Resolution of Metabolic Syndrome & Morbid Obesity Surgery

George S.Ferzli, M.D., Benjamin Chandler, Giancarlo Cires, M.D. , Rosemarie E.Hardin, M.D

Metabolic Surgery Symposium

New Mexico, 2007

Metabolic Syndrome

Also Known as:1.Syndrome “X”2.Insulin Resistance Syndrome3.Reaven’s Syndrome4.Deadly Quartet 5.CHAOS

Coronary Artery DiseaseHypertensionAdult Onset DiabetesObesityStroke

History1947: Dr.Jean Vague; made observation that upper body obesity predisposed to diabetes, Atherosclerosis, gout and calculi

1967: Avogaro & Crepaldi; described 6 moderately obese patients with diabetes hypercholesterolemia and marked triglyceridemia, all of which improved with a Hypocaloric, low carbohydrate diet

In 1977: Haller used the term “metabolic syndrome”: obesity, diabetes mellitus, hyperlipoproteinemia, hyperuricemia and steatosis hepatitis when describing the additive effects of risk factors on atherosclerosis

In 1977: Gerald B. Phillips; developed the concept that Risk factors for myocardial infarction concur to form a “constellation of abnormalities” : glucose intolerance, hyperinsulinemia,hyperlipidemia and hypertension is associated with heart disease and obesity MUST BE LINKING FACTOR

1988: Gerald M. Reaven proposed insulin resistance as the linking factor and named the constellation of abnormalities Syndrome X

X

Prevalence

Signs & Symptoms

• Fasting hyperglycemia

• Hypertension

• Central obesity / “apple-shaped adiposity”

• Decreased HDL cholesterol

• Elevated triglycerides

• Elevated uric acid levels

Definition

• World Health Organization (WHO):– Requires presence of diabetes mellitus,

impaired glucose tolerance, impaired fasting glucose or insulin resistance and two or the following:

• Blood pressure > 140/90• Dyslipidemia: Triglycerides > 1.695 mmol/L, HDL<0.9mmol/L

(male) and <1.0 (female)• Central obesity: waist:hip ratio > 0.90(male), >0.85(female)

and/or body mass index >30 kg/m2

• microalbuminuria

Definition

• European Group for the Study of Insulin Resistance (EGIR)– Requires insulin resistance and two or more of

the following:• Central obesity: waist circumference >94 cm

(male), >80 cm (female)• Dyslipidemia: TG > 2.0 mmol/L or HDL < 1.0

mg/dl• Hypertension >140/90 mmHg• Fasting plasma glucose > 6.1 mmol/L

Definition

• National Cholesterol Education Program (NCEP):– Requires at least three of the following:

• Central obesity: waist circumference >102 cm or 40 inches (male), >88 cm or 36 inches (female)

• Dyslipidemia: TG >1.695 mmol/L (150 mg/dl)

HDL < 40 mg/dl (male), <50 mg/dl (female)• Blood pressure > 130/85 mmHg• Fasting plasma glucose >6.1 mmol (110 mg/dl)

Definition

• American Heart Association– Elevated waist circumference: men > 40

inches (102 cm); women > 35 inches (88 cm)– Elevated triglycerides: > 150 mg/dl– Reduced HDL cholesterol: men< 40 mg/dl,

women <50 mg/dl– Elevated blood pressure: 130/85 mmHg– Elevated fasting glucose: >100 mg/dl

Etiology

• Aging ( more prevalent with increasing age)

• Genetics

• Lifestyle (physical inactivity and increased caloric intake)

• Systemic inflammation: inceased inflammatory markers (i.e. C-reactive protein, fibrinogen, interleukin-6 & TNF alpha)

Pathophysiology

PATHOPHYSIOLOGYExcess adipose tissue increases

available triglyceride storesBreakdown of TG leads to overabundance

of circulating fatty acids

INCREASED FATTY ACIDS

INSULIN RESISTANCEINCREASES HEPATIC TRIGLYCERIDE SYNTHESIS & PRODUCTION OF VLDL

LOSS OF VASODILATORY EFFECT OF INSULIN

PRESERVED SODIUM REABSORPTION

HYPERCHOLESTEROLEMIA

HYPERTENSION

DIABETES

OBESITY

Therapy• First Line treatment: Lifestyle modification

– Caloric restriction– Increased physical activity

• Drug treatment is often required– Diuretics and ACE inhibitors for HTN– Statin drugs to lower cholesterol– Use of drugs that decrease insulin resistance i.e.

metformin and thiazolidinediones is controversial and not FDA approved

SURGERY

BENEFITS OF SURGERY

Options

• Both procedures result in effective weight loss and resolution of Type 2 DM in obese patients

• Both result in normal plasma and insulin concentrations

• Both result in restoration of normal B-cell response to hyperglycemia

• Both may be the “next step” in solving the mystery of metabolic syndrome

Roux-en-Y Gastric Bypass (RYGB) Biliopancreatic Diversion (BPD)

Hormonal Changes after Bariatric Surgery

Metabolic Effects of Bariatric Surgery

Clinical Evidence: Bariatric Surgery & Impact on Metabolic Syndrome

EFFECT?

Resolution of diabetes mellitus and metabolic syndrome following Roux-en-Y gastric bypass and a variant of biliopancreatic

diversion in patients with morbid obesity.Alexandrides TK, Skroubis G, Kalfarentzos F.

