~Weight Loss Strategies Update 2006, Part 2

Drug Therapy for Obesity

Sibutramine. Sibutramine helps control feelings of hunger and appetite by regulating neurotransmitters involved in energy intake and expenditure. Sibutramine increases signal transmission between nerves in the central nervous system (CNS).

Sibutramine has demonstrated energy-producing (thermogenetic) effects in animal studies (Connoley et al 1999). Obese Zucker rats treated with 10 mg/kg of sibutramine were found to consume smaller amounts of carbohydrates and fats (LeBlanc et al 2003), resulting in both increased energy expenditure and decreased body weight (Casado et al 2003). Most interestingly, sibutramine targets a type of fat known as “brown” fat. “Brown” fat activation is thought to allow more calories to be burned than stored (Giordano et al 2002).

In a 24-week clinical study consisting of 1047 patients treated with varying doses of sibutramine or a placebo, sibutramine demonstrated dose-responsive weight loss ( Weintraub et al 1991; Bray et al 1996; Hanotin et al 1998; Bray et al 1999). Even intermittent sibutramine treatment was found to reduce body weight (Wirth et al 2001).

A 2004 study of obese patients with type 2 diabetes found treatment with sibutramine was associated with significant reductions in body fat mass and weight. Significant improvements in plasma glucose control, plasma lipids, and markers of insulin resistance were also observed (Tankova et al 2004).

Another study of obese patients treated for 12 months with a combination of sibutramine and a low-calorie diet demonstrated significant improvements in glucose tolerance, insulin sensitivity, and some lipid levels (Sabuncu et al 2004). Further, sibutramine, when combined with metformin, was also shown to be a useful adjunctive treatment for obese individuals with type 2 diabetes mellitus (McNulty et al 2003).

Sibutramine is generally well tolerated. However, safety concerns have arisen regarding possible increased heart rate (5–6 beats per minute increase) and blood pressure (1–2 mm Hg increase) (de Simone et al 2005; Gaciong et al 2005; Faria et al 2005; Jordan et al 2005). Individual response to sibutramine may vary; therefore, blood pressure and heart rate should be monitored carefully.

Sibutramine should not be taken with other centrally acting antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, ergotamine derivatives, opiates, herbs such as St. John's wort, supplement precursors to serotonin (e.g., L-tryptophan), and certain other medications because of the very rare but potential risk of serotonin syndrome (Trakas et al 2000; Giese et al 2001).

Orlistat. Orlistat is an inhibitor of intestinal lipase, an enzyme involved in the breakdown of dietary fat. At a therapeutic dose of 120 mg three times daily with main meals, orlistat inhibits the absorption of approximately 30 percent of the dietary fat ingested. Based on a weight-reduction diet of about 2200 calories a day, this would amount to a 200-calorie reduction in total caloric intake.

Animal studies have demonstrated orlistat'sability to inhibit absorption of fat regardless of the type of fat (e.g., saturated fat, polyunsaturated fat) (Porsgaard et al 2003), as well as the absorption of triglycerides (Isler et al 1995). Experiments in mice suggest that orlistat treatment also reduce interest in consuming dietary fat (Ackroff et al 1996). Further, in rats, the use of orlistat has demonstrated decreased atherosclerosis in the aorta (Ueshima et al 2004).

Clinical studies with orlistat have produced positive results. In double-blind, placebo-controlled, parallel-group randomized studies, a total of 171 subjects received oral daily doses that ranged from 30 to 1200 mg orlistat or a placebo three times a day for 9 to 10 days, resulting in a steep dose-response up to approximately 400 mg/day (Zhi et al 1994). Further, early dose-ranging trials showed that an additional weight loss of 1.75 kg with 360 mg a day of orlistat (120 mg three times daily) was observed in a 12-week period (Drent et al 1995).

A 2004 double-blind study showed that orlistat combined with a reduced-calorie diet produced weight loss and improvements in risk factors in overweight and obese patients with poorly controlled type 2 diabetes, hypertension, or hypercholesterolemia. (Guy-Grand et al 2004). A prospective, multicenter, open-label, randomized, controlled study showed that orlistat modified several cardiovascular risk factors in patients with both metabolic syndrome and type 2 diabetes (Didangelos et al 2004).

The Xenical in the Prevention of Diabetes in Obese Subjects trial (a four-year study involving more than 3000 patients randomized to either orlistat 120 mg three times daily or placebo) showed that orlistat treatment resulted in a greater reduction in the incidence of type 2 diabetes over four years and produced greater weight loss in a clinically representative obese population (Torgerson et al 2004).

