (OGTT) status.

Among patients with normal OGTT status at baseline, 12.4% of placebo recipients developed IGT and a further 1.5% were diabetic after 2 years. In comparison, only 6.2% of orlistat recipients had IGT and none were diagnosed as having type 2 diabetes. In addition, the progression of IGT to type 2 diabetes was reduced by over 75% with orlistat, compared to placebo, therapy.

Control in diabetes possible?

Orlistat also offers potential benefits in the management of obese patients with type 2 diabetes, said Dr Toplak.

Patients with diabetes have greater difficulty in achieving weight loss than non-diabetic patients. However, in a I-year study of> 300 obese patients with type 2 diabetes controlled with sulphonylureas, twice as many orlistat compared with placebo recipients achieved a clinically significant weight loss of> 5% (52 vs 26% of patients, respectively).

Orlistat recipients had significant improvements, compared with placebo recipients, in fasting blood glucose levels (-0.02 vs 0.54 mmollL, respectively) and glycosylated haemoglobin (-0.2 vs 0.3%; p<0.05, respectively). In addition, orlistat recipients were able to reduce their dosage of oral hypoglycaemic medication to a greater extent than placebo recipients (-23 vs -9%, respectively), added Dr Toplak.

Straining to find adverse effects

Orlistat has been well tolerated in all clinical studies. In general, its tolerability profile is com­parable to that of placebo, with the exception of an increase in certain gastrointestinal events. These adverse events, which usually occurred early during

Inpharrna- 11 Jul 19118 No. 1145

the treatment period, included oily spotting, faecal urgency and flatus with discharge. These effects are viewed as a predictable consequence of orlistat's mode of action and were generally transient and of only mild-to-moderate intensity.

IOO6l21M

~ Editorial comment: Orlistat was launched in its first market, New Zealand, last month [see Inpharma 1143: 22,27 June 1998; 800685788}.

1173-832419811145-000141$01 .r:xfO "dl.lnternatlonal Limited 19118. "II rlgtrt.....weI