Gastric Bypass in Patients With T2DM and Mild Obesity
Gastric Bypass in Patients With T2DM and Mild Obesity
There were no major intraoperative complications or conversions to laparotomy. Mean operative time was 46 ± 12 min (range 33–155). Postoperatively, there were eight port-site hematomas, one anastomotic ulcer, and one urinary tract infection (i.e., 15% minor complication rate). There were no major surgical complications (i.e., no deep-vein thrombosis, venous thromboembolism, tracheal reintubation, endoscopy, tracheostomy, percutaneous drain placement, abdominal reoperation, or failure to be discharged within 30 days). There was no mortality. Mean hospital stay was 48 ± 16 h (range 1.5–4.0 days).
We remain in personal contact with, and have recent data from, all patients in the original cohort (i.e., follow-up rate is 100%). The median follow-up time is 5 years (range 1–6). Despite patients having severe, longstanding type 2 diabetes (disease duration 12.5 ± 7.4 years), mean HbA1c for the entire cohort fell progressively throughout the study from 9.7 ± 1.5 to 5.9 ± 0.1%, and FPG fell from 156 ± 11 to 97 ± 5 mg/dL (P < 0.001 for both) (Fig. 1). Most of these changes, especially for HbA1c, occurred within the first 6 months. Likewise, insulin resistance, as roughly estimated by the homeostasis model assessment, fell markedly within the first 6 months then generally continued to decline more slowly thereafter (9.2 ± 2.3 at baseline, 3.4 ± 1.5 at 6 months, 3.3 ± 1.1 at 12 months, 2.5 ± 1.4 at 24 months, 2.0 ± 0.9 at 48 months, 2.2 ± 1.3 at 60 months, and 2.3 ± 0.8 at 72 months).
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Figure 1.
Improvement in glycemic control during 6 years following RYGB. Mean (± SE) HbA1c (A) and FPG (B) for the entire cohort decreased from values representing poorly controlled diabetes, despite all patients being on diabetes medications at baseline, to the nondiabetic or normal range from 6 months through 6 years after RYGB, with 88% of patients discontinuing all diabetes medications. n = 66 at 0, 6, and 12 months; 59 at 24 months; 48 at 48 months; 37 at 60 months; and 30 at 72 months (i.e., 6 years). These n values decrease over time because not all patients have yet made it to the longer follow-up times; no one from the original cohort has been lost to follow-up. C: At the time of the latest follow-up, 88% of patients experienced remission of diabetes (i.e., HbA1c <6.5% off all diabetes medications), 11% had improved diabetes, and only 1 individual did not display a clear change in glycemic control. Remission occurred between 3 and 26 weeks after RYGB, and no one in the "diabetes remission" group has subsequently experienced a recrudescence of diabetes during follow-up. Classification as "diabetes improved" was based on participants' status at the time of the latest follow-up. All patients who used insulin at baseline discontinued insulin usage between 3 and 14 weeks after surgery. D: Plasma glucose and C-peptide levels after an overnight fast and 120 min after a standardized mixed-macronutrient test meal, assessed before and after RYGB. Postoperative values are shown at the longest time point of individual follow-up. *Significant difference between equivalent preoperative and postoperative measurements (P < 0.004 in all cases). E–H: There was similar loss of adiposity over 6 years among patients who experienced full remission vs. only improvement of diabetes. Waist circumference (E and G) and total body weight (F and H) decreased markedly in both the "resolved" (n = 58) and "improved" (n = 7) diabetic groups. Reductions in both parameters were highly significant over the course of the study (P < 0.001 for all four panels shown in E–H), but there were no apparent differences in the magnitude of change in waist circumference or body weight between patients who experienced remission vs. only improvement of diabetes. Although mean waist circumference and body weight in the entire cohort increased modestly toward the end of the study, diabetes did not recur in any case where it had resolved. T2DM, type 2 diabetes. Data represent means ± SE.
Remission of diabetes (i.e., HbA1c <6.5% without diabetes medications) was achieved in 88% of patients (58 of 66) (Fig. 1C), whose diabetes medications were discontinued 3–26 weeks after surgery. In this group, the mean duration of known diabetes was 8.0 ± 2.5 years (range 1.5–19). Seven subjects took insulin preoperatively, and the rest used oral diabetes medications. No patient who experienced diabetes remission based on a diabetes drug–free HbA1c <6.5% subsequently exhibited an HbA1c greater than that level or resumed diabetes medications in later evaluations. In other words, there was no recurrence of diabetes following remission during our 6-year follow-up.
Improvement of diabetes without full remission was observed in 11% of patients (7 of 66) (Fig. 1C). This group achieved diabetes control (HbA1c <7.0%) with decreased usage of oral diabetes medications and withdrawal of insulin when previously used (at 3–14 weeks after surgery). The mean duration of known diabetes in this group was 7.2 ± 5.5 years (range 2–11). Preoperatively, two of the "improved" patients used insulin; the remainder used oral agents.
