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MS WordPerinatologist Corner - C.E.U/C.M.E. Modules
Diabetes In Pregnancy Series
Sponsored by The Indian Health Service Clinical Support Center
PART 2: Management, delivery, and postpartum
11. Can diabetes be prevented?
There is good Level I data to show that once a patient has developed IGT that lifestyle and medication interventions may slow the onset of further glucose intolerance.
In 2001 the Finnish
Diabetes Prevention Study Group reported on randomly assigned middle-aged,
overweight subjects (172 men and 350 women; mean age, 55 years; mean body-mass
index [weight in kilograms divided by the square of the height in meters], 31)
with impaired glucose tolerance to either the intervention group or the control
group. Each subject in the intervention group received individualized counseling
aimed at reducing weight, total intake of fat, and intake of saturated fat and
increasing intake of fiber and physical activity.
During the trial, the risk of diabetes was reduced by 58 percent (P<0.001)
in the intervention group. The reduction in the incidence of diabetes was directly
associated with changes in lifestyle. They concluded that Type 2 diabetes can
be prevented by changes in the lifestyles of high-risk subjects.
In 2002 the Diabetes Prevention Program (DPP) reported a study which randomized IGT patients to lifestyle interventions that included diet and moderate exercise a week or metformin.The DPP found that lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.
Please note these lifestyle changes were very attainable and this study included AI/AN subjects. The mean weight loss goal was only 7 percent in 2.8 years and 150 minutes of moderate exercise per week. The DPP outlined their 8 main steps for lifestyle intervention. See the DPP Description of lifestyle intervention for details.
Link between GDM and Type 2 DM can be broken: Randomized Clinical Trial
Type 2 diabetes frequently results from progressive failure of pancreatic beta-cell function in the presence of chronic insulin resistance. We tested whether chronic amelioration of insulin resistance would preserve pancreatic beta-cell function and delay or prevent the onset of type 2 diabetes in high-risk Hispanic women.
Methods: Women with previous gestational diabetes were randomized to placebo (n = 133) or the insulin-sensitizing drug troglitazone (400 mg/day; n = 133) administered in double-blind fashion. Fasting plasma glucose was measured every 3 months, and oral glucose tolerance tests (OGTTs) were performed annually to detect diabetes. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and 3 months later to identify early metabolic changes associated with any protection from diabetes. Women who did not develop diabetes during the trial returned for OGTTs and IVGTTs 8 months after study medications were stopped.
Results” During a median follow-up of 30 months on blinded medication, average annual diabetes incidence rates in the 236 women who returned for at least one follow-up visit were 12.1 and 5.4% in women assigned to placebo and troglitazone, respectively (P < 0.01).
Protection from diabetes in the troglitazone group
1) was closely related to the degree of reduction in endogenous insulin requirements 3 months after randomization,
2) persisted 8 months after study medications were stopped, and
3) was associated with preservation of beta-cell compensation for insulin resistance.
Conclusion:
Treatment with troglitazone delayed or prevented the onset of type 2 diabetes in high-risk Hispanic women. The protective effect was associated with the preservation of pancreatic beta-cell function and appeared to be mediated by a reduction in the secretory demands placed on beta-cells by chronic insulin resistance.
Buchanan TA, et al Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes. 2002 Sep;51(9):2796-803. (Level I)
OB/GYN CCC Editorial comment:
Buchanan et al is the first RCT to show prevention or delay in the onset of type 2 diabetes in former gestational diabetes mellitus (GDM) patients.
Kim et al showed that in gestational diabetes mellitus (GDM) the cumulative incidence of diabetes ranged to over 70% in studies that examined women 6 weeks postpartum to 28 years postpartum. Cumulative incidence of type 2 diabetes increased markedly in the first 5 years after delivery and appeared to plateau after 10 years. An elevated fasting glucose level during pregnancy was the risk factor most commonly associated with future risk of type 2 diabetes. Targeting women with elevated fasting glucose levels during pregnancy may prove to have the greatest effect for the effort required. The above RCT by Buchanan et al that the onset of type 2 DM could be delayed or prevented in women with a history of GDM.
There is evidence that a number of pharmacologic interventions may be of value in preventing the development of type 2 diabetes in patients with impaired glucose tolerance (or prediabetes). Drug therapy with metformin (a biguanide) or acarbose (an alpha-glucosidase inhibitor) has been shown to delay or prevent the progression of impaired glucose tolerance to type 2 diabetes.
The thiazolidinedione troglitazone, which is no longer available, has also been shown to have a similar effect to other insulin sensitizers. Current expert opinion is that this is most likely a class effect, and is not specific to troglitazone only.
Troglitazone was removed from the market due to cases of hepatic failure. That is part of the reason for the required LFT monitoring with pioglitazone and rosiglitazone. Pioglitazone and rosiglitazone do not seem to cause hepatic failure as troglitazone did. Pioglitazone and rosiglitazone are considered similar to troglitazone and safe. It was initially recommended to monitor liver function test (LFT’s) at baseline and every 2 months for the first year of therapy, periodically thereafter. The package insert has been relaxed and now recommends LFT’s at baseline and periodically thereafter.
While the particular pharmacological treatment used by Buchanan et al is no longer available to us, it appears that it was a drug class effect not limited to that particular agent. On the other hand, diet, exercise and metformin are widely available.