Endocrine Division, Department of Internal Medicine, School of Medicine, University of Patras, Greece

The objective of this study was to investigate the effects of RYGBP and BPD-RYGBP, a variant of BPD with a lower rate of metabolic deficiencies than BPD, on DM2 and the major components of metabolic syndrome in patients with morbid obesity and DM2.

METHODS: The prospective database of our unit, from June 1994 until May 2006, was analyzed and 137 patients with DM2 were found. 26 underwent RYGBP (BMI 46.1 +/- 2.9 kg/m2) and 111 BPD-RYGBP (BMI 59.7 +/- 10.6 kg/m2). 7 of the patients were on insulin (4.90%) and 37 on oral hypoglycemic agents (25.87%). Pre- and postoperative medications, and clinical and biochemical parameters were considered in the analysis. The mean

follow-up was 26.39 +/- 21.17 months.

RESULTS: Excess weight loss was approximately 70% after either procedure. DM2 resolved in 89% and 99% of the cases following RYGBP and BPD-RYGBP, respectively. 2 years after BPD-RYGBP all the patients had blood glucose < 110 mg/dl, 95% had normal cholesterol, 92% normal triglycerides and 82% normal blood pressure. The respective values following RYGBP were 66%, 33%, 78% and 44%. Uric acid decreased significantly only after BPD-RYGBP. Liver enzymes improved in both groups.

CONCLUSIONS: RYGBP and BPD-RYGBP are safe and lead to normalization of blood glucose, lipids, uric acid, liver enzymes and arterial pressure in the majority of patients, although this variant of BPD was more effective than RYGBP. We suggest that further studies should also investigate its usefulness in patients with milder degrees of obesity, DM2 and metabolic syndrome. Obes Surg. 2007 Feb;17(2):176-84.

Roux-en-Y Gastric Bypass

• Changes in GI hormones have been proposed to contribute to the restoration of euglycemia after RYGB

• Bypass of the duodenum and proximal jejunum and rapid passage of food from stomach to distal ileum augment the secretion of GLP-1

• GLP-1 potently increases insulin secretion and possibly insulin sensitivity.

Roux-en-Y Gastric Bypass

Prospective Study: enrolled 36 obese patients prior to undergoing Roux-en-Y gastric bypass compared to age and sex matched controls

Fasting glucose, HDL cholesterol, triglyceride level, BP, waist circumference & inflammatory markers were measured pre-op,6wks post op & 52 weeks post op

Roux-en-Y Gastric Bypass

Biliopancreatic Diversion (BPD)• BPD limits fat and starch

absorption while preserving the intestinal absorption of protein and non caloric essential aliments

• It is hypothesized that the increased free fatty acid oxidation that occurs in obese patients inhibits glucose oxidation, thus causing insulin resistance

• Reduced fat absorption should result in enhanced insulin sensitivity

• Lipid deprivation selectively reduces intra myocellular lipid stores; improving the action of insulin and intracellular insulin signaling

Scopinaro N, Marinari GM, Camerini GB et al. Specific Effects of Biliopancreatic Diversion on the Major Components of Metabolic Syndrome. Diabetes Care. 2005. 28:2406-2411

Biliopancreatic Diversion (BPD)• 312 BPD, obese patients with type

2 DM were followed for pre and postoperative serum glucose, triglycerides, cholesterol & arterial pressure measurements

• After BPD, fasting serum glucose fell within normal values in 310 patients; remained normal up to 10 years in all but 6 patients

• Evidence of hypertension disappeared in majority of patients

• Glycemic control translates into a reduced mortality for these patients as well as a low frequency of death from cardiovascular events

TRUE CLINICAL RECOVERY

Scopinaro N, Marinari GM, Camerini GB et al. Specific Effects of Biliopancreatic Diversion on the Major Components of Metabolic Syndrome. Diabetes Care. 2005. 28:2406-2411

Biliopancreatic Diversion (BPD)

Scopinaro N, Marinari GM, Camerini GB et al. Specific Effects of Biliopancreatic Diversion on the Major Components of Metabolic Syndrome. Diabetes Care. 2005. 28:2406-2411

Madan AK, Orth W, Ternovits CA et al. Metabolic Syndrome: yet another co-morbidity gastric bypass helps cure. Surgery for Obesity&Related Diseases. Jan 2006; 2 (1):48-51

• Retrospective Study ( n=53 )• Chart review of all patients undergoing laparoscopic gastric bypass

surgery during a 6 month period performed to identify patients with pre-op diagnosis of metabolic syndrome (using NCEP guidelines)• 32/53 (60%) pts had metabolic syndrome• No difference in pre-op body mass index between patients who had

metabolic syndrome (47.4 kg/m2 )and those who did not (49.8 kg/m2 )• The percentage of excess body weight lost after one year was 78% in

patients with metabolic syndrome

• Post-operatively, 1/53 (2%) patients had metabolic syndrome (P<.0001)

FUTURE ??

• Increasing evidence demonstrates excellent glycemic control and resolution of metabolic syndrome in obese patients following gastric bypass procedures

• Similar findings also evident in early experience with non-obese individuals with poor glycemic control or Type 2 D

• Is Type 2 Diabetes a potential “surgical disease” cured by bariatric surgery???

YES

Questions????