Orlistat is generally well tolerated, although side effects can include flatulence and frequent loose stools but not frank diarrhea or intestinal malabsorption (Harp 1999). Consistent with orlistat's mechanism of action, malabsorption of fat-soluble vitamins is a potential risk (Cahill et al 1999).

A Prescription Drug That Causes Weight Loss... and Extends Life Span

Metformin is a prescription drug used to treat type 2 diabetes. Published research shows that it also helps nondiabetics lose weight (Paolisso et al 1998) . Metformin reduces the release of glucose (sugar) stored in the liver as glycogen. This prevents blood glucose levels from rising too high, so the body does not need to produce as much insulin (Davidson et al 1997; Maggs 1997; Pugh 1997) . Metformin also prevents some of the detrimental effects associated with normal aging (Kiho et al 2005). Phenformin, a similar drug, extended the life span of mice in a Russian study (Anisimov et al 2003).

In women, a common cause of obesity is polycystic ovary syndrome, which is characterized by high blood levels of insulin. Metformin helps women with polycystic ovary syndrome lose weight (Velazquez et al 1997; Holte et al 1998; Mauras et al 1998; Morin-Papunen et al 1998; Nestler et al 1998a,b).

Metformin can be used with relative safety to lose weight (Mogul et al 2003). Consider consulting your physician about taking metformin. A typical dose is 500 mg three times a day, a few minutes before meals. Metformin is not recommended for individuals who have kidney disease, heart failure, or any medical condition that could make blood acidic (Bralow et al 2004). Consult your physician about the appropriateness of combining metformin with any of your medications. Nausea or diarrhea may occur when using metformin. Carbohydrate Misconceptions

Over the past few years, the idea that carbohydrates are responsible for obesity has gradually seeped into our national diet dialogue. As a result, many weight-conscious people cut out whole fruits from their diet, thinking that fruits contain too many carbohydrates. This carbohydrate-restriction philosophy is due to a misunderstanding of the role of insulin and the metabolic dysfunction that accompany weight gain and aging. Carbohydrate restriction is not a good approach to sustained weight loss and good health.

Obtaining dietary carbohydrates from foods (e.g., vegetables, whole fruits, and whole grains) is an important component of an effective anti-aging weight-management program. What's important to understand, however, is that not all carbohydrates are created equal. Complex carbohydrates, such as those found in leafy vegetables and whole grains, are an important part of a healthy diet. They are absorbed slowly and do not cause rapid increases in blood sugar levels.

To better monitor the kind of carbohydrates we eat, it's helpful to understand the concepts of “glycemic index” and “glycemic load.” The glycemic index is a measure of how much insulin a particular food will stimulate based on its carbohydrates. The glycemic load, which is based on the actual impact that typical meals have on blood glucose levels, is probably a better indicator because not all foods with a high glycemic index actually stimulate the rapid release of insulin (watermelon, for instance). Once again, foods with a high glycemic load tend to stimulate overproduction of insulin and should be avoided.

Table 1: Glycemic Index and Glycemic Load

Comparison of Foods with High and Low Glycemic Index

High Glycemic Index + High Glycemic Load

Low Glycemic Index + Low Glycemic Load

Glycemic Index*

Glycemic Load*

Glycemic Index*

Glycemic Load*

Instant rice**

91

24

Popcorn

72

8

Baked potato**

85

20

Watermelon

72

4

Corn Flakes ®

84

21

Carrot

71

4

Corn Chex ®

83

21

Ice cream

62

8

Pretzels

83

16

Oat bran, raw

50

2

Corn Pops ®

80

21

Green peas

48

3

Doughnut

76

17

Grapes

43

7

French fries

75

22

Orange

42

5

Bread stuffing

74

16

Apple

40

6

Cheerios ®

74

15

Strawberries

40

1

Kaiser rolls

73

12

Fish fingers

38

7

Bagel

72

25

Apple

36

8

White bread

70

21

Pear

33

4

Pancakes

67

39

Yogurt, low fat

31

9

Cranberry juice cocktail

68

24

Lentils

29

5

Fanta ® Orange soft drink

68

23

Peach

28

4

Mars bar

65

26

Milk

27

3

Rye bread

65

20

Plum

24

3

Sweet corn

60

20

Kidney beans

23

6

Macaroni and cheese

64

32

Cherries

22

3

Sushi

52

19

Cashew nuts, salted

22

3

Orange juice

52

12

Peanuts

14

1

Linguini

48

23

Broccoli

* Glycemic index and load can vary based on brand or a particular lot of a food or beverage.

** Glycemic load calculation is based on differing quantities of each food group.



Continued . . .


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