Study |
Population |
N |
Intervention |
Duration |
Results |
Da Quing |
IGT |
577 |
Diet Exercise |
6 years |
-42% |
Finnish DPS |
IGT |
521 |
Diet Exercise |
6 years |
-58% |
NIH DPP |
IGT |
3324 |
Diet + Excers Metformin |
3+ years |
-58% -31% |
TRIPOD |
GDM |
235 |
Troglitazone |
3 years |
-56% |
Stop – NIDDM |
IGT |
1429 |
Acarbose |
3 years |
-21% |
Background:
Type 2 diabetes now affects younger individuals more commonly and it is well known that a significant fraction of those with type 2 diabetes remain undiagnosed. Current estimates suggest that up to one third of adults with diabetes in this country remain undiagnosed. Historically, up to 50% of those with diabetes were diagnosed AFTER complications of diabetes developed. In the majority of cases these were cardiovascular complications.
The most important concept to remember about type 2 diabetes is that insulin resistance and ß-cell function are tightly linked. In the time period before type 2 diabetes develops (pre-diabetes), insulin resistance may already be present or may be developing. Insulin secretion is often increased, but fasting and post-meal blood glucose levels are normal during much of this period. However, at some point, those at risk for type 2 diabetes can no longer increase or maintain insulin secretion at levels that compensate for the insulin resistance.
When insulin secretion can no longer match the demands of cellular insulin resistance, glucose intolerance develops. In its earliest phases, mild to moderate glucose intolerance develops after meals. Ultimately, insulin secretion falls short of insulin demands to such a degree that even fasting hyperglycemia develops, and once fasting glucose exceeds 126 mg/dL, diabetes is said to be present However, the process leading to this disorder has likely been progressing for many years.
Once diabetes develops, two features of the natural history of diabetes should be emphasized. First, insulin resistance is very likely a persistent defect. Second, insulin deficiency is probably progressive, with declining insulin levels over time often associated with deterioration in glycemic control. For the clinician, this natural history suggests that early treatment (and even prevention) of type 2 diabetes, insulin resistance, and ß-cell dysfunction will likely be needed to best manage the hyperglycemia characteristic of this disease. In addition, this figure suggests that combination therapy for type 2 diabetes will probably be needed in a significant fraction of patients to address the dual roles of insulin resistance and insulin deficiency.
In individuals with impaired glucose tolerance or impaired fasting glucose, the loss of 5%-7% of body weight and an increase in physical activity are known to reduce the risk of diabetes by more than 50%. In addition, pharmacologic therapy with either metformin or troglitazone has been shown to reduce the risk of progression to type 2 diabetes in those at high risk.
Current recommendations emphasize the importance of identifying and educating individuals at high risk for diabetes. Screening tests are advised as part of routine health care, with intervention strategies strongly emphasizing lifestyle changes, including monitored medical nutrition and activity programs. At present, drug therapy is not routinely recommended, although increasing evidence suggests that targeted treatment of insulin resistance with drugs such as the glitazones and metformin may prove useful in those for whom lifestyle changes fail to limit the progression to type 2 diabetes.
Excercise enhances muscle intake of glucose, improves insulin sensitivity, and improves both fasting and postprandial glucose levels. Unless the patient exercises every 48-72 hours, however, the benefit is lost. Cumulative exercise is helpful, and three 10-minute sessions are almost as beneficial as a single 30-minute session. Some patients may also find tools such as pedometers helpful for meeting their goal. For example, taking 10,000 steps per day can be considered the equivalent of a 5-mile walk.
The thiazolidinediones are used in the insulin-resistant patient. They have some potential cardiovascular benefits and can improve the dyslipidemia profile seen in type 2 diabetes. Some early data indicate they may also have important properties which could aid in diabetes prevention. These agents are particularly helpful in combination therapy, and early use with metformin is gaining acceptance. They may be very helpful in combination with insulin, and even with metformin and insulin, to obtain near-normal glucose levels.
Women with a previous history of gestational diabetes may also benefit from TZD therapy, as shown by the TRIPOD study above. This study showed that women who had gestational diabetes and later took troglitazone had reduced intimal thickening of the carotid arteries, which is associated with a reduced risk of cardiovascular disease.
The progressive deterioration of β-cell over time requires that therapy must be changed in type 2 diabetes. The UKPDS showed that at the time of diagnosis of diabetes there was only 50% of β-cell function remaining in people who were diagnosed some 10-11 years after the real onset of their diabetes. β-Cell function gradually and steadily deteriorated over the next 6 years of follow-up, which is why initial therapies only work for a short time.
Prevention Resources
American Diabetes Association:
The prevention or delay of type 2 diabetes. Diabetes Care 2004;27(suppl 1):S47. (Level III)
Buchanan TA, et al Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes. 2002 Sep;51(9):2796-803 (Level I)
Chiasson JL, et al Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003 Jul 23;290(4):486-94. (Level I)
Diabetes Prevention Program Research Group Within-trial cost-effectiveness of lifestyle intervention or metformin for the primary prevention of type 2 diabetes. Diabetes Care. 2003 Sep;26(9):2518-23. (Level I)
Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002 Oct;25(10):1862-8 (Level III)
Pan XR, et al Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care. 1997 Apr;20(4):537-44. (Level I)
Rao SS, Disraeli P, McGregor T: Impaired glucose tolerance and impaired fasting glucose. Am Fam Physician 2004;69:1961-8,1971-2 (Level III)
U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes 1995;44(11):1249-58. Erratum in: Diabetes 1996 Nov;45(11):1655. (Level I)
Uusitupa M, et al The Finnish Diabetes Prevention Study. Br J Nutr. 2000 Mar;83 Suppl 1:S137-42. (Level I)