Only one patient, with 3 years of known diabetes, showed no clear postoperative disease improvement. Before surgery, he used insulin glargine 16 IU/day, pioglitazone 30 mg/day, and metformin 2 g/day. Insulin was withdrawn 7 months after surgery, and diabetes has subsequently been controlled with 50 mg vildagliptin b.i.d., pioglitazone 15 mg/day, and metformin 2 g/day. The patient experienced 72% excess weight loss at 48 months (his latest follow-up), similar to the weight loss in both the "resolved" and "improved" groups. Both at baseline and 48 months post-RYGB, his anti-GAD and islet-cell autoantibodies were negative, and his C-peptide levels were detectable (1.8 fasting and 2.8 ng/mL postmeal at baseline, 2.0 fasting and 2.1 ng/mL postmeal at 48 months).
Major, progressive reductions in waist circumference and total body weight were observed in all patients (P < 0.001 for both measures) (Fig. 1E–H). There were no apparent differences, however, in the magnitude of decrease in either parameter between patients who experienced diabetes remission and those who experienced only improved diabetes. Moreover, we could find no preoperative characteristics that predicted remission versus mere improvement in diabetes nor that influenced the kinetics of reduced glycemia, including baseline insulin usage and duration of diabetes. There also were no apparent preoperative characteristics distinguishing the one individual who experienced no clear change in diabetes status from those whose diabetes remitted or improved. This outlier patient did not seem to have misdiagnosed type 1 diabetes, given his persistently negative autoantibody studies, as well as detectable fasting and meal-stimulated C-peptide levels, both at baseline and his latest follow-up.
To investigate the relationship between the magnitude of weight loss and the degree of improved glycemia, we generated regression lines for change in body weight compared with changes in both FPG and HbA1c, with each comparison made at 6 months and also at 1, 2, 4, 5, and 6 years after RYGB. There were no significant correlations between the amount of weight loss and the magnitude of decrease in either FPG or HbA1c at any time point before 5 years (data not shown). Only at 5 and 6 years did we observe significant correlations between weight loss and decrease in FPG (r = 0.541, P = 0.001 at 5 years; r = 0.431, P = 0.017 at 6 years). There were no such correlations between weight loss and decrease in HbA1c at any time point.
Overnight-fasting and meal-stimulated plasma C-peptide levels were measured preoperatively to help exclude patients with type 1 diabetes. These parameters were reassessed postoperatively to estimate whether RYGB affected β-cell function. In response to a standardized test meal, the ratio of change in C-peptide to change in glucose increased from 18.0 preoperatively to 78.5 [ng/mL][mg/dL] at the longest time of individual follow-up (P < 0.001) (Fig. 1D), suggesting increased β-cell secretory function and sensitivity to glucose. There was no correlation between the magnitude of increase in this measure of β-cell sensitivity to glucose and the amount of body weight lost (r = 0.03, P = NS).
Among patients with other metabolic syndrome features, hypertension resolved in 58% (15 of 26), hypercholesterolemia resolved in 64% (21 of 33), and hypertriglyceridemia resolved in 58% (18 of 31). Mean blood pressure for the entire cohort decreased progressively over 6 years (P < 0.05 for diastolic and systolic) (Fig. 2), with reductions in diastolic pressure reaching statistical significance by 6 months and thereafter and reductions in systolic pressure becoming significant by 48 months and thereafter. Mean lipid parameters for the group also improved steadily for 6 years (Fig. 2). There were clear, progressive reductions in total cholesterol (P < 0.001), LDL cholesterol (P < 0.001), and triglycerides (P = 0.003) as well as an increase in HDL cholesterol (P = 0.002).
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Figure 2.
Improvements in blood pressure and lipid levels during 6 years following RYGB. There were significant, progressive decreases in average systolic and diastolic blood pressure (P < 0.05 for both) in the entire cohort over the course of the study. There also were significant, progressive decreases over the course of the study in total cholesterol (P < 0.001), LDL cholesterol (P < 0.001), and triglycerides (P = 0.003), as well as an increase in HDL cholesterol (P = 0.002). Data represent means ± SE for all patients; n values are the same as in Fig. 1.
Predicted 10-year risk of cardiovascular disease, calculated using the UKPDS risk engine, fell substantially after surgery, with the following changes in risk of events (Table 2): 71% decrease in coronary heart disease (CHD, P = 0.001), 84% decrease in fatal CHD (P = 0.001), 50% decrease in stroke (P = 0.01), and 57% decrease in fatal stroke (P = 0.009).
Results
Operative Safety
There were no major intraoperative complications or conversions to laparotomy. Mean operative time was 46 ± 12 min (range 33–155). Postoperatively, there were eight port-site hematomas, one anastomotic ulcer, and one urinary tract infection (i.e., 15% minor complication rate). There were no major surgical complications (i.e., no deep-vein thrombosis, venous thromboembolism, tracheal reintubation, endoscopy, tracheostomy, percutaneous drain placement, abdominal reoperation, or failure to be discharged within 30 days). There was no mortality. Mean hospital stay was 48 ± 16 h (range 1.5–4.0 days).
Main Outcome Measures: Glycemic Control
We remain in personal contact with, and have recent data from, all patients in the original cohort (i.e., follow-up rate is 100%). The median follow-up time is 5 years (range 1–6). Despite patients having severe, longstanding type 2 diabetes (disease duration 12.5 ± 7.4 years), mean HbA1c for the entire cohort fell progressively throughout the study from 9.7 ± 1.5 to 5.9 ± 0.1%, and FPG fell from 156 ± 11 to 97 ± 5 mg/dL (P < 0.001 for both) (Fig. 1). Most of these changes, especially for HbA1c, occurred within the first 6 months. Likewise, insulin resistance, as roughly estimated by the homeostasis model assessment, fell markedly within the first 6 months then generally continued to decline more slowly thereafter (9.2 ± 2.3 at baseline, 3.4 ± 1.5 at 6 months, 3.3 ± 1.1 at 12 months, 2.5 ± 1.4 at 24 months, 2.0 ± 0.9 at 48 months, 2.2 ± 1.3 at 60 months, and 2.3 ± 0.8 at 72 months).
(Enlarge Image)
Figure 1.
Improvement in glycemic control during 6 years following RYGB. Mean (± SE) HbA1c (A) and FPG (B) for the entire cohort decreased from values representing poorly controlled diabetes, despite all patients being on diabetes medications at baseline, to the nondiabetic or normal range from 6 months through 6 years after RYGB, with 88% of patients discontinuing all diabetes medications. n = 66 at 0, 6, and 12 months; 59 at 24 months; 48 at 48 months; 37 at 60 months; and 30 at 72 months (i.e., 6 years). These n values decrease over time because not all patients have yet made it to the longer follow-up times; no one from the original cohort has been lost to follow-up. C: At the time of the latest follow-up, 88% of patients experienced remission of diabetes (i.e., HbA1c <6.5% off all diabetes medications), 11% had improved diabetes, and only 1 individual did not display a clear change in glycemic control. Remission occurred between 3 and 26 weeks after RYGB, and no one in the "diabetes remission" group has subsequently experienced a recrudescence of diabetes during follow-up. Classification as "diabetes improved" was based on participants' status at the time of the latest follow-up. All patients who used insulin at baseline discontinued insulin usage between 3 and 14 weeks after surgery. D: Plasma glucose and C-peptide levels after an overnight fast and 120 min after a standardized mixed-macronutrient test meal, assessed before and after RYGB. Postoperative values are shown at the longest time point of individual follow-up. *Significant difference between equivalent preoperative and postoperative measurements (P < 0.004 in all cases). E–H: There was similar loss of adiposity over 6 years among patients who experienced full remission vs. only improvement of diabetes. Waist circumference (E and G) and total body weight (F and H) decreased markedly in both the "resolved" (n = 58) and "improved" (n = 7) diabetic groups. Reductions in both parameters were highly significant over the course of the study (P < 0.001 for all four panels shown in E–H), but there were no apparent differences in the magnitude of change in waist circumference or body weight between patients who experienced remission vs. only improvement of diabetes. Although mean waist circumference and body weight in the entire cohort increased modestly toward the end of the study, diabetes did not recur in any case where it had resolved. T2DM, type 2 diabetes. Data represent means ± SE.
Remission of diabetes (i.e., HbA1c <6.5% without diabetes medications) was achieved in 88% of patients (58 of 66) (Fig. 1C), whose diabetes medications were discontinued 3–26 weeks after surgery. In this group, the mean duration of known diabetes was 8.0 ± 2.5 years (range 1.5–19). Seven subjects took insulin preoperatively, and the rest used oral diabetes medications. No patient who experienced diabetes remission based on a diabetes drug–free HbA1c <6.5% subsequently exhibited an HbA1c greater than that level or resumed diabetes medications in later evaluations. In other words, there was no recurrence of diabetes following remission during our 6-year follow-up.
Improvement of diabetes without full remission was observed in 11% of patients (7 of 66) (Fig. 1C). This group achieved diabetes control (HbA1c <7.0%) with decreased usage of oral diabetes medications and withdrawal of insulin when previously used (at 3–14 weeks after surgery). The mean duration of known diabetes in this group was 7.2 ± 5.5 years (range 2–11). Preoperatively, two of the "improved" patients used insulin; the remainder used oral agents.
Only one patient, with 3 years of known diabetes, showed no clear postoperative disease improvement. Before surgery, he used insulin glargine 16 IU/day, pioglitazone 30 mg/day, and metformin 2 g/day. Insulin was withdrawn 7 months after surgery, and diabetes has subsequently been controlled with 50 mg vildagliptin b.i.d., pioglitazone 15 mg/day, and metformin 2 g/day. The patient experienced 72% excess weight loss at 48 months (his latest follow-up), similar to the weight loss in both the "resolved" and "improved" groups. Both at baseline and 48 months post-RYGB, his anti-GAD and islet-cell autoantibodies were negative, and his C-peptide levels were detectable (1.8 fasting and 2.8 ng/mL postmeal at baseline, 2.0 fasting and 2.1 ng/mL postmeal at 48 months).
Major, progressive reductions in waist circumference and total body weight were observed in all patients (P < 0.001 for both measures) (Fig. 1E–H). There were no apparent differences, however, in the magnitude of decrease in either parameter between patients who experienced diabetes remission and those who experienced only improved diabetes. Moreover, we could find no preoperative characteristics that predicted remission versus mere improvement in diabetes nor that influenced the kinetics of reduced glycemia, including baseline insulin usage and duration of diabetes. There also were no apparent preoperative characteristics distinguishing the one individual who experienced no clear change in diabetes status from those whose diabetes remitted or improved. This outlier patient did not seem to have misdiagnosed type 1 diabetes, given his persistently negative autoantibody studies, as well as detectable fasting and meal-stimulated C-peptide levels, both at baseline and his latest follow-up.
To investigate the relationship between the magnitude of weight loss and the degree of improved glycemia, we generated regression lines for change in body weight compared with changes in both FPG and HbA1c, with each comparison made at 6 months and also at 1, 2, 4, 5, and 6 years after RYGB. There were no significant correlations between the amount of weight loss and the magnitude of decrease in either FPG or HbA1c at any time point before 5 years (data not shown). Only at 5 and 6 years did we observe significant correlations between weight loss and decrease in FPG (r = 0.541, P = 0.001 at 5 years; r = 0.431, P = 0.017 at 6 years). There were no such correlations between weight loss and decrease in HbA1c at any time point.
Overnight-fasting and meal-stimulated plasma C-peptide levels were measured preoperatively to help exclude patients with type 1 diabetes. These parameters were reassessed postoperatively to estimate whether RYGB affected β-cell function. In response to a standardized test meal, the ratio of change in C-peptide to change in glucose increased from 18.0 preoperatively to 78.5 [ng/mL][mg/dL] at the longest time of individual follow-up (P < 0.001) (Fig. 1D), suggesting increased β-cell secretory function and sensitivity to glucose. There was no correlation between the magnitude of increase in this measure of β-cell sensitivity to glucose and the amount of body weight lost (r = 0.03, P = NS).
Additional Outcome Measures: Other Cardiovascular Risk Parameters
Among patients with other metabolic syndrome features, hypertension resolved in 58% (15 of 26), hypercholesterolemia resolved in 64% (21 of 33), and hypertriglyceridemia resolved in 58% (18 of 31). Mean blood pressure for the entire cohort decreased progressively over 6 years (P < 0.05 for diastolic and systolic) (Fig. 2), with reductions in diastolic pressure reaching statistical significance by 6 months and thereafter and reductions in systolic pressure becoming significant by 48 months and thereafter. Mean lipid parameters for the group also improved steadily for 6 years (Fig. 2). There were clear, progressive reductions in total cholesterol (P < 0.001), LDL cholesterol (P < 0.001), and triglycerides (P = 0.003) as well as an increase in HDL cholesterol (P = 0.002).
(Enlarge Image)
Figure 2.
Improvements in blood pressure and lipid levels during 6 years following RYGB. There were significant, progressive decreases in average systolic and diastolic blood pressure (P < 0.05 for both) in the entire cohort over the course of the study. There also were significant, progressive decreases over the course of the study in total cholesterol (P < 0.001), LDL cholesterol (P < 0.001), and triglycerides (P = 0.003), as well as an increase in HDL cholesterol (P = 0.002). Data represent means ± SE for all patients; n values are the same as in Fig. 1.
Predicted 10-year risk of cardiovascular disease, calculated using the UKPDS risk engine, fell substantially after surgery, with the following changes in risk of events (Table 2): 71% decrease in coronary heart disease (CHD, P = 0.001), 84% decrease in fatal CHD (P = 0.001), 50% decrease in stroke (P = 0.01), and 57% decrease in fatal stroke (P = 0.009).
